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Sample records for angiotensin receptor gene

  1. POLYMORPHISM OF ANGIOTENSIN Ⅱ TYPE 1 RECEPTOR GENE IN ELDERLY PATIENTS WITH ESSENTIAL HYPERTENSION

    Institute of Scientific and Technical Information of China (English)

    方宁远; 张怡; 陆惠华; 郑迪辉; 邬亦贤; 郑道声

    2003-01-01

    Objective To detect the A/C1166 polymorphism of angiotensin Ⅱ type-1 receptor (AT1 R) gene in essential hypertensive elderly.MethodsThe A/C1166 polymorphism of AT1 R gene was assessed by polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) in a case control study of 87 essential hypertensive elders (EH) and 55 normotensive elders (NT).ResultsThe genotype frequencies of AA, AC, CC were 0.805, 0.161, 0.034 in EH group and 0.927, 0.073, 0.000 in NT group respectively. The frequency of C1166 allele was higher in EH group (0.115) than in NT group (0.036)(P<0.05).ConclusionThe results indicate that A/C1166 polymorphism of AT1 R gene may be associated with essential hypertension in elderly.

  2. Angiotensin type 2 receptors

    DEFF Research Database (Denmark)

    Sumners, Colin; de Kloet, Annette D; Krause, Eric G;

    2015-01-01

    In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral....... However, stimulation of AT2R locally within the brain or the kidney apparently elicits a systemic blood pressure lowering effect. A systemic effect of AT2R stimulation on blood pressure can also be achieved, when the prevailing effect of continuous background AT1R-stimulation is attenuated by low-dose AT1......R blockade. Despite a lack of effect on blood pressure, AT2R stimulation still protects from hypertensive end-organ damage. Current data and evidence therefore suggest that AT2R agonists will not be suitable as future anti-hypertensive drugs, but that they may well be useful for end-organ protection...

  3. Vascular benefits of angiotensin receptor blockers

    NARCIS (Netherlands)

    Voors, Adriaan A.

    2007-01-01

    There is convincing evidence that angiotensin II, through activation of the angiotensin II type 1 (AT1) receptor, is involved in the atherosclerotic process. Similarly, angiotensin receptor blockers decrease vascular inflammation, hypertrophy and thrombosis, which are the key components of the progr

  4. Association of Polymorphisms in Angiotensin-converting Enzyme and Type 1 AngiotensinReceptor Genes with Coronary Heart Disease and the Severity of Coronary Artery Stenosis

    Institute of Scientific and Technical Information of China (English)

    QIU Chunguang; HAN Zhanying; LU Wenjie; ZHANG Cuntai

    2007-01-01

    To explore the relation of angiotensin-converting enzyme (ACE) and angiotensin Ⅱ type 1 receptor (AT1R) gene polymorphism with coronary heart disease (CHD) and the severity of coronary artery stenosis, 130 CHD patients who underwent coronary angiography were examined for the number of affected coronary vessels (≥75% stenosis) and coronary Jeopardy score. The inser- tion/deletion of ACE gone polymorphism and ATIR gene polymorphism (an A→C transversion at nucleotide position 1166) were detected by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) in CHD patients and 90 healthy serving as controls. The re- sults showed that DD genotype and of ACE were more frequent in CHD patients than that in control group (38.5% vs 14.4%, P<0.001). The frequency of the AT1R A/C genotypes did not differ between the patients and the controls (10% vs 13.1%, P0.05). The relative risk associated with the ACE-DD was increased by ATIR-AC genotype. Neither the number of affected coronary vessels nor the coro-nary score differed among the ACE I/D genotypes (P0.05). But the number of affected coronary vessels and the coronary score were significantly greater in the patients with the AT1R-AC genotype than in those with the AA genotype (P<0.05). In conclusion, DD genotype may he risk factor for CHD and MI in Chinese people, and is not responsible for the development of the coronary artery stenosis. The AT1R-C allele may increase the relative risk associated with the ACE-DD genotype, and may be involved in the development of the stenosis of coronary artery.

  5. Angiotensin II receptors in testes

    Energy Technology Data Exchange (ETDEWEB)

    Millan, M.A.; Aguilera, G.

    1988-05-01

    Receptors for angiotensin II (AII) were identified and characterized in testes of rats and several primate species. Autoradiographic analysis of the binding of 125I-labeled (Sar1,Ile8)AII to rat, rhesus monkey, cebus monkey, and human testicular slide-mounted frozen sections indicated specific binding to Leydig cells in the interstitium. In rat collagenase-dispersed interstitial cells fractionated by Percoll gradient, AII receptor content was parallel to that of hCG receptors, confirming that the AII receptors are in the Leydig cells. In rat dispersed Leydig cells, binding was specific for AII and its analogs and of high affinity (Kd, 4.8 nM), with a receptor concentration of 15 fmol/10(6) cells. Studies of AII receptors in rat testes during development reveals the presence of high receptor density in newborn rats which decreases toward the adult age (4934 +/- 309, 1460 +/- 228, 772 +/- 169, and 82 +/- 12 fmol/mg protein at 5, 15, 20, and 30 days of age, respectively) with no change in affinity. At all ages receptors were located in the interstitium, and the decrease in binding was parallel to the decrease in the interstitial to tubular ratio observed with age. AII receptor properties in membrane-rich fractions from prepuberal testes were similar in the rat and rhesus monkey. Binding was time and temperature dependent, reaching a plateau at 60 min at 37 C, and was increased by divalent cations, EGTA, and dithiothreitol up to 0.5 mM. In membranes from prepuberal monkey testes, AII receptors were specific for AII analogs and of high affinity (Kd, 4.2 nM) with a receptor concentration of 7599 +/- 1342 fmol/mg protein. The presence of AII receptors in Leydig cells in rat and primate testes in conjunction with reports of the presence of other components of the renin-angiotensin system in the testes suggests that the peptide has a physiological role in testicular function.

  6. DNA methylation of angiotensin II receptor gene in nonalcoholic steatohepatitis-related liver fibrosis

    Science.gov (United States)

    Asada, Kiyoshi; Aihara, Yosuke; Takaya, Hiroaki; Noguchi, Ryuichi; Namisaki, Tadashi; Moriya, Kei; Uejima, Masakazu; Kitade, Mitsuteru; Mashitani, Tsuyoshi; Takeda, Kosuke; Kawaratani, Hideto; Okura, Yasushi; Kaji, Kosuke; Douhara, Akitoshi; Sawada, Yasuhiko; Nishimura, Norihisa; Seki, Kenichiro; Mitoro, Akira; Yamao, Junichi; Yoshiji, Hitoshi

    2016-01-01

    AIM To clarify whether Agtr1a methylation is involved in the development of nonalcoholic steatohepatitis (NASH)-related liver fibrosis in adult rats. METHODS A choline-deficient amino acid (CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis. Agtr1a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid (CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR. Hepatic stellate cells (HSCs) were isolated by collagenase digestion of the liver, followed by centrifugation of the crude cell suspension through a density gradient. Agtr1a methylation and its gene expression were also analyzed during the activation of HSCs. RESULTS The mean levels of Agtr1a methylation in the livers of CDAA-fed rats (11.5% and 18.6% at 8 and 12 wk, respectively) tended to be higher (P = 0.06 and 0.09, respectively) than those in the livers of CSAA-fed rats (2.1% and 5.3% at 8 and 12 wk, respectively). Agtr1a was not methylated at all in quiescent HSCs, but was clearly methylated in activated HSCs (13.8%, P renin-angiotensin system-related gene expression during liver fibrosis. PMID:27729955

  7. Circadian expression of clock genes and angiotensin Ⅱ type 1 receptors in suprachiasmatic nuclei of sinoaortic-denervated rats

    Institute of Scientific and Technical Information of China (English)

    Hui LI; Ning-ling SUN; Jin WANG; Ai-jun LIU; Ding-feng SU

    2007-01-01

    Aim: To investigate whether the circadian expression of central clock genes and angiotensin Ⅱ type 1 (AT1) receptors was altered in sinoaortic-denervated (SAD)rats. Methods: Male Sprague-Dawley rats underwent sinoaortic denervation or a sham operation at the age of 12 weeks. Four weeks after the operation, blood pressure and heart period were measured in the conscious state in a group of sham-operated (n=10) and SAD rats (n=9). Rest SAD and sham-operated rats were divided into 6 groups (n=6 in each group). The suprachiasmatic nuclei (SCN)tissues were taken every 4 h throughout the day from each group for the determi-nation of the mRNA expression of clock genes (Per2 and Bmall) and the AT1receptor by RT-PCR; the protein expression of Per2 and Bmall was determined by Western blotting. Results: Blood pressure levels in the SAD rats were similar to those of the sham-operated rats. However, blood pressure variabilities signifi-cantly increased in the SAD rats compared with the sham-operated rats. The circadian variation of clock genes in the SCN of the sham-operated rats was char-acterized by a marked increase in the mRNA and protein expression during dark periods. Per2 and Bmall mRNA levels were significantly lower in the SAD rats,especially during dark periods. Western blot analysis confirmed an attenuation of the circadian rhythm of the 2 clock proteins in the SCN of the SAD rats. AT1 receptor mRNA expressions in the SCN were abnormally upregulated in the light phase, changed to a 12-h cycle in the SAD rats. Conclusion: The circadian varia-tion of the 2 central clock genes was attenuated in the SAD rats. Arterial baroreflex dysfunction also induced a disturbance in the expression of AT1 receptors in the SCN.

  8. Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells.

    Science.gov (United States)

    Lehman, Allison M B; Montford, John R; Horita, Henrick; Ostriker, Allison C; Weiser-Evans, Mary C M; Nemenoff, Raphael A; Furgeson, Seth B

    2014-11-01

    The retinoid X receptor (RXR) partners with numerous nuclear receptors, such as the peroxisome proliferator activated receptor (PPAR) family, liver X receptors (LXRs), and farnesoid X receptor (FXR). Although each heterodimer can be activated by specific ligands, a subset of these receptors, defined as permissive nuclear receptors, can also be activated by RXR agonists known as rexinoids. Many individual RXR heterodimers have beneficial effects in vascular smooth muscle cells (SMCs). Because rexinoids can potently activate multiple RXR pathways, we hypothesized that treating SMCs with rexinoids would more effectively reverse the pathophysiologic effects of angiotensin II than an individual heterodimer agonist. Cultured rat aortic SMCs were pretreated with either an RXR agonist (bexarotene or 9-cis retinoic acid) or vehicle (dimethylsulfoxide) for 24 hours before stimulation with angiotensin II. Compared with dimethylsulfoxide, bexarotene blocked angiotensin II-induced SM contractile gene induction (calponin and smooth muscle-α-actin) and protein synthesis ([(3)H]leucine incorporation). Bexarotene also decreased angiotensin II-mediated inflammation, as measured by decreased expression of monocyte chemoattractant protein-1 (MCP-1). Activation of p38 mitogen-activated protein (MAP) kinase but not extracellular signal-related kinase (ERK) or protein kinase B (Akt) was also blunted by bexarotene. We compared bexarotene to five agonists of nuclear receptors (PPARα, PPARγ, PPARδ, LXR, and FXR). Bexarotene had a greater effect on calponin reduction, MCP-1 inhibition, and p38 MAP kinase inhibition than any individual agonist. PPARγ knockout cells demonstrated blunted responses to bexarotene, indicating that PPARγ is necessary for the effects of bexarotene. These data demonstrate that RXR is a potent modulator of angiotensin II-mediated responses in the vasculature, partially through inhibition of p38. PMID:25169989

  9. Angiotensin receptor blockers = angiotensin converting enzyme inhibitors minus dry cough?

    Directory of Open Access Journals (Sweden)

    Ashwin Kamath

    2015-08-01

    Full Text Available Blockade of the renin angiotensin aldosterone system (RAAS is an important pharmacological intervention in cardiovascular (CV diseases. Hypertension, heart failure (HF and myocardial infarction are important indications for use of angiotensin converting enzyme inhibitors (ACEIs, which potentially decrease morbidity and prolong survival. Dry cough is an important adverse effect seen in about 20% of the patients which might require discontinuation of the drug. In such situations, angiotensin receptor blockers (ARBs serve as replacement drugs in all the indications, as they are largely devoid of this limiting adverse effect. [Int J Basic Clin Pharmacol 2015; 4(4.000: 813-814

  10. Angiotensin type 2 receptor (AT2R) and receptor Mas

    DEFF Research Database (Denmark)

    Villela, Daniel; Leonhardt, Julia; Patel, Neal;

    2015-01-01

    The angiotensin type 2 receptor (AT2R) and the receptor Mas are components of the protective arms of the renin-angiotensin system (RAS), i.e. they both mediate tissue protective and regenerative actions. The spectrum of actions of these two receptors and their signalling mechanisms display striking...

  11. ROLE OF ANGIOTENSIN-CONVERTING ENZYME AND VITAMIN D RECEPTOR GENE POLYMORPHISMS IN CANCER ANOREXIA-CACHEXIA SYNDROME

    Directory of Open Access Journals (Sweden)

    Ariele Fabris

    2012-01-01

    Full Text Available The ubiquitin-proteasome pathway is a crucial connection between aberrant immune system activation, systemic inflammation and Cancer Anorexia-Cachexia Syndrome (CACS, a syndrome that culminates in hyper-activation of the ubiquitin-proteasome pathway. Angiotensin directly up-regulates this pathway, while vitamin D down-regulates it indirectly through the insulin-like growth factor-1 pathway. We investigated the genetic predisposition towards CACS in a cancer population, examining Insertion/Deletion (I/D polymorphism of angiotensin-converting enzyme gene and FokI and BsmI polymorphisms of vitamin D receptor gene. Sixty-two cancer patients were recruited and divided into three groups: primary cachectic (C1, n = 14; dysmetabolic body weight loss ≥5% in 6 months; secondary cachectic (C2, n = 34; similar weight loss, mechanic or iatrogenic origin; and non-cachectic (NC, n = 16. C2+NC were merged in the control group. The three groups showed significant differences in average prognostic inflammatory nutritional index (C1: 26.4±23.4; C2: 5.4±5.6; NC: 0.37±0.5, C-reactive protein serum levels (C1: 6.6±2.1; C2: 2.4±2.2; NC: 1.0±2.0 mg/dL, albumin serum levels (C1: 3.1±0.6; C2: 3.5±0.4; NC 3.7±0.6 g/dL, weight loss (C1: 22±8; C2: 15±6.7; NC 5±6% and life expectancy (C1: 6.4±3.3; C2: 25±28; NC: 45±25 months. However, none of the chosen polymorphisms showed any statistically significant correlation with CACS. The complexity of the changes of the immune system in the chronic inflammation state associated with CACS is far greater than expected and further studies are required to identify genetic independent markers of progression toward CACS."

  12. Recombinant adeno-associated virus-mediated delivery of antisense angiotensinreceptor 1 gene attenuates hypertension development

    Institute of Scientific and Technical Information of China (English)

    Xu-guang LI; Jiang-tao YAN; Xi-zheng XU; Jia-ning WANG; Li-ming CHENG; Tao WANG; Ping ZUO; Dao-wen WANG

    2007-01-01

    Aim:The renin-angiotensin system plays a crucial role in the development and establishment of hypertension,and the pharmacological blockade of the system results in a reduction in blood pressure. In the present study,we investigated whether the effects of a novel,double-stranded,recombinant adeno-associated virus vector (rAAV)-mediated antisense angiotensinreceptor l (AT1R) gene efficiently prevents the development of hypertension induced by a high-salt diet in adult,male Sprague-Dawley (SD) rats. Methods:A rAAV was prepared with a cassette containing a cytomegalovirus promoter and partial cDNA (660 base pairs) for the AT1R inserted in the antisense direction (rAAV-AT1AS). A single tail vein injection of the rAAV-AT1-AS or rAAV-GFP (green fluorescent protein,a reporter gene) was performed in adult,male SD rats. Two weeks after injection,the animals were fed a diet containing 8% NaCI,and the systolic blood pressure was measured weekly using the tail-cuff method for 12 weeks. Results:The high-salt diet induced a significant rise in systolic blood pressure in the rAAV-GFP-treated animals;however,the rAAV-AT:AS treatment attenuated the rise in blood pressure (142.7±4.5 mmHg vs 117±3.8 mmHg,P<0.01),and the hypotensive effect was maintained until the experiments ended at 12 weeks. In the rAAV-GFP-treated animals AT1 was overexpressed in various tissues,especially in the aorta and kidney at mRNA levels;in contrast,rAAV-AT:AS treatment markedly attenuated AT1 expression. Furthermore,rAAV-AT:AS treatment prevented target organ damages from hypertension,including cardiac dysfunction and renal injury compared to the rAAV-GFP group. Conclusion:These results suggest that rAAVmediated anti-AT1 delivery attenuates the development of hypertension and protects against renal injury and cardiac remodeling.

  13. Association of Angiotensin-Converting Enzyme Intron 16 Insertion/Deletion and Angiotensin II Type 1 Receptor A1166C Gene Polymorphisms with Preeclampsia in South East of Iran

    Directory of Open Access Journals (Sweden)

    Saeedeh Salimi

    2011-01-01

    Full Text Available Some evidence suggests that a variety of genetic factors contributed in pathogenesis of the preeclampsia. The aim of this study was to assess the association between the angiotensin-converting enzyme (ACE I/D and angiotensin II type1 receptor A1166C polymorphisms with preeclampsia. This study was performed in 125 preeclamptic pregnant women and 132 controls. The I/D Polymorphism of the ACE gene was assessed by polymerase chain reaction and the A1166C Polymorphism of the AT1R gene was determined by restriction fragment length polymorphism. The genotype and allele frequencies of I/D polymorphism differed between two groups. The risk of preeclampsia was 3.2-fold in pregnant women with D allele (OR, 3.2 [95% CI, 1.1 to 3.8]; P=0.01. The distribution of the AT1R gene A1166C polymorphism was similar in affected and control groups. Our results supported that presence of the I/D polymorphism of ACE gene is a marker for the increased risk of preeclampsia.

  14. Angiotensin Receptors, Autoimmunity, and Preeclampsia1

    OpenAIRE

    Xia, Yang; Zhou, Cissy Chenyi; RAMIN, Susan M.; Kellems, Rodney E.

    2007-01-01

    Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Recent studies indicate that women with preeclampsia have autoantibodies that activate the angiotensin receptor, AT1, and that autoantibody-mediated receptor activation contri...

  15. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients with abdominal aortic aneurysms

    DEFF Research Database (Denmark)

    Kristensen, Karl Emil; Torp-Pedersen, Christian; Gislason, Gunnar Hilmar;

    2015-01-01

    OBJECTIVE: The renin-angiotensin system is thought to play a pivotal role in the pathogenesis of abdominal aortic aneurysms (AAAs). However, effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) on human AAAs remain unclear. We therefore ex...

  16. Differential roles of Angiotensinogen and Angiotensin Receptor type 1 polymorphisms in breast cancer risk.

    NARCIS (Netherlands)

    Gonzalez-Zuloet Ladd, A.M.; Arias Vasquez, A.; Siemes, C.; Yazdanpanah, M.; Coebergh, J.W.W.; Hofman, A.; Stricker, B.H.C.; Duijn, C.M. van

    2007-01-01

    While angiotensinogen (AGT) seems to have anti proliferative properties, angiotensin II (ATII) is a potent growth factor and it mediates its actions through the angiotensin type 1 receptor (AGTR1). In the AGT gene, the M235T polymorphism has been associated with the variation in angiotensinogen leve

  17. Angiotensin II receptors in the gonads

    Energy Technology Data Exchange (ETDEWEB)

    Aguilera, G.; Millan, M.A.; Harwood, J.P.

    1989-05-01

    The presence of components of the renin-angiotensin system in ovaries and testes suggests that angiotensin II (AII) is involved in gonadal function, and thus we sought to characterize receptors for AII in rat and primate gonads. In the testes, autoradiographic studies showed receptors in the interstitium in all species. In rat interstitial cells fractionated by Percoll gradient, AII receptors coincided with hCG receptors indicating that AII receptors are located on the Leydig cells. In Leydig cells and membranes from rat and rhesus monkey prepuberal testes, AII receptors were specific for AII analogues and of high affinity (Kd=nM). During development, AII receptor content in rat testes decreases with age parallel to a fall in the ratio of interstitial to tubular tissue. In the ovary, the distribution of AII receptors was dependent on the stage of development, being high in the germinal epithelium and stromal tissue between five and 15 days, and becoming localized in secondary follicles in 20-and 40-day-old rats. No binding was found in primordial or primary follicles. In rhesus monkey ovary, AII receptors were higher in stromal tissue and lower in granulosa and luteal cells of the follicles. Characterization of the binding in rat and monkey ovarian membranes showed a single class of sites with a Kd in the nmol/L range and specificity similar to that of the adrenal glomerulosa and testicular AII receptors. Receptors for AII were also present in membrane fractions from PMSG/hCG primed rat ovaries. Infusion of AII (25 ng/min) or captopril (1.4 micrograms/min) during the PMSG/hCG induction period had no effect on ovarian weight or AII receptor concentration in the ovaries.

  18. Documentation of angiotensin II receptors in glomerular epithelial cells

    Science.gov (United States)

    Sharma, M.; Sharma, R.; Greene, A. S.; McCarthy, E. T.; Savin, V. J.; Cowley, A. W. (Principal Investigator)

    1998-01-01

    Angiotensin II decreases glomerular filtration rate, renal plasma flow, and glomerular capillary hydraulic conductivity. Although angiotensin II receptors have been demonstrated in mesangial cells and proximal tubule cells, the presence of angiotensin II receptors in glomerular epithelial cells has not previously been shown. Previously, we have reported that angiotensin II caused an accumulation of cAMP and a reorganization of the actin cytoskeleton in cultured glomerular epithelial cells. Current studies were conducted to verify the presence of angiotensin II receptors by immunological and non-peptide receptor ligand binding techniques and to ascertain the activation of intracellular signal transduction in glomerular epithelial cells in response to angiotensin II. Confluent monolayer cultures of glomerular epithelial cells were incubated with angiotensin II, with or without losartan and/or PD-123,319 in the medium. Membrane vesicle preparations were obtained by homogenization of washed cells followed by centrifugation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of membrane proteins followed by multiscreen immunoblotting was used to determine the presence of angiotensin II receptor type 1 (AT1) or type 2 (AT2). Angiotensin II-mediated signal transduction in glomerular epithelial cells was studied by measuring the levels of cAMP, using radioimmunoassay. Results obtained in these experiments showed the presence of both AT1 and AT2 receptor types in glomerular epithelial cells. Angiotensin II was found to cause an accumulation of cAMP in glomerular epithelial cells, which could be prevented only by simultaneous use of losartan and PD-123,319, antagonists for AT1 and AT2, respectively. The presence of both AT1 and AT2 receptors and an increase in cAMP indicate that glomerular epithelial cells respond to angiotensin II in a manner distinct from that of mesangial cells or proximal tubular epithelial cells. Our results suggest that glomerular epithelial

  19. Trends in co-prescribing of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in Ireland.

    LENUS (Irish Health Repository)

    Wan Md Adnan, Wan A H

    2011-03-01

    (i) To examine the trends in co-prescribing of angiotensin converting enzyme inhibitor (ACEI) and angiotensin-II receptor blocker (ARB) therapy and (ii) to examine the influence of major clinical trials (CALM, COOPERATE, VALIANT and ONTARGET) on co-prescribing.

  20. Guanylyl cyclase/natriuretic peptide receptor-A gene disruption causes increased adrenal angiotensin II and aldosterone levels.

    Science.gov (United States)

    Zhao, Di; Vellaichamy, Elangovan; Somanna, Naveen K; Pandey, Kailash N

    2007-07-01

    Disruption of the guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) gene leads to elevated arterial blood pressure and congestive heart failure in mice lacking NPRA. This study was aimed at determining whether Npr1 (coding for GC-A/NPRA) gene copy number affects adrenal ANG II and aldosterone (Aldo) levels in a gene-dose-dependent manner in Npr1 gene-targeted mice. Adrenal ANG II and Aldo levels increased in 1-copy mice compared with 2-copy mice, but decreased in 3-copy and 4-copy mice. In contrast, renal ANG II levels decreased in 1-copy (25%), 3-copy (38%), and 4-copy (39%) mice compared with 2-copy mice. The low-salt diet stimulated adrenal ANG II and Aldo levels in 1-copy (20 and 2,441%), 2-copy (15 and 2,339%), 3-copy (20 and 424%), and 4-copy (31 and 486%) mice, respectively. The high-salt diet suppressed adrenal ANG II and Aldo levels in 1-copy (46 and 29%) and 2-copy (38 and 17%) mice. On the other hand, the low-salt diet stimulated renal ANG II levels in 1-copy (45%), 2-copy (45%), 3-copy (59%), and 4-copy (48%) mice. However, the high-salt diet suppressed renal ANG II levels in 1-copy (28%) and 2-copy (27%) mice. In conclusion, NPRA signaling antagonizes adrenal ANG II and Aldo levels in a gene-dose dependent manner. Increased adrenal ANG II and Aldo levels may play an important role in elevated arterial blood pressure and progressive hypertension, leading to renal and vascular injury in Npr1 gene-disrupted mice.

  1. ROLE OF ANGIOTENSIN-CONVERTING ENZYME AND VITAMIN D RECEPTOR GENE POLYMORPHISMS IN CANCER ANOREXIA-CACHEXIA SYNDROME

    OpenAIRE

    Ariele Fabris; Paolo Biagioni; Tiziana Punzi; Gabriele Morucci; Massimo Gulisano; Stefania Pacini; Marco Ruggiero

    2012-01-01

    The ubiquitin-proteasome pathway is a crucial connection between aberrant immune system activation, systemic inflammation and Cancer Anorexia-Cachexia Syndrome (CACS), a syndrome that culminates in hyper-activation of the ubiquitin-proteasome pathway. Angiotensin directly up-regulates this pathway, while vitamin D down-regulates it indirectly through the insulin-like growth factor-1 pathway. We investigated the genetic predisposition towards CACS in a cancer population, examining Insertion/De...

  2. Review: Novel roles of nuclear angiotensin receptors and signaling mechanisms

    OpenAIRE

    Gwathmey, TanYa M.; Alzayadneh, Ebaa M.; Karl D. Pendergrass; Chappell, Mark C.

    2011-01-01

    The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT1R) antagonists is an effective therapy to attenuate hype...

  3. The Angiotensin AT2 Receptor

    DEFF Research Database (Denmark)

    Unger, Thomas; Steckelings, Ulrike M.; Dzau, Victor J.

    2015-01-01

    Since its discovery, 25 years ago, the angiotensin AT2 receptor (AT2R) has puzzled the scientific community because of its distinct -localization, regulation, signaling pathways, and biological effects separating it clearly from the classical features of the renin......-angiotensin system (RAS) mediated by the angiotensin AT1 receptor. Intensive research over the years has revealed major characteristics of the AT2R as a modulatory player involved in antiproliferation, anti-inflammation, natriuresis, neuroregeneration, and apoptosis, that is, -biological...

  4. Assignment of the human angiotensin II type 2 receptor gene (AGTR2) to chromosome Xq22-q23 by fluorescence in situ hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Chassagne, C.; Meloche, S. [Hotel-Dieu de Montreal, Quebec (Canada); Beatty, B.G. [Hospital for Sick Children, Toronto, Ontario (Canada)

    1995-01-20

    Angiotensin II (AII), the biologically active effector of the renin-angiotensin system, is a major regulator of blood pressure and electrolyte balance and a growth factor for diverse cell types. AII exerts its physiological effects by interacting with two pharmacologically distinct subtypes of receptors, designated AT{sub 1}, and AT{sub 2}. Most of the known responses to AII are mediated by the AT{sub 1} subtype, whereas the function of the AT{sub 2} receptor remains largely unknown. AT{sub 2} receptor expression is abundant in particular tissues such as adrenal medulla, specific brain regions, uterine myometrium, and ovarian granuloma cells. This specific localization in adult coupled to the demonstration that some actions of AII such as secretion of luteinizing hormone and prolactine, dilation of brain arterioles, or drinking response in rats can be inhibited in vitro by an AT{sub 2} receptor antagonist suggests that the AT{sub 2} subtype may play a role in neuronal and reproductive function. In addition, a growing amount of evidence indicates that the AT{sub 2} receptor may play a most important role in processes involving cellular growth and differentiation. It is abundantly and widely expressed in the mesenchymal tissues of the developing fetus and in the immature brain and is up-regulated in the heart and in vascular smooth muscle cells in the first days following birth. Moreover, AT{sub 2} receptor expression is enhanced in the adult in wound healing, in the neointima of injured vessels, and in pheochromocytoma. 12 refs., 1 fig.

  5. Study of correlation between polymorphism of angiotensin II-1 receptor gene A1166 genotype and complications in atrial fibrillation

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of genetic polymorphism on atrial fibrillation. Methods: Polymerase chain reaction-restrictive fragment length polymorphism(PCR-RFLP) was used to identify and compare the genotype of the location of AT1R gene 1166, and color echo-ultrasound was performed with logistic regression used to analyse the independent risk of various genotypes for atrial fibrillation in 121 patients with atrial fibrillation and 100 controls. Results: (1) Frequency of genotype AC + CC, iso-gene C in atrial fibrillation group was higher than that in control group (P=0.017, 0.013), the risk ratio in patients with genotype AC + CC to develop atrial fibrillation was 3.657 compared with genotype AA (95% CI:1.181∼11.322), and genotype difference as well as systolic pressure were involved in occurrence of overall atrial fibrillation. The OR to develop atrial fibrillation in patients with genotype AC + CC was 4.132 compared with genotype AA (95% CI:1.263∼13.513). (2) There were no significant differences of clinical manifestation (heart failure, cerebral embolism) or ultrasonic parameters among patients with different genotypes (AA vs AC + CC)(P>0.05). Conclusion: People carrying iso-gene C in AT1R gene 1166 were more liable to develop atrial fibrillation, but there were no correlationship with development of complications. (authors)

  6. Intrarenal renin-angiotensin system modulates glomerular angiotensin receptors in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Wilkes, B.M.; Pion, I.; Sollott, S.; Michaels, S.; Kiesel, G. (North Shore Univ. Hospital and Cornell Univ. Medical College, Manhasset, NY (USA))

    1988-03-01

    The aim of this study was to test the hypothesis that the intrarenal renin-angiotensin system (RAS) modulates glomerular angiotensin II (ANG II) receptors. In one protocol ANG II receptors were measured 7 days after unilateral denervation of the left kidney in rats. There were 50% more receptors in the glomeruli from denervated compared with innervated kidneys, which was associated with a 63% reduction in left renal vein renin. The differences in ANG II receptors between the left and right kidneys were not longer present when angiotensin-converting enzyme was inhibited with enalapril or when pharmacological amounts of ANG II were infused. In a second protocol, renal cortical renin content was raised in the left kidney by placing a 0.20-mm clip on the left renal artery. At 7 days, glomerular ANG II receptors were reduced by 72.3% in the clipped compared with the contralateral kidneys. The differences in ANG II receptors were no longer present after enalapril treatment. Pharmacological maneuvers that either blocked ANG II formation or increased circulating ANG II resulted in an equal number of ANG II receptors in the right and left kidneys. The data indicate that the intrarenal RAS modulates the density of glomerular ANG II receptors and is a more important receptor modulation than plasma ANG II.

  7. Cerebrovascular angiotensin AT1 receptor regulation in cerebral ischemia

    DEFF Research Database (Denmark)

    Edvinsson, L.

    2008-01-01

    The mechanism behind the positive response to the inhibition of the angiotensin II receptor AT(1) in conjunction with stroke is elusive. Here we demonstrate that cerebrovascular AT(1) receptors show increased expression (upregulation) after cerebral ischemia via enhanced translation. This enhanced...

  8. Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

    OpenAIRE

    Mehdi, Uzma F.; Adams-Huet, Beverley; Raskin, Philip; Vega, Gloria L.; Toto, Robert D.

    2009-01-01

    Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We co...

  9. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    Science.gov (United States)

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. PMID:25439533

  10. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral cir...

  11. Vascular Endothelin and Angiotensin Receptors Regulation in Inflammatory Arterial Disorders

    OpenAIRE

    Dimitrijevic, Ivan

    2010-01-01

    The present thesis is aimed to examine the hypothesis that the degree of vascular inflammation correlates with the expression of vascular endothelin and angiotensin receptors. The receptor changes were studied in subcutaneous resistance arteries in patients with different degrees of ischemic heart disease (IHD). In addition, patients with giant cell arteritis (GCA) were also investigated because of the massive inflammatory activity in affected vessels. For functional studies of the resistance...

  12. Structural determinants for binding to angiotensin converting enzyme 2 (ACE2 and angiotensin receptors

    Directory of Open Access Journals (Sweden)

    Daniel eClayton

    2015-01-01

    Full Text Available Angiotensin converting enzyme 2 (ACE2 is a zinc carboxypeptidase involved in the renin angiotensin system (RAS and inactivates the potent vasopressive peptide angiotensin II (Ang II by removing the C-terminal phenylalanine residue to yield Ang1-7. This conversion inactivates the vasoconstrictive action of Ang II and yields a peptide that acts as a vasodilatory molecule at the Mas receptor and potentially other receptors. Given the growing complexity of RAS and level of cross-talk between ligands and their corresponding enzymes and receptors, the design of molecules with selectivity for the major RAS binding partners to control cardiovascular tone is an on-going challenge. In previous studies we used single β-amino acid substitutions to modulate the structure of Ang II and its selectivity for ACE2, AT1R and angiotensin type 2 (AT2R receptor. We showed that modification at the C-terminus of Ang II generally resulted in more pronounced changes to secondary structure and ligand binding, and here we further explore this region for the potential to modulate ligand specificity. In this study, 1 a library of forty-seven peptides derived from the C-terminal tetra-peptide sequence (-IHPF of Ang II was synthesised and assessed for ACE2 binding, 2 the terminal group requirements for high affinity ACE2 binding were explored by and N- and C-terminal modification, 3 high affinity ACE2 binding chimeric AngII analogues were then synthesized and assessed, 4 the structure of the full-length Ang II analogues were assessed by circular dichroism, and 5 the Ang II analogues were assessed for AT1R/AT2R selectivity by cell-based assays. Studies on the C-terminus of Ang II demonstrated varied specificity at different residue positions for ACE2 binding and four Ang II chimeric peptides were identified as selective ligands for the AT2 receptor. Overall, these results provide insight into the residue and structural requirements for ACE2 binding and angiotensin receptor

  13. Development of polyclonal antibodies against angiotensin type 2 receptors

    OpenAIRE

    1994-01-01

    Murine neuroblastoma N1E-115 cells are a useful system in which to study neuronal angiotensin II (AngII) receptors. N1E-115 cells possess both type 1 (AT1) and type 2 (AT2) AngII receptor subtypes, as does mammalian brain. AT2 receptors in brain or N1E-115 cells can be solubilized in 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. In the present study, heparin-Sepharose chromatography was used to partially purify solubilized N1E-115 membranes to produce an enriched population of AT...

  14. Cerebrovascular angiotensin AT1 receptor regulation in cerebral ischemia

    DEFF Research Database (Denmark)

    Edvinsson, Lars

    2008-01-01

    The mechanism behind the positive response to the inhibition of the angiotensin II receptor AT(1) in conjunction with stroke is elusive. Here we demonstrate that cerebrovascular AT(1) receptors show increased expression (upregulation) after cerebral ischemia via enhanced translation. This enhanced...... expression of AT(1) receptors occurs in the ischemic cerebral arteries and microvessels, and their inhibition results in a reduction in infarct volume. These findings add to the understanding of the vascular component in stroke, and the identified inhibition provides a new way to reduce the extent...... of cerebral ischemic damage....

  15. Molecular determinants of angiotensin II type 1 receptor functional selectivity

    DEFF Research Database (Denmark)

    Aplin, Mark; Bonde, Marie Mi; Hansen, Jakob Lerche

    2008-01-01

    The angiotensin AT(1) receptor is an important pharmacological target in the treatment of cardiovascular disorders, such as hypertension, diabetic nephropathy, cardiac hypertrophy, arrhythmia and failure. Simultaneously, the AT(1) receptor has emerged to be a prominent model for the emerging...... concept that receptors may attain multiple active states with differentiated functional outcomes. Two major signalling pathways are employed by the AT(1) receptor, namely 1) the canonical G(q) protein-dependent activation of inositol phosphate turnover and intracellular calcium release, and 2) G protein......-independent recruitment of beta-arrestin-scaffolded signalling complexes that activate protein kinase pathways. Different states of receptor activation with preference for individual downstream pathways (functional selectivity) have been demonstrated in mutational studies of the AT(1) receptor and by pharmacological...

  16. Angiotensin II receptors and peritoneal dialysis-induced peritoneal fibrosis.

    Science.gov (United States)

    Morinelli, Thomas A; Luttrell, Louis M; Strungs, Erik G; Ullian, Michael E

    2016-08-01

    The vasoactive hormone angiotensin II initiates its major hemodynamic effects through interaction with AT1 receptors, a member of the class of G protein-coupled receptors. Acting through its AT1R, angiotensin II regulates blood pressure and renal salt and water balance. Recent evidence points to additional pathological influences of activation of AT1R, in particular inflammation, fibrosis and atherosclerosis. The transcription factor nuclear factor κB, a key mediator in inflammation and atherosclerosis, can be activated by angiotensin II through a mechanism that may involve arrestin-dependent AT1 receptor internalization. Peritoneal dialysis is a therapeutic modality for treating patients with end-stage kidney disease. The effectiveness of peritoneal dialysis at removing waste from the circulation is compromised over time as a consequence of peritoneal dialysis-induced peritoneal fibrosis. The non-physiological dialysis solution used in peritoneal dialysis, i.e. highly concentrated, hyperosmotic glucose, acidic pH as well as large volumes infused into the peritoneal cavity, contributes to the development of fibrosis. Numerous trials have been conducted altering certain components of the peritoneal dialysis fluid in hopes of preventing or delaying the fibrotic response with limited success. We hypothesize that structural activation of AT1R by hyperosmotic peritoneal dialysis fluid activates the internalization process and subsequent signaling through the transcription factor nuclear factor κB, resulting in the generation of pro-fibrotic/pro-inflammatory mediators producing peritoneal fibrosis. PMID:27167177

  17. Association of Renin-angiotensin-aldosterone System Gene Polymorphism with the Effect of Angiotensin Receptor Blockers%肾素-血管紧张素-醛固酮系统基因多态性与血管紧张素受体阻滞剂降压疗效相关性的研究进展

    Institute of Scientific and Technical Information of China (English)

    贾坚; 门琛

    2012-01-01

    People recognize that the difference of genetic polymorphism results in the individual difference of drug effect, as the development of the human genome project and pharmacogenomics. This paper reviews association of renin-angiotensin-aldosterone system gene polymorphism with the effect of angiotensin receptor blockers which are used commonly in clinic. The paper also analyzes the possible causes of the contradiction of the research results in the past.%随着人类基因组计划的实施以及药物基因组学研究的进展,人们认识到基因多态性的不同导致了药物治疗效果的个体差异.现综述肾素-血管紧张素-醛固酮系统基因多态性与临床上常用的血管紧张素受体阻滞剂降压疗效的相关性,并分析以往研究结果矛盾的可能原因.

  18. Angiotensin II receptor mRNA expression and vasoconstriction in human coronary arteries

    DEFF Research Database (Denmark)

    Wackenfors, Angelica; Pantev, Emil; Emilson, Malin;

    2004-01-01

    Angiotensin II is a potent vasoconstrictor that is implicated in the pathogenesis of hypertension, heart failure and atherosclerosis. In the present study, angiotensin II receptor mRNA expression levels were quantified by real-time polymerase chain reaction and the vasocontractile responses...... to angiotensin II were characterised by in vitro pharmacology in endothelium-denuded human coronary arteries. Angiotensin II type 1 (AT(1)) and type 2 (AT(2)) receptor mRNA expression levels were significantly down-regulated in arteries from patients with heart failure as compared to controls. The angiotensin II...

  19. The angiotensin Ⅱ type 1 receptor and receptor-associated proteins

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The mechanisms of regulation, activation and signal transduction of the angiotensin Ⅱ(Ang Ⅱ) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang Ⅱ. Among the structures required for regulation and activation of the receptor, its carboxylterminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstreamsignaling pathway by G proteins and the Ang Ⅱ signal transduction pathways leading to specific cellularresponses are discussed. In addition, recent work on the identification and characterization of novel proteinsassociated with carboxyl-terminus of the AT1 receptor is presented. These novel proteins will advance ourunderstanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.

  20. Novel roles of nuclear angiotensin receptors and signaling mechanisms.

    Science.gov (United States)

    Gwathmey, TanYa M; Alzayadneh, Ebaa M; Pendergrass, Karl D; Chappell, Mark C

    2012-03-01

    The renin-angiotensin system (RAS) constitutes an important hormonal system in the physiological regulation of blood pressure. The dysregulation of the RAS is considered a major influence in the development and progression of cardiovascular disease and other pathologies. Indeed, experimental and clinical evidence indicates that blockade of this system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT1R) antagonists is an effective therapy to attenuate hypertension and diabetic renal injury, and to improve heart failure. Originally defined as a circulating system, multiple tissues express a complete RAS, and compelling evidence now favors an intracellular system involved in cell signaling and function. Within the kidney, intracellular expression of the three predominant ANG receptor subtypes is evident in the nuclear compartment. The ANG type 1 receptor (AT1R) is coupled to the generation of reactive oxygen species (ROS) through the activation of phosphoinositol-3 kinase (PI3K) and PKC. In contrast, both ANG type 2 (AT2R) and ANG-(1-7) (AT7R) receptors stimulate nitric oxide (NO) formation, which may involve nuclear endothelial NO synthase (eNOS). Moreover, blockade of either ACE2-the enzyme that converts ANG II to ANG-(1-7)-or the AT7 receptor exacerbates the ANG II-ROS response on renal nuclei. Finally, in a model of fetal programmed hypertension, the nuclear ROS response to ANG II is enhanced, while both AT2 and AT7 stimulation of NO is attenuated, suggesting that an imbalance in the intracellular RAS may contribute to the development of programming events. We conclude that a functional intracellular or nuclear RAS may have important implications in the therapeutic approaches to cardiovascular disease. PMID:22170620

  1. Renal graft failure after addition of an angiotensin II receptor antagonist to an angiotensin-converting enzyme inhibitor

    DEFF Research Database (Denmark)

    Kamper, Anne-Lise; Nielsen, Arne Høj; Baekgaard, Niels;

    2002-01-01

    Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report...... describes a case of acute renal graft dysfunction following the addition of an ARB to existing ACE inhibition. This unmasked an unknown iliac artery stenosis. The case indicates a possible important role of Ang II generated by non-ACE pathways in this situation....

  2. Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II-infused rats.

    Science.gov (United States)

    Minas, Jacqueline N; Thorwald, Max A; Conte, Debra; Vázquez-Medina, Jose-Pablo; Nishiyama, Akira; Ortiz, Rudy M

    2015-11-01

    Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II-dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague-Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II-induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II-mediated increase in plasma and heart aldosterone 2.3- and 1.8-fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1-mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4-hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress-associated cardiovascular damage in Ang II-dependent hypertension. PMID:26234762

  3. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral...... circulation is uncertain. Hence, the present study investigated the effect on CBF autoregulation of blocking of angiotensin AT2-receptors with PD 123319 in spontaneously hypertensive rats (SHR). Anaesthetised and ventilated SHR were given PD 123319, 0.36 mg/kg/min, intravenously, and compared with a control...

  4. Local and systemic effects of angiotensin receptor blockade in an emphysema mouse model

    OpenAIRE

    Raupach, Tobias; Lüthje, Lars; Kögler, Harald; de Duve, Christian; Schweda, Frank; Hasenfuß, Gerd; Andreas, Stefan

    2011-01-01

    Abstract Objectives COPD with emphysema causes marked neurohumoral activation. Angiotensin II receptors are highly expressed within the lung and interfere with mechanisms involved in the progression of emphysema. This study examined the effects of an angiotensin II receptor blocker (ARB) on pulmonary and systemic manifestations of emphysema in a mouse model. Methods Female NMRI mice received five intratracheal instillations of porcine pancreatic ela...

  5. Angiotensin II receptor alterations during pregnancy in rabbits

    Energy Technology Data Exchange (ETDEWEB)

    Brown, G.P.; Venuto, R.C.

    1986-07-01

    Despite activation of the renin-angiotensin system during pregnancy, renal and peripheral vascular blood flows increase, and the systemic blood pressure and the pressor response to exogenous angiotensin II (Ang II) fall. Gestational alterations in Ang II receptors could contribute to these changes. Ang II binding parameters were determining utilizing SVI-Ang II in vascular (glomeruli and mesenteric arteries) and nonvascular (adrenal glomerulosa) tissues from 24- to 28-day pregnant rabbits. Comparisons were made utilizing tissues from nonpregnant rabbits. Binding site concentrations (N) and dissociation constants (K/sub d/) were obtained by Scatchard analyses of binding inhibition data. Meclofenamate (M) inhibits prostaglandin synthesis, reduces plasma renin activity, and enhances the pressor response to infused Ang II in pregnant rabbits. Administration of M to pregnant rabbits increased N in glomerular and in mesenteric artery membranes. These data demonstrate that Ang II receptors in glomeruli and mesenteric arteries are down regulated during gestation in rabbits. Elevated endogenous Ang II during pregnancy in rabbits may contribute to the down regulation of vascular Ang II receptors.

  6. Hyperkalemia associated with use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

    Science.gov (United States)

    Raebel, Marsha A

    2012-06-01

    The aims of this article are to review the current understanding of hyperkalemia associated with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy. This includes reviewing the pathophysiology of how these agents affect potassium handling within the kidney, risk factors for developing hyperkalemia, incidence, clinical signs and symptoms, and providing a practical approach to treatment of the patient who is either at risk of, or experiencing, hyperkalemia. ACEi and ARB are effective therapeutic agents used in a variety of clinical scenarios. However, related to their effects on the renin-angiotensin-aldosterone system, their use can be associated with hyperkalemia, particularly in patients who have chronic renal insufficiency. Published incidence estimates of hyperkalemia associated with ACEi or ARB vary, but up to 10% of patients may experience at least mild hyperkalemia. Important considerations when initiating ACEi or ARB therapy include obtaining an estimate of glomerular filtration rate and a baseline serum potassium concentration, as well as assessing whether the patient has excessive potassium intake from diet, supplements, or drugs that can also increase serum potassium. Serum potassium monitoring shortly after initiation of therapy can assist in preventing hyperkalemia. If hyperkalemia does develop, prompt recognition of cardiac dysrhythmias and effective treatment to antagonize the cardiac effects of potassium, redistribute potassium into cells, and remove excess potassium from the body is important.Understanding the mechanism of action of ACEi and ARB coupled with judicious drug use and clinical vigilance can minimize the risk to the patient of developing hyperkalemia. Should hyperkalemia occur, prompt recognition and management can optimize clinical outcome.

  7. New targets for renal interstitial fibrosis: relaxin family peptide receptor 1-angiotensin type 2 receptor heterodimers.

    Science.gov (United States)

    Sasser, Jennifer M

    2014-07-01

    The signal transduction mechanisms involved in the renoprotective effects of relaxin are not well understood. Chow et al. demonstrate that relaxin family peptide receptor 1 (RXFP1) forms heterodimer complexes with the angiotensin type 2 receptor (AT2), even in the absence of ligand, and that these heterodimers are required for relaxin's antifibrotic effects. These findings identify a previously unknown link between relaxin and angiotensin II signaling that could be a potential new target for slowing the progression of fibrotic renal diseases. PMID:24978374

  8. Activation of the Retinoid X Receptor Modulates Angiotensin II-Induced Smooth Muscle Gene Expression and Inflammation in Vascular Smooth Muscle Cells

    OpenAIRE

    Lehman, Allison M.B.; Montford, John R.; Horita, Henrick; Ostriker, Allison C.; Weiser-Evans, Mary C. M.; Nemenoff, Raphael A.; Furgeson, Seth B.

    2014-01-01

    The retinoid X receptor (RXR) partners with numerous nuclear receptors, such as the peroxisome proliferator activated receptor (PPAR) family, liver X receptors (LXRs), and farnesoid X receptor (FXR). Although each heterodimer can be activated by specific ligands, a subset of these receptors, defined as permissive nuclear receptors, can also be activated by RXR agonists known as rexinoids. Many individual RXR heterodimers have beneficial effects in vascular smooth muscle cells (SMCs). Because ...

  9. New Targets for Renal Interstitial Fibrosis: Relaxin Family Peptide Receptor 1 - Angiotensin Type 2 Receptor Heterodimers

    OpenAIRE

    Sasser, Jennifer M.

    2014-01-01

    Recent findings have shown that relaxin has potent anti-fibrotic effects within the kidney; however, the signal transduction mechanisms involved in the renoprotective effects of relaxin are not well understood. Chow et al demonstrate that the relaxin receptor, RXFP1, forms heterodimer complexes with the angiotensin type 2 receptor, AT2, even in the absence of ligand and that these heterodimer complexes are required for relaxin’s antifibrotic effects. These findings identify a previously unkno...

  10. Contributions of renin-angiotensin system-related gene interactions to obesity in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Jian-Bo Zhou

    Full Text Available BACKGROUND: Gene-gene interactions may be partly responsible for complex traits such as obesity. Increasing evidence suggests that the renin-angiotensin system (RAS contributes to the etiology of obesity. How the epistasis of genes in the RAS contributes to obesity is still under research. We aim to evaluate the contribution of RAS-related gene interactions to a predisposition of obesity in a Chinese population. METHODOLOGY AND PRINCIPAL FINDINGS: We selected six single nucleotide polymorphisms (SNPs located in angiotensin (AGT, angiotensin converting enzyme (ACE, angiotensin type 1 receptor (AGTR1, MAS1, nitric oxide synthase 3 (NOS3 and the bradykinin B2 receptor gene (BDKRB2, and genotyped them in 324 unrelated individuals with obesity (BMI ≥ 28 kg/m(2 and 373 non-obese controls (BMI 18.5 to <24 kg/m(2 from a large scale population-based cohort. We analyzed gene-gene interactions among 6 polymorphic loci using the Generalized Multifactor Dimensionality Reduction (GMDR method, which has been shown to be effective for detecting gene-gene interactions in case-control studies with relatively small samples. Then we used logistic regression models to confirm the best combination of loci identified in the GMDR. It showed a significant gene-gene interaction between the rs220721 polymorphism in the MAS1 gene and the rs1799722 polymorphism in the gene BDKB2R. The best two-locus combination scored 9 for cross-validation consistency and 9 for sign test (p = 0.0107. This interaction showed the maximum consistency and minimum prediction error among all gene-gene interaction models evaluated. Moreover, the combination of the MAS1 rs220721 and the BDKRB2 rs1799722 was associated with a significantly increased risk of obesity (OR 1.82, CI 95%: 1.15-2.88, p = 0.0103. CONCLUSIONS AND SIGNIFICANCE: These results suggest that the SNPs from the RAS-related genes may contribute to the risk of obesity in an interactive manner in a Chinese population. The gene-gene

  11. Combined Angiotensin Receptor Modulation in the Management of Cardio-Metabolic Disorders

    DEFF Research Database (Denmark)

    Paulis, Ludovit; Foulquier, Sébastien; Namsolleck, Pawel;

    2016-01-01

    Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R...

  12. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen

    Directory of Open Access Journals (Sweden)

    Siew Mei Joyce-Tan

    2016-01-01

    Full Text Available Genome-wide association studies (GWAS have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM. However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE, angiotensinogen (AGT, and angiotensin II type 1 receptor (AGTR1. There were significant differences in allele frequencies between cases and controls for AGT variants (P=0.05 but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15–3.20, permuted P=0.012; however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk.

  13. Renin-Angiotensin System Gene Variants and Type 2 Diabetes Mellitus: Influence of Angiotensinogen.

    Science.gov (United States)

    Joyce-Tan, Siew Mei; Zain, Shamsul Mohd; Abdul Sattar, Munavvar Zubaid; Abdullah, Nor Azizan

    2016-01-01

    Genome-wide association studies (GWAS) have been successfully used to call for variants associated with diseases including type 2 diabetes mellitus (T2DM). However, some variants are not included in the GWAS to avoid penalty in multiple hypothetic testing. Thus, candidate gene approach is still useful even at GWAS era. This study attempted to assess whether genetic variations in the renin-angiotensin system (RAS) and their gene interactions are associated with T2DM risk. We genotyped 290 T2DM patients and 267 controls using three genes of the RAS, namely, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AGTR1). There were significant differences in allele frequencies between cases and controls for AGT variants (P = 0.05) but not for ACE and AGTR1. Haplotype TCG of the AGT was associated with increased risk of T2DM (OR 1.92, 95% CI 1.15-3.20, permuted P = 0.012); however, no evidence of significant gene-gene interactions was seen. Nonetheless, our analysis revealed that the associations of the AGT variants with T2DM were independently associated. Thus, this study suggests that genetic variants of the RAS can modestly influence the T2DM risk. PMID:26682227

  14. Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus

    NARCIS (Netherlands)

    Pena, Michelle J; Heinzel, Andreas; Rossing, Peter; Parving, Hans-Henrik; Dallmann, Guido; Rossing, Kasper; Andersen, Steen; Mayer, Bernd; Heerspink, Hiddo J L

    2016-01-01

    BACKGROUND: Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response

  15. Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus

    NARCIS (Netherlands)

    Pena, Michelle J.; Heinzel, Andreas; Rossing, Peter; Parving, Hans-Henrik; Dallmann, Guido; Rossing, Kasper; Andersen, Steen; Mayer, Bernd; Heerspink, Hiddo J. L.

    2016-01-01

    Background: Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response

  16. (Prorenin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.

    Directory of Open Access Journals (Sweden)

    Anne-Mari Moilanen

    Full Text Available BACKGROUND: Activation of the renin-angiotensin-system (RAS plays a key pathophysiological role in heart failure in patients with hypertension and myocardial infarction. However, the function of (prorenin receptor ((PRR is not yet solved. We determined here the direct functional and structural effects of (PRR in the heart. METHODOLOGY/PRINCIPAL FINDINGS: (PRR was overexpressed by using adenovirus-mediated gene delivery in normal adult rat hearts up to 2 weeks. (PRR gene delivery into the anterior wall of the left ventricle decreased ejection fraction (P<0.01, fractional shortening (P<0.01, and intraventricular septum diastolic and systolic thickness, associated with approximately 2-fold increase in left ventricular (PRR protein levels at 2 weeks. To test whether the worsening of cardiac function and structure by (PRR gene overexpression was mediated by angiotensin II (Ang II, we infused an AT(1 receptor blocker losartan via osmotic minipumps. Remarkably, cardiac function deteriorated in losartan-treated (PRR overexpressing animals as well. Intramyocardial (PRR gene delivery also resulted in Ang II-independent activation of extracellular-signal-regulated kinase1/2 phosphorylation and myocardial fibrosis, and the expression of transforming growth factor-β1 and connective tissue growth factor genes. In contrast, activation of heat shock protein 27 phosphorylation and apoptotic cell death by (PRR gene delivery was Ang II-dependent. Finally, (PRR overexpression significantly increased direct protein-protein interaction between (PRR and promyelocytic zinc-finger protein. CONCLUSIONS/SIGNIFICANCE: These results indicate for the first time that (PRR triggers distinct Ang II-independent myocardial fibrosis and deterioration of cardiac function in normal adult heart and identify (PRR as a novel therapeutic target to optimize RAS blockade in failing hearts.

  17. The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Olsen, Kristine Boisen; Erikstrup, Niels;

    2011-01-01

    The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately...... connected and some of the cardioprotective effects of Losartan are abolished by blocking the bradykinin B2 receptor (B2R) signaling. In this study, we investigated the ability of six clinically available ARBs to specifically bind and activate the B2R. First, we investigated their ability to activate...... phosphoinositide (PI) hydrolysis in COS-7 cells transiently expressing the B2R. We found that only Losartan activated the B2R, working as a partial agonist compared to the endogenous ligand bradykinin. This effect was blocked by the B2R antagonist HOE 140. A competitive binding analysis revealed that Losartan does...

  18. Association of Polymorphisms of β3-Adrenergic Receptor,Angiotensinogen and Angiotensin-Converting Enzyme Gene with Hypertension in type 2 DM

    Institute of Scientific and Technical Information of China (English)

    丁国宪; 沈捷; 陈家伟

    2002-01-01

    ObjectiveTo explore the relationship between the mutant genes of ACE,ATN,β3-AR and hypertension in patients with type 2 DM.Methods281 recruited Chinese subjects were divided into two groups according to the mellitus (DM):112 cases.The subjects were genotyped for the ACE gene,the ATN gene and the codon 64 of β3-AR gene polymorphisms by applying polymerase chain reaction (PCR),PCR restriction fragment-length polymorphisms screening with the use of endonuclease.ResultsOur study found that the frequency of D/D genotype and D allele of ACE gene,a/a genotype and an allele of ATN gene in HT patients without DM were increased (P all <0.05);that the frequency of codon 64 mutation of β3-AR gene also increased in HT patients with NGT (P <0.05).In the model of multiple factors non-condition-al Logistic regression analyses,HT had relationship with history of hypertension,age and glucose tolerance (OR=10.745 7,1.780 4,2.034 6;P=0.000 4,0.000 0,0.024 6;respectively),with polymorphism of ATN gene,β3AR gene,ACE gene (OR=2.273 6,1.935 3,1.830 9;P=0.054 3,0.028 7,0.043 2;resceptively).ConclusionThese results suggest that variants of ACE gene,β3AR gene,ATN gene were associated with HT in type 2 DM.``

  19. Quantitative autoradiography of angiotensin II receptors in the brain and kidney

    Energy Technology Data Exchange (ETDEWEB)

    Gehlert, D.R.

    1985-01-01

    The renin-angiotensin system is an important component in the regulation of systemic blood pressure. Angiotensin II is the principal effector peptide of this system. Interaction of angiotensin II with specific receptors can produce in several organic systems. When administered into the brain this octa-peptide produces a variety of responses including a stimulation of drinking, increased systemic blood pressure and several neuroendocrine responses. Its effects on the kidney include alterations in arteriolar resistance, mesangial cell contraction and a feedback inhibition of the release of renin. Since this peptide produces profound effects on homeostatis by an interaction with specific receptors, the quantitative technique of in vitro autoradiography was applied to localize receptor populations for angiotensin II. Specific binding sites for a radiolabeled form of angiotensin II were localized in various brain and kidney regions. In the rat brain high densities of angiotensin II receptors were observed in the paraventricular and suprachiasmatic nuclei of the hypothalamus, supraoptic nucleus and the posterior lobe of the pituitary, brain areas in which angiotensin II modified neuroendocrine functions.

  20. Angiotensin receptor blocker telmisartan suppresses renal gluconeogenesis during starvation

    Directory of Open Access Journals (Sweden)

    Tojo A

    2015-02-01

    Full Text Available Akihiro Tojo, Saaya Hatakeyama, Satoshi Kinugasa, Masaomi Nangaku Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan Abstract: The kidney plays an important role in gluconeogenesis during starvation. To clarify the anti-diabetic action of angiotensin receptor blockers, we examined the effects of telmisartan on the sodium-glucose co-transporters (SGLT and the pathways of renal gluconeogenesis in streptozotocin-induced diabetes mellitus (DM rats. At 4 weeks, the DM rats treated with/without telmisartan for 2 weeks and normal control rats were used for the study after a 24-hour fast. SGLT2 expressed on the brush border membrane of the proximal convoluted tubules increased in the DM rats, but decreased in the rats treated with telmisartan. The expression of restriction enzymes of gluconeogenesis, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased in the proximal tubules in the DM rats, whereas these enzymes decreased in the kidneys of the rats treated with telmisartan. The elevated cytoplasmic glucose-6-phosphate and glucose levels in the kidney of DM rats significantly decreased in those treated with telmisartan, whereas those levels in the liver did not show significant change. Meanwhile, the high plasma glucose levels in the DM rats during the intravenous insulin tolerance tests were ameliorated by telmisartan. The increased fasting plasma glucose levels after 24 hours of starvation in the DM rats thus returned to the control levels by telmisartan treatment. In conclusion, the increased renal SGLT2 expression, elevated renal gluconeogenesis enzymes and extent of insulin-resistance in the DM rats were ameliorated by telmisartan therapy, thus resulting in decreased plasma glucose levels after 24 hours of fasting. Keywords: SGLT2, renal gluconeogenesis, diabetes, angiotensin II

  1. 老年原发性高血压AT1一R基因多态性的研究%The Polymorphism of Angiotensin Ⅱ Type 1 Receptor Gene in Essential Hypertensive Elders

    Institute of Scientific and Technical Information of China (English)

    方宁远; 张怡; 陆惠华; 邬亦贤; 郑迪辉; 郑道声

    2000-01-01

    目的 研究老年原发性高血压(EH)血管紧张素Ⅱ型受体(AT1一R)基因A/C1166多态性的特征。方法 应用聚合酶链反应一限制性片段长度多态性(PCR—RFLP)技术检测87例汉族老年EH患者和55例正常老年人的AT1-R基因A/C1166多态性分布。结果87例老年EH患者的C1166等位基因频率为0.115,55例正常老年人为0.036,经统计学分析两组间有显著差异(P<0.05)。结论老年EH的患者C1166等位基因频率明显升高,可能为EH发病的危险因素。%Objective This study was to detect the A/C1166 polymorphism of angiotensin Ⅱtype 1 receptor (AT1 - R) gene in the essential hypertensive elder. Methods The A/C1166 polymor-phism of AT1 - R gene was assessed by polymerase chain reaction- restriction fragment length polymor-phism (PCR- RFLP) in a case- control study of 87 EH elders and 55 normotensive elders (NT).Results The genotype frequencies of AA, AC, CC were 0. 805, 0. 161, 0. 034 in EH group and0. 927, 0. 073, 0. 000 in NT group. The frequency of A/C1166 allele was higher in EH group (0. 115)than in NT group (0. 036) (P < 0.05). Conclusion The frequency of C1166 allele was significantlyhigher in EH group than in NT group, which indicated that A/C1166 polymorphism of AT1 - R gene maybe associated with EH in the elderly.

  2. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit+ bosentan group and Nit+ losartan group. Nitroglycerin tolerance was induced by 2-day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg- 1· d- 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg- 1· d- 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit+ losartan group and Nit+ bosentan group compared with Nit group [(31.95± 4.45 ) % vs (21.00± 3.69 ) % , P Conclusion. Endothelin receptor antagonist and angiotensinreceptor antagonist could prevent against the Nit tolerance .

  3. Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Wilkes, B.M.

    1987-04-01

    Glomerular angiotensin II receptors are reduced in number in early diabetes mellitus, which may contribute to hyperfiltration and glomerular injury. The time course and role of the renin-angiotensin-aldosterone system in the pathogenesis of the receptor abnormality were studied in male Sprague-Dawley rats made diabetic with streptozotocin (65 mg, iv). Glomerular angiotensin II receptors were measured by Scatchard analysis; insulin, renin activity, angiotensin II, and aldosterone were measured by RIA. Diabetes mellitus was documented at 24 h by a rise in plasma glucose (vehicle-injected control, 133 +/- 4; diabetic, 482 +/- 22 mg/dl and a fall in plasma insulin (control, 53.1 +/- 5.7; diabetic, 35.6 +/- 4.0 microIU/ml. At 24 h glomerular angiotensin II receptor density was decreased by 26.5% in diabetic rats (control, 75.5 +/- 9.6 X 10(6); diabetic, 55.5 +/- 8.3 X 10(6) receptors/glomerulus. Receptor occupancy could not explain the defect, because there was reduced binding in diabetic glomeruli after pretreatment with 3 M MgCl/sub 2/, a maneuver that caused dissociation of previously bound hormone. There was a progressive return of the receptor density toward normal over the 60 days following induction of diabetes, with diabetic glomeruli measuring 22.7%, 14.8%, and 3.7% fewer receptors than age-matched controls at 11 days, 1 month, and 2 months, respectively.

  4. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    张建梅; 陈永红; 王晓红; 唐朝枢

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n =6, each): Control group, Nitroglycerin (Nit) group, Nit + bosentan group and Nit + losartan group. Nitroglycerin tolerance was induced by 2-day treatment ofnitroglycerin patch (0. 05mg/h). Angiotensin I1 receptor antagonist losartan (10mg ·kg-1·d-1) and endothe-lin receptor antagonist bosentan ( 100 mg·kg-1· d-1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group. The effec-tive percentages of hypotensive response to SNP were increased in both Nit + losartan group and Nit + bosentangroup compared with Nit group [(31.95±4.45) % vs (21.00±3.69) %, P <0.01and (33. 18±6. 16)% vs (21.00±3.69 ) %, P < 0. 01 , respectivelyl. The maximal vessel relaxation induced by SNP was thesame in 4 different groups but the highest EC50 (concentration which produces 50% of the maximal response toSNP) was found in tolerant group[ (34 ±10) nmol/L, P < 0. 01 ]. The ET-1 amounts in plasma and vasculartissue were markedly increased by 54% and 60% in Nit group compared with those in control group( P<0. 01). The ET-1 amounts in plasma and vascular tissue were decreased by 30% and 37% in Nit + losartangroup compared with those in Nit group ( P < 0.01 ). Conclusion. Endothelin receptor antagonist and angiotensinreceptor antagonist could prevent against the Nit tolerance.

  5. Angiotensin AT1-receptor blockers and cerebrovascular protection: do they actually have a cutting edge over angiotensin-converting enzyme inhibitors?

    DEFF Research Database (Denmark)

    Oprisiu-Fournier, Roxana; Faure, Sébastien; Mazouz, Hakim;

    2009-01-01

    is presented to support the hypothesis that antihypertensive drugs that increase angiotensin II formation, such as diuretics, AT1-receptor blockers and dihydropyridines, may have greater brain anti-ischemic effects than antihypertensive drugs that decrease angiotensin II formation, such as beta-blockers...

  6. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial

    DEFF Research Database (Denmark)

    NN, NN; Yusuf, S; Teo, K;

    2008-01-01

    BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular...

  7. Renin-angiotensin system genes polymorphism in Egyptians with premature coronary artery disease.

    Science.gov (United States)

    Abd El-Aziz, Tarek A; Hussein, Yousri M; Mohamed, Randa H; Shalaby, Sally M

    2012-05-01

    Genetics polymorphism of the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the RAS genes and premature CAD (PCAD) in Egyptians. 116 patients with PCAD, 114 patients with late onset CAD and 119 controls were included in the study. Angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (ATR1) and angiotensinogen (AGT) genes polymorphisms were analyzed by polymerase chain reaction (PCR). We found that ACE DD, AGT TT and ATR1 CC increased the risk of PCAD by 2.7, 2.8 and 2.86 respectively). Smoking, hypertension, diabetes, total cholesterol, triglycerides and LDL cholesterol were independent risk factors for the development of PCAD. We conclude that the ACE DD, AGT TT and ATR1 CC genotypes may increase the susceptibility of an individual to have PCAD. The coexistence of CAD risk factors with these risky RAS genotypes may lead to the development of PCAD in Egyptian patients. PMID:22387727

  8. Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11- hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India

    Indian Academy of Sciences (India)

    Manisha Patnaik; Pallabi Pati; Surendra N. Swain; Manoj K. Mohapatra; Bhagirathi Dwibedi; Shantanu K. Kar; Manoranjan Ranjit

    2015-06-01

    Essential hypertension which accounts 90–95% of the total hypertension cases is affected by both genetic and environmental factors. This study was undertaken to investigate the association of aldosterone synthase C-344T, angiotensin II type I receptor A1166C and 11- hydroxysteroid dehydrogenase type 2 G534A polymorphisms with essential hypertension in the population of Odisha, India. A total of 246 hypertensive subjects (males, 159; females, 87) and 274 normal healthy individuals (males, 158; females, 116) were enrolled in this study based on the inclusion and exclusion criteria. Analysis of genetic and biochemical data revealed that in this population the CT and TT genotypes of aldosterone synthase C-344T polymorphism, frequency of alcohol consumption and aldosterone levels were significantly high among the total as well as male hypertensives, while the AC and CC genotypes of angiotensin II type I receptor A1166C polymorphism were significantly high among the total as well as female hypertensives. High density lipoprotein levels were higher in male hypertensives.

  9. Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11- hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India

    Indian Academy of Sciences (India)

    Manisha Patnaik; Pallabi Pati; Surendra N. Swain; Manoj K. Mohapatra; Bhagirathi Dwibedi; Shantanu K. Kar; Manoranjan Ranjit

    2014-12-01

    Essential hypertension which accounts 90–95% of the total hypertension cases is affected by both genetic and environmental factors. This study was undertaken to investigate the association of aldosterone synthase C-344T, angiotensin II type I receptor A1166C and 11- hydroxysteroid dehydrogenase type 2 G534A polymorphisms with essential hypertension in the population of Odisha, India. A total of 246 hypertensive subjects (males, 159; females, 87) and 274 normal healthy individuals (males, 158; females, 116) were enrolled in this study based on the inclusion and exclusion criteria. Analysis of genetic and biochemical data revealed that in this population the CT and TT genotypes of aldosterone synthase C-344T polymorphism, frequency of alcohol consumption and aldosterone levels were significantly high among the total as well as male hypertensives, while the AC and CC genotypes of angiotensin II type I receptor A1166C polymorphism were significantly high among the total as well as female hypertensives. High density lipoprotein levels were higher in male hypertensives.

  10. Angiotensin II receptor blocker attenuates intrarenal renin-angiotensin-system and podocyte injury in rats with myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Zhu-zhi Wen

    Full Text Available The mechanisms and mediators underlying common renal impairment after myocardial infarction (MI are still poorly understood. The present study aimed to test the hypothesis that angiotensin II type 1 receptor blockers (ARBs provides renoprotective effects after MI by preventing augmented intrarenal renin-angiotensin-system (RAS-induced podocyte injury. Sprague-Dawley rats that underwent ligation of their coronary arteries were treated with losartan (20 mg/kg/d or vehicle for 3 or 9 weeks. Renal function, histology and molecular changes were assessed. The current study revealed that MI-induced glomerular podocyte injury was identified by increased immunostaining for desmin and p16(ink4a, decreased immunostaining for Wilms' tumor-1 and podocin mRNA expression, and an induced increase of blood cystatin C at both 3 and 9 weeks. These changes were associated with increased intrarenal angiotensin II levels and enhanced expressions of angiotensinogen mRNA and angiotensin II receptor mRNA and protein. These changes were also associated with decreased levels of insulin-like growth factor (IGF-1 and decreased expressions of IGF-1 receptor (IGF-1R protein and mRNA and phosphorylated(p-Akt protein at 9 weeks, as well as increased expressions of 8-hydroxy-2'-deoxyguanosine at both time points. Treatment with losartan significantly attenuated desmin- and p16(ink4a-positive podocytes, restored podocin mRNA expression, and decreased blood cystatin C levels. Losartan also prevented RAS activation and oxidative stress and restored the IGF-1/IGF-1R/Akt pathway. In conclusion, ARBs prevent the progression of renal impairment after MI via podocyte protection, partially by inhibiting the activation of the local RAS with subsequent enhanced oxidative stress and an inhibited IGF-1/IGF-1R/Akt pathway.

  11. Chromatographic resolution of angiotensin II receptor antagonists (sartans).

    Science.gov (United States)

    Tahir, Muhammad Saqlain; Adnan, Ahmad; Syed, Quratulain

    2016-08-01

    First time a simple, sensitive and unified quantification method has been developed to analyze the complete class of angiotensin II receptor antagonists which are used in the treatment of hypertension either alone or in combination with some other drugs. The most important advantage of developed method was that the eight separate drugs can be determined on a single chromatographic system without modifications in detection wavelength and mobile phase. The drugs were separated on a Purospher Star 4.6mm×25cm, 5μm, C18 column maintained at 40°C with 1mLmin(-1) flow rate using ultra violet detection at 254nm. Good separation (Rs>2.0) was achieved in a short analysis allowing simultaneous determination of all eight sartans. The effect of variation in flow rate, detection wavelength and column oven temperature was also studied. The proposed method was statistically validated in terms of precision, accuracy, linearity, specificity and robustness. The newly developed method proved to be specific, robust and accurate for the quantification of eight sartans in commercial pharmaceutical formulations. PMID:27258943

  12. Recent advances and findings of angiotensin type 2 receptor:a review

    Institute of Scientific and Technical Information of China (English)

    ZUO Yu-mei; WANG Yuan; LIU Jian-ping

    2010-01-01

    @@ Angiotensinogen is a member of the serpin family. It is produced constitutively and released into the circulation mainly by the liver. Angiotensinogen forms angiotensin Ⅰ by action of the circulated renin released from the kidney. Angiotensin Ⅱ (Ang Ⅱ), an octapeptide hormone with sequence Asp-Arg-Val-Tyr-Ile-His-Pro-Phe,is converted from angiotensin Ⅰ through removal of two terminal residues by the angiotensin-converting enzyme (ACE) mostly catalyzed in the lung.1 This peptide binds to two subtype receptors, angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R),members of the superfamily of heptahelical G protein coupled receptors, with different affinities.2 It is well known that AT1R and AT2R crosstalk and lead to counterregulatory functions in many systems, especially the cardiovascular system.3 Accumulating data established the roles of AT1R in the classic actions of Ang Ⅱ including vasoconstriction and cardiovascular hypertrophy, whereas AT2R is suggested to exert direct functions in vasodilation and antigrowth effects.4 Recent publications provide new insights into the roles of AT2R with increasing responsibilities. Recent progresses in AT2R research are reviewed in this article.

  13. Functional interactions between 7TM receptors in the renin-angiotensin system--dimerization or crosstalk?

    DEFF Research Database (Denmark)

    Lyngsø, Christina; Erikstrup, Niels; Hansen, Jakob L

    2008-01-01

    The Renin-Angiotensin System (RAS) is important for the regulation of cardiovascular physiology, where it controls blood pressure, and salt- and water homeostasis. Dysregulation of RAS can lead to severe diseases including hypertension, diabetic nephropathy, and cardiac arrhythmia, and -failure....... The importance of the RAS is clearly emphasised by the widespread use of drugs targeting this system in clinical practice. These include, renin inhibitors, angiotensin II receptor type I blockers, and inhibitors of the angiotensin converting enzyme. Some of the important effectors within the system are 7...

  14. High Order Gene-Gene Interactions in Eight Single Nucleotide Polymorphisms of Renin-Angiotensin System Genes for Hypertension Association Study

    Directory of Open Access Journals (Sweden)

    Cheng-Hong Yang

    2015-01-01

    Full Text Available Several single nucleotide polymorphisms (SNPs of renin-angiotensin system (RAS genes are associated with hypertension (HT but most of them are focusing on single locus effects. Here, we introduce an unbalanced function based on multifactor dimensionality reduction (MDR for multiloci genotypes to detect high order gene-gene (SNP-SNP interaction in unbalanced cases and controls of HT data. Eight SNPs of three RAS genes (angiotensinogen, AGT; angiotensin-converting enzyme, ACE; angiotensin II type 1 receptor, AT1R in HT and non-HT subjects were included that showed no significant genotype differences. In 2- to 6-locus models of the SNP-SNP interaction, the SNPs of AGT and ACE genes were associated with hypertension (bootstrapping odds ratio [Boot-OR] = 1.972~3.785; 95%, confidence interval (CI 1.26~6.21; P<0.005. In 7- and 8-locus model, SNP A1166C of AT1R gene is joined to improve the maximum Boot-OR values of 4.050 to 4.483; CI = 2.49 to 7.29; P<1.63E−08. In conclusion, the epistasis networks are identified by eight SNP-SNP interaction models. AGT, ACE, and AT1R genes have overall effects with susceptibility to hypertension, where the SNPs of ACE have a mainly hypertension-associated effect and show an interacting effect to SNPs of AGT and AT1R genes.

  15. Ischemic heart disease down-regulates angiotensin type 1 receptor mRNA in human coronary arteries

    DEFF Research Database (Denmark)

    Wackenfors, Angelica; Emilson, Malin; Ingemansson, Richard;

    2004-01-01

    Angiotensin II is important in the development of cardiovascular disease. In the present study, angiotensin II receptor mRNA levels were quantified by real-time polymerase chain reaction (real-time PCR) in human coronary arteries from patients with ischemic heart disease and controls. Furthermore......, the suitability of artery culture for studying angiotensin receptor changes was evaluated by in vitro pharmacology and real-time PCR. The angiotensin type 1 (AT1) receptor mRNA levels were down-regulated in human coronary arteries from patients with ischemic heart disease as compared to controls (P

  16. 血管紧张素Ⅱ1型受体基因多态性与原发性高血压的关系%Association of angiotensin Ⅱ type 1 receptor gene polymorphism with essential hypertension

    Institute of Scientific and Technical Information of China (English)

    龚洪涛; 杜凤和

    2010-01-01

    Objective To investigate whether angiotensin Ⅱ type 1 receptor(AT1R)gene polymorphism is associated with essential hypertension(EH). Methods A total of 200 hypertension patients and 192 normotensive controls were enrolled. The AT1R gene 1166A/C and -810A/T polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-PFLP), and the association between the SNPs and the EH were analyzed statistically. Some biochemical index such as serum glucose (GLU) and total cholesterol (TC),triglyceride (TG), high density lipoprotein (HDL-C) and low density lipoprotein (LDL-C) were also measured. Results There was no significant difference between two groups of 1166A/C polymorphisms of AT1R gene(P > 0.05 ). However, for the -810A/T polymorphism of AT1R gene, -810 AT and TT genotypes frequencies were significantly higher in EH patients than control (P = 0. 004). The -810T allele frequencies were higher in case than in control (22.5% vs. 11.5% ;P =0.000). We also found an association between EH and -810AT and TT genotypes by logistic regression analysis ( P = 0. 003 ), adjusted for other risk factors. The odds ratio was 2.57 (95% CI:1. 37 ~4. 84). Conclusions AT1R -810A/T polymorphism is associated with EH and -810T allele may be a risk factor of hypertension%目的 探讨血管紧张素Ⅱ1型受体(AT1R)基因多态性与原发性高血压(EH)之间的关系.方法 应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)对200例汉族EH患者(EH组)和192例正常血压者(对照组)的AT1R基因1166A/C及-810A/T多态性进行检测,测定空腹血糖、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)及高密度脂蛋白胆固醇(HDL-C)等生物化学指标,分析各基因型和等位基因频率与EH的关系.结果 1166A/C等位基因和基因型频率在EH组和对照组的分布无统计学差异(P均>0.05),-810A/T各基因型在EH组和对照组间差异有统计学意义(x2=10.862,P=0

  17. ATⅡ受体基因多态性与原发性醛固酮增多症的相关性研究%Association of polymorphisms in angiotensinreceptor gene with primary aldosteronism

    Institute of Scientific and Technical Information of China (English)

    杜馥曼; 王嵬民; 段滨红; 向朝峰; 王丹

    2015-01-01

    目的:探讨血管紧张素Ⅱ受体(ATR)基因多态性与原发性醛固酮增多症(PA)的关联性。方法应用聚合酶链式反应-限制性片段长度多态性方法(PCR-RFLP)检测及85例 PA 患者与100例健康对照者的 AT1 R 基因1166A /C 和 AT2R 基因1675A /G 多态性。结果患者组 AT1 R 基因1166A /C 基因型(AA、AC、CC)与等位基因(A、C)频率分布与对照组比较差异无统计学意义(χ2=0.430,P =0.806),AT2R 基因1675A /G 基因型(AA、AG、GG)与等位基因(A、G)频率分布与对照组差异有统计学意义(χ2=6.121,P =0.013),G 等位基因频率较 A 等位基因频率显著升高(χ2=6.767,P =0.009)。结论AT2R 1675A /G 的基因突变可能是 PA 发病的危险因素之一。%Objective To investigate the relationship between the polymorphisms of angiotensinreceptor gene and the risk of primary aldosteronism (PA).Methods Polymerase chain reaction -restriction fragment length polymorphism (PCR -RFLP)was used to examine the 1 1 66A /C polymorphism of AT1 R gene and 1 675A /G poly-morphism of AT2R gene in 85 patients with PA and 1 00 healthy controls.Results There was no significant difference of AT1 R 1 1 66A /C genotypes (AA,AC,CC)and allele (A and C)frequency among patients and controls (χ2 =0.430,P =0.806).There was obvious difference of AT2R 1 675A /G genotypes (AA,AG,GG)and allele (A and G) frequency among two groups (χ2 =6.1 21 ,P =0.01 3).The G allele was higher than A allele in PA group (χ2 =6.767,P =0.009).Conclusion Homogenic mutation of 1 675A /G site in AT2R gene may be one of risk factors of PA.

  18. Heart Failure Therapeutics on the Basis of a Biased Ligand of the Angiotensin-2 Type 1 Receptor Rationale and Design of the BLAST-AHF Study (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure)

    NARCIS (Netherlands)

    Felker, G. Michael; Butler, Javed; Collins, Sean P.; Cotter, Gad; Davison, Beth A.; Ezekowitz, Justin A.; Filippatos, Gerasimos; Levy, Phillip D.; Metra, Marco; Ponikowski, Piotr; Soergel, David G.; Teerlink, John R.; Violin, Jonathan D.; Voors, Adriaan A.; Pang, Peter S.

    2015-01-01

    The BLAST-AHF (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure) study is designed to test the efficacy and safety of TRV027, a novel biased ligand of the angiotensin-2 type 1 receptor, in patients with acute heart failure (AHF). AHF remains a major public health problem, and n

  19. Renin-angiotensin system gene polymorphisms and endometrial cancer.

    Science.gov (United States)

    Pringle, Kirsty G; Delforce, Sarah J; Wang, Yu; Ashton, Katie A; Proietto, Anthony; Otton, Geoffrey; Blackwell, C Caroline; Scott, Rodney J; Lumbers, Eugenie R

    2016-05-01

    Endometrial cancer (EC) is the most common gynaecological malignancy and its incidence is increasing. Dysregulation of the endometrial renin-angiotensin system (RAS) could predispose to EC; therefore, we studied the prevalence of RAS single nucleotide polymorphisms (SNPs) in Australian women with EC. SNPs assessed were AGT M235T (rs699); AGTR1 A1166C (rs5186); ACE A240T and T93C (rs4291, rs4292) and ATP6AP2 (rs2968915). They were identified using TaqMan SNP Genotyping Assays. The C allele of the AGTR1 SNP (rs5186) was more prevalent in women with EC (odds ratio (OR) 1.7, 95% confidence interval (CI) (1.2-2.3), P=0.002). The CC genotype of this SNP is associated with upregulation of the angiotensin II type 1 receptor (AGTR1). The G allele of AGT rs699, which is associated with higher angiotensinogen (AGT) levels, was less prevalent in women with EC (OR 0.54, 95% CI (0.39-0.74), P<0.001) compared with controls. AGT and AGT formed by removal of angiotensin I (des(Ang I)AGT) are both anti-angiogenic. In women with EC who had had hormone replacement therapy (HRT), the prevalence of the AGTR1 SNP (rs5186) and the ACE SNPs (rs4291 and rs4292) was greater than in women who had no record of HRT; SNP rs4291 is associated with increased plasma ACE activity. These data suggest there is an interaction between genotype, oestrogen replacement therapy and EC. In conclusion, the prevalence of two SNPs that enhance RAS activity was different in women with EC compared with healthy controls. These genetic factors may interact with obesity and hyperoestrogenism, predisposing ageing, obese women to EC.

  20. Promyelocytic leukemia zinc finger protein activates GATA4 transcription and mediates cardiac hypertrophic signaling from angiotensin II receptor 2.

    Directory of Open Access Journals (Sweden)

    Ning Wang

    Full Text Available BACKGROUND: Pressure overload and prolonged angiotensin II (Ang II infusion elicit cardiac hypertrophy in Ang II receptor 1 (AT(1 null mouse, whereas Ang II receptor 2 (AT(2 gene deletion abolishes the hypertrophic response. The roles and signals of the cardiac AT(2 receptor still remain unsettled. Promyelocytic leukemia zinc finger protein (PLZF was shown to bind to the AT(2 receptor and transmit the hypertrophic signal. Using PLZF knockout mice we directed our studies on the function of PLZF concerning the cardiac specific transcription factor GATA4, and GATA4 targets. METHODOLOGY AND PRINCIPAL FINDINGS: PLZF knockout and age-matched wild-type (WT mice were treated with Ang II, infused at a rate of 4.2 ng·kg(-1·min(-1 for 3 weeks. Ang II elevated systolic blood pressure to comparable levels in PLZF knockout and WT mice (140 mmHg. WT mice developed prominent cardiac hypertrophy and fibrosis after Ang II infusion. In contrast, there was no obvious cardiac hypertrophy or fibrosis in PLZF knockout mice. An AT(2 receptor blocker given to Ang II-infused wild type mice prevented hypertrophy, verifying the role of AT(2 receptor for cardiac hypertrophy. Chromatin immunoprecipitation and electrophoretic mobility shift assay showed that PLZF bound to the GATA4 gene regulatory region. A Luciferase assay verified that PLZF up-regulated GATA4 gene expression and the absence of PLZF expression in vivo produced a corresponding repression of GATA4 protein. CONCLUSIONS: PLZF is an important AT(2 receptor binding protein in mediating Ang II induced cardiac hypertrophy through an AT(2 receptor-dependent signal pathway. The angiotensin II-AT(2-PLZF-GATA4 signal may further augment Ang II induced pathological effects on cardiomyocytes.

  1. Renin-angiotensin system gene polymorphisms as risk factors for multiple sclerosis.

    Science.gov (United States)

    Živković, Maja; Kolaković, Ana; Stojković, Ljiljana; Dinčić, Evica; Kostić, Smiljana; Alavantić, Dragan; Stanković, Aleksandra

    2016-04-15

    The components of renin-angiotensin system, such as angiotensin-converting enzyme (ACE), angiotensin II and angiotensin II receptor type 1 and 2 (AT1R and AT2R), are expressed in the central nervous system and leukocytes and proposed to be involved in the inflammation and pathogenesis of multiple sclerosis (MS). ACE I/D, AT1R 1166A/C and AT2R -1332A/G are functional polymorphisms associated with phenotypes of diverse chronic inflammatory diseases. The aim of this study was to investigate the association between ACE I/D, AT1R 1166A/C and AT2R -1332A/G gene polymorphisms and MS in Serbian population. A total of 470 MS patients and 478 controls participated in the study. Allele-specific polymerase chain reaction (PCR) was performed for genotyping of the ACE polymorphism. The AT1R and AT2R genotyping was done by duplex PCR and restriction fragment length polymorphism analysis. Both ACE homozygotes, II and DD, were significantly overrepresented in MS patients, compared to controls (χ(2) test p=0.03). Neither genotype nor allele frequencies of AT1R 1166A/C polymorphism were significantly different between patients and controls. Significant overrepresentation of AT2R -1332 AA genotype in female patients, compared to female controls, was detected (OR=1.67, 95%CI=1.13-2.49, χ(2) test p=0.01), suggesting that this genotype could be a gender-specific genetic risk factor for MS.

  2. Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders

    OpenAIRE

    Saavedra, Juan M.

    2012-01-01

    The effects of brain AngII (angiotensin II) depend on AT1 receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT1 receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood–brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurod...

  3. BR 04-3 DEVELOPMENT OF NEW ANGIOTENSIN RECEPTOR BLOCKER.

    Science.gov (United States)

    Choe, Seong-Choon

    2016-09-01

    There are several classes of anti-hypertensive agents in the world, the most recently developed agent is angiotensin receptor blocker (ARB). There are already 8 ARBs in the market, but still medical unmet need for treatment of hypertension is existed. The 'ideal' anti-hypertensive agent would have a number of characteristics: (1) effective in lowering blood pressure to recommend goals; (2) high efficacy as monotherapy; (3) rapid onset of effect; (4) convenient once-daily administration to maximize compliance; (5) sustained efficacy over 24 hours; (6) response increases with higher doses (clear dose-response effect); and (7) optimum tolerability profile. ARB is nearly closed to this kind of 'ideal' anti-hypertensive agent, but there are some issues to be resolved in order to meet current medical need. These are (1) BP lowering is not satisfactory all around the world; (2) adverse effects of anti-hypertensive agents are hurdles to be relieved; (3) sometimes 24 hour coverage is not demonstrated for optimal blood pressure control; (4) monotherapy is not usually enough; (5) safety issues may interfere the use of optimal anti-hypertensive agents; (6) combination may be helpful, but may not be helpful, even harmful to the patients.Fimasartan was developed by Korean pharmaceutical company, starting from 1999, and got market authorization right in 2010 from Korea. The compound fimasartan was developed via full clinical development pathway from first-in-human phase 1 trial in UK and subsequent phase 1 trials, proof of concept phase 2 trial, dose finding phase 2 trial and confirmatory phase 3 trial in Korea. Recently for the global clinical trial, phase 3 trials of fimasartan were executed in Mexico and Russia, will be followed in China very soon. Also the patient's convenience, the combo products of fimasartan including hydrochlorothiazide, amlodipine and rosuvastatin were developed via relevant clinical development programs.For the life cycle management, other combo

  4. Angiotensin converting enzyme gene polymorphism in familial hypertrophic cardiomyopathy patients

    Energy Technology Data Exchange (ETDEWEB)

    Yu, B; Peric, S.; Ross, D. [Royal Prince Alfred Hospital, Campertown (Australia)] [and others

    1994-09-01

    An insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene is a useful predictor of human plasma ACE levels. ACE levels tend to be lowest in subjects with ACE genotype DD and intermediate in subjects with ACE genotype ID. Angiotensin II (Ang II) as a product of ACE is a cardiac growth factor and produces a marked hypertrophy of the chick myocyte in cell culture. Rat experiments also suggest that a small dose of ACE inhibitor that does not affect the afterload results in prevention or regression of cardiac hypertrophy. In order to study the relationship of ACE and the severity of hypertrophy, the ACE genotype has been determined in 28 patients with a clinical diagnosis of familial hypertrophic cardiomyopathy (FHC) and 51 normal subjects. The respective frequencies of I and D alleles were: 0.52 and 0.48 (in FHC patients) and 0.44 and 0.56 (in the normal controls). There was no significant difference in the allele frequencies between FHC and normal subjects ({chi}{sup 2}=0.023, p>0.05). The II, ID, and DD genotypes were present in 7, 15, and 6 FHC patients, respectively. The averages of maximal thickness of the interventricular septum measured by echocardiography or at autopsy were 18 {plus_minus}3, 19{plus_minus}4, and 19{plus_minus}3 mm in II, ID and DD genotypes, respectively. The ACE gene polymorphism did not correlate with the severity of left ventricular hypertrophy in FHC patients (r{sub s}=0.231, p>0.05). These results do not necessarily exclude the possible effect of Ang II on the hypertrophy since the latter may be produced through the action of chymase in the human ventricles. However, ACE gene polymorphism is not a useful predictor of the severity of myocardial hypertrophy in FHC patients.

  5. Interaction of a non-peptide agonist with angiotensin II AT1 receptor mutants

    DEFF Research Database (Denmark)

    Costa-Neto, Claudio M; Miyakawa, Ayumi A; Pesquero, João B;

    2002-01-01

    To identify residues of the rat AT1A angiotensin II receptor involved with signal transduction and binding of the non-peptide agonist L-162,313 (5,7-dimethyl-2-ethyl-3-[[4-[2(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazol[4,5,6]-pyridine) we have performed ligand bindi...

  6. Role of angiotensin receptor blockers in patients with left ventricular dysfunction : lessons from CHARM and VALIANT

    NARCIS (Netherlands)

    Voors, AA; van Veldhuisen, DJ

    2004-01-01

    The role of angiotensin receptor blockers (ARBs) in patients with left ventricular dysfunction has changed after the VALIANT and CHARM trials. CHARM proved that candesartan is a good alternative for patients with chronic heart failure who cannot tolerate ACE-inhibitors. Moreover, VALIANT demonstrate

  7. INHIBITION OF KIDNEY DISORDERS IN CARDIOVASCULAR DISEASES: THE ROLE OF ANGIOTENSIN II RECEPTOR BLOCKERS

    Directory of Open Access Journals (Sweden)

    V. V. Fomin

    2008-01-01

    Full Text Available Mechanisms of renal disorders in cardiovascular diseases are presented. The main of these mechanisms is an endothelium dysfunction. It is related with some factors: arterial hypertension, insulin resistance syndrome, diabetes type 2, dyslipidemia, obesity. Approaches to prevention of kidney disorder and cardiovascular complications are discussed with focus on usage of angiotensin II receptor blockers.

  8. Renoprotective effect of combining angiotensinreceptor blockers and statins in diabetic rats

    Institute of Scientific and Technical Information of China (English)

    GAO Ping; JIA Ru-han; YANG Ding-ping; LIU Hong-yan; SONG En-feng; CHU Gui-li; DING Guo-hua

    2005-01-01

    @@ Recent studies suggest that treatment with angiotensin Ⅱ type 1 (AT1) receptor blockers and lipid lowering agents, namely the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins may have beneficial effects on renal function independent of lowering actions on blood pressure and cholesterol.

  9. Comparison of the antagonistic effects of different angiotensin II receptor blockers in human coronary arteries

    DEFF Research Database (Denmark)

    Pantev, Emil; Stenman, Emelie; Wackenfors, Angelica;

    2002-01-01

    BACKGROUND: Angiotensin II (Ang II) is a potent vasoconstrictor and a deleterious factor in cardiovascular pathophysiology. Ang II receptor blockers (ARBs) have recently been introduced into clinical practice for treatment of hypertension and congestive heart failure. AIMS: This study was underta...

  10. Angiotensin II Receptors Modulate Muscle Microvascular and Metabolic Responses to Insulin In Vivo

    OpenAIRE

    Chai, Weidong; Wang, WenHui; Dong, Zhenhua; Cao, Wenhong; Liu, Zhenqi

    2011-01-01

    OBJECTIVE Angiotensin (ANG) II interacts with insulin-signaling pathways to regulate insulin sensitivity. The type 1 (AT1R) and type 2 (AT2R) receptors reciprocally regulate basal perfusion of muscle microvasculature. Unopposed AT2R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT1R activity decreases both. The current study examined whether ANG II receptors modulate muscle insulin delivery and sensitivity. RESEARCH DESIGN AND METHODS Ove...

  11. Effect of angiotensin Ⅱ and angiotensin Ⅱ type 1 receptor antagonist on the proliferation,contraction and collagen synthesis in rat hepatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    LIU Jun; GONG Hao; ZHANG Zhong-tao; WANG Yu

    2008-01-01

    Background Angiotensin Ⅱ(Ang Ⅱ)is a very important vasoactive peptide that acts upon hepatic stellate cells(HSCs),which are major effector cells in hepatic cirrhosis and portal hypertension.The present study was aimed to investigate the effects of Ang Ⅱ and angiotensin Ⅱ type 1 receptor antagonist(AT1RA)on the proliferation,contraction and collagen synthesis in HSCs.Methods HSC-T6 rat hepatic stellate cell Iine was studied.The proliferation of the HSC cells was evaluated by MTT colorimetric assay while HSC DNA synthesis was measured by3 H-thymidine incorporation.The effects of angiotensin Ⅱ and AT1 RA on HSCs contraction were studied by analVSIs of the contraction of the collagen Iattice.CelI culture media were analyzed by RT-PCR to detect secretion of collagen Ⅰ(Col Ⅰ),collagen Ⅲ(Col Ⅲ)and transforming growth factor β1 (TGF-β1)by enzyme Iinked Immunosorbent assay.HSC was harvested to measure collagen Ⅰ,collagen Ⅲ and tissue inhibitor of metalloproteinase-1(TIMP-1)mRNA expression.Results Ang Ⅱ((1 x10-10-1×10-4)mol/L)stimulated DNA synthesis and proliferation in HSCs compared with untreated control cells.AT1 RA inhibited angiotensin Ⅱ induced proliferation of HSCs.A Iinear increase in the contractive area of collagen lattice correlated with the concentration of angiotensin Ⅱ(1×10-9-1×10-5mol/L)and with time over 48 hours.ATlRA blocks angiotensin Ⅱ induced contraction of collagen Iattice.Coll,Col Ⅲ and TGF-β1 levels of the Ang Ⅱ group were higher than those of control group and this increase was downregulated by AT1RA.The mRNA expressions of ColⅠ,CoI Ⅲ and TIMP-1 were higher in HSCs from the Ang Ⅱ group than the control group and downregulated by AT1RA.Conclusions Angiotensin Ⅱ increased DNA synthesis and proliferation of HSCs in a dose-dependent manner,stimulated the contraction of HSCs dose-and time-dependently.Angiotensin also promoted excretion of Col Ⅰ,ColⅢand TGF-β1 Ievels and stimulated Col Ⅰ,Col Ⅲ and

  12. No significant effect of angiotensin II receptor blockade on intermediate cardiovascular end points in hemodialysis patients

    DEFF Research Database (Denmark)

    Peters, Christian Daugaard; Kjaergaard, Krista D; Jensen, Jens D;

    2014-01-01

    Agents blocking the renin-angiotensin-aldosterone system are frequently used in patients with end-stage renal disease, but whether they exert beneficial cardiovascular effects is unclear. Here the long-term effects of the angiotensin II receptor blocker, irbesartan, were studied in hemodialysis...... the study period significantly correlated with changes in both left ventricular mass and arterial stiffness. Thus, significant effects of irbesartan on intermediate cardiovascular end points beyond blood pressure reduction were absent in hemodialysis patients.Kidney International advance online publication...

  13. Cardiovascular risk reduction in hypertension: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers. Where are we up to?

    Science.gov (United States)

    Sindone, A; Erlich, J; Lee, C; Newman, H; Suranyi, M; Roger, S D

    2016-03-01

    Previously, management of hypertension has concentrated on lowering elevated blood pressure. However, the target has shifted to reducing absolute cardiovascular (CV) risk. It is estimated that two in three Australian adults have three or more CV risk factors at the same time. Moderate reductions in several risk factors can, therefore, be more effective than major reductions in one. When managing hypertension, therapy should be focused on medications with the strongest evidence for CV event reduction, substituting alternatives only when a primary choice is not appropriate. Hypertension management guidelines categorise angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) interchangeably as first-line treatments in uncomplicated hypertension. These medications have different mechanisms of action and quite different evidence bases. They are not interchangeable and their prescription should be based on clinical evidence. Despite this, currently ARB prescriptions are increasing at a higher rate than those for ACEI and other antihypertensive classes. Evidence that ACEI therapy prevents CV events and death, in patients with coronary artery disease or multiple CV risk factors, emerged from the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) and Heart Outcomes Prevention Evaluation (HOPE) trials respectively. The consistent benefit has been demonstrated in meta-analyses. The clinical trial data for ARB are less consistent, particularly regarding CV outcomes and mortality benefit. The evidence supports the use of ACEI (Class 1a) compared with ARB despite current prescribing trends. PMID:26968600

  14. BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy.

    Science.gov (United States)

    Shahid, Mohd; Spagnolli, Ester; Ernande, Laura; Thoonen, Robrecht; Kolodziej, Starsha A; Leyton, Patricio A; Cheng, Juan; Tainsh, Robert E T; Mayeur, Claire; Rhee, David K; Wu, Mei X; Scherrer-Crosbie, Marielle; Buys, Emmanuel S; Zapol, Warren M; Bloch, Kenneth D; Bloch, Donald B

    2016-04-15

    Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis. PMID:26873969

  15. Estimation of the number of angiotensin II AT1 receptors in rat kidney afferent and efferent arterioles

    DEFF Research Database (Denmark)

    Razga, Zsolt; Nyengaard, Jens Randel

    2007-01-01

    OBJECTIVE: To examine the effects of the renin-angiotensin system (RAS) on renal arterioles to determine the association between the distribution of angiotensin II AT1 receptors and the morphologic and physiologic heterogeneity of renal arterioles. STUDY DESIGN: To estimate the number of angioten...... surface is controlled may furnish a new path for pharmacologically changing RAS activity on SMCs. Udgivelsesdato: 2007-Aug...

  16. Influence of myocardial infarction on changes in the expression of angiotensin type 1 receptor in the rat prostate

    Directory of Open Access Journals (Sweden)

    Kamila Domińska

    2011-10-01

    Full Text Available Angiotensin II (AngII is the biologically active peptide of the renin-angiotensin system (RAS. Tissue- based, local RAS has been identified in the prostate, testis, epididymis and coagulating glands. Experimental and clinical studies have consistently shown that myocardial infarction (MI is associated with activation of the systemic RAS with increased concentration of angiotensin peptides in the blood and changes in expression of angiotensin receptors (AT. Changes in angiotensin receptors in the renal and cardiovascular system after MI are well recognized, but the effects of MI influence on changes in other tissue like the prostate gland are unknown. In the present study, we investigated the effect of myocardial infarction on angiotensin receptor protein and mRNA expression in the rat prostate gland. MI model was established in Wistar rats by ligating the left coronary artery (modified Selye method. The levels of AT1a-b and AT2 receptor mRNAs and proteins were measured in the rat prostate. Our study demonstrates tissue-specific changes in AT1a-b and AT2 receptor expression after myocardial infarction. The results show that MI has a strong influence on the expression of angiotensin receptor type AT1 in the prostate at the protein and mRNA level. (Folia Histochemica et Cytobiologica 2011, Vol. 49, No. 3, 497–503

  17. Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond

    Directory of Open Access Journals (Sweden)

    Singh JSS

    2015-06-01

    Full Text Available Jagdeep SS Singh, Chim C Lang Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK Abstract: Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction. Keywords: heart failure, angiotensin receptor-neprilysin inhibitor, heart failure with preserved ejection fraction, nesiritide, candoxatril, omapatrilat, hypertension, renal impairment, myocardial infarction

  18. Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Færch, Louise H; Thorsteinsson, Birger; Tarnow, Lise;

    2015-01-01

    INTRODUCTION: High spontaneous activity of the renin-angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function...

  19. Arterial stiffness in insulin resistance: The role of nitric oxide and angiotensin II receptors

    Directory of Open Access Journals (Sweden)

    Divina G Brillante

    2008-12-01

    Full Text Available Divina G Brillante1, Anthony J O’Sullivan1, Laurence G Howes21St. George Clinical School, University of New South Wales, Kogarah, NSW, Australia; 2Department of Pharmacology and Therapeutics and Department of Cardiology, Griffith and Bond University, Gold Coast Hospital, Southport, QLD, AustraliaAbstract: The insulin resistance syndrome (INSR is associated with increased cardiovascular risk, and affects up to 25% of the Australian population aged >20 years. Increased arterial stiffness has been proposed as a common pathway by which INSR leads to increased cardiovascular risk. We have reviewed the role of nitric oxide (NO and angiotensin II receptors in the modulation of arterial stiffness in the setting of insulin resistance. There is emerging evidence that early stages of INSR may be characterized by increased basal nitric oxide activity and increased activity of non-NO vasodilators such as endothelial derived hyperpolarization factor (EDHF which is manifest by reduced arterial stiffness. Depletion of NO or ineffectiveness of NO mediated vasodilator mechanisms associated with the progression of INSR to type 2 diabetes may result in increased arterial stiffness, which predicts the development of cardiovascular disease. Thus in the early stages of INSR, increased NO and EDHF activity may represent compensatory mechanisms to early vascular damage. The renin-angiotensin system is activated in diseased vascular beds, with up regulation of the two known angiotensin II receptors: the angiotensin II type 1 receptor (AT1R and the angiotensin II type 2 receptor (AT2R. Increased AT1R mediated activity in the vasculature is central to the development of increased arterial stiffness and is enhanced in INSR states. AT2R activity is increased in early in INSR and may contribute to the apparent increase in basal NO activity. AT1R blockade may therefore be valuable treatment for early INSR as antagonism of AT1 receptors would allow angiotensin II to act

  20. Bradykinin antagonist counteracts the acute effect of both angiotensin-converting enzyme inhibition and of angiotensin receptor blockade on the lower limit of autoregulation of cerebral blood flow

    DEFF Research Database (Denmark)

    Sigurdsson, Sigurdur T; Paulson, Olaf B; Høj Nielsen, Arne;

    2014-01-01

    The lower limit of autoregulation of cerebral blood flow (CBF) can be modulated with both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). The influence of bradykinin antagonism on ARB-induced changes was the subject of this study. CBF was measured in Sprague......-Dawley rats with laser Doppler technique. The blood pressure was lowered by controlled bleeding. Six groups of rats were studied: a control group and five groups given drugs intravenously: an ACE inhibitor (enalaprilat), an ARB (candesartan), a bradykinin-2 receptor antagonist (Hoe 140), a combination...

  1. Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report

    Directory of Open Access Journals (Sweden)

    Podda Mauro

    2010-05-01

    Full Text Available Abstract Introduction A combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been used to control proteinuria, following initial demonstration of its efficacy. However, recently concerns about the safety of this therapy have emerged, prompting several authors to urge for caution in its use. In the following case report, we describe the occurrence of a serious and unexpected adverse drug reaction after administration of a combination of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to a patient with nephrotic syndrome and liver cirrhosis with severe portal hypertension. Case presentation We administered this combination therapy to a 40-year-old Caucasian man with liver cirrhosis in our Hepatology Clinic, given the concomitant presence of glomerulopathy associated with severe proteinuria. While the administration of one single drug appeared to be well-tolerated, our patient developed severe acute encephalopathy after the addition of the second one. Discontinuation of the therapy led to the disappearance of the side-effect. A tentative rechallenge with the same drug combination led to a second episode of acute severe encephalopathy. Conclusion We speculate that this adverse reaction may be directly related to the effect of angiotensin II on the excretion of blood ammonia. Therefore, we suggest that patients with liver cirrhosis and portal hypertension are at risk of developing clinically relevant encephalopathy when angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker combination therapy is administered, thus indicating the need for a careful clinical follow-up. In addition, the incidence of this serious side-effect should be rigorously evaluated in all patients with liver cirrhosis administered with this common treatment combination.

  2. Immunohistochemical detection of angiotensin receptors AT1 and AT2 in adrenal tumors.

    Directory of Open Access Journals (Sweden)

    Marek Pawlikowski

    2008-02-01

    Full Text Available Angiotensin II is well known to affect the adrenal cell growth and function. Angiotensin receptors AT1 and AT2 were found to be present in the normal adrenal gland. However, the data on the expression of the angiotensin receptors in the adrenal tumors are very scarce. To overcome this gap, the paraffin sections of the adrenal cortical tumors and of pheochromocytomas from the archival material were immunostained with antibodies raised against AT1 (sc-1173 and AT2 (sc-9040 receptor proteins. In hyperplasia of the adrenal cortex and in benign adrenocortical adenomas, both functioning and non-functioning, the AT1 immunostaining was present mainly in the cell membranes. A positive immunoreaction was also found in the subpopulation of cell nuclei and within the cytoplasm. In the adrenal cancer, as well as in pheochromocytomas, neither cell membranes nor cell nuclei were immunostained with anti-AT1 antibody. However, a weak AT1 immunostaining was present within the cytoplasm of tumoral cells. With anti-AT2 antibody, in all tumors investigated, the tumoral cells were immunonegative but moderate to strong AT2 immunostaining was observed in the walls of intratumoral blood vessels and in the interstitial tissue. Our data indicates that the expression of AT1 receptors is altered in adrenal cancer and in pheochromocytomas. The expression of AT2 receptors, in turn, may be connected with the process of tumoral neo-angiogenesis.

  3. Individual long-term albuminuria exposure during angiotensin receptor blocker therapy is the optimal predictor for renal outcome

    NARCIS (Netherlands)

    Felix Kröpelin, Tobias; de Zeeuw, Dick; Holtkamp, Frank Arjan; Packham, David Kenneth; L Heerspink, Hiddo J

    2016-01-01

    BACKGROUND: Albuminuria reduction due to angiotensin receptor blockers (ARBs) predicts subsequent renoprotection. Relating the initial albuminuria reduction to subsequent renoprotection assumes that the initial ARB-induced albuminuria reduction remains stable during follow-up. The aim of this study

  4. Inhibition of angiotensin Ⅱ and blockade of endothelin receptors reduce arterial calcification in rats

    Institute of Scientific and Technical Information of China (English)

    Juxiang LI; Shengying WU; Chunshui PAN; Yongfen QI; Bin GENG; Xiuhua LIU; Chaoshu TANG

    2004-01-01

    Objective To examine whether the two vascular paracrine/autocrine factors, angiotensin Ⅱ (Ang Ⅱ) and endothelin, participate in the pathogenesis of arterial calcification. Methods Nicotine and vitamin D3 treated rats were studied. Vascular calcification was confirmed by using Von Kossa staining, measurement of calcium content,45Ca2+ uptake assay and alkaline phosphatase (ALP) activity. The plasma and vascular Ang Ⅱ and endothelin levels were measured by using radioimmunoassay. Angiotensinogen and endothelin mRNA levels were determined by RTPCR. Results The arterial calcium content, 45Ca2+ uptake and ALP activity were increased in calcification groups compared with control ( P < 0.01 ). Administration of the angiotensin receptor antagonist losartan, the endothelin receptor antagonist bosentan, and the angiotensin-converting enzyme inhibitor captopril reduced significantly the arterial calcium content, 45Ca2+ uptake and ALP activity. In addition, the plasma and aortic Ang Ⅱ and endothelin contents, and vascular angiotensinogen and endothelin mRNA expression were significantly up-regulated ( P <0.05).Conclusions These findings suggest that functional renin-angiotensin system and endothelin pathway are involved in vascular calcification, and that activation of these systems could potentiate pathogenesis of arterial calcification. ( J Geriatr Cardiol 2004;1(2) :108-113. )

  5. Inactivation of the EP3 receptor attenuates the Angiotensin II pressor response via decreasing arterial contractility

    Science.gov (United States)

    Chen, Lihong; Miao, Yifei; Zhang, Yahua; Dou, Dou; Liu, Limei; Tian, Xiaoyu; Yang, Guangrui; Pu, Dan; Zhang, Xiaoyan; Kang, Jihong; Gao, Yuansheng; Wang, Shiqiang; Breyer, Matthew D.; Wang, Nanping; Zhu, Yi; Huang, Yu; Breyer, Richard M; Guan, Youfei

    2012-01-01

    Objective The present studies aimed at elucidating the role of prostaglandin E2 (PGE2) receptor subtype 3 (EP3) in regulating blood pressure. Methods and Results Mice bearing a genetic disruption of the EP3 gene (EP3−/−) exhibited reduced baseline mean arterial pressure monitored by both tail-cuff and carotid arterial catheterization. The pressor responses induced by EP3 agonists M&B28767 and sulprostone were markedly attenuated in EP3−/− mice, while the reduction of BP induced by PGE2 was comparable in both genotypes. Vasopressor effect of acute or chronic infusion of angiotensin II (AngII) was attenuated in EP3−/− mice. AngII–induced vasoconstriction in mesenteric arteries decreased in EP3−/− group. In mesenteric arteries from wild type mice, AngII–induced vasoconstriction was inhibited by EP3 selective antagonist DG-041 or L798106. The expression of Arhgef-1 is attenuated in EP3 deficient mesenteric arteries. EP3 antagonist DG-041 diminished AngII-induced phosphorylation of MLC20 and MYPT1 in isolated mesenteric arteries. Furthermore, in vascular smooth muscle cells (VSMCs), AngII induced intracellular Ca2+ increase was potentiated by EP3 agonist sulprostone, while inhibited by DG-041. Conclusions Activation of the EP3 receptor raises baseline blood pressure and contributes to AngII-dependent hypertension at least partially via enhancing Ca2+ sensitivity and intracellular calcium concentration in VSMCs. Selective targeting of the EP3 receptor may represent a potential therapeutic target for the treatment of hypertension. PMID:23065824

  6. Activation of the Cardiac Renin-Angiotensin System in High Oxygen-Exposed Newborn Rats: Angiotensin Receptor Blockade Prevents the Developmental Programming of Cardiac Dysfunction.

    Science.gov (United States)

    Bertagnolli, Mariane; Dios, Anne; Béland-Bonenfant, Sarah; Gascon, Gabrielle; Sutherland, Megan; Lukaszewski, Marie-Amélie; Cloutier, Anik; Paradis, Pierre; Schiffrin, Ernesto L; Nuyt, Anne Monique

    2016-04-01

    Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin-angiotensin system. Cardiac renin-angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin-angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3-P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin-angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions. PMID:26857347

  7. Activation of the Cardiac Renin-Angiotensin System in High Oxygen-Exposed Newborn Rats: Angiotensin Receptor Blockade Prevents the Developmental Programming of Cardiac Dysfunction.

    Science.gov (United States)

    Bertagnolli, Mariane; Dios, Anne; Béland-Bonenfant, Sarah; Gascon, Gabrielle; Sutherland, Megan; Lukaszewski, Marie-Amélie; Cloutier, Anik; Paradis, Pierre; Schiffrin, Ernesto L; Nuyt, Anne Monique

    2016-04-01

    Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin-angiotensin system. Cardiac renin-angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin-angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3-P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin-angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions.

  8. Cerebral ischemia enhances vascular angiotensin AT1 receptor-mediated contraction in rats

    DEFF Research Database (Denmark)

    Stenman, Emelie; Edvinsson, Lars

    2004-01-01

    BACKGROUND AND PURPOSE: The aim of the study was to examine how focal cerebral ischemia affects the expression and function of vascular angiotensin II receptors. MATERIALS AND METHODS: We used an intraluminal filament occlusion technique to occlude the right middle cerebral artery (MCA) of the rat...... with nonoccluded MCAs 48 hours after occlusion (Pcerebral ischemia in the rat upregulated the contractile....... These results support a role for AT1 receptors in cerebral ischemia, and we think that AT1 receptors might be a future therapeutic target in ischemic stroke....

  9. The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

    DEFF Research Database (Denmark)

    Chow, Bryna S M; Koulis, Christine; Krishnaswamy, Pooja;

    2016-01-01

    AIMS/HYPOTHESIS: Angiotensin II is well-recognised to be a key mediator in driving the pathological events of diabetes-associated atherosclerosis via signalling through its angiotensin II type 1 receptor (AT1R) subtype. However, its actions via the angiotensin II type 2 receptor (AT2R) subtype...... are still poorly understood. This study is the first to investigate the role of the novel selective AT2R agonist, Compound 21 (C21) in an experimental model of diabetes-associated atherosclerosis (DAA). METHODS: Streptozotocin-induced diabetic Apoe-knockout mice were treated with vehicle (0.1 mol/l citrate...

  10. Deficiency of Angiotensin Type 1a Receptors in Adipocytes Reduces Differentiation and Promotes Hypertrophy of Adipocytes in Lean Mice

    OpenAIRE

    Putnam, Kelly; Batifoulier-Yiannikouris, Frederique; Bharadwaj, Kalyani G.; Lewis, Eboni; Karounos, Michael; Daugherty, Alan; Cassis, Lisa A.

    2012-01-01

    Adipocytes express angiotensin receptors, but the direct effects of angiotensin II (AngII) stimulating this cell type are undefined. Adipocytes express angiotensin type 1a receptor (AT1aR) and AT2R, both of which have been implicated in obesity. In this study, we determined the effects of adipocyte AT1aR deficiency on adipocyte differentiation and the development of obesity in mice fed low-fat (LF) or high-fat (HF) diets. Mice expressing Cre recombinase under the control of the aP2 promoter w...

  11. Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition.

    Science.gov (United States)

    Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M; Chen, Shi-You; Konkalmatt, Prasad; Wang, Xiaoyan; Asico, Laureano D; Jones, John E; Yang, Yu; Sanada, Hironobu; Felder, Robin A; Eisner, Gilbert M; Weir, Matthew R; Armando, Ines; Jose, Pedro A

    2016-02-01

    The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure regulation. G-protein-coupled receptor kinase type 4 (GRK4) is one such gene. We have reported that the expression of its variant hGRK4γ(142V) in mice results in hypertension because of impaired dopamine D1 receptor. Signaling through dopamine D1 receptor and angiotensin II type I receptor (AT1R) reciprocally modulates renal sodium excretion and blood pressure. Here, we demonstrate the ability of the hGRK4γ(142V) to increase the expression and activity of the AT1R. We show that hGRK4γ(142V) phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT1R expression and greater pressor response to angiotensin II. AT1R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4γ(142V) mice. These findings illustrate the unique role of GRK4 by targeting receptors with opposite physiological activity for the same goal of maintaining blood pressure homeostasis, and thus making the GRK4 a relevant therapeutic target to control blood pressure.

  12. Prospects for angiotensin receptor blockers in diabetic retinopathy

    DEFF Research Database (Denmark)

    Sjølie, Anne Katrin

    2007-01-01

    Retinopathy is the most common microvascular complication of diabetes mellitus, and is an important cause of blindness worldwide. Clinical trials have demonstrated that tight metabolic control inhibits the progression of retinopathy. Good blood pressure control has been shown to be protective...... in type 2 diabetes, and it may also reduce proliferative retinopathy in type 1 diabetes. However, such control is often difficult to achieve in clinical practice, and may be associated with problems such as hypoglycaemia. New therapies are therefore needed to reduce the risk of retinopathy....... There is growing evidence that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of diabetic retinopathy, and this has led to interest in RAS inhibitors as agents to prevent retinopathy. Several trials have suggested that ACE inhibitor therapy can inhibit progression of retinopathy...

  13. The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation

    DEFF Research Database (Denmark)

    Hansen, Jakob Lerche; Aplin, Mark; Hansen, Jonas Tind;

    2008-01-01

    (1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1......) receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT(1) receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling...

  14. Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

    DEFF Research Database (Denmark)

    Zhao, Yi; Lützen, Ulf; Fritsch, Jürgen;

    2015-01-01

    densities in mitochondria. Activation of the cell membrane AT2 receptors by a concomitant treatment with angiotensin II and the AT1 receptor antagonist, losartan, induces apoptosis but does not affect the rate of cell death. We demonstrate for the first time that the high-affinity, non-peptide AT2 receptor...... of apoptosis and cell death in cultured human uterine leiomyosarcoma (SK-UT-1) cells and control human uterine smooth muscle cells (HutSMC). The intracellular levels of the AT2 receptor are low in proliferating SK-UT-1 cells but the receptor is substantially up-regulated in quiescent SK-UT-1 cells with high...... agonist, Compound 21 (C21) penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT2 receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped from the cell death, displayed activation of the mitochondrial apoptotic pathway, i...

  15. Use of ACE Inhibitors and Angiotensin Receptor Blockers and Primary Breast Cancer Outcomes

    OpenAIRE

    Chae, Young Kwang; Brown, Erika N.; Lei, Xiudong; Melhem-Bertrandt, Amal; Giordano, Sharon H.; Litton, Jennifer K.; Hortobagyi, Gabriel N; Gonzalez-Angulo, Ana M.; Chavez-MacGregor, Mariana

    2013-01-01

    BACKGROUND: ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may have anti-tumor properties. We investigated whether the use of ACEI/ARBs affects the clinical outcomes of primary breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy. METHODS: We included 1449 patients with diagnosis of invasive primary breast cancer diagnosed at the MD Anderson Cancer Center between 1995 and 2007 who underwent neoadjuvant chemotherapy. Of them, 160 (11%) patie...

  16. Angiotensin II Receptor Blocker Ameliorates Stress-Induced Adipose Tissue Inflammation and Insulin Resistance

    OpenAIRE

    Motoharu Hayashi; Kyosuke Takeshita; Yasuhiro Uchida; Koji Yamamoto; Ryosuke Kikuchi; Takayuki Nakayama; Emiko Nomura; Xian Wu Cheng; Tadashi Matsushita; Shigeo Nakamura; Toyoaki Murohara

    2014-01-01

    A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restra...

  17. Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B

    OpenAIRE

    Bhatt, Siddhartha R.; Lokhandwala, Mustafa F.; Banday, Anees Ahmad

    2014-01-01

    The association of oxidative stress with hypertension is well known. However, a causal role of oxidative stress in hypertension is unclear. Vascular angiotensin II type 1 receptor (AT1R) upregulation is a prominent contributor to pathogenesis of hypertension. However, the mechanisms causing this upregulation are unknown. Oxidative stress is an important regulator of protein expression via activation of transcription factors such as nuclear factor kappa B (NFκB). The present study was carried ...

  18. Differential involvement of hippocampal angiotensin 1 receptors in learning and memory processes in bulbectomized rats

    OpenAIRE

    Tashev E. Roman; Margarita S. Ivanova; Stiliana P. Belcheva; Iren P. Belcheva

    2016-01-01

    There is conflicting evidence regarding the effect of AT1 receptor antagonists on learning and memory processes. The effects of angiotensin II and losartan administration into CA1 hippocampal area on the avoidance performance in olfactory bulbectomized (OBX) rats using active avoidance (shuttle box) test and passive avoidance (step through) test were investigated. Rats were microinjected unilaterally through implanted guide cannulas into the CA1 area of the dorsal hippocampus and the drugs we...

  19. Direct Angiotensin II Type 2 Receptor Stimulation Ameliorates Insulin Resistance in Type 2 Diabetes Mice with PPARγ Activation

    DEFF Research Database (Denmark)

    Ohshima, Kousei; Mogi, Masaki; Jing, Fei;

    2012-01-01

    The role of angiotensin II type 2 (AT(2)) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in ty...... 2 diabetes (T2DM) with PPARγ activation, mainly focusing on adipose tissue.......The role of angiotensin II type 2 (AT(2)) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type...

  20. Effect of angiotensinreceptor 1 antisense oligodoexynucleotides on physiological and pathophysiological growth of cardiomyocytes

    Institute of Scientific and Technical Information of China (English)

    Ying WANG; Jin-ming WANG; Shu-xun Yan; Ming-jiang LI; Jian-jun LI

    2004-01-01

    AIM: To evaluate the role of angiotensinreceptor 1 antisense oligodexynucleotides (AT1R-AS-ODNs) on physiological and pathophysiological growth of cardiomyocytes from normotensive rats. METHODS: Cardiomyocytes were transfected with AT1R-AS-ODNs (200 nmol/L) followed by treatment with or without angiotensin Ⅱ (1 μmol/L).In situ hybridization and Western blot were used for AT1R mRNA and protein detection, respectively. c-Jun Nterminal protein kinase (JNK) activity was characterized by immune complex kinase assay. c-Jun protein expression was examined by immunocytochemistry. DNA content was detected by flow cytometric assay. Atrial natriuretic factor (ANF) expression was identified by radioimmunoassay. RESULTS: Treatment with AT1R-AS-ODNs for 24 h resulted in 51.2 % decrease in AT1R mRNA and 60.7 % in protein (P<0.05 vs control). However, the basal level of JNK activity, c-Jun protein expression, and DNA content were not altered by AT1R-AS treatment in absence of overactive hormonal system. After treatment with angiotensin Ⅱ for 30 min, both p46JNK and p54JNK were robustly activated. By 2 h, c-Jun protein expression was increased. By 24 h, angiotensin Ⅱ caused a marked increase both in G0/G1 and G2/M DNA content, and increased ANF expression by 1.8-fold. All these were inhibited by AT1R-AS-ODNs pretreatment. In contrast, sense sequence was ineffective. CONCLUSION: Decrease of AT1R expression by AS-ODNs did not interfere with normal growth, but protected cardiomyocytes from angiotensin Ⅱ-dependent pathophysiological growth.

  1. The relationship between angiotensin Ⅱ type 1 receptor gene A1166C polymorphism and chronic heart failure%血管紧张素Ⅱ1型受体基因A1166C多态性与慢性心力衰竭的相关性研究

    Institute of Scientific and Technical Information of China (English)

    郑晓明; 刘俊双; 李宏芬; 刘英

    2008-01-01

    Objective To investigate the relationship of angiotensin Ⅱ typel receptor gene A1166C polymorphism and chronic heart failure.Method Polymerase chain reaction and restriction fragment length polymorphism(PCR-RFLP)was used to detect the A1166C polymorphism of AT1R gene of 135 chronic heart failure patients and 121 controls.Results The genotype frequency of the patients and controls of AA,AC,CC were 87.6%.12.4%,0%and 87.6%,11.6%,0.8%respectively.Allele frequency of the patients and controls were 93.8%,6.2%and 93.6%,6.4%respectively.There was no significant difference of the frequency of AT1R genotype and allele between CHF and controls(P>0.05).Conclusion Angiotensin Ⅱ type 1 receptor gene A1166C polymorphism is not associated with CHF.%目的 研究血管紧张素Ⅱ1型受体(AT1R)基因A1166C多态性与慢性心力衰竭的相关性.方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测135例慢性心力衰竭患者和121例正常对照者的AT1R基因A1166C位点的基因型.结果 病例组AA、AC、CC基因型频率为87.6%、12.4%、0,等位基因频率为93.8%、6.2%;正常对照组AA、AC、CC基因型频率为87.6%、11.6%、0.8%,等位基因频率为93.6%、6.4%;病例组基因型及等位基因频率与正常对照组比较差异均无统计学意义(均P>0.05).结论AT1R基因A1166C多态性与慢性心力衰竭无关.

  2. A combined role of calcium channel blockers and angiotensin receptor blockers in stroke prevention

    Directory of Open Access Journals (Sweden)

    Ji-Guang Wang

    2009-07-01

    Full Text Available Ji-Guang WangCentre for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaAbstract: Stroke is a leading cause of death and disability worldwide. The importance of lowering blood pressure for reducing the risk of stroke is well established. However, not all the benefits of antihypertensive treatments in stroke can be accounted for by reductions in BP and there may be differences between antihypertensive classes as to which provides optimal protection. Dihydropyridine calcium channel blockers, such as amlodipine, and angiotensin receptor blockers, such as valsartan, represent the two antihypertensive drug classes with the strongest supportive data for the prevention of stroke. Therefore, when combination therapy is required, a combination of these two antihypertensive classes represents a logical approach.Keywords: stroke, angiotensin, calcium channel, cerebrovascular, hypertension, blood pressure

  3. The Prorenin and (Prorenin Receptor: New Players in the Brain Renin-Angiotensin System?

    Directory of Open Access Journals (Sweden)

    Wencheng Li

    2012-01-01

    Full Text Available It is well known that the brain renin-angiotensin (RAS system plays an essential role in the development of hypertension, mainly through the modulation of autonomic activities and vasopressin release. However, how the brain synthesizes angiotensin (Ang II has been a debate for decades, largely due to the low renin activity. This paper first describes the expression of the vasoconstrictive arm of RAS components in the brain as well as their physiological and pathophysiological significance. It then focus on the (prorenin receptor (PRR, a newly discovered component of the RAS which has a high level in the brain. We review the role of prorenin and PRR in peripheral organs and emphasize the involvement of brain PRR in the pathogenesis of hypertension. Some future perspectives in PRR research are heighted with respect to novel therapeutic target for the treatment of hypertension and other cardiovascular diseases.

  4. Association between angiotensin-converting-enzyme gene polymorphism and failure of renoprotective therapy

    NARCIS (Netherlands)

    vanEssen, GG; Rensma, PL; deZeeuw, D; Sluiter, WJ; Scheffer, H; Apperloo, AJ; deJong, PE

    1996-01-01

    Background Polymorphism in the gene for angiotensin-converting enzyme (ACE), especially the DD genotype, is associated with risk for cardiovascular disease. Glomerulosclerosis has similarities to atherosclerosis, and we looked at ACE gene polymorphism in patients with kidney disease who were in a tr

  5. Comparative Effects of Angiotensin Receptor BlockadeandACE Inhibition on the Fibrinolytic and Inflammatory Responses to Cardiopulmonary Bypass

    OpenAIRE

    Billings, Frederic T.; Balaguer, Jorge M.; Yu, Chang; Wright, Patricia; Petracek, Michael R.; Byrne, John G; Brown, Nancy J.; Pretorius, Mias

    2012-01-01

    The effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor blockade (ARB) on fibrinolysis and inflammation following cardiopulmonary bypass (CPB) are uncertain. This study tested the hypothesis that ACE inhibition enhances fibrinolysis and inflammation to greater extent than ARB in patients undergoing CPB.One week to five days prior to surgery, patients were randomized to ramipril 5mg/day,candesartan 16mg/day or placebo.ACE inhibition increased intraopera...

  6. Angiotensin Receptor Blockade Increases Pancreatic Insulin Secretion and Decreases Glucose Intolerance during Glucose Supplementation in a Model of Metabolic Syndrome

    OpenAIRE

    Rodriguez, Ruben; Viscarra, Jose A.; Minas, Jacqueline N.; Nakano, Daisuke; Nishiyama, Akira; Ortiz, Rudy M.

    2012-01-01

    Renin-angiotensin system blockade improves glucose intolerance and insulin resistance, which contribute to the development of metabolic syndrome. However, the contribution of impaired insulin secretion to the pathogenesis of metabolic syndrome is not well defined. To assess the contributions of angiotensin receptor type 1 (AT1) activation and high glucose intake on pancreatic function and their effects on insulin signaling in skeletal muscle and adipose tissue, an oral glucose tolerance test ...

  7. Pharmacologic perspectives of functional selectivity by the angiotensin II type 1 receptor

    DEFF Research Database (Denmark)

    Aplin, Mark; Christensen, Gitte Lund; Hansen, Jakob Lerche

    2008-01-01

    The angiotensin II type 1 (AT(1)) receptor plays a key role in cardiovascular pathophysiology, and it is a major pharmacologic target in the treatment of many cardiovascular disorders. However, AT(1) receptor activation is also involved in adaptive responses to altered hemodynamic demands and to...... sudden injury occurring in the circulatory system. Hence, current drugs that block all AT(1) receptor actions most likely leave room for improvement. Recent developments show that two major signaling pathways used by the AT(1) receptor may be dissected by pharmacologic means. Key pathologic responses...... blockade of G protein actions and simultaneous activation of G protein-dependent or -independent signaling could therefore be desirable in certain situations. The previously unappreciated concept of "functional selectivity" makes this exact strategy feasible and may yield improved drugs for cardiovascular...

  8. Heteromerization Between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences.

    Science.gov (United States)

    Cerrato, Bruno D; Carretero, Oscar A; Janic, Brana; Grecco, Hernán E; Gironacci, Mariela M

    2016-10-01

    Bradykinin B2 receptor (B2R) and angiotensin-(1-7) Mas receptor (MasR)-mediated effects are physiologically interconnected. The molecular basis for such cross talk is unknown. It is hypothesized that the cross talk occurs at the receptor level. We investigated B2R-MasR heteromerization and the functional consequences of such interaction. B2R fused to the cyan fluorescent protein and MasR fused to the yellow fluorescent protein were transiently coexpressed in human embryonic kidney293T cells. Fluorescence resonance energy transfer analysis showed that B2R and MasR formed a constitutive heteromer, which was not modified by their agonists. B2R or MasR antagonists decreased fluorescence resonance energy transfer efficiency, suggesting that the antagonist promoted heteromer dissociation. B2R-MasR heteromerization induced an 8-fold increase in the MasR ligand-binding affinity. On agonist stimulation, the heteromer was internalized into early endosomes with a slower sequestration rate from the plasma membrane, compared with single receptors. B2R-MasR heteromerization induced a greater increase in arachidonic acid release and extracellular signal-regulated kinase phosphorylation after angiotensin-(1-7) stimulation, and this effect was blocked by the B2R antagonist. Concerning serine/threonine kinase Akt activity, a significant bradykinin-promoted activation was detected in B2R-MasR but not in B2R-expressing cells. Angiotensin-(1-7) and bradykinin elicited antiproliferative effects only in cells expressing B2R-MasR heteromers, but not in cells expressing each receptor alone. Proximity ligation assay confirmed B2R-MasR interaction in human glomerular endothelial cells supporting the interaction between both receptors in vivo. Our findings provide an explanation for the cross talk between bradykinin B2R and angiotensin-(1-7) MasR-mediated effects. B2R-MasR heteromerization induces functional changes in the receptor that may lead to long-lasting protective properties. PMID

  9. Reduced expression of angiotensin II and angiotensin receptor type 1 and type 2 in resistance arteries from nasal lesions in granulomatosis with polyangiitis (Wegener's granulomatosis)

    DEFF Research Database (Denmark)

    Dimitrijevic, I; Rissler, P; Luts, L;

    2011-01-01

    OBJECTIVES: Angiotensin II (ANGII) is involved in vessel inflammation and is important in the development of cardiovascular disorders such as atherosclerosis. During active disease, patients with granulomatosis with polyangiitis (GPA; Wegener's granulomatosis) have accelerated atherosclerosis...... and ANGII inhibitors are recommended to these patients to reduce atherosclerosis. We assessed the hypothesis that the expression of ANGII and its receptors in arteries in granulomatous lesions change in GPA. METHODS: ANGII and angiotensin receptors were quantified in vessels from granulomatous lesions from...... patients with GPA using immunohistochemistry. Anti- ANGI type 1 (AT1) and type 2 (AT2) antibodies were applied on formalin-fixed and paraffin-embedded biopsies from nasal mucous membranes from eight patients with GPA and eight controls. RESULTS: ANGII expression was localized to the endothelial cells (ECs...

  10. Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

    Directory of Open Access Journals (Sweden)

    Malmsjö Malin

    2009-08-01

    Full Text Available Abstract Background Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease. Methods Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG surgery because of ischemic heart disease (n = 15, patients with angina pectoris without established myocardial infarction (n = 15 and matched cardiovascular healthy controls (n = 15. Endothelin type A (ETA and type B (ETB, and angiotensin type 1 (AT1 and type 2 (AT2 receptors expression and function were examined using immunohistochemistry, Western blot and in vitro pharmacology. Results ETA and, to a lesser extent, ETB receptor staining was observed in the healthy vascular smooth muscle cells. The level of ETB receptor expression was higher in patients undergoing CABG surgery (250% ± 23%; P B receptor agonist sarafotoxin S6c, compared to healthy controls (P A receptors. AT1 and, to a lesser extent, AT2 receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT1 receptor expression was higher in both the angina pectoris (128% ± 25%; P 1 receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s. Conclusion The results demonstrate, for the first time, upregulation of ETB and AT1 receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.

  11. A different role of angiotensin II type 1a receptor in the development and hypertrophy of plantaris muscle in mice.

    Science.gov (United States)

    Zempo, Hirofumi; Suzuki, Jun-Ichi; Ogawa, Masahito; Watanabe, Ryo; Isobe, Mitsuaki

    2016-02-01

    The role of angiotensin II type 1 (AT1) receptors in muscle development and hypertrophy remains unclear. This study was designed to reveal the effects that a loss of AT1 receptors has on skeletal muscle development and hypertrophy in mice. Eight-week-old male AT1a receptor knockout (AT1a(-/-)) mice were used for this experiment. The plantaris muscle to body weight ratio, muscle fiber cross-sectional area, and number of muscle fibers of AT1a(-/-) mice was significantly greater than wild type (WT) mice in the non-intervention condition. Next, the functional overload (OL) model was used to induce plantaris muscle hypertrophy by surgically removing the two triceps muscles consisting of the calf, soleus, and gastrocnemius muscles in mice. After 14 days of OL intervention, the plantaris muscle weight, the amount of fiber, and the fiber area increased. However, the magnitude of the increment of plantaris weight was not different between the two strains. Agtr1a mRNA expression did not change after OL in WT muscle. Actually, the Agt mRNA expression level of WT-OL was lower than WT-Control (C) muscle. An atrophy-related gene, atrogin-1 mRNA expression levels of AT1a(-/-)-C, WT-OL, and AT1a(-/-)-OL muscle were lower than that of WT-C muscle. Our findings suggest that AT1 receptor contributes to plantaris muscle development via atrogin-1 in mice. PMID:26025227

  12. Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory

    Directory of Open Access Journals (Sweden)

    V S Nade

    2015-01-01

    Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV.

  13. Incidence and influencing factors of aldosterone breakthrough during therapy with angiotensinreceptor bockers alone,or combined with angiotensin-converting enzyme inhibitors in patients with non-diabetic nephropathy

    Institute of Scientific and Technical Information of China (English)

    梁敏

    2013-01-01

    Objective To investigate the incidence and influen-cing factors of aldosterone breakthrough during therapy with angiotensinreceptor blockers(ARB) alone,or combined with angiotensin-converting enzyme inhibitors(ACEI) in Chinese patients with non-diabetic

  14. Impact of drug price adjustments on utilization of and expenditures on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in Taiwan

    Directory of Open Access Journals (Sweden)

    Huang Shiou-Huei

    2012-05-01

    Full Text Available Abstract Background A previous study has suggested that drug price adjustments allow physicians in Taiwan to gain greater profit by prescribing generic drugs. To better understand the effect of price adjustments on physician choice, this study used renin-angiotensin drugs (including angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs] to examine the impact of price adjustments on utilization of and expenditures on patented and off-patent drugs with the same therapeutic indication. Methods Using the Taiwan’s Longitudinal Health Insurance Database (2005, we identified 147,157 patients received ACEIs and/or ARBs between 1997 and 2008. The annual incident and prevalent users of ACEIs, ARBs and overall renin-angiotensin drugs were examined. Box-Tiao intervention analysis was applied to assess the impact of price adjustments on monthly utilization of and expenditures on these drugs. ACEIs were divided into patented and off-patent drugs, off-patent ACEIs were further divided into original brands and generics, and subgroup analyses were performed. Results The number of incident renin-angiotensin drug users decreased over the study period. The number of prevalent ARB users increased and exceeded the cumulative number of first-time renin-angiotensin drug users starting on ARBs, implying that some patients switched from ACEIs to ARBs. After price adjustments, long term trend increases in utilization were observed for patented ACEIs and ARBs; a long-term trend decrease was observed for off-patent ACEIs; long-term trend change was not significant for overall renin-angiotensin drugs. Significant long-term trend increases in expenditures were observed for patented ACEIs after price adjustment in 2007 (200.9%, p = 0.0088 and in ARBs after price adjustments in 2001 (173.4%, p  Conclusions Price adjustments did not achieve long-term cost savings for overall renin-angiotensin drugs. Possible switching from ACEIs to ARBs

  15. Chronic ACE inhibitor treatment increases angiotensin type 1 receptor binding in vivo in the dog kidney

    Energy Technology Data Exchange (ETDEWEB)

    Zober, Tamas G. [Johns Hopkins University, Departments of Radiology and Surgery, Baltimore, MD (United States); Semmelweis University, Department of Pathophysiology, Budapest (Hungary); Fabucci, Maria E.; Zheng, Wei; Sandberg, Kathryn [Georgetown University, Department of Medicine, Washington, DC (United States); Brown, Phillip R.; Seckin, Esen; Mathews, William B. [Johns Hopkins University, Departments of Radiology and Surgery, Baltimore, MD (United States); Szabo, Zsolt [Johns Hopkins University, Departments of Radiology and Surgery, Baltimore, MD (United States); Johns Hopkins Outpatient Center, Division of Nuclear Medicine, Baltimore, MD (United States)

    2008-06-15

    PET imaging has been recently introduced for investigating the type 1 angiotensin II receptor (AT{sub 1}R) in vivo. The goal of the present study was to investigate the effects of acute and chronic exposure to angiotensin converting enzyme inhibitors (ACEI) on the AT{sub 1}R in the dog kidney. Animals were imaged at baseline, after acute intravenous ACEI treatment and after a chronic 2-week exposure to an oral ACEI. Control animals were imaged at identical time points in the absence of ACEI treatment. In vivo AT{sub 1}R binding expressed by K{sub i} was increased in the renal cortex by chronic ACEI treatment (p < 0.05). In vitro measurements of AT{sub 1}R density (B{sub max}) also revealed significant increases in AT{sub 1}R in isolated glomeruli (p < 0.05). Plasma renin activity was increased, but angiotensin II (Ang II) and the Ang II/Ang I ratio showed a weak correlation with chronic ACEI treatment, consistent with an Ang II escape phenomenon. This study reveals, for the first time, that chronic ACEI treatment increases AT{sub 1}R binding in vivo in the dog renal cortex. (orig.)

  16. Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.

    Science.gov (United States)

    Buggey, Jonathan; Mentz, Robert J; DeVore, Adam D; Velazquez, Eric J

    2015-09-01

    Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future.

  17. Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Malmsjö, Malin; Andersson, Christina;

    2009-01-01

    immunohistochemical study of temporal arteries using archival formalin-fixed, paraffin-embedded tissue. PARTICIPANTS: Ten patients with GCA and 10 control patients, who were clinically suspected of having GCA but were diagnosed as not having GCA, were included. METHODS: Immunohistochemistry, using anti-AT(1) and anti......-AT(2) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries. MAIN OUTCOME MEASURES: AT(1) and AT(2) receptor immunostaining intensity was quantified. RESULTS: Hematoxylin-eosin-stained sections of temporal arteries from patients with GCA showed intimal hyperplasia...... with antibodies for the AT(2) receptor was similar in the patients with GCA and in controls. CONCLUSIONS: These results suggest that AT(1) receptors play a role in the development of GCA. Inhibition of the angiotensin system may thus provide a noncorticosteroid alternative for the treatment of GCA. FINANCIAL...

  18. Cost effectiveness of angiotensin receptor blocker monotherapy in patients with hypertension in the Netherlands : a comparative analysis using clinical trial and drug utilization data

    NARCIS (Netherlands)

    Boersma, C.; Voors, A.A.; Visser, Sipke; de Jong-van den Berg, L.T.W.; Postma, M.J.

    2010-01-01

    Background and Objective: Health gains and related cost savings achieved by optimizing treatment in hypertensive patients is highly important. The aim of this study was to evaluate the costs and cost effectiveness of treatment with angiotensin II receptor antagonists (angiotensin II receptor blocker

  19. Differential involvement of hippocampal angiotensin 1 receptors in learning and memory processes in bulbectomized rats

    Directory of Open Access Journals (Sweden)

    Tashev E. Roman

    2016-04-01

    Full Text Available There is conflicting evidence regarding the effect of AT1 receptor antagonists on learning and memory processes. The effects of angiotensin II and losartan administration into CA1 hippocampal area on the avoidance performance in olfactory bulbectomized (OBX rats using active avoidance (shuttle box test and passive avoidance (step through test were investigated. Rats were microinjected unilaterally through implanted guide cannulas into the CA1 area of the dorsal hippocampus and the drugs were administered separately, 5 minutes before each training session. The microinjections of losartan into the left, but not the right CA1 hippocampal area improved the acquisition and retention of active and passive avoidance learning, thus suggesting dependence on the side of injection. The unilateral (left or right administration of angiotensin II did not significantly affect the performance of OBX rats in the avoidance tasks. A differential distribution of the AT1 receptors in the left and right hemisphere could contribute for the asymmetry in the behavioral effects of the AT receptor antagonist.

  20. Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Edvinsson, Marie-Louise; Chen, Qingwen;

    2009-01-01

    expression in subcutaneous arteries from patients with different degrees of ischemic heart disease. METHODS: Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina...... receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.......BACKGROUND: Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor...

  1. Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Edvinsson, Lars; Chen, Qingwen;

    2009-01-01

    expression in subcutaneous arteries from patients with different degrees of ischemic heart disease. METHODS: Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina......BACKGROUND: Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor...... receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions....

  2. The angiotensin type 2 receptor agonist Compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke

    DEFF Research Database (Denmark)

    Joseph, Jason P; Mecca, Adam P; Regenhardt, Robert W;

    2014-01-01

    Evidence indicates that angiotensin II type 2 receptors (AT2R) exert cerebroprotective actions during stroke. A selective non-peptide AT2R agonist, Compound 21 (C21), has been shown to exert beneficial effects in models of cardiac and renal disease, as well as hemorrhagic stroke. Here, we...... artery occlusion (MCAO), a model of cerebral ischemia. Rats infused centrally (intracerebroventricular) with C21 before endothelin-1 induced MCAO exhibited significant reductions in cerebral infarct size and the neurological deficits produced by cerebral ischemia. Similar cerebroprotection was obtained...

  3. Angiotensin AT2 receptor agonist prevents salt-sensitive hypertension in obese Zucker rats

    OpenAIRE

    Ali, Quaisar; Patel, Sanket; Hussain, Tahir

    2015-01-01

    High-sodium intake is a risk factor for the pathogenesis of hypertension, especially in obesity. The present study is designed to investigate whether angiotensin type 2 receptor (AT2R) activation with selective agonist C21 prevents high-sodium diet (HSD)-induced hypertension in obese animals. Male obese rats were treated with AT2R agonist C21 (1 mg·kg−1·day−1, oral) while maintained on either normal-sodium diet (NSD; 0.4%) or HSD (4%) for 2 wk. Radiotelemetric recording showed a time-dependen...

  4. Association of polymorphisms in angiotensin-converting enzyme gene with gestational diabetes mellitus in Indian women

    OpenAIRE

    Aggarwal, Parul; Agarwal, Nutan; Das, Nibhriti; Dalal, Krishna

    2016-01-01

    Background: Numerous genes have been reported in relation with gestational diabetes mellitus (GDM), but the findings were not consistently replicated across populations, or there have been no detailed studies on them. Previous literatures suggested that, out of all angiotensin converting enzyme (ACE) gene polymorphisms, only ACE insertion/deletion (I/D) gene polymorphism has a strong association with GDM in Asian Indian women. Aim: This study was devoted to evaluate the association of four si...

  5. [Assessment of the utilization of angiotensin receptor blockers in hypertension].

    Science.gov (United States)

    Peña Cabia, S; Ricote Lobera, I; Santos Mena, B; Hidalgo Correas, F J; Climent Florez, B; García Díaz, B

    2013-01-01

    Objetivo: Evaluar en nuestra área de Salud el grado en que la utilización de antagonistas de los receptores de la angiotensina II (ARA-II) se ajusta a los criterios propuestos por la Comunidad Autónoma de Madrid (CAM) antes de la instauración del «Plan de Actuación de ARA-II». Estudiar las indicaciones para las que se prescriben e identificar aquellos factores que han podido influir en su prescripción. Métodos: Estudio de utilización de medicamentos del tipo indicación- prescripción, descriptivo y transversal, en el que se seleccionaron pacientes con hipertensión arterial y en tratamiento con ARA-II ingresados en un Hospital General Universitario durante un periodo de estudio de 3 meses. De acuerdo con las situaciones clínicas recogidas en el Documento de la CAM «Criterios para establecer el lugar en la terapéutica de los antagonistas de los receptores de la angiotensina II», se calculó el porcentaje de pacientes con «prescripción adecuada» y «prescripción no adecuada» de ARA-II y se analizó si la edad y el sexo tenían influencia en el tipo de prescripción o en las principales indicaciones para las que se prescribieron. Resultados: De los 153 pacientes que se incluyeron en el estudio, el 67,3% tuvieron una «prescripción no adecuada», el 47,6% de ellos por prescripción de ARA-II como primer fármaco antagonista del sistema renina angiotensina aldosterona y el 34,0% por mal control de la tensión arterial con inhibidores de la enzima convertidora de angiotensina (IECA). No se encontraron diferencias estadísticamente significativas por edad o sexo en cuanto al tipo de prescripción o en las principales indicaciones para las que se prescribieron. Conclusiones: La adecuación a los criterios de uso del Documento de ARA-II se produjo en el 32,7% de los casos. Además, no se observó que factores como la edad y el sexo influyeran en el tipo de prescripción. Asimismo, se evidenciaron percep-

  6. Angiotensin-converting enzyme gene I/D polymorphism and renal disease

    NARCIS (Netherlands)

    Navis, G; van der Kleij, FGH; de Zeeuw, D; de Jong, PE

    1999-01-01

    In recent years a vast amount of data has been published on the association between the insertion/deletion (VD) polymorphism of the gene coding for angiotensin-converting enzyme and renal disease. It has be come clear that the polymorphism does not affect the prevalence of renal disease. However, da

  7. Evidence that the angiotensin at 2-receptor agonist compound 21 is also a low affinity thromboxane TXA2-receptor antagonist

    DEFF Research Database (Denmark)

    Fredgart, M.; Leurgans, T.; Stenelo, M.;

    2015-01-01

    Objective: The objective of this study was to test whether Compound 21 (C21), a high-affinity, non-peptide angiotensinAT2-receptor agonist, is also an antagonist of thromboxane A2 (TXA2) receptors thus reducing both vasoconstriction and platelet aggregation. Design and method: Binding of C21 to the...... TXA2 receptor was determined by TBXA2R Arrestin Biosensor Assay. Mouse mesenteric arteries were mounted in wire myographs, and responses to increasing concentrations of C21 (1nM- 10muM) were recorded during submaximal contractions with 0.1muM U46619 (TXA2 analogue) or 1muMphenylephrine. To control for...

  8. Expression of AngiotensinReceptors in Aldosterone-producing Adenoma of the Adrenal Gland and Their Clinical Significance

    Institute of Scientific and Technical Information of China (English)

    吴准; 倪栋; 闫永吉; 李俊; 王保军; 欧阳金枝; 张国玺; 马鑫; 李宏召; 张旭

    2010-01-01

    The expression of angiotensin Ⅱ type 1 receptor (AT1R) and angiotensin Ⅱ type 2 receptor (AT2R) in aldosterone-producing adenoma (APA) of the adrenal gland was detected, and their relationship with clinical indexes of APA was analyzed. The mRNA expression of AT1R and AT2R in 50 cases of APA and tissues adjacent to tumors and 12 cases of normal adrenal tissues was detected by using reverse transcriptase polymerase chain reaction (RT-PCR). The expression of AT1R and AT2R proteins in paraffin-embedded slices o...

  9. Effects of Autoantibodies Against At1-receptor and Angiotensin II on Refractory Hypertension

    Institute of Scientific and Technical Information of China (English)

    廖玉华; 魏宇淼; 王敏; 董继华; 王朝晖; 苑海涛

    2001-01-01

    Objective The study will explore effects of the autoantibodies against AT1 receptor and angiotensin Ⅱ on the refractory hypertension. Methods Seventy-seven patients (46 men and 31 women) with essential hypertension were divided into groups of refractory hypertension (RH) and hypertension (HT) according to the 1999 WHO -ISH Guidelines for the Management of Hypertension. Forty normotensives (22 men) were recruited as controls.The mean age was 54. 3 ± 13 years old in RH group,53.5±9 years old in HT group and 51.2±11.9years old in normotensives (NT) group. The mean blood pressure was 154.2 ± 9.4/98.4 ± 8.2 mmHg in RH group and 130.1 ±7.6/80.5 ±6.7 mmHg in HT group after combination drug therapy of hypertension for 4 weeks. Blood pressure in NT group was 120. 8 ± 11.7/76. 4 ± 7.2 mmHg. The epitope of the 2nd extracellular loops of AT1 receptor was synthesized and used as antigens to screen the autoantibodies by ELISA. Plasma angiotensin (Ang) Ⅱ were examined by a radioimmunoassay. Results The autoantibodies against AT1 receptor were positive in 18 (46. 15% ) patients with RH, in 4 (10. 5 % ) hypertension and in 3 (7.5 % ) normotensives, P < 0.01. Ang Ⅱwas 57.01 ± 52.63 pmol/L in patients with RH. Both the autoantibodies positive and the Ang Ⅱ increasing were 4 (10. 3 %) cases, both normal were 7 (17.9% ) cases, the autoantibodies positive or Ang Ⅱ in creasing was all of 14 (35.9 % ) cases (χ2 =0. 09,P > 0. 05) There was no relationship between the autoantibodies against AT1 receptor and the angiotensin Ⅱ in refractory hypertension. Conclusion The autoantibodies against AT1 receptor and Ang Ⅱ might be two independent factors in developing of refractory hypertension. The findings suggest that AT1 receptor antagnist used in the treatment of refractory hypertension might have an important value.

  10. Expression of a naturally occurring angiotensin AT1 receptor cleavage fragment elicits caspase-activation and apoptosis

    OpenAIRE

    Cook, Julia L.; Singh, Akannsha; DeHaro, Dawn; Alam, Jawed; Re, Richard N.

    2011-01-01

    Several transmembrane receptors are documented to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. Our prior studies indicate that a population of the 7-transmembrane angiotensin type-1 receptor (AT1R) is cleaved in a ligand-augmented manner after which the cytoplasmic, carboxy-terminal cleavage fragment (CF) traffics to the nucleus. In the present report, we determine the precise cleavage site within the AT1R by mass spectrometry and Edman sequencing. Clea...

  11. Angiotensin II Type 1 Receptor-Mediated Electrical Remodeling in Mouse Cardiac Myocytes.

    Directory of Open Access Journals (Sweden)

    Jeremy Kim

    Full Text Available We recently characterized an autocrine renin angiotensin system (RAS in canine heart. Activation of Angiotensin II Type 1 Receptors (AT1Rs induced electrical remodeling, including inhibition of the transient outward potassium current Ito, prolongation of the action potential (AP, increased calcium entry and increased contractility. Electrical properties of the mouse heart are very different from those of dog heart, but if a similar system existed in mouse, it could be uniquely studied through genetic manipulations. To investigate the presence of a RAS in mouse, we measured APs and Ito in isolated myocytes. Application of angiotensin II (A2 for 2 or more hours reduced Ito magnitude, without affecting voltage dependence, and prolonged APs in a dose-dependent manner. Based on dose-inhibition curves, the fast and slow components of Ito (Ito,fast and IK,slow appeared to be coherently regulated by [A2], with 50% inhibition at an A2 concentration of about 400 nM. This very high K0.5 is inconsistent with systemic A2 effects, but is consistent with an autocrine RAS in mouse heart. Pre-application of the microtubule destabilizing agent colchicine eliminated A2 effects on Ito and AP duration, suggesting these effects depend on intracellular trafficking. Application of the biased agonist SII ([Sar1-Ile4-Ile8]A2, which stimulates receptor internalization without G protein activation, caused Ito reduction and AP prolongation similar to A2-induced changes. These data demonstrate AT1R mediated regulation of Ito in mouse heart. Moreover, all measured properties parallel those measured in dog heart, suggesting an autocrine RAS may be a fundamental feedback system that is present across species.

  12. Angiotensin receptor antagonists to prevent sudden death in heart failure: does the dose matter?

    Science.gov (United States)

    Francia, Pietro; Palano, Francesca; Tocci, Giuliano; Adduci, Carmen; Ricotta, Agnese; Semprini, Lorenzo; Caprinozzi, Massimo; Balla, Cristina; Volpe, Massimo

    2014-01-01

    International guidelines recommend ICD implantation in patients with severe left ventricular dysfunction of any origin only after careful optimization of medical therapy. Indeed, major randomized clinical trials suggest that suboptimal use of fundamental drugs, such as ACE inhibitors (ACE-i) and beta-blockers, may affect ICD shock-free survival, sudden cardiac death (SCD), and overall mortality. While solid evidence in favour of pharmacological therapy based on ACE-i with or without beta-blockers is available, data on SCD in HF patients treated with angiotensin receptor blockers (ARBs) are limited. The present paper systematically analyses the impact of ARBs on SCD in HF and reviews the contributory role of the renin-angiotensin system (RAS) to the establishment of arrhythmic substrates. The following hypothesis is supported: (1) the RAS is a critical component of the electrical remodelling of the failing myocardium, (2) RAS blockade reduces the risk of SCD, and (3) ARBs represent a powerful tool to improve overall survival and possibly reduce the risk of SCD provided that high doses are employed to achieve optimal AT1-receptor blockade.

  13. AT1a Receptor Has Interacted with Angiotensin-converting Enzymes 2 mRNA Expression in Mouse Brainstem

    Institute of Scientific and Technical Information of China (English)

    Zhanyi Lin; Shuguang Lin

    2008-01-01

    Objectives To examine in vivo interactions between angiotensin Ⅱ(Ang Ⅱ) AT1a receptor (AT1aR),angiotensin-converting enzymes (ACE) and ACE2 using small hairpin RNA (shRNA) gene-silencing methods in mice brainstem nucleus ttactus solitarius (NTS).Methods C57BL mice (n=8) were used as animal model.Method of microinjection in the nucleus of NTS was adopted.After ten days,mice were killed and their brain tissue were fixed and sectioned.The expression levels of AT1 aR,ACE and ACE2 mRNA at both sides of NTS were examined by in situ hybridization.Based on compared t-test,the changing for mRNA expression was examined.Results After the expression of AT1aR mRNA was significantly inhibited (61.6%±6.8% ) by AT1aR-shRNA,it was associated with decreases in ACE2 mRNA expression from (1.05±0.12) μCi/mg to (0.74±0.09) μCi/mg (29.0%±14.5%,P<0.01) on the same side of the brainstem.ACE mRNA expression was consistent at both sides (0.50 μCi/mg±0.09 μCi/mg and 0.53 μCi/mg±0.08 μCi/mg),with insignificant difference (P>0.05).Condusions The gene silencing result showed that there were interactions between brainstem AT1aR and ACE2.ACE mRNA expression was not altered by RNA interference treatment at AT1aR.

  14. The angiotensin-converting enzyme (ACE) gene family of Anopheles gambiae.

    OpenAIRE

    Isaac R Elwyn; Lee Alison J; Smith Judith A; Burnham Susan; Shirras Alan D

    2005-01-01

    Abstract Background Members of the M2 family of peptidases, related to mammalian angiotensin converting enzyme (ACE), play important roles in regulating a number of physiological processes. As more invertebrate genomes are sequenced, there is increasing evidence of a variety of M2 peptidase genes, even within a single species. The function of these ACE-like proteins is largely unknown. Sequencing of the A. gambiae genome has revealed a number of ACE-like genes but probable errors in the Ensem...

  15. Platelet-derived growth factor receptor-β in myocyte was upregulated by angiotensin II

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    To observe the regulation of platelet-derived growth factor (PDGF) receptor-βin myocyte stimulated by angiotensin II (AngII) at both integrated and cellular levels and reveal the signal transduction mechanism in cell, two kidneys, one clip (2K1C) renal hypertension were performed by placing a sliver clip around the left renal artery. Blood pressure and the ratio of left ventricular weight to body weight were measured at 4 and 8 weeks after operation. The content of AngII in heart was detected by radioimmunology assay; the protein level of PDGF receptor-βin heart was measured by Western blot analysis. The alteration of PDGF receptor-βstimulated by AngII and several inhibitors was observed on cultured neonatal rat ventricular myocyte (NRVM). The content of AngII in heart of 2K1C renal hypertensive rat at 4 and 8 weeks after operation was increased. Compared with sham group, 4 and 8 weeks after operation, PDGF receptor-βin heart of 2K1C group was upregulated by 100.3% and 127.1% (P < 0.05), respectively. This upregulation could be inhibited by captopril. For cultured myocyte, PDGF receptor-βwas increased by 47.1% after being stimulated by AngII and this upregulation could be inhibited by losartan which was an inhibitor of AT1 receptor. PLC inhibitor (U73122) and MEK inhibitor (PD98059) could partly inhibit PDGF receptor-βupregulation induced by AngII. These results suggested that AngII could upregulate PDGF receptor-βin myocyte by its AT1 receptor and this effect was at least partly dependent on PLC and extracellular signal-regulated kinase (ERK).

  16. Individualized prediction of the effect of angiotensin receptor inhibition on renal and cardiovascular outcomes in patients with diabetic nephropathy

    NARCIS (Netherlands)

    van der Sande, Nicolette G C; Dorresteijn, Jannick A N; Visseren, Frank L J; Dwyer, Jamie P; Blankestijn, Peter J; van der Graaf, Yolanda; Heerspink, Hiddo L

    2016-01-01

    Aims Angiotensin receptor blockers (ARBs) reduce cardiovascular and renal complications in patients with diabetic nephropathy but treatment effects may vary across patients. Predicting individualized treatment effect of ARBs on both outcomes may help clinicians and patients to assess the benefit of

  17. Effectiveness of Angiotensin II Receptor Antagonists in a Cohort of Dutch Patients With Type 2 Diabetes Mellitus (ZODIAC-14)

    NARCIS (Netherlands)

    van Hateren, Kornelis J. J.; Landman, Gijs W. D.; Groenier, Klaas H.; Bilo, Henk J. G.; Kleefstra, Nanne

    2015-01-01

    OBJECTIVE: There is limited evidence with respect to the between-group effects of various angiotensin receptor blockers (ARBs) on blood pressure and albuminuria in patients with type 2 diabetes mellitus. Therefore, we aimed to investigate the effects of differing ARBs on systolic blood pressure (SBP

  18. Nitric oxide up-regulates endothelial expression of angiotensin II type 2 receptors.

    Science.gov (United States)

    Dao, Vu Thao-Vi; Medini, Sawsan; Bisha, Marion; Balz, Vera; Suvorava, Tatsiana; Bas, Murat; Kojda, Georg

    2016-07-15

    Increasing vascular NO levels following up-regulation of endothelial nitric oxide synthase (eNOS) is considered beneficial in cardiovascular disease. Whether such beneficial effects exerted by increased NO-levels include the vascular renin-angiotensin system remains elucidated. Exposure of endothelial cells originated from porcine aorta, mouse brain and human umbilical veins to different NO-donors showed that expression of the angiotensin-II-type-2-receptor (AT2) mRNA and protein is up-regulated by activation of soluble guanylyl cyclase, protein kinase G and p38 mitogen-activated protein kinase without changing AT2 mRNA stability. In mice, endothelial-specific overexpression of eNOS stimulated, while chronic treatment with the NOS-blocker l-nitroarginine inhibited AT2 expression. The NO-induced AT2 up-regulation was associated with a profound inhibition of angiotensin-converting enzyme (ACE)-activity. In endothelial cells this reduction of ACE-activity was reversed by either the AT2 antagonist PD 123119 or by inhibition of transcription with actinomycin D. Furthermore, in C57Bl/6 mice an acute i.v. bolus of l-nitroarginine did not change AT2-expression and ACE-activity suggesting that inhibition of ACE-activity by endogenous NO is crucially dependent on AT2 protein level. Likewise, three weeks of either voluntary or forced exercise training increased AT2 expression and reduced ACE-activity in C57Bl/6 but not in mice lacking eNOS suggesting significance of this signaling interaction for vascular physiology. Finally, aortic AT2 expression is about 5 times greater in female as compared to male C57Bl/6 and at the same time aortic ACE activity is reduced in females by more than 50%. Together these findings imply that endothelial NO regulates AT2 expression and that AT2 may regulate ACE-activity. PMID:27235748

  19. Melatonin Receptor Genes in Vertebrates

    Directory of Open Access Journals (Sweden)

    Hua Dong Yin

    2013-05-01

    Full Text Available Melatonin receptors are members of the G protein-coupled receptor (GPCR family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A and MT2 (or Mel1b or MTNR1B receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C, has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.

  20. Changes in cardiac structure and function in rats immunized by angiotensin type 1 receptor peptides

    Institute of Scientific and Technical Information of China (English)

    Zhu Jin; Jin Wang; Wenhui Zhang; Guohua Zhang; Xiang ying Jiao; Jianming Zhi

    2011-01-01

    Angiotensin II (Ang II) is known to induce cardiomyocyte hypertrophy by activating the Ang II type 1 (AT1) receptor.Some studies have demonstrated that the autoantibodies against angiotensin AT1 receptor (AT1-AAs)cause functional effects,which is similar to those observed for the natural agonist Ang Ⅱ.In this study,we investigated the effects of AT1-AAs on cardiomyocytes' structure and function.Male Wistar rats were immunized with synthetic peptides corresponding to the second extracellular loop of AT1 receptor and Freund's adjuvant.The titers of AT1-AAs in rat serum were detected by enzymelinked immunosorbent assay every week.Hemodynamic analysis and heart weight (HW) indices were measured on the 4th and 8th months after initial immunization,respectively.Cultured neonatal rat cardiomyocytes were used to observe the hypertrophic effects of AT1-AAs.Results showed that systolic blood pressure and heart rate were significantly increased,the titers of AT1-AAs were also increased after 4 weeks of initial immunization.Compared with control group,the HW/body weight (BV)and left ventricular weight/BW of immunized rats were increased significantly and cardiac function was enhanced compensatively.The cultured neonatal rat cardiomyocytes respond to AT1-AAs stimulation with increased 3H-leucine incorporation and cell surface area in a dosedependent manner. These results suggest that the AT1-AAs have an agonist effect similar to Ang II in hypertrophy of cardiomyocytes in vivo and in vitro.AT1-AAs are involved in the pathogenesis of cardiovascular diseases and hypertension.

  1. Angiotensin-converting enzyme gene polymorphism and middle cerebral artery stenosis in a Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    Chunshu Rong; Yingqi Xing; Xinmei Jiang; Juan Wang; Baoshan Gao; Jianjun Zhao; Kangding Liu

    2013-01-01

    The angiotensin-converting enzyme gene is a candidate gene of stroke. The present study involved 62 healthy volunteers and 148 patients with middle cerebral artery stenosis as confirmed by brain color ultrasound from a Han population in North China, and determined the peripheral blood angiotensin-converting enzyme genotype using PCR-restriction fragment length polymorphism analysis. The results showed that the frequencies of the DD genotype and D allele were increased in patients with middle cerebral artery stenosis, but the difference was not statistically significant compared with healthy controls. The findings of this study on the relationship between stroke genes and middle cerebral artery stenosis indicate no significant correlation between the frequencies of the DD genotype and D allele of angiotensin-converting enzyme and middle cerebral artery stenosis in this Han population from North China. In the future, studies will be carried out to investigate correlations between multiple stroke candidate gene synergy and middle cerebral artery stenosis to provide a foundation for the development of gene therapy.

  2. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive.

    Directory of Open Access Journals (Sweden)

    Antoine eHuart

    2015-02-01

    Full Text Available Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease. Currently, inhibitors of the renin angiotensin system (RAS remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra with that of an angiotensin type 1 receptor antagonist (AT1a in the unilateral ureteral obstruction (UUO model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors.

  3. Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive

    Science.gov (United States)

    Huart, Antoine; Klein, Julie; Gonzalez, Julien; Buffin-Meyer, Bénédicte; Neau, Eric; Delage, Christine; Calise, Denis; Ribes, David; Schanstra, Joost P.; Bascands, Jean-Loup

    2015-01-01

    Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease (CKD). Currently, inhibitors of the renin–angiotensin system (RAS) remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R) reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies. Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra) with that of an angiotensin type 1 receptor antagonist (AT1a) in the unilateral ureteral obstruction (UUO) model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone. Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However, bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level. Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors. PMID:25698969

  4. Functional interaction between angiotensin II receptor type 1 and chemokine (C-C Motif) receptor 2 with implications for chronic kidney disease

    OpenAIRE

    Mohammed Akli Ayoub; Yuan Zhang; Kelly, Robyn S.; Heng B See; Johnstone, Elizabeth K.M.; McCall, Elizabeth A.; Williams, James H; Kelly, Darren J.; Pfleger, Kevin D.G.

    2015-01-01

    Understanding functional interactions between G protein-coupled receptors is of great physiological and pathophysiological importance. Heteromerization provides one important potential mechanism for such interaction between different signalling pathways via macromolecular complex formation. Previous studies suggested a functional interplay between angiotensin II receptor type 1 (AT1) and Chemokine (C-C motif) Receptor 2 (CCR2). However the molecular mechanisms are not understood. We investiga...

  5. Angiotensin-2-mediated Ca2+ signaling in the retinal pigment epithelium: role of angiotensin-receptor-associated-protein and TRPV2 channel.

    Directory of Open Access Journals (Sweden)

    Rene Barro-Soria

    Full Text Available Angiotensin II (AngII receptor (ATR is involved in pathologic local events such as neovascularisation and inflammation including in the brain and retina. The retinal pigment epithelium (RPE expresses ATR in its AT1R form, angiotensin-receptor-associated protein (Atrap, and transient-receptor-potential channel-V2 (TRPV2. AT1R and Atrap co-localize to the basolateral membrane of the RPE, as shown by immunostaining. Stimulation of porcine RPE (pRPE cells by AngII results in biphasic increases in intracellular free Ca(2+inhibited by losartan. Xestospongin C (xest C and U-73122, blockers of IP3R and PLC respectively, reduced AngII-evoked Ca(2+response. RPE cells from Atrap(-/- mice showed smaller AngII-evoked Ca(2+peak (by 22% and loss of sustained Ca(2+elevation compared to wild-type. The TRPV channel activator cannabidiol (CBD at 15 µM stimulates intracellular Ca(2+-rise suggesting that porcine RPE cells express TRPV2 channels. Further evidence supporting the functional expression of TRPV2 channels comes from experiments in which 100 µM SKF96365 (a TRPV channel inhibitor reduced the cannabidiol-induced Ca(2+-rise. Application of SKF96365 or reduction of TRPV2 expression by siRNA reduced the sustained phase of AngII-mediated Ca(2+transients by 53%. Thus systemic AngII, an effector of the local renin-angiotensin system stimulates biphasic Ca(2+transients in the RPE by releasing Ca(2+from cytosolic IP3-dependent stores and activating ATR/Atrap and TRPV2 channels to generate a sustained Ca(2+elevation.

  6. Postprandial fatty acid uptake and adipocyte remodeling in angiotensin type 2 receptor-deficient mice fed a high-fat/high-fructose diet.

    Science.gov (United States)

    Noll, Christophe; Labbé, Sébastien M; Pinard, Sandra; Shum, Michael; Bilodeau, Lyne; Chouinard, Lucie; Phoenix, Serge; Lecomte, Roger; Carpentier, André C; Gallo-Payet, Nicole

    2016-01-01

    The role of the angiotensin type-2 receptor in adipose physiology remains controversial. The aim of the present study was to demonstrate whether genetic angiotensin type-2 receptor-deficiency prevents or worsens metabolic and adipose tissue morphometric changes observed following a 6-week high-fat/high-fructose diet with injection of a small dose of streptozotocin. We compared tissue uptake of nonesterified fatty acid and dietary fatty acid in wild-type and angiotensin type-2 receptor-deficient mice by using the radiotracer 14(R,S)-[(1) (8)F]-fluoro-6-thia-heptadecanoic acid in mice fed a standard or high-fat diet. Postprandial fatty acid uptake in the heart, liver, skeletal muscle, kidney and adipose tissue was increased in wild-type mice after a high-fat diet and in angiotensin type-2 receptor-deficient mice on both standard and high-fat diets. Compared to the wild-type mice, angiotensin type-2 receptor-deficient mice had a lower body weight, an increase in fasting blood glucose and a decrease in plasma insulin and leptin levels. Mice fed a high-fat diet exhibited increased adipocyte size that was prevented by angiotensin type-2 receptor-deficiency. Angiotensin type-2 receptor-deficiency abolished the early hypertrophic adipocyte remodeling induced by a high-fat diet. The small size of adipocytes in the angiotensin type-2 receptor-deficient mice reflects their inability to store lipids and explains the increase in fatty acid uptake in non-adipose tissues. In conclusion, a genetic deletion of the angiotensin type-2 receptor is associated with metabolic dysfunction of white adipose depots, and indicates that adipocyte remodeling occurs before the onset of insulin resistance in the high-fat fed mouse model. PMID:27144096

  7. Aspirin suppresses cardiac fibroblast proliferation and collagen formation through downregulation of angiotensin type 1 receptor transcription

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xianwei, E-mail: XWang2@UAMS.edu; Lu, Jingjun; Khaidakov, Magomed; Mitra, Sona; Ding, Zufeng; Raina, Sameer; Goyal, Tanu; Mehta, Jawahar L., E-mail: MehtaJL@UAMS.edu

    2012-03-15

    Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiac fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22{sup phox}, p47{sup phox}, p67{sup phox}, NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H{sub 2}O{sub 2}. Since SA had similar effect as ASA on AT1R expression, we suggest that ASA's effect is mediated by its SA moiety. -- Highlights: ► Aspirin in therapeutic concentrations decreases mouse cardiac

  8. The influence of certain molecular descriptors of fecal elimination of angiotensin II receptor antagonists

    Directory of Open Access Journals (Sweden)

    Trbojević-Stanković Jasna B.

    2015-01-01

    Full Text Available Angiotensin II receptor antagonists (ARBs modulate the function of the renin-angiotensin-aldosterone system and are commonly prescribed antihypertensive drugs, especially in patients with renal failure. In this study, the relationship between several molecular properties of seven ARBs (candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan and their fecal elimination data obtained from the literature were investigated. The ARB molecular descriptors were calculated using three software packages. Simple linear regression analysis showed the best 2 correlation between fecal elimination data and lipophilicity descriptor, ClogP values (R2 = 0.725. Multiple linear regression was applied to examine the correlation of ARBs’ fecal elimination data with their lipophilicity and one additional, calculated descriptor. The best correlation (R2 = 0.909 with an acceptable probability value, P <0.05 was established between the ARB fecal elimination data and their lipophilicity and aqueous solubility data. Applying computed molecular descriptors for evaluating drug elimination is of great importance in drug research.

  9. CORRECTION OF ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH CHRONIC COR PULMONALE BY ANGIOTENSIN II RECEPTORS ANTAGONISTS

    Directory of Open Access Journals (Sweden)

    V. S. Zadionchenko

    2007-01-01

    Full Text Available Aim. To evaluate intensity of endothelial dysfunction, processes of apoptosis, state of central and peripheral hemodynamics and to evaluate how these characteristics are influenced by angiotensin II receptors antagonists (ARA II – candesartan (Atacand and losartan (Cosaar in patients with chronic cor pulmonale (CCP at different stages of disease.Material and methods. 100 patients with chronic obstructive pulmonary disease (COPD, complicated by CCP were included into the study. Caspase activity as apoptosis induction marker, von Willebrand factor, production of nitric oxide in blood plasma and condensate of breathing out air were assessed. 70 patients received ARA II (50 patients – candesartan 4-8 mg daily, 20 patients – losartan 50-100 mg daily, 30 patients received neither ARA II nor angiotensin converting enzyme inhibitors (ACEI.Results. Significant increase in intensity of endothelial dysfunction and activation of apoptosis processes were registered according to growth of CCP severity. After 6 months of therapy von Willebrand factor decreased by 25,2% and 27,7% in candesartan and losartan groups respectively (p<0.01 for both groups. In the control group only 13.2% of von Willebrand factor reduction was seen.Conclusion. ARA II added to common therapy of COPD complicated by CCP improves functional state of endothelium restricting hyperproduction of nitric oxide and its toxic effects and slowing down apoptotic cell death.

  10. CORRECTION OF ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH CHRONIC COR PULMONALE BY ANGIOTENSIN II RECEPTORS ANTAGONISTS

    Directory of Open Access Journals (Sweden)

    V. S. Zadionchenko

    2015-12-01

    Full Text Available Aim. To evaluate intensity of endothelial dysfunction, processes of apoptosis, state of central and peripheral hemodynamics and to evaluate how these characteristics are influenced by angiotensin II receptors antagonists (ARA II – candesartan (Atacand and losartan (Cosaar in patients with chronic cor pulmonale (CCP at different stages of disease.Material and methods. 100 patients with chronic obstructive pulmonary disease (COPD, complicated by CCP were included into the study. Caspase activity as apoptosis induction marker, von Willebrand factor, production of nitric oxide in blood plasma and condensate of breathing out air were assessed. 70 patients received ARA II (50 patients – candesartan 4-8 mg daily, 20 patients – losartan 50-100 mg daily, 30 patients received neither ARA II nor angiotensin converting enzyme inhibitors (ACEI.Results. Significant increase in intensity of endothelial dysfunction and activation of apoptosis processes were registered according to growth of CCP severity. After 6 months of therapy von Willebrand factor decreased by 25,2% and 27,7% in candesartan and losartan groups respectively (p<0.01 for both groups. In the control group only 13.2% of von Willebrand factor reduction was seen.Conclusion. ARA II added to common therapy of COPD complicated by CCP improves functional state of endothelium restricting hyperproduction of nitric oxide and its toxic effects and slowing down apoptotic cell death.

  11. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications.

    Science.gov (United States)

    Saavedra, Juan M; Sánchez-Lemus, Enrique; Benicky, Julius

    2011-01-01

    Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT(1) receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT(1) receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT(1) receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT(1) receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT(1) receptors in humans is also neuroprotective

  12. Enhanced water and salt intake in transgenic mice with brain-restricted overexpression of angiotensin (AT1) receptors

    OpenAIRE

    Lazartigues, Eric; Sinnayah, Puspha; Augoyard, Ginette; Gharib, Claude; Johnson, Alan Kim; Davisson, Robin L.

    2008-01-01

    To address the relative contribution of central and peripheral angiotensin II (ANG II) type 1A receptors (AT1A) to blood pressure and volume homeostasis, we generated a transgenic mouse model [neuron-specific enolase (NSE)-AT1A] with brain-restricted overexpression of AT1A receptors. These mice are normotensive at baseline but have dramatically enhanced pressor and bradycardic responses to intracerebroventricular ANG II or activation of endogenous ANG II production. Here our goal was to exami...

  13. AT1 Receptor Gene Polymorphisms in relation to Postprandial Lipemia

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    B. Klop

    2012-01-01

    Full Text Available Background. Recent data suggest that the renin-angiotensin system may be involved in triglyceride (TG metabolism. We explored the effect of the common A1166C and C573T polymorphisms of the angiotensin II type 1 receptor (AT1R gene on postprandial lipemia. Methods. Eighty-two subjects measured daytime capillary TG, and postprandial lipemia was estimated as incremental area under the TG curve. The C573T and A1166C polymorphisms of the AT1R gene were determined. Results. Postprandial lipemia was significantly higher in homozygous carriers of the 1166-C allele (9.39±8.36 mM*h/L compared to homozygous carriers of the 1166-A allele (2.02±6.20 mM*h/L (P<0.05. Postprandial lipemia was similar for the different C573T polymorphisms. Conclusion. The 1166-C allele of the AT1R gene seems to be associated with increased postprandial lipemia. These data confirm the earlier described relationships between the renin-angiotensin axis and triglyceride metabolism.

  14. Brain angiotensin AT1 receptors as specific regulators of cardiovascular reactivity to acute psychoemotional stress.

    Science.gov (United States)

    Mayorov, Dmitry N

    2011-02-01

    1. Cardiovascular reactivity, an abrupt rise in blood pressure (BP) and heart rate in response to psychoemotional stress, is a risk factor for heart disease. Pharmacological and molecular genetic studies suggest that brain angiotensin (Ang) II and AT(1) receptors are required for the normal expression of sympathetic cardiovascular responses to various psychological stressors. Moreover, overactivity of the brain AngII system may contribute to enhanced cardiovascular reactivity in hypertension. 2. Conversely, brain AT(1) receptors appear to be less important for the regulation of sympathetic cardiovascular responses to a range of stressors involving an immediate physiological threat (physical stressors) in animal models. 3. Apart from threatening events, appetitive stimuli can induce a distinct, central nervous system-mediated rise in BP. However, evidence indicates that brain AT(1) receptors are not essential for the regulation of cardiovascular arousal associated with positively motivated behaviour, such as anticipation and the consumption of palatable food. The role of central AT(1) receptors in regulating cardiovascular activation elicited by other types of appetitive stimuli remains to be determined. 4. Emerging evidence also indicates that brain AT(1) receptors play a limited role in the regulation of cardiovascular responses to non-emotional natural daily activities, sleep and exercise. 5. Collectively, these findings suggest that, with respect to cardiovascular arousal, central AT(1) receptors may be involved primarily in the regulation of the defence response. Therefore, these receptors could be a potential therapeutic target for selective attenuation of BP hyperreactivity to aversive stressors, without altering physiologically important cardiovascular adjustments to normal daily activities, sleep and exercise.

  15. [Angiotensin-receptor- and neprilysin-inhibition: a new option against heart failure].

    Science.gov (United States)

    Bruhn, Claudia

    2016-01-01

    The molecular combination of sacubitril and valsartan (Entresto) is a new drug for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is usually administered in conjunction with other heart failure therapies, instead of an ACE inhibitor or an angiotensin-receptor blocker (ARB). In studies, sacubitril/ valsartan was superior to enalapril in reducing the risks of death and hospitalization for heart failure. Possible side effects of sacubitril/valsartan are hypotension, angioedema, impaired renal function and elevation in serum potassium levels. The drug should not be used in times of pregnancy and breast feeding, in patients with servere hepatic impairment (Child-Pugh C) and in combination with aliskiren in patients with diabetes. PMID:26975167

  16. Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy

    DEFF Research Database (Denmark)

    Axelsson, Anna; Iversen, Kasper; Vejlstrup, Niels;

    2015-01-01

    are predictive of an adverse outcome. We aimed to assess the effect of the angiotensin II receptor blocker losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. METHODS: In this single-centre, randomised, double-blind, placebo-controlled trial, adult patients (aged...... 18 years and older) with obstructive or non-obstructive hypertrophic cardiomyopathy were randomly assigned via computer-based system to losartan (100 mg per day) or placebo for 12 months. Patients and investigators were masked to assigned treatment. The primary endpoint was change in left ventricular......, and May 1, 2013, 318 patients were screened. 133 patients (mean age 52 years [SD 13], 35% women) consented and were randomly assigned to placebo (n=69) or losartan (n=64). 124 (93%) patients completed the study and were included in the modified intention-to-treat analysis for the primary endpoint. After...

  17. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST)

    DEFF Research Database (Denmark)

    Sandset, Else Charlotte; Bath, Philip M W; Boysen, Gudrun;

    2011-01-01

    BACKGROUND: Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised...... blood pressure. METHODS: Participants in this randomised, placebo-controlled, double-blind trial were recruited from 146 centres in nine north European countries. Patients older than 18 years with acute stroke (ischaemic or haemorrhagic) and systolic blood pressure of 140 mm Hg or higher were included...... to treatment allocation. There were two co-primary effect variables: the composite endpoint of vascular death, myocardial infarction, or stroke during the first 6 months; and functional outcome at 6 months, as measured by the modified Rankin Scale. Analyses were by intention to treat. The study is registered...

  18. Neuroprotective effect of angiotensin II type 2 receptor during cerebral ischemia/reperfusion.

    Science.gov (United States)

    Ma, Chun-Ye; Yin, Lin

    2016-07-01

    Angiotensin II type 2 receptor (AT2R) activation has been shown to protect against stroke, but its precise mechanism remains poorly understood. We investigated whether the protective effect of AT2R against ischemia/reperfusion injury is mediated by the suppression of immune and inflammatory responses. Rat models of middle cerebral artery occlusion were intraperitoneally injected with physiological saline, the AT2R agonist CGP42112 (1 mg/kg per day) or antagonist PD123319 (1 mg/kg per day). In the CGP42112 group, AT2R expression increased, the infarct area decreased, interleukin-1β and tumor necrosis factor-α expression decreased, and interleukin-10 expression increased compared with the saline group. Antagonisin AT2R using PD123319 produced the opposite effects. These results indicate that AT2R activation suppresses immune and inflammatory responses, and protects against cerebral ischemia/reperfusion injury. PMID:27630693

  19. Analysis of renin-angiotensin-aldosterone system gene polymorphisms in resistant hypertension

    Directory of Open Access Journals (Sweden)

    S.R.S. Freitas

    2007-03-01

    Full Text Available Essential hypertension is a disease multifactorially triggered by genetic and environmental factors. The contribution of genetic polymorphisms of the renin-angiotensin-aldosterone system and clinical risk factors to the development of resistant hypertension was evaluated in 90 hypertensive patients and in 115 normotensive controls living in Southwestern Brazil. Genotyping for insertion/deletion of angiotensin-converting enzyme, angiotensinogen M235T, angiotensin II type 1 receptor A1166C, aldosterone synthase C344T, and mineralocorticoid receptor A4582C polymorphisms was performed by PCR, with further restriction analysis when required. The influence of genetic polymorphisms on blood pressure variation was assessed by analysis of the odds ratio, while clinical risk factors were evaluated by logistic regression. Our analysis indicated that individuals who carry alleles 235-T, 1166-A, 344-T, or 4582-C had a significant risk of developing resistant hypertension (P < 0.05. Surprisingly, when we tested individuals who carried the presumed risk genotypes A1166C, C344T, and A4582C we found that these genotypes were not associated with resistant hypertension. However, a gradual increase in the risk to develop resistant hypertension was detected when the 235-MT and TT genotypes were combined with one, two or three of the supposedly more vulnerable genotypes - A1166C (AC/AA, C344T (TC/TT and A4582C (AC/CC. Analysis of clinical parameters indicated that age, body mass index and gender contribute to blood pressure increase (P < 0.05. These results suggest that unfavorable genetic renin-angiotensin-aldosterone system patterns and clinical risk variables may contribute to increasing the risk for the development of resistant hypertension in a sample of the Brazilian population.

  20. Angiotensin-converting enzyme gene and retinal arteriolar narrowing: The Funagata Study

    OpenAIRE

    Tanabe, Y; Kawasaki, R.; J. J. Wang; Wong, T Y; Mitchell, P; Daimon, M; Oizumi, T; Kato, T.; Kawata, S.; Kayama, T; Yamashita, H.

    2009-01-01

    The purpose of this study is to determine whether the angiotensin-converting enzyme (ACE) gene polymorphism is associated with retinal arteriolar narrowing, a subclinical marker of chronic hypertension. The Funagata Study examined a population-based sample of Japanese aged 35+ years; 368 participants had both retinal vessel diameter measurements and ACE insertion/deletion (ACE I/D) polymorphism analyses performed. Assessment of retinal vessel diameter and retinal vessel wall signs followed th...

  1. Regulation of angiotensin-(1-7) and angiotensin Ⅱ type 1 receptor by telmisartan and losartan in adriamycin-induced rat heart failure

    Institute of Scientific and Technical Information of China (English)

    Wen-na ZONG; Xin-zheng LU; Xiao-hui YANG; Xiu-mei CHEN; Hong-juan HUANG; Hong-jian ZHENG; Xiao-yi QIN; Yong-hong YONG; Ke-jiang CAO; Jun HUANG

    2011-01-01

    Aim:To investigate the possible effects of telmisartan and losartan on cardiac function in adriamycin (ADR)-induced heart failure in rats,and to explore the changes in plasma level of angiotensin-(1-7)[Ang-(1-7)] and myocardial expression of angiotensin Ⅱ type 1/2 receptors (AT1R / AT2R) and Mas receptor caused by the two drugs.Methods:Male Sprague-Dawley rats were randomly divided into 4 groups:the control group,ADR-treated heart failure group (ADR-HF),telmisartan plus ADR-treated group (Tel+ADR) and losartan plus ADR-treated group (Los+ADR).ADR was administrated (2.5 mg/kg,ip,6 times in 2 weeks).The rats in the Tel+ADR and Los+ADR groups were treated orally with telmisartan (10 mg/kg daily po) and losartan (30 mg/kg daily),respectively,for 6 weeks.The plasma level of Ang-(1-7) was determined using ELISA.The mRNA and protein expression of myocardial Mas receptor,AT1R and AT2R were measured using RT-PCR and Western blotting,respectively.Results:ADR significantly reduced the plasma level of Ang-(1-7) and the expression of myocardial Mas receptor and myocardial AT2R,while significantly increased the expression of myocardial AT1R.Treatment with telmisartan and losartan effectively increased the plasma level of Ang-(1-7) and suppressed myocardial AT1R expression,but did not influence the expression of Mas receptor and AT2R.Conclusion:The protective effects of telmisartan and losartan in ADR-induced heart failure may be partially due to regulation of circulating Ang-(1-7) and myocardial AT1R expression.

  2. Angiopoietin-like protein 2 expression is suppressed by angiotensin II via the angiotensin II type 1 receptor in rat cardiomyocytes

    Science.gov (United States)

    Wang, Shuya; Li, Ying; Miao, Wei; Zhao, Hong; Zhang, Feng; Liu, Nan; Su, Guohai; Cai, Xiaojun

    2016-01-01

    The present study aimed to determine the inhibitory effects of angiotensin II (AngII) on angiopoietin-like protein 2 (Angptl2) in rat primary cardiomyocytes, and to investigate the potential association between angiotensin II type 1 receptor (AT1R) and these effects. Cardiomyocytes were isolated from 3-day-old Wistar rats, and were cultured and identified. Subsequently, the expression levels of Angptl2 were detected following incubation with various concentrations of AngII for various durations using western blotting, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence. Finally, under the most appropriate conditions (100 nmol/l AngII, 24 h), the cardiomyocytes were divided into six groups: Normal, AngII, AngII + losartan, normal + losartan, AngII + PD123319 and normal + PD123319 groups, in order to investigate the possible function of AT1R in Angptl2 suppression. Losartan and PD123319 are antagonists of AT1R and angiotensin II type 2 receptor, respectively. The statistical significance of the results was analyzed using Student's t-test or one-way analysis of variance. The results demonstrated that Angptl2 expression was evidently suppressed (P<0.05) following incubation with 100 nmol/l AngII for 24 h. Conversely, the expression levels of Angptl2 were significantly increased in the AngII + losartan group compared with the AngII group (P<0.01). However, no significant difference was detected between the AngII + PD123319, normal + losartan or normal + PD123319 groups and the normal group. The present in vitro study indicated that AngII was able to suppress Angptl2 expression, whereas losartan was able to significantly reverse this decrease by inhibiting AT1R. PMID:27483989

  3. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders.

    Science.gov (United States)

    Saavedra, Juan M

    2012-11-01

    The effects of brain AngII (angiotensin II) depend on AT(1) receptor (AngII type 1 receptor) stimulation and include regulation of cerebrovascular flow, autonomic and hormonal systems, stress, innate immune response and behaviour. Excessive brain AT(1) receptor activity associates with hypertension and heart failure, brain ischaemia, abnormal stress responses, blood-brain barrier breakdown and inflammation. These are risk factors leading to neuronal injury, the incidence and progression of neurodegerative, mood and traumatic brain disorders, and cognitive decline. In rodents, ARBs (AT(1) receptor blockers) ameliorate stress-induced disorders, anxiety and depression, protect cerebral blood flow during stroke, decrease brain inflammation and amyloid-β neurotoxicity and reduce traumatic brain injury. Direct anti-inflammatory protective effects, demonstrated in cultured microglia, cerebrovascular endothelial cells, neurons and human circulating monocytes, may result not only in AT(1) receptor blockade, but also from PPARγ (peroxisome-proliferator-activated receptor γ) stimulation. Controlled clinical studies indicate that ARBs protect cognition after stroke and during aging, and cohort analyses reveal that these compounds significantly reduce the incidence and progression of Alzheimer's disease. ARBs are commonly used for the therapy of hypertension, diabetes and stroke, but have not been studied in the context of neurodegenerative, mood or traumatic brain disorders, conditions lacking effective therapy. These compounds are well-tolerated pleiotropic neuroprotective agents with additional beneficial cardiovascular and metabolic profiles, and their use in central nervous system disorders offers a novel therapeutic approach of immediate translational value. ARBs should be tested for the prevention and therapy of neurodegenerative disorders, in particular Alzheimer's disease, affective disorders, such as co-morbid cardiovascular disease and depression, and traumatic

  4. Vascular hypothesis revisited: Role of stimulating antibodies against angiotensin and endothelin receptors in the pathogenesis of systemic sclerosis.

    Science.gov (United States)

    Cabral-Marques, Otavio; Riemekasten, Gabriela

    2016-07-01

    Systemic sclerosis (SSc) is a connective tissue disorder of unknown etiology characterized by the presence of multiple autoantibodies, including those against angiotensin and endothelin receptors. Patients with SSc can develop heterogeneous clinical manifestations including microvascular damage, the dysregulation of innate and adaptive immunity, and generalized fibrosis of multiple organs. Autoantibodies against angiotensin II type I receptor (AT1R) and endothelin-1 type A receptor (ETAR) play important roles in the pathogenesis of SSc. These autoantibodies regulate physiological processes ranging from production of collagen by skin fibroblasts to angiogenesis modulation. Understanding the mechanisms behind autoantibodies against AT1R and ETAR could provide insight to future novel therapies for SSc patients. In this review, we focus on elucidating the immunopathological mechanisms triggered by anti-AT1R and anti-ETAR autoantibodies to summarize current knowledge about vascular abnormalities resulting in progressive damage of organs seen in patients with SSc.

  5. Interaction of angiotensin II with the C-terminal 300-320 fragment of the rat angiotensin II receptor AT1a monitored by NMR.

    Science.gov (United States)

    D'Amelio, Nicola; Gaggelli, Elena; Gaggelli, Nicola; Lozzi, Luisa; Neri, Paolo; Valensin, Daniela; Valensin, Gianni

    2003-10-01

    Interaction between angiotensin II (Ang II) and the fragment peptide 300-320 (fCT300-320) of the rat angiotensin II receptor AT1a was demonstrated by relaxation measurements, NOE effects, chemical shift variations, and CD measurements. The correlation times modulating dipolar interactions for the bound and free forms of Ang II were estimated by the ratio of the nonselective and single-selective longitudinal relaxation rates. The intermolecular NOEs observed in NOESY spectra between HN protons of 9Lys(fCT) and 6His(ang), 10Phe(fCT) and 8Phe(ang), HN proton of 3Tyr(fCT) and Halpha of 4Tyr(ang), 5Phe(fCT)Hdelta and Halpha of 4Tyr(ang) indicated that Ang II aromatic residues are directly involved in the interaction, as also verified by relaxation data. Some fCT300-320 backbone features were inferred by the CSI method and CD experiments revealing that the presence of Ang II enhances the existential probability of helical conformations in the fCT fragment. Restrained molecular dynamics using the simulated annealing protocol was performed with intermolecular NOEs as constraints, imposing an alpha-helix backbone structure to fCT300-320 fragment. In the built model, one strongly preferred interaction was found that allows intermolecular stacking between aromatic rings and forces the peptide to wrap around the 6Leu side chain of the receptor fragment.

  6. Relaxin requires the angiotensin II type 2 receptor to abrogate renal interstitial fibrosis.

    Science.gov (United States)

    Chow, Bryna S Man; Kocan, Martina; Bosnyak, Sanja; Sarwar, Mohsin; Wigg, Belinda; Jones, Emma S; Widdop, Robert E; Summers, Roger J; Bathgate, Ross A D; Hewitson, Tim D; Samuel, Chrishan S

    2014-07-01

    Fibrosis is a hallmark of chronic kidney disease, for which there is currently no effective cure. The hormone relaxin is emerging as an effective antifibrotic therapy; however, its mechanism of action is poorly understood. Recent studies have shown that relaxin disrupts the profibrotic actions of transforming growth factor-β1 (TGF-β1) by its cognate receptor, relaxin family peptide receptor 1 (RXFP1), extracellular signal-regulated kinase phosphorylation, and a neuronal nitric oxide synthase-dependent pathway to abrogate Smad2 phosphorylation. Since angiotensin II also inhibits TGF-β1 activity through its AT2 receptor (AT2R), we investigated the extent to which relaxin interacts with the AT2R. The effects of the AT2R antagonist, PD123319, on relaxin activity were examined in primary rat kidney myofibroblasts, and in kidney tissue from relaxin-treated male wild-type and AT2R-knockout mice subjected to unilateral ureteric obstruction. Relaxin's antifibrotic actions were significantly blocked by PD123319 in vitro and in vivo, or when relaxin was administered to AT2R-knockout mice. While heterodimer complexes were formed between RXFP1 and AT2Rs independent of ligand binding, relaxin did not directly bind to AT2Rs but signaled through RXFP1-AT2R heterodimers to induce its antifibrotic actions. These findings highlight a hitherto unrecognized interaction that may be targeted to control fibrosis progression. PMID:24429402

  7. Association of angiotensin Ⅱ type 1 receptor gene polymorphism with essential hypertension%血管紧张素Ⅱ受体1基因多态性与原发性高血压的相关性研究

    Institute of Scientific and Technical Information of China (English)

    蒋珍妮; 俞锋; 徐耕; 赵文胜

    2001-01-01

    Objective To determine whether the polymorphism A1166C in the angiotensin Ⅱ type 1 receptor (AT1R) gene is associated with essential hypertension Methods A casecontrol study was carried out using 125 hypertensive and 103 normotensive subjects The AC variant at position 1166 (A1166C) of the AT 1R gene was identified by polymerase chain reaction (PCR) and PCR/restriction fragment length polymorphism (PCR/RFLP) analysis The digestion products were separated on 2% agarose gels and visualized with ethidium bromide under ultraviolet ray Results The differences in C1166 allele frequency and in the AC genotype distribution of the AT 1R gene between the hypertensive and normotensive groups were statistically significant (C allele: 0.092 vs 0.034, χ2=6.1.86,P<0.05; AC genotype: 0.184 vs 0.068, χ2=6.654,P<0.05) Conclusion The AC genotype is associated with essential hypertension, and the C allele may be a marker for predisposition to hypertension in Chinese Han population%目的本研究旨在观察中国汉族人血管紧张素Ⅱ受体1基因多态性与原发性高血压的关系。方法应用聚合酶链反应-限制性内切酶片段长度多态(PCR-RFLP)与电泳分型的方法检测125例原发性高血压患者和103例正常者AT1R基因1166位(A1166C)的多态性分布。结果原发性高血压患者AT1R基因AC型频率比正常对照组高(0.184 vs 0.068, χ2=6.654,P<0.05),C1166等位基因频率原发性高血压组高于正常对照组(0.092 vs 0.034,χ2=6.186,P<0.05)。结论在中国汉族人群中,AC基因型与原发性高血压有关,C等位基因可能是高血压的易感基因。

  8. 血管紧张素Ⅱ-1型受体基因多态性与老年原发性高血压水平的关系%Relationship between angiotensin II type 1 receptor gene polymorphism and blood pressure levels in essential hypertensive elders

    Institute of Scientific and Technical Information of China (English)

    张怡; 陆惠华; 方宁远; 邬亦贤; 郑迪辉; 易雅萍

    2001-01-01

    Objective To investigate the relationship of angiotensin II type 1 receptor (AT1-R) gene A/C1166 polymorphism and blood pressure levels in essential hypertensive elders.Methods The A/C1166 polymorphism of AT1R gene was assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a casecontrol study of 87 EH elders and 55 normotensive elders. In EH elders blood pressure was measured by 24 hours noninvasive ambulatory blood pressure monitoring. Results (1) The frequency of C1166 allele in EH elders was higher than that in normotensive elders (0.115 vs 0. 036,P<0.05). (2) The mean levels of 24 hours and nighttime SBP and MA, daytime SBP,and nighttime DBP were higher in the group with C allele (AC + CC) than that in AA group (P <0.05). Conclusion The results indicate that A/C1166 polymorphism of AT1-R gene is associated with EH elders.The frequency of C1166 allele is higher in EH elders than that in norrnotensive elders. The C1166 allele may contribute to the higher level of blood pressure in EH elders.%目的研究血管紧张素Ⅱ-1型受体(ATl-R)基因A/C1166多态性与老年原发性高血压(EH)血压水平的关系。方法应用PCR-RFLP技术检测87例老年EH患者和55例正常老年人的AT1-R基因A/C1166多态性,同时对老年EH患者作24小时动态血压监测。结果 (1)老年EH的C1166等位基因频率为0.115,明显高于正常人(0.036)(P<0.05)。(2)AC、CC基因型EH患者24小时及夜间SBP、MAP和白天SBP、夜间DBP水平明显高于基因型AA组(P<0.05)。结论研究提示AT1-R基因的A/C1166多态性与老年EH相关,C1166等位基因频率在EH患者明显升高,并与血压水平升高有关。

  9. Attenuation of Immune-Mediated Renal Injury by Telmisartan, an Angiotensin Receptor Blocker and a Selective PPAR-γ Activator

    Directory of Open Access Journals (Sweden)

    Yuki Hamano

    2011-09-01

    Full Text Available Background/Aims: Anti-glomerular basement membrane (GBM nephritis is characterized by activation of the renin-angiotensin system. This study aimed to determine the question of whether a temporary angiotensin II blockade at the initial stage of anti-GBM nephritis is able to attenuate the disease as well as differences in renoprotection among angiotensin II receptor blockers (ARBs with distinct peroxisome proliferator-activated receptor (PPAR-γ-modulating activities. Methods: C57BL/6J mice were immunized with rabbit IgG, followed by intravenous injection of rabbit anti-mouse antibodies. Mice were then treated with telmisartan, losartan, and telmisartan + GW9662 (a PPAR-γ antagonist for 5 days, or hydralazine for 9 days. On days 8 and 13, mice were sacrificed to obtain tissues for histological analysis. Results: The temporary administration of telmisartan significantly suppressed glomerular damage compared to hydralazine. Losartan showed a similar effect but was less effective. Co-administration of GW9662 attenuated the renoprotective effect of telmisartan, almost to levels observed with losartan. In particular, it limited the decreased infiltration of inflammatory cells and preservation of capillaries in the glomeruli induced by telmisartan. Conclusion: Temporary angiotensin II blockade at the initial stage of anti-GBM disease dramatically inhibited its progression. In addition to a class effect of ARBs, telmisartan modified inflammation and endothelial damage in the kidney through its PPAR-γ-agonistic action.

  10. A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers

    Directory of Open Access Journals (Sweden)

    Seyed Ali Sadjadi

    2009-07-01

    Full Text Available Seyed Ali Sadjadi1, James I McMillan1, Navin Jaipaul1, Patricia Blakely1, Su Su Hline21Section of Nephrology (111N, Jerry L Pettis Memorial Veterans Medical Center, Loma Linda, CA, USA; 2Divison of Nephrology, Loma Linda University Medical Center, Loma Linda, CA, USABackground and objectives: Angiotensin-converting enzyme inhibitors (ACEI and angiotensin receptor blockers (ARB are increasingly used in a variety of settings including heart failure, renal failure, arterial hypertension, and diabetic nephropathy. The objective of this study was to investigate the prevalence of hyperkalemia with ACEI and ARB use, in a population of the United States veterans.Design, settings, material, and measurements: Retrospective observational cohort study of 1163 patients on ACEIs and 1168 patients on ARBs in a single Veterans Affairs Medical Center. Electronic medical records were reviewed over a 12-month period with data collected on various demographic, laboratory, comorbidity, and medication related variables. Results: Hyperkalemia (>5 mEq/L was observed in 20.4% of patients on ACEIs and 31.0% on ARBs. Severe hyperkalemia (6 mEq/L or higher, was observed in 0.8% of ACEI and 2.8% of ARB users. In univariate logistic regression analyses, diabetes mellitus; serum glucose, total carbon dioxide content, creatinine, and estimated glomerular filtration rate (GFR were significantly associated with hyperkalemia. ARB use, when compared to ACEI, was associated with a 42% increase in odds of hyperkalemia (odds ratio [OR] = 1.42; p = 0.001 in a model including adjustment for GFR and a 56% increase in odds of hyperkalemia (OR = 1.56; p < 0.001 in a model including adjustment for serum creatinine.Conclusions: Hyperkalemia, associated with the use of ACEIs and ARBs, is usually mild and severe hyperkalemia is rare. Hyperkalemia is more common with ARBs than ACEIs. ARB use, when compared to ACEI use, may significantly and independently be associated with increased odds of

  11. Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

    DEFF Research Database (Denmark)

    Christoffersen, Tue E.H.; Aplin, Mark; Strom, Claes C.;

    2006-01-01

    Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system...... also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg.kg(-1).day(-1)) to investigate a possible role of the renin-angiotensin system in...

  12. Long-term Angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARγ.

    OpenAIRE

    Zorad, Stefan; Jing-tao DOU; Benicky, Julius; Hutanu, Daniel; Tybitanclova, Katarina; Zhou, Jin; Saavedra, Juan M

    2006-01-01

    To clarify the mechanism of the effects of angiotensin II AT1 receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT1 receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum ...

  13. Long-term use of angiotensin receptor blockers and the risk of cancer.

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    Laurent Azoulay

    Full Text Available The association between angiotensin receptor blockers (ARBs and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs and 95% confidence intervals (CIs of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years. When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96-1.03 or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06-1.20 and RR: 1.19; 95% CI: 1.12-1.27, respectively. This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.

  14. INHIBITORY EFFECT OF ANGIOTENSIN Ⅱ TYPE 1 RECEPTOR-ASSOCIATED PROTEIN ON VASCULAR SMOOTH MUSCLE CELL GROWTH AND NEOINTIMAL FORMATION

    Institute of Scientific and Technical Information of China (English)

    Zhen Li; Zhong-gao Wang; Xiu Chen; Xiao-dong Chen

    2007-01-01

    Objective To investigate the mechanism of a novel angiotensin n type 1 receptor-associated protein (ATRAP) interfering with angiotensin Ⅱ type 1 (AT1) receptor-mediated vascular smooth muscle cell (VSMC) growth and neointimal formation. Methods VSMCs isolated from thoracic aorta of adult Sprague-Dawley ( SD) rats were used in this study. ATRAP Cdna was subcloned into pcDNA3 vector and then transfected into VSMCs. DNA synthesis and extracellular signal-regulated kinase (ERK) and phospho-ERK expressions in VSMCs were assayed by measurement of 3H thymidine incorporation and Western blotting, respectively. Morphological changes were observed in the balloon injured artery with or without transfection of ATRAP Cdna using 12-week-old male SD rats. Results ATRAP overexpression in VSMCs inhibited angiotensin Ⅱ (Ang Ⅱ) -induced 3H thymidine incorporation 48 hours after Ang Ⅱ stimulation (P < 0.05). In VSMC, Ang Ⅱ stimulation increased the phosphorylation of ERK, which reached the peak around 60 minutes. The activation of phospho-ERK was significantly decreased by ATRAP (P < 0.05). Neointimal formation was markedly inhibited by ATRAP overexpression in injuried arteries. Conclusions The AT1 receptor-derived activation of ERK plays an essential role in Ang Ⅱ-induced VSMC growth. The growth inhibitory effects of ATRAP might be due to interfering with AT1 receptor-mediated activation of ERK in VSMC growth and neointimal formation.

  15. Mechanical stress triggers cardiomyocyte autophagy through angiotensin II type 1 receptor-mediated p38MAP kinase independently of angiotensin II.

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    Li Lin

    Full Text Available Angiotensin II (Ang II type 1 (AT1 receptor is known to mediate a variety of physiological actions of Ang II including autophagy. However, the role of AT1 receptor in cardiomyocyte autophagy triggered by mechanical stress still remains elusive. The aim of this study was therefore to examine whether and how AT1 receptor participates in cardiomyocyte autophagy induced by mechanical stresses. A 48-hour mechanical stretch and a 4-week transverse aorta constriction (TAC were imposed to cultured cardiomyocytes of neonatal rats and adult male C57B/L6 mice, respectively, to induce cardiomyocyte hypertrophy prior to the assessment of cardiomyocyte autophagy using LC3b-II. Losartan, an AT1 receptor blocker, but not PD123319, the AT2 inhibitor, was found to significantly reduce mechanical stretch-induced LC3b-II upregulation. Moreover, inhibition of p38MAP kinase attenuated not only mechanical stretch-induced cardiomyocyte hypertrophy but also autophagy. To the contrary, inhibition of ERK and JNK suppressed cardiac hypertrophy but not autophagy. Intriguingly, mechanical stretch-induced autophagy was significantly inhibited by Losartan in the absence of Ang II. Taken together, our results indicate that mechanical stress triggers cardiomyocyte autophagy through AT1 receptor-mediated activation of p38MAP kinase independently of Ang II.

  16. Human fetal malformations associated with the use of an angiotensin II receptor antagonist: Case Report

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    Henri Augusto Korkes

    2014-09-01

    Full Text Available Introduction: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. Case report: A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. Discussion: Angiotensin-converting enzyme inhibitors (ACEIs and angiotensin receptor antagonists (ARAs are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. Conclusion: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.

  17. Angiotensin-(1-7 attenuates disuse skeletal muscle atrophy in mice via its receptor, Mas

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    María Gabriela Morales

    2016-04-01

    Full Text Available Immobilization is a form of disuse characterized by a loss of strength and muscle mass. Among the main features are decreased IGF-1/Akt signalling and increased ubiquitin-proteasome pathway signalling, which induce greater myosin heavy chain degradation. Activation of the classical renin-angiotensin system (RAS causes deleterious effects in skeletal muscle, including muscle wasting. In contrast, angiotensin-(1-7 [Ang-(1-7], a peptide of the non-classical RAS, produces beneficial effects in skeletal muscle. However, the role of Ang-(1-7 in skeletal muscle disuse atrophy and independent of classical RAS activation has not been evaluated. Therefore, we assessed the functions of Ang-(1-7 and the Mas receptor in disuse muscle atrophy in vivo using unilateral cast immobilization of the hind limb in male, 12-week-old wild-type (WT and Mas-knockout (Mas KO mice for 1 and 14 days. Additionally, we evaluated the participation of IGF-1/IGFR-1/Akt signalling and ubiquitin-proteasome pathway expression on the effects of Ang-(1-7 immobilization-induced muscle atrophy. Our results found that Ang-(1-7 prevented decreased muscle strength and reduced myofiber diameter, myosin heavy chain levels, and the induction of atrogin-1 and MuRF-1 expressions, all of which normally occur during immobilization. Analyses indicated that Ang-(1-7 increases IGF-1/IGFR-1/Akt pathway signalling through IGFR-1 and Akt phosphorylation, and the concomitant activation of two downstream targets of Akt, p70S6K and FoxO3. These anti-atrophic effects of Ang-(1-7 were not observed in Mas KO mice, indicating crucial participation of the Mas receptor. This report is the first to propose anti-atrophic effects of Ang-(1-7 via the Mas receptor and the participation of the IGF-1/IGFR-1/Akt/p70S6K/FoxO3 mechanism in disuse skeletal muscle atrophy.

  18. Conditional expression of the type 2 angiotensin II receptor in mesenchymal stem cells inhibits neointimal formation after arterial injury.

    Science.gov (United States)

    Feng, Jian; Liu, Jian-Ping; Miao, Li; He, Guo-Xiang; Li, De; Wang, Hai-Dong; Jing, Tao

    2014-10-01

    Percutaneous coronary interventions (PCIs) are an effective treatment for obstructive coronary artery diseases. However, the procedure's success is limited by remodeling and formation of neointima. In the present study, we engineered rat mesenchymal stem cells (MSCs) to express type 2 angiotensin II receptor (AT2R) using a tetracycline-regulated system that can strictly regulate AT2R expression. We tested the ability of the modified MSCs to reduce neointima formation following arterial injury. We subjected rats to balloon injury, and reverse transcriptase polymerase chain reaction (RT-PCR) indicated no significant AT2R expression in normal rat arteries. Low expression of AT2R was observed at 28 days after balloon-induced injury. Interestingly, MSCs alone were unable to reduce neointimal hyperplasia after balloon-induced injury; after transplantation of modified MSCs, doxycycline treatment significantly upregulated neointimal AT2R expression and inhibited osteopontin mRNA expression, as well as neointimal formation. Taken together, these results suggest that transplantation of MSCs conditionally expressing AT2R could effectively suppress neointimal hyperplasia following balloon-induced injury. Therefore, MSCs with a doxycycline-controlled gene induction system may be useful for the management of arterial injury after PCI. PMID:25119854

  19. Changes in angiotensin II receptor bindings in the hen neurohypophysis before and after oviposition.

    Science.gov (United States)

    Takahashi, T; Nozaki, Y; Nakagawa-Mizuyachi, K; Nakayama, H; Kawashima, M

    2011-11-01

    The present study was performed to elucidate whether the angiotensin II (ANG II) receptor exists in the plasma membrane fraction of the neurohypophysis in hens, to estimate the time of action of ANG II on the neurohypophysis before and after oviposition, and to examine relationships between the action of ANG II on the neurohypophysis and those of estrogen and prostaglandin F(2α) (PGF(2α)) in relation to arginine vasotocin (AVT) release. The specific binding had a binding specificity to chicken ANG II (cANG II), reversibility, and saturation in the [(125)I]cANG II binding assay. Scatchard analysis revealed that the binding sites are of a single class. The equilibrium dissociation constant (K(d)) obtained by kinetic analysis and Scatchard analysis suggested a high affinity, and the maximum binding capacity (B(max)) obtained by Scatchard analysis suggested a limited capacity. These results suggest that an ANG II receptor exists in the neurohypophysis of hens. The K(d) and the B(max) value was significantly smaller in laying hens than in nonlaying hens, which suggests that bindings of the cANG II receptor change, depending on the difference in laying condition. Values of the K(d) and the B(max) decreased approximately 15 min before oviposition in laying hens, and decreased 1 h after an intramuscular injection of estradiol-17β and 5 min after an intravenous injection of cANG II in nonlaying hens. The amount of specific binding of PGF(2α) receptor in the neurohypophysis also decreased and AVT concentration in blood increased after the cANG II injection. It seems likely that the action of cANG II in the neurohypophysis increases due to the effect of estrogen approximately 15 min before oviposition, and the cANG II action stimulates AVT release through the increase in the PGF(2α) action in this tissue. PMID:22010242

  20. Predicting kinase activity in angiotensin receptor phosphoproteomes based on sequence-motifs and interactions.

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    Rikke Bøgebo

    Full Text Available Recent progress in the understanding of seven-transmembrane receptor (7TMR signalling has promoted the development of a new generation of pathway selective ligands. The angiotensin II type I receptor (AT1aR is one of the most studied 7TMRs with respect to selective activation of the β-arrestin dependent signalling. Two complimentary global phosphoproteomics studies have analyzed the complex signalling induced by the AT1aR. Here we integrate the data sets from these studies and perform a joint analysis using a novel method for prediction of differential kinase activity from phosphoproteomics data. The method builds upon NetworKIN, which applies sophisticated linear motif analysis in combination with contextual network modelling to predict kinase-substrate associations with high accuracy and sensitivity. These predictions form the basis for subsequently nonparametric statistical analysis to identify likely activated kinases. This suggested that AT1aR-dependent signalling activates 48 of the 285 kinases detected in HEK293 cells. Of these, Aurora B, CLK3 and PKG1 have not previously been described in the pathway whereas others, such as PKA, PKB and PKC, are well known. In summary, we have developed a new method for kinase-centric analysis of phosphoproteomes to pinpoint differential kinase activity in large-scale data sets.

  1. 血管紧张素Ⅱ受体-1基因A1166C多态性与脑梗死的关系%Relationship between polymorphism of angiotensin Ⅱ trpe 1 receptor gene A1166C and cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    柳四新; 谭红; 王家琪

    2011-01-01

    Objective To investigate the relationship between polymorphism of angiotensin Ⅱ type 1 receptor (AT1R) gene A1166C and cerebral infarction.Methods Frequencies of AT1R gene A1166C genotype and allele were sequenced in 120 cerebral infarction patienta (CI group) and 150 normal controls (NC group) by PCR and restriction fragment length polymorphism technique, and the result were compared.Results The distributions of genotype frequency Al 166C in CI group and NC group had group representation through Hardy-Weinberg analysis.Frequency of AC genotype and C allele in CI group were 35.0%, 17.5% respectively; in NC group were 16.0%,8.0% respectively.There were significant differences between the two groups ( all P < 0.05 ).Conclusion The AC genotype and C allele of AT1R A1166C may be the risk factor of cerebral infarction.%目的 研究血管紧张素Ⅱ受体-1(AT1R)基因A1166C多态性与脑梗死的相关性.方法 应用PCR及限制性片段长度多态性技术,对120例脑梗死患者(脑梗死组)和150名健康对照者(正常对照组)的AT1R基因A1166C多态位点进行检测,并比较两组间AT1R基因A1166C基因型和等位基因频率.结果 经Hardy-Weinberg检验结果表明,A1166C多态位点在脑梗死组和正常对照组的频率分布具有群体代表性.脑梗死组ATIR基因A1166C位点AC基因型频率和C等位基因频率分别为35.0%和17.5%,正常对照组分别为16.0%和8.0%,两组比较差异有统计学意义(均P<0.05).结论 ATIR基因A1166C位点的AC基因型和C等位基因可能是脑梗死患者的发病危险因素.

  2. Association between angiotensin H type 1 receptor gene A1166C polymorphism and extent of coronary stenosis in patients with acute myocardial infarction%AT1R基因A1166C的多态性与急性心肌梗死患者冠脉病变程度的关系

    Institute of Scientific and Technical Information of China (English)

    彭建业; 张玲; 尹凯; 罗琼; 桂庆军

    2011-01-01

    AIM: To study the relationship between the angiotensin II type 1 receptor ( AT1R) gene A1166C polymorphism and the extent of coronary stenosis in patients with acute myocardial infarction (AMI). METHODS; The A1166C polymorphism of 105 primary AMI patients was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). All patients underwent coronary angiography, and the number of affected coronary vessels ( ≥50% stenosis) and the coronary Censini score were determined by the results of coronary angiography. RESULTS; Either the number of affected coronary vessels or the coronary Gensini score in AC + CC genotype carriers was significantly higher than in AA genotype carriers (P<0.05). CONCLUSION; The AT1R gene A1166C polymorphism may be related to the extent of coronary stenosis in AMI patients.%目的:研究血管紧张素Ⅱ1型受体(AT1R)基因A1166C的多态性与急性心肌梗死(AMI)患者冠脉病变程度的关系.方法:采用多聚酶链反应-限制性片段长度多态性( PCR-RFLP)技术检测105例初发AMI患者的ATIR基因A1166C的多态性.对所有患者进行冠脉造影,根据结果判定冠脉病变的支数(狭窄程度≥50%)和冠脉病变的Gensini积分.结果:AMI患者中,AC+ CC基因型携带者冠脉病变的支数和Gensini积分均显著高于AA基因型携带者(P<0.05).结论:AT1R基因A1166C的多态性与AMI患者冠脉病变程度有关.

  3. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: Effectiveness in combination with diuretics or β-blockers for treating hypertension

    Science.gov (United States)

    Bisognano, John D; McLaughlin, Trent; Roberts, Craig S; Tang, Simon SK

    2007-01-01

    This retrospective database analysis compared the effectiveness of dihydropyridine calcium channel blockers (DHPs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) added to diuretics or β-blockers. Adults with hypertension treated with diuretic or β-blocker monotherapy between 1998 and 2001 were identified from a large US electronic medical records database of primary care practices. Patients were required to have a baseline blood pressure (BP) ≥140/90 mmHg (≥130/80 mmHg for diabetes mellitus) and recorded BP measurements within 6 months before and 1–12 months following index date. Patients were matched 1:1:1 by propensity score to correct for differences in baseline characteristics. 1875 patients met study criteria and 660 (220 in each cohort) were matched based on propensity scores. Matched cohorts had no significant differences in baseline characteristics. Mean changes in systolic/diastolic BP were −17.5/−8.8, −15.7/−6.3, and −13.0/−8.0 mmHg with DHPs, ACE inhibitors, and ARBs, respectively. Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High BP 6/7 goal attainment for each regimen was 47.3%, 40.0%, and 32.2%, respectively. DHPs, ACE inhibitors, and ARBs improved BP when added to patients’ β-blocker or diuretic therapy. The greatest benefits were observed with DHPs, followed by ACE inhibitors, then ARBs. PMID:18078009

  4. Initial reduction of oxidative stress by angiotensin receptor blocker contributes long term outcomes after percutaneous coronary intervention

    OpenAIRE

    Noro, Tadanori; Takehara, Naofumi; Sumitomo, Kazuhiro; Takeuchi, Toshiharu; Ishii, Yoshinao; Kato, Jun-ichi; Kawabe, Jun-ichi; Hasebe, Naoyuki

    2014-01-01

    Background: It remains unclear whether administration of ARB with reactive oxygen species (ROS) scavenging effects improves the prognosis of patients undergoing PCI. Objectives: This study investigated whether the pre-intervention antioxidant effect of angiotensin receptor blocker (ARB) affects long-term outcomes in patients after successful percutaneous coronary intervention (PCI) without early adverse events. Methods: Fifty-two patients who underwent elective PCI were randomly assigned for ...

  5. Changes in Angiotensin Receptor Distribution and in Aortic Morphology Are Associated with Blood Pressure Control in Aged Metabolic Syndrome Rats

    OpenAIRE

    Verónica Guarner-Lans; Elizabeth Soria-Castro; Rocío Torrico-Lavayen; Araceli Patrón-Soberano; Karla G. Carvajal-Aguilera; Vicente Castrejón-Tellez; María Esther Rubio-Ruiz

    2016-01-01

    The role of the renin-angiotensin system (RAS) in blood pressure regulation in MS during aging is unknown. It participates in metabolic syndrome (MS) and aging regulating vascular tone and remodeling. RAS might participate in a compensatory mechanism decreasing blood pressure and allowing MS rats to reach 18 months of age and it might form part of therapeutical procedures to ameliorate MS. We studied histological changes and distribution of RAS receptors in aortas of MS aged rats. Electron mi...

  6. Preventive Effects of the Angiotensin-II Receptor Blocker on Atrial Remodeling in an Ischemic Heart Failure Model of Rats

    OpenAIRE

    Yoon, Namsik; Kim, Kye Hun; Park, Keun Ho; Sim, Doo Sun; Youn, Hyun Ju; Hong, Young Joon; Park, Hyung Wook; Kim, Ju Han; Ahn, Youngkeun; Jeong, Myung Ho; Cho, Jeong Gwan; Park, Jong Chun

    2013-01-01

    Background and Objectives It is widely known that angiotensin-II receptor blockers (ARBs) have reverse remodeling effects in atrium. Although atrial fibrillation is frequent in ischemic heart failure clinically, experiments to demonstrate ARB's effects on atrial remodeling in a heart failure model are rare. Materials and Methods A heart failure model and a sham-operated group were formed in 25 Sprague-Dawley male rats of roughly 260 g in weight. Ischemic heart failure models were obtained via...

  7. Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function

    OpenAIRE

    McLachlan, Jennifer; Beattie, Elisabeth; Murphy, Michael P; Koh-Tan, Caline H.H.; Olson, Erin; Beattie, Wendy; Dominiczak, Anna F.; Nicklin, Stuart A.; Graham, Delyth

    2014-01-01

    Objective: Mitochondria-derived reactive oxygen species (ROS) play important roles in the development of cardiovascular disease highlighting the need for novel targeted therapies. This study assessed the potential therapeutic benefit of combining the mitochondria-specific antioxidant, MitoQ10, with the low-dose angiotensin receptor blocker (ARB), losartan, on attenuation of hypertension and left ventricular hypertrophy. In parallel, we investigated the impact of MitoQ10 on cardiac hypertro...

  8. The Effect of an Angiotensin Receptor Blocker on Arterial Stiffness in Type 2 Diabetes Mellitus Patients with Hypertension

    OpenAIRE

    Ji Hyun Kim; Su Jin Oh; Jung Min Lee; Eun Gyoung Hong; Jae Myung Yu; Kyung Ah Han; Kyung Wan Min; Hyun Shik Son; Sang Ah Chang

    2011-01-01

    Background Hypertension and type 2 diabetes mellitus are major risk factors for cardiovascular disease. This study analyzed the changes in central aortic waveforms and pulse wave velocity as well as related parameters after treatment with valsartan, an angiotensin II type 1 receptor blocker, in patients with type 2 diabetes and hypertension. Methods We used pulse wave analysis to measure central aortic waveform in a total of 98 subjects. In 47 of these patients, pulse wave velocity measuremen...

  9. Changes of chymase, angiotensin converting enzyme and angiotensin Ⅱ type 1 receptor expressions in the hamster heart during the development of heart failure

    Institute of Scientific and Technical Information of China (English)

    CHEN Peng-min; LENG Xi-gang; FAN Li-li; MA Jun; WANG Ya-fang; CHEN Lan-ying

    2005-01-01

    Background Little is known about the role of dual angiotensin Ⅱ forming pathways during heart failure. In the present study, the changes of chymase and angiotensin converting enzyme (ACE) expressions in the failing hearts of hamsters were analysed.Methods Heart failure was induced by ligation of left anterior descending branch of the coronary artery. Chymase, ACE and angiotensin Ⅱ type 1 receptor (AT1R) mRNA levels were analysed by reverse transcription polymerase chain reaction (RT-PCR). The activities of chymase and ACE were determined by radioimmunoassay (RIA). Myocardial collagen fibre analysis was performed under optical microscope.Results Left ventricular systolic pressure (LVSP) and maximum left ventricular developed pressure increase rate (dp/dtmax, mmHg/s) gradually moved lower at 2, 3, 4 and 8 weeks after operation. On the other hand, left ventricular end-diastolic pressure (LVEDP) increased gradually after operation. Compared with the control group (3.55±0.06, 4.79±0.70), the heart weight/body weight ratio in operation group had increased significantly at 4 weeks and 8 weeks (4.28±0.43, 6.17±0.73) (P<0.01). Collagen staining showed that the quantity of myocardial collagen fibre increased significantly in the operation group. RT-PCR showed that the chymase mRNA level in the operation group was consistently greater than that in the control group. AT1R mRNA level was also increased significantly at 3 weeks and 4 weeks, both being 1.3 times that of the control group (P<0.01), whereas ACE mRNA level was not changed. Higher activity of chymase was detected in operation group, being 4, 8, 13 and 19 times that of the control group at 2, 3, 4 and 8 weeks (P<0.01), respectively. ACE activity was also significantly higher at the same time, being 7, 10, 10 and 3.5 times that of the control (P<0.01). Angiotensin Ⅱ (Ang Ⅱ) level in operation group increased significantly, being 2.5, 2.7, 3.5 and 2 times that of the control group at 2, 3, 4 and 8 weeks

  10. AT(1) receptor Gαq protein-independent signalling transcriptionally activates only a few genes directly, but robustly potentiates gene regulation from the β2-adrenergic receptor

    DEFF Research Database (Denmark)

    Christensen, Gitte Lund; Knudsen, Steen; Schneider, Mikael;

    2011-01-01

    of Gαq protein-dependent and -independent regulation of AT(1)R mediated gene expression. We found angiotensin II to regulate 212 genes, whereas Gαq-independent signalling obtained with the biased agonist, SII angiotensin II only regulated few genes. Interestingly, SII angiotensin II, like Ang II vastly...

  11. Evolution of the nuclear receptor gene superfamily.

    OpenAIRE

    Laudet, V; Hänni, C; Coll, J.; F. Catzeflis; Stéhelin, D

    1992-01-01

    Nuclear receptor genes represent a large family of genes encoding receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid and thyroid hormones. This family also contains genes encoding putative receptors for unknown ligands. Nuclear receptor gene products are composed of several domains important for transcriptional activation, DNA binding (C domain), hormone binding and dimerization (E domain). It is not known whether these genes have evolved through gene duplica...

  12. Mineralocorticoid and angiotensin II type 1 receptors in the subfornical organ mediate angiotensin II - induced hypothalamic reactive oxygen species and hypertension.

    Science.gov (United States)

    Wang, Hong-Wei; Huang, Bing S; White, Roselyn A; Chen, Aidong; Ahmad, Monir; Leenen, Frans H H

    2016-08-01

    Activation of angiotensinergic pathways by central aldosterone (Aldo)-mineralocorticoid receptor (MR) pathway plays a critical role in angiotensin II (Ang II)-induced hypertension. The subfornical organ (SFO) contains both MR and angiotensin II type 1 receptors (AT1R) and can relay the signals of circulating Ang II to downstream nuclei such as the paraventricular nucleus (PVN), supraoptic nucleus (SON) and rostral ventrolateral medulla (RVLM). In Wistar rats, subcutaneous (sc) infusion of Ang II at 500ng/min/kg for 1 or 2weeks increased reactive oxygen species (ROS) as measured by dihydroethidium (DHE) staining in a nucleus - specific pattern. Intra-SFO infusion of AAV-MR- or AT1aR-siRNA prevented the Ang II-induced increase in AT1R mRNA expression in the SFO and decreased MR mRNA. Both MR- and AT1aR-siRNA prevented increases in ROS in the PVN and RVLM. MR- but not AT1aR-siRNA in the SFO prevented the Ang II-induced ROS in the SON. Both MR- and AT1aR-siRNA in the SFO prevented most of the Ang II-induced hypertension as assessed by telemetry. These results indicate that Aldo-MR signaling in the SFO is needed for the activation of Ang II-AT1R-ROS signaling from the SFO to the PVN and RVLM. Activation of Aldo-MR signaling from the SFO to the SON may enhance AT1R dependent activation of pre-sympathetic neurons in the PVN. PMID:27163380

  13. Angiopoietin-like protein 2 expression is suppressed by angiotensin II via the angiotensin II type 1 receptor in rat cardiomyocytes.

    Science.gov (United States)

    Wang, Shuya; Li, Ying; Miao, Wei; Zhao, Hong; Zhang, Feng; Liu, Nan; Su, Guohai; Cai, Xiaojun

    2016-09-01

    The present study aimed to determine the inhibitory effects of angiotensin II (AngII) on angiopoietin‑like protein 2 (Angptl2) in rat primary cardiomyocytes, and to investigate the potential association between angiotensin II type 1 receptor (AT1R) and these effects. Cardiomyocytes were isolated from 3-day-old Wistar rats, and were cultured and identified. Subsequently, the expression levels of Angptl2 were detected following incubation with various concentrations of AngII for various durations using western blotting, reverse transcription‑quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence. Finally, under the most appropriate conditions (100 nmol/l AngII, 24 h), the cardiomyocytes were divided into six groups: Normal, AngII, AngII + losartan, normal + losartan, AngII + PD123319 and normal + PD123319 groups, in order to investigate the possible function of AT1R in Angptl2 suppression. Losartan and PD123319 are antagonists of AT1R and angiotensin II type 2 receptor, respectively. The statistical significance of the results was analyzed using Student's t‑test or one‑way analysis of variance. The results demonstrated that Angptl2 expression was evidently suppressed (P<0.05) following incubation with 100 nmol/l AngII for 24 h. Conversely, the expression levels of Angptl2 were significantly increased in the AngII + losartan group compared with the AngII group (P<0.01). However, no significant difference was detected between the AngII + PD123319, normal + losartan or normal + PD123319 groups and the normal group. The present in vitro study indicated that AngII was able to suppress Angptl2 expression, whereas losartan was able to significantly reverse this decrease by inhibiting AT1R. PMID:27483989

  14. Effect of renin-angiotensin-aldosterone system gene polymorphisms on blood pressure response to antihypertensive treatment

    Institute of Scientific and Technical Information of China (English)

    JIANG Xiao; SHENG Hai-hui; LIN Gang; LI Jian; LU Xin-zheng; CHENG Yun-lin; HUANG Jun; XIAO Hua-sheng; ZHAN Yi-yang

    2007-01-01

    Background The renin-angiotensin-aldosterone system (RAAS) is important for the development of essential hypertension, and many antihypertensive drugs target it. This study was undertaken to determine whether polymorphisms in the renin-angiotensin-aldosterone system are related to the blood pressure (BP) response to diuretic treatment in a Chinese Han ethnic population.Methods Fifty-four patients with essential hypertension received hydrochlorothiazide (12.5 mg, once daily) as monotherapy for four weeks. Seven polymorphisms in RAAS genes were genotyped by gene chip technology. The relationship between these polymorphisms and the change in blood pressure was observed after the 4-week treatment.Results The patients with angiotensinogen (AGT) -6G allele showed a greater reduction in diastolic BP (P= 0.025) and mean BP (P=0.039) than those carrying AA genotype. Patients carrying aldosterone synthase (CYP11B2) CC genotype exhibited a greater BP reduction than those carrying CT and TT genotypes (systolic BP: P= 0.030; diastolic BP: P= 0.026; mean BP: P=0.003). In addition, patients with a combination of CYP11B2 CC genotype and angiotensin converting enzyme (ACE) D allele might have a more pronounced reduction of systolic BP than those with any other genotypic combinations of the two genes (P= 0.007).Conclusions AGT-6G allele, CYP11B2 -344CC genotype and its combination with ACE D allele are associated with BP response to hydrochlorothiazide treatment. Larger studies are warranted to validate this finding.

  15. Distribution of Angiotensin Ⅱ Type 1 Receptor Gene A1166C Polymorphism in Yi Nationality Population in Yunnan Province%血管紧张素Ⅱ1型受体A1166C多态性在云南彝族人群中的分布

    Institute of Scientific and Technical Information of China (English)

    杨榆玲; 龙莉; 瞿秋; 吴玲; 何永蜀; 张彦

    2012-01-01

    目的 了解云南省晋宁县彝族人群AT1R基因A1166C多态性分布的情况,为研究AT1R基因相关性疾病的发病机制奠定基础.方法 采用PCR-RFLP技术对居住在云南省晋宁县180例彝族健康个体的AT1R基因A1166C多态性进行分析,获得其基因型频率和等位基因频率分布情况,并与其他人群该位点多态性进行比较.结果 云南省晋宁县彝族AT1R基因的AA、AC、CC基因型频率分别为95.6%、4.4%和0%,A、C等位基因频率分别为97.8%和2.2%.此位点多态性分布与不同人群比较,除凉山彝族外,差异均有统计学意义(P<0.05).结论 AT1R基因A1166C多态性分布存在民族、种族差异.%Objective To investigate the angiotensin II type 1 receptor (AT1R) gene A1166C polymorphism in a Yi nationality population in Yunnan province, and to provide evidence for the research of AT1R related diseases. Methods We recruited 180 healthy subjects of Yi nationality in rural area of Jinning, Yunnan province. The AT1R A1166C polymorphism was determined by polymerase chain reaction- restriction fragment (PCR- RFLP) technique. The genotype frequencies and allele frequencies were obtained and compared with those collected from other population. Results In healthy Yi people of Yunnan province, frequencies for the AA, AC and CC genotypes were 95.6%, 4.4% and 0%. Derived allele frequencies for the A and C allele were 97.8% and 2.2%. The distribution of AT1R genotypes and the allele frequencies in Yunnan Yi people were significantly different from other nationality (P<0.05) . Conclusion The frequency of the genotype or the allele of AT1R A1166C polymorphism is different significantly in different ethnic populations.

  16. Biased signaling of the angiotensin II type 1 receptor can be mediated through distinct mechanisms.

    Directory of Open Access Journals (Sweden)

    Marie Mi Bonde

    Full Text Available BACKGROUND: Seven transmembrane receptors (7TMRs can adopt different active conformations facilitating a selective activation of either G protein or β-arrestin-dependent signaling pathways. This represents an opportunity for development of novel therapeutics targeting selective biological effects of a given receptor. Several studies on pathway separation have been performed, many of these on the Angiotensin II type 1 receptor (AT1R. It has been shown that certain ligands or mutations facilitate internalization and/or recruitment of β-arrestins without activation of G proteins. However, the underlying molecular mechanisms remain largely unresolved. For instance, it is unclear whether such selective G protein-uncoupling is caused by a lack of ability to interact with G proteins or rather by an increased ability of the receptor to recruit β-arrestins. Since uncoupling of G proteins by increased ability to recruit β-arrestins could lead to different cellular or in vivo outcomes than lack of ability to interact with G proteins, it is essential to distinguish between these two mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We studied five AT1R mutants previously published to display pathway separation: D74N, DRY/AAY, Y292F, N298A, and Y302F (Ballesteros-Weinstein numbering: 2.50, 3.49-3.51, 7.43, 7.49, and 7.53. We find that D74N, DRY/AAY, and N298A mutants are more prone to β-arrestin recruitment than WT. In contrast, receptor mutants Y292F and Y302F showed impaired ability to recruit β-arrestin in response to Sar1-Ile4-Ile8 (SII Ang II, a ligand solely activating the β-arrestin pathway. CONCLUSIONS/SIGNIFICANCE: Our analysis reveals that the underlying conformations induced by these AT1R mutants most likely represent principally different mechanisms of uncoupling the G protein, which for some mutants may be due to their increased ability to recruit β-arrestin2. Hereby, these findings have important implications for drug discovery and 7TMR

  17. Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension.

    Science.gov (United States)

    Antunes, Tayze T; Callera, Glaucia E; He, Ying; Yogi, Alvaro; Ryazanov, Alexey G; Ryazanova, Lillia V; Zhai, Alexander; Stewart, Duncan J; Shrier, Alvin; Touyz, Rhian M

    2016-04-01

    Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg(2+))/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase-deficient mice (TRPM7Δkinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7Δkinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg(2+) was lower in TRPM7Δkinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7Δkinase versus WT groups (Phypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II-induced hypertension and associated vascular and target organ damage.

  18. G protein-independent effects of the Angiotensin II type I receptor

    DEFF Research Database (Denmark)

    Christensen, Gitte Lund

    2010-01-01

    SII Angiotensin II (SII Ang II). På baggrund af massespektrometrianalyse fremlægger vi data som giver ny indsigt i Angotensin II’s (Ang II) signaltransduktion og som samtidig viser forskellen mellem fuld AT1R aktivering med Ang II og G protein uafhængig aktivering med SII Ang II. Resultaterne viser...... kinase i den G protein uafhængige AT1R signalering. Vi har undersøgt genekspression på mRNA og microRNA niveau vha. microarray-teknologi. På trods af at vi ser en mangfoldig signaltransduktion initieret af SII Ang II, som også resulterer i fosforylering af nukleare proteiner, er SII Ang II ikke centralt...... involveret i regulering af genekspression. Alligevel observerer vi at SII Ang II markant potentierer Isoproterenol og den β-adrenerge receptors evne til at inducere transkription, hvilket kan tyde på at G protein uafhængig signalering har en modulatorisk rolle i regulering af genekspression. Studierne der...

  19. Role of mineralocorticoid receptor and renin-angiotensin-aldosterone system in adipocyte dysfunction and obesity.

    Science.gov (United States)

    Feraco, Alessandra; Armani, Andrea; Mammi, Caterina; Fabbri, Andrea; Rosano, Giuseppe M C; Caprio, Massimiliano

    2013-09-01

    The mineralocorticoid receptor (MR) classically mediates aldosterone effects on salt homeostasis and blood pressure regulation in epithelial target tissues. In recent years, functional MRs have been identified in non classical targets of aldosterone actions, in particular in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids in the control of adipogenesis, adipose expansion and its pro-inflammatory capacity. In this context, inappropriate MR activation has been demonstrated to be a causal factor in several pathologic conditions such as vascular inflammation, endothelial dysfunction, insulin resistance and obesity. The aim of this review is to summarize the latest developments in this rapidly developing field, and will focus on the role of MR and renin-angiotensin-aldosterone system (RAAS) as potential leading characters in the early steps of adipocyte dysfunction and obesity. Indeed modulation of MR activity in adipose tissue has promise as a novel therapeutic approach to treat obesity and its related metabolic complications. This article is part of a Special Issue entitled 'CSR 2013'. PMID:23454117

  20. 汉族人群中血管紧张素转换酶抑制剂所致咳嗽与血管紧张素转换酶基因及缓激肽β2受体基因多态性的关系%The Association between ACE Inhibitor (ACEI)-Induced Cough and the Polymorphism of Angiotensin Converting Enzyme (ACE) Gene and Bradykinin β2 Receptor(BDKRB2) Gene in Han Nationality

    Institute of Scientific and Technical Information of China (English)

    王刚; 杨军; 唐振旺; 宁国庆; 曹燕; 万娟

    2012-01-01

    Objective: To investigate the association between angiotensin converting enzyme inhibitor (ACEI)-induced cough and the polymorphism of angiotensin converting enzyme (ACE) gene and bradykinin ($2 receptor (BDKRB2) gene in Han nationality. Methods: Polymerase chain reaction (PCR) was used to examine ACE I/D and BDKRB2 CT polymorphism in 151 ACEI-induced cough subjects and 151 no cough subjects in Han population. And UV-method was used to detect the ACE activity. Results:ACE gene distribution in the cough group: type II was 47.0%, ID genotype was 42.4%, DD genotype was 10.6%; Non-cough group were 39.7%, 47.0%, 13.3% respectively, and there was statistically significant difference between the two groups(P 0.05); The level of ACE activity in the Cough group [(28.3 ± 10.1) U / L,] was significantly lower than non-cough group [(40.2 ± 9.4) U / L,(P <0.01).]. Conclusions: For han population, ACEI-induced cough related to ACE gene polymorphism and serum ACE activity, and there was no statistically significant association between BDKRB2 C / T and cough.%目的:探讨汉族人群中血管紧张素转换酶抑制剂(ACEI)所致咳嗽与血管紧张素转换酶(ACE)基因及缓激肽β2受体(BDKRB2)基因多态性的关系.方法:应用聚合酶链反应(PCR)方法,检测汉族人群中151例由于服用ACEI引起的咳嗽患者及151例未发生咳嗽的患者的ACEI/D及BDKRB2C/T的多态性,并采用紫外法检测ACE活性.结果:发现ACE基因分布在咳嗽组中Ⅱ型为47.0%,ID型为42.4%,DD型为10.6%;无咳嗽组分别为39.7%、47.0%、13.3%,两组相比其差异具有统计学意义(P<0.01);BDKRB2基因分布在咳嗽组中CC型为21.3%,CT型为50.0%,TT型为28.7%,无咳嗽组分别为22.5%、47.7%、29.8%,两组相比其差异无统计学意义(P>0.05);咳嗽组ACE活性水平为[(28.3±10.1)U/L]明显低于无咳嗽组[(40.2± 9.4)U/L],两组相比其差异具有统计学意义(P<0.01).结论:汉族人群中ACEI所致咳嗽

  1. Angiotensin II type 1 and 2 receptors and lymphatic vessels modulate lung remodeling and fibrosis in systemic sclerosis and idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Edwin Roger Parra

    2014-01-01

    Full Text Available OBJECTIVE: To validate the importance of the angiotensin II receptor isotypes and the lymphatic vessels in systemic sclerosis and idiopathic pulmonary fibrosis. METHODS: We examined angiotensin II type 1 and 2 receptors and lymphatic vessels in the pulmonary tissues obtained from open lung biopsies of 30 patients with systemic sclerosis and 28 patients with idiopathic pulmonary fibrosis. Their histologic patterns included cellular and fibrotic non-specific interstitial pneumonia for systemic sclerosis and usual interstitial pneumonia for idiopathic pulmonary fibrosis. We used immunohistochemistry and histomorphometry to evaluate the number of cells in the alveolar septae and the vessels stained by these markers. Survival curves were also used. RESULTS: We found a significantly increased percentage of septal and vessel cells immunostained for the angiotensin type 1 and 2 receptors in the systemic sclerosis and idiopathic pulmonary fibrosis patients compared with the controls. A similar percentage of angiotensin 2 receptor positive vessel cells was observed in fibrotic non-specific interstitial pneumonia and usual interstitial pneumonia. A significantly increased percentage of lymphatic vessels was present in the usual interstitial pneumonia group compared with the non-specific interstitial pneumonia and control groups. A Cox regression analysis showed a high risk of death for the patients with usual interstitial pneumonia and a high percentage of vessel cells immunostained for the angiotensin 2 receptor in the lymphatic vessels. CONCLUSION: We concluded that angiotensin II receptor expression in the lung parenchyma can potentially control organ remodeling and fibrosis, which suggests that strategies aimed at preventing high angiotensin 2 receptor expression may be used as potential therapeutic target in patients with pulmonary systemic sclerosis and idiopathic pulmonary fibrosis.

  2. Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma.

    Science.gov (United States)

    Zorad, Stefan; Dou, Jing-tao; Benicky, Julius; Hutanu, Daniel; Tybitanclova, Katarina; Zhou, Jin; Saavedra, Juan M

    2006-12-15

    To clarify the mechanism of the effects of angiotensin II AT(1) receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT(1) receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum leptin levels and epididymal leptin mRNA, increased serum adiponectin levels and epididymal adiponectin mRNA, decreased epididymal tumor necrosis factor alpha (TNFalpha) mRNA, and increased fatty acid synthase mRNA. Considered free of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist activity, Candesartan cilexetil increased epididymal expression of PPARgamma mRNA. The effects of Candesartan cilexetil on adipokine production and release may be attributable to PPARgamma activation and/or decrease in adipocyte cell size. In addition, Candesartan cilexetil treatment increased the expression of epididymal angiotensin II AT(2) receptor mRNA and protein and decreased the expression of renin receptor mRNA. These results suggest that Candesartan cilexetil influences lipid metabolism in adipose tissue by promoting adipose tissue rearrangement and modulating adipokine expression and release. These effects are probably consequences of local angiotensin II AT(1) receptor inhibition, angiotensin II AT(2) receptor stimulation, and perhaps additional angiotensin II-independent mechanisms. Our results indicate that the activity of local renin-angiotensin system plays an important role in adipose tissue metabolism. The decrease in the pro-inflammatory cytokine TNFalpha and the increase in the anti-inflammatory adipokine adiponectin indicate that Candesartan cilexetil may exert significant anti-inflammatory properties. PMID:17064684

  3. The effects of angiotensin II receptor antagonist (candesartan on rat renal vascular resistance

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    Supatraviwat, J

    2004-05-01

    Full Text Available The present study aimed to investigate the action of angiotensin II (AII on renal perfusion pressure and renal vascular resistance using noncompetitive AT1-receptor antagonist (candesartan or CV 11974. Experiments were performed in isolated kidney of adult male Wistar rats. Kreb's Henseleit solution was perfused into the renal artery at the rate of 3.5 ml/min. This flow rate was designed in order to maintain renal perfusion pressure between 80-120 mm Hg. Dose-response relationship between perfusion flow rate and AII concentration were studied. Renal perfusion pressure in response to 1, 10 and 100 nM AII were increased from basal perfusion pressure of 94±8 mm Hg to 127±6, 157±12 and 190±16 mm Hg, respectively. Administration of perfusate containing 11.4 μM candesartan for 30 min had no effect on the basal perfusion pressure. However, this significantly reduced renal perfusion pressure in the presence of AII (1, 10 and 100 nM by 39%, 47% and 61%, (n=7, P<0.05 respectively. At the basal perfusion pressure, calculated renal vascular resistance was 27±2 mm Hg · min · ml-1. However, the vascular resistance were found to be 41±1, 45±2 and 47±2 mm Hg · min · ml-1 when 1, 10 and 100 nM AII were added. Moreover, this dose of candesartan also showed a significant decrease in renal vascular resistance at the corresponding doses of AII by 38%, 48% and 43%, (n=7, P<0.05 respectively. The higher dose of candesartan (22.7 μM completely inhibited the action of 1, 10 and 100 nM AII on renal vasoconstriction. These results may indicate that the action of AII on renal vascular resistance is via AT1-receptor, at least in rat isolated perfusion kidney.

  4. Angiotensin AT2 receptor agonist prevents salt-sensitive hypertension in obese Zucker rats.

    Science.gov (United States)

    Ali, Quaisar; Patel, Sanket; Hussain, Tahir

    2015-06-15

    High-sodium intake is a risk factor for the pathogenesis of hypertension, especially in obesity. The present study is designed to investigate whether angiotensin type 2 receptor (AT2R) activation with selective agonist C21 prevents high-sodium diet (HSD)-induced hypertension in obese animals. Male obese rats were treated with AT2R agonist C21 (1 mg·kg(-1)·day(-1), oral) while maintained on either normal-sodium diet (NSD; 0.4%) or HSD (4%) for 2 wk. Radiotelemetric recording showed a time-dependent increase in systolic blood pressure in HSD-fed obese rats, being maximal increase (∼27 mmHg) at day 12 of the HSD regimen. C21 treatment completely prevented the increase in blood pressure of HSD-fed rats. Compared with NSD controls, HSD-fed obese rats had greater natriuresis/diuresis and urinary levels of nitrates, and these parameters were further increased by C21 treatment. Also, C21 treatment improved glomerular filtration rate in HSD-fed rats. HSD-fed rats expressed higher level of cortical ANG II, which was reduced to 50% by C21 treatment. HSD feeding and/or C21 treatment had no effects on cortical renin activity and the expression of angiotensin-converting enzyme (ACE) and chymase, which are ANG II-producing enzymes. However, ANG(1-7) concentration and ACE2 activity in the renal cortex were reduced by HSD feeding, and C21 treatment rescued both the parameters. Also, C21 treatment reduced the cortical expression of AT1R in HSD-fed rats, but had no effect of AT2R expression. We conclude that chronic treatment with the AT2R agonist C21 prevents salt-sensitive hypertension in obese rats, and a reduction in the renal ANG II/AT1R and enhanced ACE2/ANG(1-7) levels may play a potential role in this phenomenon. PMID:25855512

  5. The Functional Angiotensin Converting Enzyme Gene I/D Polymorphism Does not Alter Susceptibility to Chronic Pancreatitis

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    Whitcomb DC

    2004-11-01

    Full Text Available CONTEXT: Alterations of the renin-angiotensin system have been implicated in the pathogenesis of various diseases. The angiotensin converting enzyme is a key enzyme in the renin-angiotensin system. A deletion polymorphism of a 287-bp fragment of intron 16 of the angiotensin converting enzyme gene allele results in higher levels of circulating enzyme. ACE deletion genotype has been linked to heart diseases, sarcoidosis and liver fibrosis. The pancreatic renin-angiotensin system plays a role in the development of pancreatic fibrosis and ACE inhibitors decrease pancreatic fibrosis in experimental models. OBJECTIVES: We investigated the frequency of the ACE gene insertion/deletion polymorphism in chronic pancreatitis patients and controls. PATIENTS: Subjects with familial pancreatitis (n=51, sporadic chronic pancreatitis (n=104, and healthy controls (n=163 were evaluated. MAIN OUTCOME MEASURE: The presence of ACE insertion/deletion polymorphism. RESULTS: The frequency of the ACE gene deletion allele was similar in familial pancreatitis (49.0% sporadic pancreatitis (51.0% and controls (55.8%. Furthermore, there was no significant difference in clinical features between patients with ACE-insertion or insertion/deletion genotypes vs. patients with ACE-deletion genotype. CONCLUSION: We conclude that the ACE deletion genotype does not make a significant contribution to the pathogenesis and the progression of chronic pancreatitis.

  6. Nitric oxide impacts on angiotensin AT2 receptor modulation of high-pressure baroreflex control of renal sympathetic nerve activity in anaesthetized rats

    OpenAIRE

    Abdulla, M H; Johns, E. J.

    2013-01-01

    Aim Nitric oxide (NO) interacts with the local brain renin-angiotensin system to modulate sympathetic outflow and cardiovascular homoeostasis. This study investigated whether NO influenced the ability of angiotensin AT2 receptor activation to modify the high-pressure baroreceptor regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR). Methods Anaesthetized (chloralose/urethane) rats were prepared to allow generation of baroreflex gain curves for RSNA or HR following intrace...

  7. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: Effectiveness in combination with diuretics or β-blockers for treating hypertension

    Directory of Open Access Journals (Sweden)

    John D Bisognano

    2007-11-01

    Full Text Available John D Bisognano1, Trent McLaughlin2, Craig S Roberts3, Simon SK Tang31Internal Medicine Department, Cardiology Division, the University of Rochester Medical Center, Rochester, NY, USA; 2NDC Health, Phoenix, Arizona, USA; 3Pfizer Inc, New York, NY, USAAbstract: This retrospective database analysis compared the effectiveness of dihydropyridine calcium channel blockers (DHPs, angiotensin-converting enzyme (ACE inhibitors, and angiotensin receptor blockers (ARBs added to diuretics or β-blockers. Adults with hypertension treated with diuretic or β-blocker monotherapy between 1998 and 2001 were identified from a large US electronic medical records database of primary care practices. Patients were required to have a baseline blood pressure (BP ≥140/90 mmHg (≥130/80 mmHg for diabetes mellitus and recorded BP measurements within 6 months before and 1–12 months following index date. Patients were matched 1:1:1 by propensity score to correct for differences in baseline characteristics. 1875 patients met study criteria and 660 (220 in each cohort were matched based on propensity scores. Matched cohorts had no significant differences in baseline characteristics. Mean changes in systolic/diastolic BP were –17.5/–8.8, –15.7/–6.3, and –13.0/–8.0 mmHg with DHPs, ACE inhibitors, and ARBs, respectively. Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High BP 6/7 goal attainment for each regimen was 47.3%, 40.0%, and 32.2%, respectively. DHPs, ACE inhibitors, and ARBs improved BP when added to patients’ β-blocker or diuretic therapy. The greatest benefits were observed with DHPs, followed by ACE inhibitors, then ARBs.Keywords: hypertension, amlodipine besylate, lisinopril, valsartan, Joint National Committee (JNC 6 and 7

  8. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers on lymphangiogenesis of gastric cancer in a nude mouse model

    Institute of Scientific and Technical Information of China (English)

    WANG Liang; CAI Shi-rong; ZHANG Chang-hua; HE Yu-long; ZHAN Wen-hua; WU Hui; PENG Jian-jun

    2008-01-01

    Background Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) can inhibit tumor growth by inhibition of angiogenesis.This study was designed to study the anticancer effects of ACEI and ARB on tumor growth and lymphangiogenesis in an implanted gastric cancer mouse model.Methods A model of gastric cancer was established by subcutaneously inoculating human gastric cancer cell line SGC-7901 into 60 nude mice.One week later,all mice were randomly divided into 5 groups.A control group received physiologic saline once daily for 21 days.Mice in the 4 treatment groups received one of the following agents by gavage once daily for 21 days:perindopril,2 mg/kg;captopril,5 mg/kg;Iosartan,50 mg/kg;or valsartan,40 mg/kg.Twenty-one clays after treatment,all the mice were sacrificed and the tumors were removed.Tumor sections were processed,and immunohistochemical methods were used to observe the expressions of vascular endothelial growth factor C (VEGF-C),matrix metalloproteinase 7 (MMP-7),and lymphatic microvessel density (LMVD).Results Tumor volume was significantly inhibited in all ACEI and ARB groups,compared with the control group (all P <0.01).LMVD in the ACEI and ARB groups was also significantly lower than that of the control group (all P<0.01).In the ACEI groups,the expressions of VEGF-C and MMP-7 were both significantly decreased,compared with the control group (all P<0.05).In the ARB groups,expression of VEGF-C was significantly decreased compared with the control group (all P<0.05).However,no significant difference was found in the expression of MMP-7 between ARB groups and the control group.Conclusion In a mouse model,ACEI and ARB might inhibit gastric cancer tumor growth by suppressing lymphangiogenesis.

  9. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model.

    Science.gov (United States)

    Ongali, Brice; Nicolakakis, Nektaria; Tong, Xin-Kang; Aboulkassim, Tahar; Papadopoulos, Panayiota; Rosa-Neto, Pedro; Lecrux, Clotilde; Imboden, Hans; Hamel, Edith

    2014-08-01

    Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-β (Aβ) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aβ pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aβ species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors.

  10. Structure and Function of Cross-class Complexes of G Protein-coupled Secretin and Angiotensin 1a Receptors.

    Science.gov (United States)

    Harikumar, Kaleeckal G; Augustine, Mary Lou; Lee, Leo T O; Chow, Billy K C; Miller, Laurence J

    2016-08-12

    Complexes of secretin (SecR) and angiotensin 1a (Atr1a) receptors have been proposed to be functionally important in osmoregulation, providing an explanation for overlapping and interdependent functions of hormones that bind and activate different classes of GPCRs. However, the nature of these cross-class complexes has not been well characterized and their signaling properties have not been systematically explored. We now use competitive inhibition of receptor bioluminescence resonance energy transfer and bimolecular fluorescence complementation to establish the dominant functionally important state as a symmetrical homodimeric form of SecR decorated by monomeric Atr1a, interacting through lipid-exposed faces of Atr1a TM1 and TM4. Conditions increasing prevalence of this complex exhibited negative allosteric modulatory impact on secretin-stimulated cAMP responses at SecR. In contrast, activating Atr1a with full agonist in such a complex exhibited a positive allosteric modulatory impact on the same signaling event. This modulation was functionally biased, with secretin-stimulated calcium responses unaffected, whereas angiotensin-stimulated calcium responses through the complex were reduced or absent. Further supporting this interpretation, Atr1a with mutations of lipid-exposed faces of TM1 and TM4 that did not affect its ability to bind or signal, could be expressed in the same cell as SecR, yet not exhibit either the negative or positive allosteric impact on cAMP observed with the inactive or activated states of wild type Atr1a on function, and not interfere with angiotensin-stimulated calcium responses like complexes with Atr1a. This may provide a more selective means of exploring the physiologic functional impact of this cross-class receptor complex without interfering with the function of either component receptor. PMID:27330080

  11. Troglitazone stimulates {beta}-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1{sub A} receptor

    Energy Technology Data Exchange (ETDEWEB)

    Tilley, Douglas G., E-mail: douglas.tilley@jefferson.edu [Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University (United States); Center for Translational Medicine, Thomas Jefferson University (United States); Nguyen, Anny D. [Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University (United States); Rockman, Howard A. [Department of Medicine, Duke University Medical Center (United States); Department of Cell Biology, Duke University Medical Center (United States); Department of Molecular Genetics and Microbiology, Duke University Medical Center (United States)

    2010-06-11

    Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPAR{gamma}-independent signaling events. Select angiotensin receptor blockers (ARBs) interact with and modulate PPAR{gamma} activity, thus we hypothesized that a PPAR{gamma} agonist may exert physiologic effects via the angiotensin II type 1{sub A} receptor (AT1{sub A}R). In AT1{sub A}R-overexpressing HEK 293 cells, both angiotensin II (Ang II) and the PPAR{gamma} agonist troglitazone (Trog) enhanced AT1{sub A}R internalization and recruitment of endogenous {beta}-arrestin1/2 ({beta}arr1/2) to the AT1{sub A}R. A fluorescence assay to measure diacylglycerol (DAG) accumulation showed that although Ang II induced AT1{sub A}R-G{sub q} protein-mediated DAG accumulation, Trog had no impact on DAG generation. Trog-mediated recruitment of {beta}arr1/2 was selective to AT1{sub A}R as the response was prevented by an ARB- and Trog-mediated {beta}arr1/2 recruitment to {beta}1-adrenergic receptor ({beta}1AR) was not observed. In isolated mouse cardiomyocytes, Trog increased both % and rate of cell shortening to a similar extent as Ang II, effects which were blocked with an ARB. Additionally, these effects were found to be {beta}arr2-dependent, as cardiomyocytes isolated from {beta}arr2-KO mice showed blunted contractile responses to Trog. These findings show for the first time that the PPAR{gamma} agonist Trog acts at the AT1{sub A}R to simultaneously block G{sub q} protein activation and induce the recruitment of {beta}arr1/2, which leads to an increase in cardiomyocyte contractility.

  12. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study

    Science.gov (United States)

    Lapi, Francesco; Azoulay, Laurent; Yin, Hui; Nessim, Sharon J

    2013-01-01

    Objectives To assess whether a double therapy combination consisting of diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with addition of non-steroidal anti-inflammatory drugs (NSAIDs) and the triple therapy combination of two of the aforementioned antihypertensive drugs to which NSAIDs are added are associated with an increased risk of acute kidney injury. Design Retrospective cohort study using nested case-control analysis. Setting General practices contributing data to the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database. Participants A cohort of 487 372 users of antihypertensive drugs. Main outcome measures Rate ratios with 95% confidence intervals of acute kidney injury associated with current use of double and triple therapy combinations of antihypertensive drugs with NSAIDs. Results During a mean follow-up of 5.9 (SD 3.4) years, 2215 cases of acute kidney injury were identified (incidence rate 7/10 000 person years). Overall, current use of a double therapy combination containing either diuretics or angiotensin converting enzyme inhibitors or angiotensin receptor blockers with NSAIDs was not associated with an increased rate of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12 to 1.53). In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35 to 2.46). Conclusions A triple therapy combination consisting of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs was associated with an increased risk of acute kidney injury. The risk was greatest at the start of treatment. Although antihypertensive drugs have cardiovascular benefits, vigilance may be warranted when they are used concurrently with NSAIDs. PMID:23299844

  13. Modulation of Calcium Signaling of Angiotensin AT1, Endothelin ETA, and ETB Receptors by Silibinin, Quercetin, Crocin, Diallyl Sulfides, and Ginsenoside Rb1.

    Science.gov (United States)

    Bahem, Ruba; Hoffmann, Anja; Azonpi, Arnaud; Caballero-George, Catherina; Vanderheyden, Patrick

    2015-06-01

    Angiotensin II and endothelin-1 are potent vasoconstrictive peptides that play a central role in blood pressure regulation. Both peptides exert their pleiotropic effects via binding to their respective G-protein-coupled receptors, i.e., angiotensin AT1 and endothelin type A and type B receptors. In the present study, we have selected six structurally different plant-derived compounds with known cardioprotective properties to evaluate their ability to modulate calcium signaling of the above-mentioned receptors. For this purpose, we used and validated a cellular luminescence-based read-out system in which we measured intracellular calcium signaling in Chinese hamster ovary cells that express the calcium sensitive apo-aequorin protein. Firstly, silibinin, a flavanolignan that occurs in milk thistle (Silybum marianum), was investigated and found to be an antagonist for the human angiotensin AT1 receptor with an affinity constant of about 9 µM, while it had no effect on endothelin type A or type B receptor activation. Quercetin and crocin partially impeded intracellular calcium signaling resulting in a non-receptor-related reduction of the responses recorded for the three investigated G-protein-coupled receptors. Two organosulfur compounds, diallyl disulfide and diallyl trisulfide, as well as the triterpene saponin ginsenoside Rb1 did not affect the activation of the angiotensin AT1 and endothelin type A and type B receptors. In conclusion, we were able, by using a nonradioactive cellular read-out system, to identify a novel pharmacological property of the flavanolignan silibinin.

  14. Activation of ERK, JNK, Akt, and G-protein coupled signaling by hybrid angiotensin II AT1/bradykinin B2 receptors expressed in HEK-293 cells

    DEFF Research Database (Denmark)

    Yu, Jun; Lubinsky, David; Tsomaia, Natia;

    2007-01-01

    Bradykinin (BK) and angiotensin II (AngII) often have opposite roles in cardiovascular diseases. Our aim here was to construct hybrid receptors which bind AngII but signal as BK. Various sequences of the intracellular face of the AngII type I receptor, AT1R, were replaced with corresponding seque...

  15. The PGE(2)-EP4 receptor is necessary for stimulation of the renin-angiotensin-aldosterone system in response to low dietary salt intake in vivo

    DEFF Research Database (Denmark)

    Pöschke, Antje; Kern, Niklas; Maruyama, Takayuki;

    2012-01-01

    renal PGE(2) synthesis, which stimulates the renin-angiotensin-aldosterone system by activation of EP4 receptor. Most likely, defects at the step of EP4 receptor block negative feedback mechanisms on the renal COX system, leading to persistently high PGE(2) levels, diuresis, and K(+) loss....

  16. Angiotensin-converting enzyme gene I/D genotype affected metoprolol-induced reduction in 24-hour average heart rate

    Institute of Scientific and Technical Information of China (English)

    LIU Li-wei; LIU Hong; CHEN Guo-liang; HUANG Yi-ling; HAN Lu-lu; XU Zhi-min; JIANG Xiong-jing; LI Yi-shi

    2010-01-01

    Background Genetic factors can influence antihypertensive response to metoprolol, and many studies focused on the relationship between the genotype in β1-adrenergic receptor and blood pressure (BP), little was known about the association of angiotensin-converting enzyme (ACE) genotype with the therapeutic result of metoprolol. The present study aimed to investigate whether the ACE gene insertion (I) / deletion (D) polymorphism Is related to the response to metoprolol in Chinese Han hypertensive patients.Methods Ninety-six patients with essential hypertension received metoprolol (100 mg once daily) as monotherapy for 8 weeks. Twenty-four hours ambulatory blood pressure monitoring and dynamic electrocardiogram were performed before and after treatment. Genotyping analysis was performed using PCR. The association of the ACE gene I/D polymorphism with variations in BP and heart rate (HR) was observed after the 8-week treatment.Results The patients with ACE gene II polymorphism showed greater reduction in 24-hour average HR than those with ID or DD polymorphisms (P=0.045), no effect of this genotype on the reduction in seating HR or in BP was observed. After adjusting for age, gender, body mass index, BP and HR at baseline, the ACE gene I/D polymorphism was still an independent predictor for variations in 24-hour average HR.Conclusions The II polymorphism in ACE gene could be a candidate predictor for greater reduction in 24-hour average HR in Chinese Han hypertensive patients treated by metoprolol. Greater benefits would be obtained by patients with II polymorphism from the treatment with metoprolol. Larger studies are warranted to validate this finding.

  17. Role of angiotensin II and vasopressin receptors within the supraoptic nucleus in water and sodium intake induced by the injection of angiotensin II into the medial septal area

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    Antunes V.R.

    1998-01-01

    Full Text Available In this study we investigated the effects of the injection into the supraoptic nucleus (SON of non-peptide AT1- and AT2-angiotensin II (ANG II receptor antagonists, DuP753 and PD123319, as well as of the arginine-vasopressin (AVP receptor antagonist d(CH25-Tyr(Me-AVP, on water and 3% NaCl intake induced by the injection of ANG II into the medial septal area (MSA. The effects on water or 3% NaCl intake were assessed in 30-h water-deprived or in 20-h water-deprived furosemide-treated adult male rats, respectively. The drugs were injected in 0.5 ml over 30-60 s. Controls were injected with a similar volume of 0.15 M NaCl. Antagonists were injected at doses of 20, 80 and 180 nmol. Water and sodium intake was measured over a 2-h period. Previous administration of the AT1 receptor antagonist DuP753 into the SON decreased water (65%, N = 10, P<0.01 and sodium intake (81%, N = 8, P<0.01 induced by the injection of ANG II (10 nmol into the MSA. Neither of these responses was significantly changed by injection of the AT2-receptor antagonist PD123319 into the SON. On the other hand, while there was a decrease in water intake (45%, N = 9, P<0.01, ANG II-induced sodium intake was significantly increased (70%, N = 8, P<0.01 following injection of the V1-type vasopressin antagonist d(CH25-Tyr(Me-AVP into the SON. These results suggest that both AT1 and V1 receptors within the SON may be involved in water and sodium intake induced by the activation of ANG II receptors within the MSA. Furthermore, they do not support the involvement of MSA AT2 receptors in the mediation of these responses.

  18. Angiotensin AT(2 receptor contributes towards gender bias in weight gain.

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    Preethi Samuel

    Full Text Available Obesity is a major disease condition, in turn leading to pathological changes collectively recognized as metabolic syndrome. Recently angiotensin receptor AT(2R has been associated negatively with body weight (BW gain in male mice. However, the gender differences in AT(2R and BW changes have not been studied. To understand the gender based role of AT(2R involving BW changes, we fed male and female wild type (WT and AT(2R knock out (AT(2KO mice with C57BL6 background with high fat diet (HFD for 16 weeks. The male AT(2KO had higher HFD calorie intake (WT: 1280±80; AT(2KO:1680±80 kcal but gained less BW compared with the WT (WT: 13; AT(2KO: 6 g. Contrary to the male animals, the female AT(2KO mice with equivalent caloric intake (WT: 1424±48; AT(2KO:1456±80 kcal gained significantly more BW than the WT mice (WT: 9 g; AT(2KO: 15 g. The male AT(2KO on HFD displayed lower plasma insulin level, less impaired glucose tolerance (GT, and higher plasma T3 compared with WT males on HFD; whereas the female AT(2KO mice on HFD showed elevated levels of plasma insulin, more impaired GT, lower plasma T3 and higher free fatty acid and hepatic triglycerides compared with WT females on HFD. Interestingly, compared with WT, AT(2KO female mice had significantly lower estrogen, which was further reduced by HFD. These results suggest that AT(2R in female mice via potentially regulating estrogen may have protective role against BW gain and impaired glucose tolerance and lipid metabolism.

  19. Angiotensin-receptor blockers as therapy for mildto- moderate hypertension-associated non-alcoholic steatohepatitis

    Institute of Scientific and Technical Information of China (English)

    Eugen Florin Georgescu; Reanina Ionescu; Mihaela Niculescu; Laurentiu Mogoanta; Liliana Vancica

    2009-01-01

    AIM: To evaluate insulin resistance, cytolysis and nonalcoholic steatohepatitis (NASH) score (NAS) using the Kleiner and Brunt criteria in 54 patients with NASH and mild-to-moderate hypertension, treated with telmisartan vs valsartan for 20 mo. METHODS: All patients met the NCEP-ATP Ⅲ criteria for metabolic syndrome. Histology confirmed steatohepatitis, defined as a NAS greater than five up to 3 wk prior inclusion, using the current criteria. Patients with viral hepatitis, chronic alcohol intake, drug abuse or other significant immune or metabolic hepatic pathology were excluded. Subjects were randomly as -signed either to the valsartan (V) group (standard dose 80 mg o.d., n = 26), or to the telmisartan (T) group (standard dose 20 mg o.d., n = 28). Treatment had to be taken daily at the same hour with no concomitant medication or alcohol consumption allowed. Neither the patient nor the medical staff was aware of treatment group allocation. Paired liver biopsies obtained at inclusion (visit 1) and end of treatment (EOT) were assessed by a single blinded pathologist, not aware of patient or treatment group. Blood pressure, BMI, ALT, AST, HOMA-IR, plasma triglycerides (TG) and total cholesterol (TC) were evaluated at inclusion and every 4 mo until EOT (visit 6). RESULTS: At EOT we noticed a significant decrease in ALT levels vs inclusion in all patients and this decrease did not differ significantly in group T vs group V. HOMA-IR significantly decreased at EOT vs inclusion in all patients but in group T, the mean HOMA-IR decrease per month was higher than in group V. NAS significantly diminished at EOT in all patients with a higher decrease in group T vs group V. CONCLUSION: Angiotensin receptor blockers seem to be efficient in hypertension-associated NASH. Telmisartan showed a higher efficacy regarding insulin resistance and histology, perhaps because of its specific PPAR-gamma ligand effect.

  20. Combined effects of ramipril and angiotensinreceptor blocker TCV116 on rat congestive heart failure after myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    TAO Ze-wei; HUANG Yuan-wei; XIA Qiang; XU Qi-wen

    2005-01-01

    Background Congestive heart failure (CHF) is a major cause of morbidity and mortality worldwide and angiotensin converting-enzyme inhibitor (ACEI) is the cornerstone in its treatment. However, CHF continues to progress despite this therapy, perhaps because of production of angiotensin Ⅱ (Ang Ⅱ) by alternative pathways. The present study was conducted to examine the combined effects of a chronic ACEI, ramipril, and a chronic Ang Ⅱ type 1 receptor blocker, TCV116, on rat CHF after myocardial infarction (MI). Methods Congestive heart failure was caused by MI in rats, which was induced by ligating the left anterior descending coronary artery. The experiment protocol included sham-operated rats (Sham), MI-control rats (MI-control), MI rats treated with ramipril 3 mg/kg (MI-ramipril) or TCV116 2 mg/kg (MI-TCV116) per day, half dosage (MI-1/2R&T) or full dosage (MI-R&T) combination of the two. At 22 weeks, cardiac hemodynamic parameters such as mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), maximal rate of left ventricule pressure development and decline (LV dP/dtmax) and left ventricular end diastolic pressure (LVEDP), and cardiac morphometric parameters such as heart weight (HW), left ventricular weight (LVW) and left ventricular cavity area (LVCA) were measured, mRNA expressions of cardiac molecule genes such as β myosin heavy chain (βMHC), B-type natriuretic peptide (BNP), transforming growth factor-β1 (TGF-β1), collagen I and Ⅲ were quantified with reverse transcription polymerase chain reaction (RT-PCR) in the surviving septum myocardium, and survival rates were calculated. Results There were no significant differences in MI sizes (%) among each MI related experimental groups (33±13, 34±14, 33±13, 35±13 and 33±14 for MI-control, MI-ramipril, MI-TCV116, MI-1/2R&T and MI-R&T, respectively, no statistical significance for all). Compared with sham-operated rats, MI rats without therapy showed significant increases in

  1. 瘦素受体外显子突变与ACE基因联合作用对肥胖儿童血脂的影响%Combined effects of variation of exon of leptin receptor and the angiotensin-converting enzyme gene on blood lipid of obese children

    Institute of Scientific and Technical Information of China (English)

    郎琼; 刘长云; 朱海玲; 陈雪; 李梅

    2012-01-01

    Objective To investigate the combined effects of variation of exon of leptin receptor (LEPR) and the angiotensin-converting enzyme (ACE) gene on blood lipid of obese children. Methods A total of 116 obese children and 78 healthy children were recruited. Blood was drawn after fasting over 12 hours. The variation of the exon 20 of LEPR and ACE gene w-crc analyzed by polymerase chain reation-rcstneted fragments length polymorphism (PCR-RFLP) and polyacry-lamide gel clectrophoresis. The blood lipid, height and weight were measured. Results The cion 20 of LEPR gene had three genotypes, A/A, C/A, and G/C. Compared with healthy group, the frequency of the gene variation at 3057 nudeotide C→A transversion was higher in obese group. ACE gene had three genotype, DD, DI and II. Compared with healthy group, the frequency of D allele of ACE gene was higher in obese group. The variation of both exon 20 of LEPR and ACE had effect on the lipid metabolism, and had synergies. The obese children with LEPR A/A genotype and carrying I) allele are more susceptible to abnormal lipid metabolism. Conclusions The frequency of the gene variation at 3057 nudeotide G→A transversion, and the D allele of the ACE gene were higher in obese children than those in healthy children. The variation of both genes had combined effects on the lipid metabolism.%目的 探讨瘦素受体(LEPR)外显子突变与血管紧张素转换酶(ACE)基因(I/D)多态性联合作用对肥胖儿童血脂的影响.方法 选择肥胖儿童116例(肥胖组)和非肥胖的健康儿童78例(健康组)为研究对象.空腹12 h后抽取静脉血.用聚合酶链反应-限制性片段多态性(PCR-RFLP)方法及聚丙烯凝胶电泳分析瘦素受体第20外显子的基因频率及其突变频率,对ACE基因型进行分析.测定血清总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)的水平.于相同条件下测身高、体质量,计算BMI

  2. Quinoxaline N-oxide containing potent angiotensin II receptor antagonists: synthesis, biological properties, and structure-activity relationships.

    Science.gov (United States)

    Kim, K S; Qian, L; Bird, J E; Dickinson, K E; Moreland, S; Schaeffer, T R; Waldron, T L; Delaney, C L; Weller, H N; Miller, A V

    1993-08-01

    A series of novel quinoxaline heterocycle containing angiotensin II receptor antagonist analogs were prepared. This heterocycle was coupled to the biphenyl moiety via an oxygen atom linker instead of a carbon atom. Many of these analogs exhibit very potent activity and long duration of effect. Interestingly, the N-oxide quinoxaline analog was more potent than the nonoxidized quinoxaline as in the comparison of compounds 5 vs 30. In order to improve oral activity, the carboxylic acid function of these compounds was converted to the double ester. This change did result in an improvement in oral activity as represented by compound 44.

  3. Expression of Astrocytic Type 2 Angiotensin Receptor in Central Nervous System Inflammation Correlates With Blood-Brain Barrier Breakdown

    DEFF Research Database (Denmark)

    Füchtbauer, Laila; Toft-Hansen, Henrik; Khorooshi, Reza;

    2010-01-01

    is involved during BBB breakdown. We studied the type 2 angiotensin receptor AT(2) because of its suggested neuroprotective role. Two models of brain inflammation were used to distinguish solute versus cellular barrier functions. Both leukocytes and horseradish peroxidase (HRP) accumulated in the perivascular...... space of transgenic mice expressing the chemokine CCL2 in the CNS, indicating selective endothelial effects. Cellular infiltration and HRP leakage across the glia limitans to the parenchyma were induced by pertussis toxin (PTx) treatment. By contrast, there was no detectable HRP leakage...

  4. Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance.

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    Motoharu Hayashi

    Full Text Available A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1, tumor necrosis factor-α, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1 and glucose transporter 4 (GLUT4 in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress-induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results

  5. Angiotensin Ⅱ type 2 receptor gene mediated by the tetracycline-regulatable system inhibits neointimal hyperplasia in rat carotid arteries after balloon angioplasty%血管紧张素Ⅱ2型受体在体可调控表达对大鼠颈动脉新生内膜增生的影响

    Institute of Scientific and Technical Information of China (English)

    苗莉; 罗先润; 景涛; 张辉; 刘安丰; 娄云霄; 何国祥

    2011-01-01

    Objective Transducing the angiotensin Ⅱ type 2 receptor (AT2R) gene into rat balloon injury carotid arteries can attenuate neointimal hyperplasia, but how to regulate the expression of the AT2.R gene according to our need is very important in utilizing transgenie technology. The purpose of the current study is to investigate the effects of the AT2R gene medicated by the tetracy-cline regulatable system on neointimal hyperplasia in rat carotid arteries after balloon angioplasty. Methods After establishment of the rat model of carotid balloon injury restenosis, we locally perfused into the rat carotid arteries PBS (the control group), mesenchy-mal stem cells (the MSC group) or MSC/AT2R (the MSC/AT2R group) with AT2R medicated by the tetracycline regulatable system, the latter again subdivided into a doxycycline administration (Dox) and non-doxycycline Dox administration (non-Dox) group. At 14 and 28 days after the operation, we evaluated the expression of AT2R by immunohistochemistry and RT-PCR and measured the neointi-ma/media (I/M) area ratio was by morphometric analysis. Results In the MSC/AT2R + Dox group, the expressions of AT2R mRNA and protein in the neointima were significantly up-regulated from day 14 to 28 after injury (P <0.01), and the I/M ratio significantly reduced (P<0.01). The transplanted MSC showed no obvious effect on the neointimal hyperplasia. Conclusion The expression of the AT2R gene can be regulated efficiently in vivo by local delivery of MSC with dual-stable expression of the AT2R gene, and thus inhibit neointimal hyperplasia.%目的 血管紧张素Ⅱ2型受体(angiotensinⅡtype 2 receptor,AT2R)基因转染可减轻血管损伤后新生内膜的过度增生,但如何主动调控转入体内基因的表达有着重要的临床意义.文中以四环素可调控系统下的AT2R基因转染的骨髓间充质干细胞(mesenchymal stem cell,MSC)为载体,探讨AT2R在体可调控表达及对大鼠颈动脉新生内膜的影响.方法 大鼠

  6. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist

    NARCIS (Netherlands)

    Woesten-van Asperen, Roelie M.; Lutter, Rene; Specht, Patricia A.; Moll, Gert N.; van Woensel, Job B.; van der Loos, Chris M.; van Goor, Harry; Kamilic, Jelena; Florquin, Sandrine; Bos, Albert P.

    2011-01-01

    Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome. Angiotensin-converting enzyme (ACE) and its effector peptide angiotensin (Ang) II have been implicated in the pathogenesis of ARDS. A counter-regulatory enzyme of ACE, ie ACE2 that degrades Ang II to Ang-(1-7), offers a p

  7. IMPACT OF ANGIOTENSIN-CONVERTING ENZYME GENE POLYMORPHISM ON THE DEVELOPMENT OF INSULIN RESISTANCE SYNDROME

    Directory of Open Access Journals (Sweden)

    G. E. Roitberg

    2013-01-01

    Full Text Available Objective: to analyze the distribution of components of insulin resistance (IR syndrome and to study the frequency of their combinations in relation to the genotypes and allelic variants of the angiotensin-converting enzyme (ACE gene.Subjects and methods. A group of clinically healthy patients (50 women and 42 men with different genotypes of the ACE gene was examined.The distribution of IR syndrome components and the frequency of their combinations were analyzed in relation to the genotypes and allelicvariants of the ACE gene.Results. A group of D allele carriers compared to A allele ones showed a pronounced tendency for the frequency of IR to reduce due to thehigher proportion of patients with complete IR syndrome. This observation becomes statistically significant in the assessment of homozygous variants of the ACE gene. At the same time dyslipidemia and hypertension in the presence of IR significantly more frequently occurred in patients with the DD genotype than in those with genotype II.Conclusion. There was a marked predominance of the manifestations of IR syndrome with a complete set of components in the DD genotypicgroup, which confirms the significant strong association between ACE gene polymorphism and IR syndrome.

  8. Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice.

    Science.gov (United States)

    de Kloet, Annette D; Pitra, Soledad; Wang, Lei; Hiller, Helmut; Pioquinto, David J; Smith, Justin A; Sumners, Colin; Stern, Javier E; Krause, Eric G

    2016-08-01

    It is known that angiotensin-II acts at its type-1 receptor to stimulate vasopressin (AVP) secretion, which may contribute to angiotensin-II-induced hypertension. Less well known is the impact of angiotensin type-2 receptor (AT2R) activation on these processes. Studies conducted in a transgenic AT2R enhanced green fluorescent protein reporter mouse revealed that although AT2R are not themselves localized to AVP neurons within the paraventricular nucleus of the hypothalamus (PVN), they are localized to neurons that extend processes into the PVN. In the present set of studies, we set out to characterize the origin, phenotype, and function of nerve terminals within the PVN that arise from AT2R-enhanced green fluorescent protein-positive neurons and synapse onto AVP neurons. Initial experiments combined genetic and neuroanatomical techniques to determine that γ-aminobutyric acid (GABA)ergic neurons derived from the peri-PVN area containing AT2R make appositions onto AVP neurons within the PVN, thereby positioning AT2R to negatively regulate neuroendocrine secretion. Subsequent patch-clamp electrophysiological experiments revealed that selective activation of AT2R in the peri-PVN area using compound 21 facilitates inhibitory (ie, GABAergic) neurotransmission and leads to reduced activity of AVP neurons within the PVN. Final experiments determined the functional impact of AT2R activation by testing the effects of compound 21 on plasma AVP levels. Collectively, these experiments revealed that AT2R expressing neurons make GABAergic synapses onto AVP neurons that inhibit AVP neuronal activity and suppress baseline systemic AVP levels. These findings have direct implications in the targeting of AT2R for disorders of AVP secretion and also for the alleviation of high blood pressure. PMID:27267713

  9. The angiotensin-converting enzyme (ACE gene family of Anopheles gambiae

    Directory of Open Access Journals (Sweden)

    Isaac R Elwyn

    2005-12-01

    Full Text Available Abstract Background Members of the M2 family of peptidases, related to mammalian angiotensin converting enzyme (ACE, play important roles in regulating a number of physiological processes. As more invertebrate genomes are sequenced, there is increasing evidence of a variety of M2 peptidase genes, even within a single species. The function of these ACE-like proteins is largely unknown. Sequencing of the A. gambiae genome has revealed a number of ACE-like genes but probable errors in the Ensembl annotation have left the number of ACE-like genes, and their structure, unclear. Results TBLASTN and sequence analysis of cDNAs revealed that the A. gambiae genome contains nine genes (AnoACE genes which code for proteins with similarity to mammalian ACE. Eight of these genes code for putative single domain enzymes similar to other insect ACEs described so far. AnoACE9, however, has several features in common with mammalian somatic ACE such as a two domain structure and a hydrophobic C terminus. Four of the AnoACE genes (2, 3, 7 and 9 were shown to be expressed at a variety of developmental stages. Expression of AnoACE3, AnoACE7 and AnoACE9 is induced by a blood meal, with AnoACE7 showing the largest (approximately 10-fold induction. Conclusion Genes coding for two-domain ACEs have arisen several times during the course of evolution suggesting a common selective advantage to having an ACE with two active-sites in tandem in a single protein. AnoACE7 belongs to a sub-group of insect ACEs which are likely to be membrane-bound and which have an unusual, conserved gene structure.

  10. RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes

    Science.gov (United States)

    Benter, Ibrahim F.; Babiker, Fawzi; Al-Rashdan, Ibrahim; Yousif, Mariam; Akhtar, Saghir

    2013-01-01

    Aims. We evaluated the effects of RU28318 (RU), a selective mineralocorticoid receptor (MR) antagonist, Captopril (Capt), an angiotensin converting enzyme inhibitor, and Losartan (Los), an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R-) induced cardiac dysfunction in hearts obtained from normal and diabetic rats. Methods. Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I) followed by a period of 30 min of reperfusion (R). Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple). Recovery of cardiac hemodynamics was evaluated. Results. Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. Conclusions. RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving −dP/dt (a measure of diastolic function) when administered to diabetic hearts after ischemia. PMID:24066305

  11. Dosage of angiotensin-II receptor blockers in heart failure patients following changes in Danish drug reimbursement policies

    DEFF Research Database (Denmark)

    Selmer, Christian; Lamberts, Morten; Kristensen, Søren Lund;

    2014-01-01

    PURPOSE: National reimbursement policies in Denmark were changed in November 2010 favouring a shift in angiotensin-II receptor blocker (ARB) treatment to generic losartan for heart failure (HF) patients. We examined how changes in reimbursement policies affected the fraction of HF patients up-tit......), compared with May-Jul 2010 (reference). CONCLUSION: Probability of being up-titrated in ARB treatment was reduced 20% following changes in drug reimbursement policies.......PURPOSE: National reimbursement policies in Denmark were changed in November 2010 favouring a shift in angiotensin-II receptor blocker (ARB) treatment to generic losartan for heart failure (HF) patients. We examined how changes in reimbursement policies affected the fraction of HF patients up....... Individual-level linkage of nationwide registries of hospitalization and drug dispensing in Denmark was used to describe patterns of ARB prescriptions and estimate dosage before and after November 2010. Logistic regression models were used to assess the probability for being up-titrated in the period...

  12. RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes

    Directory of Open Access Journals (Sweden)

    Ibrahim F. Benter

    2013-01-01

    Full Text Available Aims. We evaluated the effects of RU28318 (RU, a selective mineralocorticoid receptor (MR antagonist, Captopril (Capt, an angiotensin converting enzyme inhibitor, and Losartan (Los, an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R- induced cardiac dysfunction in hearts obtained from normal and diabetic rats. Methods. Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I followed by a period of 30 min of reperfusion (R. Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple. Recovery of cardiac hemodynamics was evaluated. Results. Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. Conclusions. RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving -dP/dt (a measure of diastolic function when administered to diabetic hearts after ischemia.

  13. Disposition and metabolism of [(14)C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects.

    Science.gov (United States)

    Flarakos, Jimmy; Du, Yancy; Bedman, Timothy; Al-Share, Qusai; Jordaan, Pierre; Chandra, Priya; Albrecht, Diego; Wang, Lai; Gu, Helen; Einolf, Heidi J; Huskey, Su-Er; Mangold, James B

    2016-11-01

    1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor. 2. Following oral administration, [(14)C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5-1 h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ∼1.3, ∼12 and ∼21 h, respectively. 3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7-67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and feces, total accounting for ∼85.5% of the total dose. 4. Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions clinically was found to be low. PMID:26931777

  14. Effects of Hyperglycemia on Angiotensin II Receptor Type 1 Expression and Insulin Secretion in an INS-1E Pancreatic Beta-Cell Line

    Directory of Open Access Journals (Sweden)

    Kwan Keung Leung

    2008-05-01

    Full Text Available Context A local pancreatic islet renin-angiotensin system has been identified and found to be upregulated in type 2 diabetes mellitus. Inhibition of this system improves beta-cell function and structure. The effects of hyperglycemia, a condition observed in diabetes, on angiotensin II type 1 receptor (AT1R expression and beta-cell secretory function have yet to be explored. Objective This study investigated the effects of chronic hyperglycemia (glucotoxicity on the expression of AT1Rs, and possibly thereby on oxidative stress-induced insulin release, in an INS-1E beta-cell line. Settings INS-1E beta-cells cultured and incubated in different glucose concentrations with a varying time course. Main outcome measures Immunocytochemistry was employed for the precise localization of AT1Rs in INS-1E cells. The effects of hyperglycemia-induced AT1R expression changes in gene and protein levels were examined by real-time RT-PCR and Western blot analysis, respectively. AT1R activation-mediated oxidative stress was assessed by changes in NADPH oxidase expression, and the level of superoxide production was determined by nitroblue tetrazolium (NBT assay. Glucotoxicity-induced AT1R activation- mediated secretory dysfunction was also assessed by insulin release from INS-1E cells Results AT1R immunoreactivity was found to be localized specifically on the cell membrane. Chronic hyperglycemia resulted in dose-dependent upregulation of AT1R gene and protein expression accompanied by concomitantly-enhanced oxidative stress. Glucose-stimulated insulin secretion via AT1R activation was impaired by hyperglycemia. Conclusion These data indicate that hyperglycemia-induced AT1R activation impairs insulin secretion; this impairment may be mediated via AT1R-dependent oxidative stress.

  15. New Aspects of Ace Inhibition: Importance of ACE co-localization with angiotensin and bradykinin receptors

    NARCIS (Netherlands)

    B. Tom (Beril)

    2003-01-01

    textabstractThe beneficial effect of angiotensin-converting enzyme (ACE) inhibitors in hypertension and heart failure may relate, at least in part, to their capacity to interfere with bradykinin metabolism. In addition, recent studies have provided evidence for bradykinin-potentiating effects of ACE

  16. Antihypertensive, insulin-sensitising and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models.

    Science.gov (United States)

    Kusumoto, Keiji; Igata, Hideki; Ojima, Mami; Tsuboi, Ayako; Imanishi, Mitsuaki; Yamaguchi, Fuminari; Sakamoto, Hiroki; Kuroita, Takanobu; Kawaguchi, Naohiro; Nishigaki, Nobuhiro; Nagaya, Hideaki

    2011-11-01

    The pharmacological profile of a novel angiotensin II type 1 receptor blocker, azilsartan medoxomil, was compared with that of the potent angiotensin II receptor blocker olmesartan medoxomil. Azilsartan, the active metabolite of azilsartan medoxomil, inhibited the binding of [(125)I]-Sar(1)-I1e(8)-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24h. ID(50) values were 0.12 and 0.55 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In conscious spontaneously hypertensive rats (SHRs), oral administration of 0.1-1mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24h after dosing. Oral administration of 0.1-3mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24h after dosing. ED(25) values were 0.41 and 1.3mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1-1mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3-3mg/kg olmesartan medoxomil. In a 2-week study in SHRs, azilsartan medoxomil showed more stable antihypertensive effects than olmesartan medoxomil and improved the glucose infusion rate, an indicator of insulin sensitivity, more potently (≥ 10 times) than olmesartan medoxomil. Azilsartan medoxomil also exerted more potent antiproteinuric effects than olmesartan medoxomil in Wistar fatty rats. These results suggest that azilsartan medoxomil is a potent angiotensin II receptor blocker that has an attractive pharmacological profile as an antihypertensive agent.

  17. Association of Angiotensin Converting Enzyme Gene I/D Polymorphism With Type 2 Diabetes Mellitus

    Institute of Scientific and Technical Information of China (English)

    MIN YANG; CHANG-CHUN QIU; QUN XU; HONG-DING XIANG

    2006-01-01

    To investigate the association of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D)polymorphism with type 2 diabetes mellitus (T2DM). Methods Two hundred and nine patients with T2DM diagnosed based on the criteria for diabetes mellitus in 1999 by WHO and 221 controls were recruited from general population of Dongcheng District in Beijing. All subjects were genotyped for the I/D polymorphism of ACE gene by PCR-fragment length polymorphism (FLP) assay. Blood pressure, levels of plasma glucose, lipids and serum insulin were determined. Body mass index (BMI),waist-hip ratio (WHR) and homeostasis model assessment-insulin resistance index (HOMA-IR) were calculated. Results The genotype frequencies for ACE genes DD, ID, and Ⅱ were 19.1%, 42.1%, and 38.8% in patients, respectively, and 9.6%,49.4%, and 41.0% in controls, respectively. The ACE DD genotype frequency was significantly higher in patients than in controls (χ2=7.61, P=0.022). Multivariate logistic regression analysis showed that the ACE DD genotype was a risk factor for T2DM, with the OR of 2.35 (95% CI 1.17-4.71) adjusted for age, sex, BMI, WHR, blood pressure, and serum cholesterol levels.Conclusion The ACE DD genotype is associated with the increased susceptibility to type 2 diabetes mellitus.

  18. Insertion/deletion polymorphism of the angiotensin-converting enzyme gene and the risk of hypertension among residents of two cities, South-South Nigeria

    Directory of Open Access Journals (Sweden)

    Mary Esien Kooffreh

    2014-01-01

    Conclusion: The I/D polymorphism of the angiotensin-converting enzyme gene was a risk factor for hypertension in the sample population of Calabar and Uyo. This research will form baseline information for subsequent molecular studies in this population.

  19. Modulation of the delayed rectifier K+ current in neurons by an angiotensin II type 2 receptor fragment.

    Science.gov (United States)

    Kang, J; Richards, E M; Posner, P; Sumners, C

    1995-01-01

    Angiotensin II (ANG II) stimulates the delayed rectifier K+ current (IK) in neurons cultured from rat hypothalamus and brain stem via AT2 receptors, and this effect involves activation of a Gi protein and protein phosphatase 2A (PP2A). However, there was no evidence that the AT2 receptor involved in this response was the same as the recently cloned AT2 receptor. In the present study, intracellular injection of a 22-amino acid peptide (PEP-22) corresponding to the putative third intracellular loop of the cloned AT2 receptor elicited an increase in IK in cultured neurons that was similar to the effect produced by ANG II. Furthermore, this effect of PEP-22 was abolished by pertussis toxin (200 ng/ml, 24 h) pretreatment and also by superfusion of the PP2A inhibitor okadaic acid (10 nM), suggesting the involvement of Gi protein and PP2A, respectively. Intracellular injection of a random peptide or normal pipette solution did not affect neuronal IK. This is direct evidence to link the cloned AT2 receptor to a defined response elicited by ANG II.

  20. An initial reduction in serum uric acid during angiotensin receptor blocker treatment is associated with cardiovascular protection : a post-hoc analysis of the RENAAL and IDNT trials

    NARCIS (Netherlands)

    Smink, Paul A.; Bakker, Stephan J. L.; Laverman, Gozewijn D.; Berl, Tomas; Cooper, Mark E.; de Zeeuw, Dick; Lambers Heerspink, Hiddo J.

    2012-01-01

    Objective: Increased levels of serum uric acid (SUA) are thought to be an independent risk marker for cardiovascular complications. Treatment with the angiotensin receptor blocker (ARB) losartan lowers SUA in contrast to other ARBs. Whether reductions in SUA during ARB therapy are associated with ca

  1. Specific single chain variable fragment (ScFv) antibodies to angiotensin II AT(2) receptor: evaluation of the angiotensin II receptor expression in normal and tumor-bearing mouse lung.

    Science.gov (United States)

    Tamura, Masaaki; Yan, Heping; Zegarra-Moro, Ofelia; Edl, Jennifer; Oursler, Stephanie; Chard-Bergstrom, Cindy; Andrews, Gordon; Kanehira, Tsutomu; Takekoshi, Susumu; Mernaugh, Ray

    2008-08-01

    To gain insight into the mechanism by which angiotensin II type 2 receptor (AT(2)) regulates carcinogen-induced lung tumorigenesis, we have newly developed anti-AT(2) single chain variable fragment (ScFv) antibodies using a rodent phage-displayed recombinant antibody library with various peptide fragments of the receptor protein, and investigated the expression of the AT(2) receptor protein. The specificity of the antibodies was verified using AT(2) over-expressing COS-7 cells and AT(2) naturally expressing PC12W cells. In control wild type mouse lung, a stronger immunoreactivity was observed in bronchial epithelial cells. A moderate immunoreactivity was detected in pulmonary vascular walls and vascular endothelial cells. In the lungs possessing tobacco-specific nitrosamine (NNK)-induced tumors, significantly increased AT(2) and AT(1 )immunostaining was observed in adenomatous lesions. These data suggest that the increase in both receptors' expression in the alveolar epithelial cells may be accompanied with the onset of NNK-induced tumorigenesis and hence play important roles in lung tumorigenesis.

  2. Effect of angiotensin Ⅱ type 1 receptor on delayed rectifier potassium current in catecholaminergic CATH.a cells

    Institute of Scientific and Technical Information of China (English)

    Jian-qing DU; Cheng-wen SUN; Jing-shi TANG

    2004-01-01

    AIM: To study the modulatory effects of angiotensin Ⅱ (Ang Ⅱ) on the delayed rectifier potassium (Kv) current(IKv) and its underlying intracellular mechanism in the catecholaminergic system of rats. METHODS: AT1 and AT2receptors of the differentiated and undifferentiated CATH.a cells were determined by radioligands binding assay.The IKv was recorded with the whole cell patch-clamp configuration in voltage clamp mode on CATH.a cells.RESULTS: The Ang Ⅱ receptor proteins including AT1 and AT2 receptors were expressed in CATH.a cells, and the number of the former was significantly more than the latter (P<0.01). The IKv of CATH.a cells was reduced by superfusion with the Ang Ⅱ (100 nmol/L) (P<0.05) in the presence of the AT2 receptor antagonist PD123319, but was not affected by only superfusion with PD123319. The effect of Ang Ⅱ on IKv in CATH.a cells was completely inhibited by addition of AT1 receptor antagonist losartan. Superfusion with Ang Ⅱ (100 nmol/L) plus U73122, an inhibitor of phospholipase C (PLC) in the presence of PD 123319 had no effect on the IKv [(20.2+2.8) pA/pF]. AngⅡ-induced reduction of IKv was attenuated (P<0.05) but not abolished by PKC inhibitor calphostin C (Cal) and selective CaMK Ⅱ inhibitor KN-93 (10 μmol/L) respectively. However, IKv reduction was completely abolished by superfusion with both Cal and KN-93. CONCLUSION: The inhibition of Kv currents in CATH.a cells by Ang Ⅱ is mediated by AT1 receptor, and the PLC, PKC and CaMK Ⅱ may be involved in signal transduction of AT1 receptor.The differentiated CATH.a cell is a useful cell model to study Ang Ⅱ receptor-mediated functional modulation of catecholaminergic system.

  3. Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.

    Science.gov (United States)

    Kozako, Tomohiro; Soeda, Shuhei; Yoshimitsu, Makoto; Arima, Naomichi; Kuroki, Ayako; Hirata, Shinya; Tanaka, Hiroaki; Imakyure, Osamu; Tone, Nanako; Honda, Shin-Ichiro; Soeda, Shinji

    2016-05-01

    Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients. PMID:27419050

  4. Polymorphisms of renin-angiotensin-aldosterone system gene in chinese han patients with nonfamilial atrial fibrillation.

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    Li-Qun Zhao

    Full Text Available Atrial fibrillation(AF is the most common arrhythmia in the adult population. The activated renin-angiotensin-aldosterone system (RAS has been reported to play an important role in the pathogenesis of atrial fibrillation. The aim of this study was to investigate the association between nonfamilial AF and polymorphisms in RAS gene.A total of 931 patients with nonfamilial AF, 663 non-AF heart disease patients and 727 healthy subjects were selected. 10 tagSNPs (tSNPs (ACE gene rs8066114, AGT gene rs7539020, rs3789678, rs2478544, rs11568023, rs2478523, rs4762, rs699 and CYP11B2 rs3802230, rs3097 were chosen and genotyped in our study. Single-locus analysis and haplotype analysis were used in this study.In single-locus analysis, we found rs11568023 and rs3789678 in AGT gene were associated with nonfamilial AF in Chinese Han population. AF risk was associated with rs3789678 between the AF group and control groups. Under dominant model, the significant AF risk was observed in rs3789678 between the AF group and non AF heart control group; And the protective effect was found in rs11568023, compared with the non-AF heart disease control group. In multilocus haplotype analysis, the association between frequencies of the haplotypes and AF risk was showed in AGT gene (rs7539020-rs3789678, compared 'TT' haplotype with the common 'TC' haplotype, adjusted for age, gender, LVEF, LVEDD, LAD and frequency of hypertension and diabetes. The diplotype with 'TC', carrying rs3789678-C-allele, was associated with reduced risk of AF between the AF group and the healthy control group. The diplotype with 'TT' haplotype in the same block, carrying rs3789678-T-allele, was associated with increased risk of AF.Via a large-scale case-control study, we found that rs3789678 site was potential susceptible locus of AF whereas rs11568023 was protective factor.

  5. Carotid remodeling of hypertensive subjects and polymorphism of the angiotensin-converting enzyme gene

    Institute of Scientific and Technical Information of China (English)

    李世军; 孙宁玲; 周素敏

    2004-01-01

    Background This study was designed to investigate the relationships between changes in the structure and function of carotid arteries and angiotensin converting enzyme (ACE) gene polymorphism in Chinese hypertensive subjects. Methods Multiplex polymerase chain reaction amplification was used to evaluate the ACE gene insertion/deletion (I/D) polymorphism. High-resolution B-mode ultrasound examinations were performed to detect parameters of carotid artery remodeling. Results Intima-media thickness (IMT) was significantly different among the DD, ID and II genotypes of ACE (DD>ID>II, P0.05) in hypertensive subjects. The frequency of the DD gene and D allele of ACE were higher in patients with thickening carotid than in patients with normal carotid (70.4% vs 24.1%, and 79.5% vs 40.5%, respectively, P<0.001). In multiple stepwise regression analysis, independent risk factors for increased carotid IMT in hypertensive subjects were ACE genotypes (P<0.001), age (P<0.001) and carotid internal diameter (P=0.032). Moreover, triglycerides and total cholesterol were higher in patients with the DD genotype than in those with the II genotype (P<0.05). Conclusions The I/D polymorphism of the ACE gene was related to IMT, but not to internal diameter, distensibility and stiffness of the carotid in Chinese hypertensive subjects. ACE gene polymorphism was a main risk factor for increased carotid IMT. These results may imply that there is a link between lipid metabolism and ACE genotype polymorphism in Chinese hypertensive subjects.

  6. Determinants and Changes Associated with Aldosterone Breakthrough after Angiotensin II Receptor Blockade in Patients with Type 2 Diabetes with Overt Nephropathy

    Science.gov (United States)

    Moranne, Olivier; Bakris, George; Fafin, Coraline; Favre, Guillaume; Pradier, Christian

    2013-01-01

    Summary Background and objectives Inhibition of the renin-angiotensin-aldosterone system decreases proteinuria and slows estimated GFR decline in patients with type 2 diabetes mellitus with overt nephropathy. Serum aldosterone levels may increase during renin-angiotensin-aldosterone system blockade. The determinants and consequences of this aldosterone breakthrough remain unknown. Design, setting, participants, & measurements This study examined the incidence, determinants, and changes associated with aldosterone breakthrough in a posthoc analysis of a randomized study that compared the effect of two angiotensin II receptor blockers in patients with type 2 diabetes mellitus with overt nephropathy. Results Of 567 of 860 participants included in this posthoc analysis, 28% of participants developed aldosterone breakthrough, which was defined by an increase greater than 10% over baseline values of serum aldosterone levels after 1 year of angiotensin II receptor blocker treatment. Factors independently associated with aldosterone breakthrough at 1 year were lower serum aldosterone and potassium levels at baseline, higher decreases in sodium intake, systolic BP, and estimated GFR from baseline to 1 year, and use of losartan versus telmisartan. Aldosterone breakthrough at 6 months was not sustained at 1 year in 69% of cases, and it did not predict estimated GFR decrease and proteinuria increase between 6 months and 1 year. Conclusions Aldosterone breakthrough is a frequent event 1 year after initiating renin-angiotensin-aldosterone system blockade, particularly in participants exposed to intensive lowering of BP with sodium depletion and short-acting angiotensin II receptor blockers. Short-term serum aldosterone level increases at 6 months are not associated with negative kidney outcomes between 6 months and 1 year. PMID:23929924

  7. Vascular change and opposing effects of the angiotensin type 2 receptor in a mouse model of vascular cognitive impairment

    Science.gov (United States)

    Füchtemeier, Martina; Brinckmann, Marie P; Foddis, Marco; Kunz, Alexander; Po, Chrystelle; Curato, Caterina; Dirnagl, Ulrich; Farr, Tracy D

    2015-01-01

    Our aims were to assess the spatiotemporal development of brain pathology in a mouse model of chronic hypoperfusion using magnetic resonance imaging (MRI), and to test whether the renin-angiotensin system (RAS) can offer therapeutic benefit. For the first time, different patterns of cerebral blood flow alterations were observed in hypoperfused mice that ranged from an immediate and dramatic to a delayed decrease in cerebral perfusion. Diffusion tensor imaging revealed increases in several quantitative parameters in different brain regions that are indicative of white-matter degeneration; this began around 3 weeks after induction of hypoperfusion. While this model may be more variable than previously reported, neuroimaging tools represent a promising way to identify surrogate markers of pathology. Vascular remodelling was observed in hypoperfused mice, particularly in the anterior part of the Circle of Willis. While the angiotensin II receptor type 2 agonist, Compound 21 (C21), did not influence this response, it did promote expansion of the basilar artery in microcoil animals. Furthermore, C21-treated animals exhibited increased brain lymphocyte infiltration, and importantly, C21 had opposing effects on spatial reference memory in hypoperfused and sham mice. These results suggest that the RAS may have a role in vascular cognitive impairment. PMID:25492118

  8. Role of Mas receptor in renal blood flow response to angiotensin-(1-7 in ovariectomized estradiol treated rats

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    Shadan Saberi

    2016-01-01

    Full Text Available The angiotensin 1-7 (Ang 1-7, is abundantly produced in kidneys and antagonizes the function of angiotensin II through Mas receptor (MasR or other unknown mechanisms. In the current study, the role of MasR and steroid hormone estrogen on renal blood flow response to Ang 1-7 administration was investigated in ovariectomized (OV female rats. OV female Wistar-rats received estradiol (500 μg/kg/week or vehicle for two weeks. In the day of the experiment, the animals were anesthetized, cannulated, and the responses including mean arterial pressure, renal blood flow (RBF, and renal vascular resistance at the constant level of renal perfusion pressure to graded infusion of Ang 1-7 at 0, 100 and 300 ng/kg/min were determined in OV and OV estradiol-treated (OVE rats, treated with vehicle or MasR antagonist; A779. RBF response to Ang 1-7 infusion increased dose-dependently in vehicle (P dose <0.001 and A779-treated (P dose<0.01 animals. However, when MasR was blocked, the RBF response to Ang 1-7 significantly increased in OV animals compared with OVE rats (P<0.05. When estradiol was limited by ovariectomy, A779 increased RBF response to Ang 1-7 administration, while this response was attenuated in OVE animals.

  9. Angiotensin II receptor blockers in the prevention of complications from atrial fibrillation

    OpenAIRE

    Eide, Stephanie

    2009-01-01

    Gerald V Naccarelli,1 Frank Peacock21Penn State Heart and Vascular institute, Hershey, Pennsylvania, USA; 2Cleveland Clinic, Cleveland, Ohio, USAAbstract: Atrial fibrillation (AF) is the most common form of cardiac arrhythmia and is associated with an increased risk of cardiovascular morbidity and mortality, especially due to ischemic stroke. The occurrence of AF leads to atrial electrical and structural remodeling. The renin-angiotensin system appears to play a role in the development of atr...

  10. Angiotensin II receptor blockers in the prevention of complications from atrial fibrillation

    OpenAIRE

    Gerald V. Naccarelli; Peacock, Frank

    2009-01-01

    Atrial fibrillation (AF) is the most common form of cardiac arrhythmia and is associated with an increased risk of cardiovascular morbidity and mortality, especially due to ischemic stroke. The occurrence of AF leads to atrial electrical and structural remodeling. The renin-angiotensin system appears to play a role in the development of atrial arrhythmias by its involvement in both of these processes. Large-scale hypertension trials and heart failure trials have indicated the potential value ...

  11. Angiotensin Converting Enzyme Gene Polymorphism in Egyptian Patients with Systemic Lupus Erythematosus

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    El-Shafeey M.M., El-Shayeb M., Othman E. and Elfawy N

    2005-12-01

    Full Text Available Systemic lupus erythematosus (SLE shows various clinical manifestations with various immunological abnormalities. The development of lupus nephritis and vasculitis is common in patients with SLE. As angiotensin I-converting enzyme (ACE has been reported to be associated with various immunological phenomena, we investigated the correlation between insertion(I / deletion(D polymorphism of the ACE gene and SLE. Fifty Egyptian patients with SLE and thirty healthy control persons were involved in this study. ACE gene was detected by the polymerase chain reaction (PCR. In SLE patients, there is a significant difference when comparing DD and II genotypes (P<0.05,being higher in the DD genotype. And a highly significant difference when comparing ID and II genotypes (P=0.001, being much higher in ID genotype than II genotype. According to vasculitis, there is a significant relationship between vasculitis and patients genotypes when comparing ID genotype with both II and DD genotypes (P<0.05, being highest in ID genotype. There is a significant relationship found when comparing ID genotype with both II and DD genotypes, being highest in ID genotype in patients with score 21. These results suggest that the ACE genotype could be associated with SLE.

  12. Renin-Angiotensin System Genes Polymorphisms and Essential Hypertension in Burkina Faso, West Africa

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    Daméhan Tchelougou

    2015-01-01

    Full Text Available Objective. This study aimed to investigate the association between three polymorphisms of renin-angiotensin system and the essential hypertension in the population of Burkina Faso. Methodology. This was a case-control study including 202 cases and 204 matched controls subjects. The polymorphisms were identified by a classical and a real-time PCR. Results. The AGT 235M/T and AT1R 1166A/C polymorphisms were not associated with the hypertension while the genotype frequencies of the ACE I/D polymorphism between patients and controls (DD: 66.83% and 35.78%, ID: 28.22% and 50.98%, II: 4.95% and 13.24%, resp. were significantly different (p < 10−4. The genotype DD of ACE gene (OR = 3.40, p < 0.0001, the increasing age (OR = 3.83, p < 0.0001, obesity (OR = 4.84, p < 0.0001, dyslipidemia (OR = 3.43, p = 0.021, and alcohol intake (OR = 2.76, p < 0.0001 were identified as the independent risk factors for hypertension by multinomial logistic regression. Conclusion. The DD genotype of the ACE gene is involved in susceptibility to hypertension. Further investigations are needed to better monitor and provide individualized care for hypertensive patients.

  13. Renin-Angiotensin System Genes Polymorphisms and Essential Hypertension in Burkina Faso, West Africa

    Science.gov (United States)

    Tchelougou, Daméhan; Kologo, Jonas K.; Karou, Simplice D.; Yaméogo, Valentin N.; Bisseye, Cyrille; Djigma, Florencia W.; Ouermi, Djeneba; Compaoré, Tegwindé R.; Assih, Maléki; Pietra, Virginio; Zabsonré, Patrice; Simpore, Jacques

    2015-01-01

    Objective. This study aimed to investigate the association between three polymorphisms of renin-angiotensin system and the essential hypertension in the population of Burkina Faso. Methodology. This was a case-control study including 202 cases and 204 matched controls subjects. The polymorphisms were identified by a classical and a real-time PCR. Results. The AGT 235M/T and AT1R 1166A/C polymorphisms were not associated with the hypertension while the genotype frequencies of the ACE I/D polymorphism between patients and controls (DD: 66.83% and 35.78%, ID: 28.22% and 50.98%, II: 4.95% and 13.24%, resp.) were significantly different (p < 10−4). The genotype DD of ACE gene (OR = 3.40, p < 0.0001), the increasing age (OR = 3.83, p < 0.0001), obesity (OR = 4.84, p < 0.0001), dyslipidemia (OR = 3.43, p = 0.021), and alcohol intake (OR = 2.76, p < 0.0001) were identified as the independent risk factors for hypertension by multinomial logistic regression. Conclusion. The DD genotype of the ACE gene is involved in susceptibility to hypertension. Further investigations are needed to better monitor and provide individualized care for hypertensive patients. PMID:26351579

  14. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.

    Science.gov (United States)

    Wang, Lei; de Kloet, Annette D; Pati, Dipanwita; Hiller, Helmut; Smith, Justin A; Pioquinto, David J; Ludin, Jacob A; Oh, S Paul; Katovich, Michael J; Frazier, Charles J; Raizada, Mohan K; Krause, Eric G

    2016-06-01

    Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ∼62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the

  15. AT1R基因、ACE基因和CYP基因多态性与妊娠期高血压疾病的相关性研究%Polymorphism of angiotension Ⅱ type 1 receptor gene, angiotensin converting enzyme gene and aldosterone synthase gene and hypertensive disorder complicating pregnancy

    Institute of Scientific and Technical Information of China (English)

    牛建清; 李宏芬; 沈志霞; 范淑英; 代琪; 张蕴霞

    2009-01-01

    目的 探讨血管紧张素Ⅱ-1型受体(AT1R)基因A1166-C、血管紧张素转换酶(ACE)基因插入/缺失(I/D)和醛固酮合成酶(CYP11B2)基因-344T/C位点多态性与妊娠期高血压疾病(HDCP)的相关关系.方法 采用聚合酶链反应-限制性内切酶片段长度多态性技术(PCR-RFLP),分别检测HDCP组86例和正常对照组175例AT1R基因A1166-C、ACE基因I/D和CYP11B2基因-344T/C突变位点的基因型.结果 HDCP组和正常对照组AT1R基因A1166-C、ACE基因I/D和CYPllB2基因-344T/C多态性18种组合的分布不同,构成比不同;这18种组合中,相对于AT1R-AA+ACE-Ⅱ+CYP 1182-TT基因型,携带AT1R-AA+ACE-DD+CYP11B2-TC基因型人群的OR值为7.289;携带AT1R-AC+ACE-ID+CYP11B2-TC基因型人群的OR值为5.315;携带AT1R.AC+ACE-DD+CYP11B2-TC基因型人群的OR值为5.694.其余联合基因型,差异均无统计学意义(P均0.05);或者由于样本量小,不具有代表性.结论 HDCP组和正常对照组AT1R基因A1166-C、ACE基因I/D和CYPllB2基因-344T/C多态性18种组合中,AT1R-AA+ACE-DD+CYP11B2-TC联合基因型、AT1R-AC+ACE-ID+CYP11B2-TC联合基因型、AT1R-AC+ACE-DD+CYP11B2-TC联合基因型可能增加HDCP的遗传易感性;HDCP的发生,可能是多个基因共同作用的结果 .%Objective To explore the relationship among genetic polymorphism of angiotension Ⅱ type 1 re-ceptor(AT1 R) A1166-C, angiotensin converting enzyme (ACE) insertion/deletion (I/D), aldosterone synthase (CYP11B2)-344T/C and hypertensive disorder complicating pregnancy.Methods Polymerase chain reaction-re-striction fragment length polymorphism (PCR-RFLP) assay was used to detect the genotypes of AT1 R A1166-C ,ACE (I/O) ,CYP11B2 -344T/C in 86 cases of hypertensive disorder complicating pregnancy and 175 cases of normal control.Results There was 18 combined types in hypertensive disorder complicating pregnancy cases and normal control cases.Compared to AT1R-AA + ACE-Ⅱ + CYP11B2-TT, Odds ratios (OR) of AT1R-AA + ACE-DO +CYP11

  16. Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation.

    Science.gov (United States)

    Xue, Baojian; Yu, Yang; Zhang, Zhongming; Guo, Fang; Beltz, Terry G; Thunhorst, Robert L; Felder, Robert B; Johnson, Alan Kim

    2016-05-01

    Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high-fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin II administration that is mediated at least, in part, by increased activity of brain renin-angiotensin system and proinflammatory cytokines. This study tested whether leptin mediates this HFD-induced sensitization of angiotensin II-elicited hypertension by interacting with brain renin-angiotensin system and proinflammatory cytokine mechanisms. Rats fed an HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels, and mRNA expression of leptin and its receptors in the lamina terminalis and hypothalamic paraventricular nucleus. Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of angiotensin II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the angiotensin II type 1 receptor antagonist irbesartan, the tumor necrosis factor-α synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus. The leptin antagonist and the inhibitors of angiotensin II type 1 receptor, tumor necrosis factor-α synthesis, and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of angiotensin II-elicited hypertension is mediated by leptin through upregulation of central renin-angiotensin system and proinflammatory cytokines.

  17. Simultaneous determination of multiple angiotensin type 1 receptor antagonists and its application to high-throughput pharmacokinetic study

    Science.gov (United States)

    Zhu, Xiaoyan; Sun, Jianguo; Hao, Haiping; Wang, Guangji; Hu, Xiaoling; Lv, Hua; Gu, Shenghua; Wu, Xiaoming; Xu, Jinyi

    2008-05-01

    A rapid and sensitive high performance liquid chromatography-electrospray tandem mass spectrometry (HPLC-ESI-MS/MS) detection was developed for the simultaneous determination of multiple angiotensin type 1 receptor antagonists (AT1RAs) WX472, WX581, 1b and telmisartan in rat plasma for the purpose of high-throughout pharmacokinetic screening. The method was operated under selected reaction monitoring (SRM) mode in the positive ion mode. The analytes and the internal standard (pitavastatin) were extracted from 100 [mu]L rat plasma under acidic conditions by liquid-liquid extraction with ethyl acetate. The analytes and internal standard were baseline separated on a Gemini analytical column (3 [mu]m, 150 mm × 2.0 mm) with the adoption of a gradient elution using acetonitrile and 0.05% aqueous formic acid. The standard curves were linear in the concentration ranges of 4.5-900 ng/mL for WX472, 5-1000 ng/mL for WX581 and 0.5-100 ng/mL for 1b and telmisartan. Intra- and inter-batch precisions (R.S.D.%) were all within 15% and the method assessed a quite good accuracy (R.E.%). Recoveries were found to be >65% for all the compounds and no obvious matrix effects were found. This method has been successfully applied to the high-throughput pharmacokinetic screening study for both cassette dosing and cassette analysis of four compounds to rats. Significant drug-drug interactions were observed after cassette dosing. The study suggested that cassette analysis of pooled samples would be a better choice for the high-throughput pharmacokinetic screening of angiotensin type 1 receptor antagonists.

  18. Impact of cell type and epitope tagging on heterologous expression of G protein-coupled receptor: a systematic study on angiotensin type II receptor.

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    Lili Jiang

    Full Text Available Despite heterologous expression of epitope-tagged GPCR is widely adopted for functional characterization, there is lacking of systematic analysis of the impact of expression host and epitope tag on GPCR expression. Angiotensin type II (AT2 receptor displays agonist-dependent and -independent activities, coupling to a spectrum of signaling molecules. However, consensus has not been reached on the subcellular distributions, signaling cascades and receptor-mediated actions. To examine the contributions of host cell and epitope tag on receptor expression and activity, epitope-tagged AT2 receptor variants were transiently or stably expressed in HEK293, CHO-K1 and PC12 cells. The epitope-tagged AT2 receptor variants were detected both on the cell membrane and in the perinuclear region. In transiently transfected HEK293 cells, Myc-AT2 existed predominantly as monomer. Additionally, a ladder of ubiquitinated AT2 receptor proteins was detected. By contrast, stably expressed epitope-tagged AT2 receptor variants existed as both monomer and high molecular weight complexes, and the latter was enriched in cell surface. Glycosylation promoted cell surface expression of Myc-AT2 but had no effect on AT2-GFP in HEK293 cells. In cells that stably expressed Myc-AT2, serum starvation induced apoptosis in CHO-K1 cells but not in HEK293 or PC12 cells. Instead, HEK293 and PC12 cells stably expressing Myc-AT2 exhibited partial cell cycle arrest with cells accumulating at G1 and S phases, respectively. Taken together, these results suggest that expression levels, subcellular distributions and ligand-independent constitutive activities of AT2 receptor were cell type-dependent while posttranslational processing of nascent AT2 receptor protein was modulated by epitope tag and mode of expression.

  19. Transactivation of ErbB Family of Receptor Tyrosine Kinases Is Inhibited by Angiotensin-(1-7 via Its Mas Receptor.

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    Saghir Akhtar

    Full Text Available Transactivation of the epidermal growth factor receptor (EGFR or ErbB family members, namely EGFR and ErbB2, appears important in the development of diabetes-induced vascular dysfunction. Angiotensin-(1-7 [Ang-(1-7] can prevent the development of hyperglycemia-induced vascular complications partly through inhibiting EGFR transactivation. Here, we investigated whether Ang-(1-7 can inhibit transactivation of ErbB2 as well as other ErbB receptors in vivo and in vitro. Streptozotocin-induced diabetic rats were chronically treated with Ang-(1-7 or AG825, a selective ErbB2 inhibitor, for 4 weeks and mechanistic studies performed in the isolated mesenteric vasculature bed as well as in cultured vascular smooth muscle cells (VSMCs. Ang-(1-7 or AG825 treatment inhibited diabetes-induced phosphorylation of ErbB2 receptor at tyrosine residues Y1221/22, Y1248, Y877, as well as downstream signaling via ERK1/2, p38 MAPK, ROCK, eNOS and IkB-α in the mesenteric vascular bed. In VSMCs cultured in high glucose (25 mM, Ang-(1-7 inhibited src-dependent ErbB2 transactivation that was opposed by the selective Mas receptor antagonist, D-Pro7-Ang-(1-7. Ang-(1-7 via Mas receptor also inhibited both Angiotensin II- and noradrenaline/norephinephrine-induced transactivation of ErbB2 and/or EGFR receptors. Further, hyperglycemia-induced transactivation of ErbB3 and ErbB4 receptors could be attenuated by Ang-(1-7 that could be prevented by D-Pro7-Ang-(1-7 in VSMC. These data suggest that Ang-(1-7 via its Mas receptor acts as a pan-ErbB inhibitor and might represent a novel general mechanism by which Ang-(1-7 exerts its beneficial effects in many disease states including diabetes-induced vascular complications.

  20. Adventitial gene transfer of catalase attenuates angiotensin II-induced vascular remodeling.

    Science.gov (United States)

    Liu, Cun-Fei; Zhang, Jia; Shen, Kai; Gao, Ping-Jin; Wang, Hai-Ya; Jin, Xin; Meng, Chao; Fang, Ning-Yuan

    2015-04-01

    Vascular adventitia and adventitia‑derived reactive oxygen species (ROS) contribute to vascular remodeling following vascular injury. A previous ex vivo study in adventitial fibroblasts showed that catalase, one of most important anti‑oxide enzymes, was downregulated by angiotensin II (AngII). The aim of the present study was to investigate whether adventitial gene transfer of catalase affects AngII‑induced vascular remodeling in vivo. Adenoviruses co‑expressing catalase and enhanced green fluorescent protein (eGFP) or expressing eGFP only were applied to the adventitial surface of common carotid arteries of Sprague‑Dawley rats. Alzet minipumps administering AngII (0.75 mg/kg/day) were then implanted subcutaneously for 14 days. Systolic blood pressure and biological parameters of vascular remodeling were measured in each group. Adventitial fibroblasts were cultured and p38 mitogen‑activated protein kinase (MAPK) phosphorylation was measured using western blot analysis. The results showed that adventitial gene transfer of catalase had no effect on AngII‑induced systolic blood pressure elevation. However, catalase adenovirus transfection significantly inhibited AngII‑induced media hypertrophy compared with that of the control virus (Pcatalase transfection significantly attenuated AngII‑induced ROS generation, macrophage infiltration, collagen deposition and adventitial α‑smooth muscle actin expression. Furthermore, catalase transfection significantly inhibited the AngII‑induced increase in p38MAPK phosphorylation. In conclusion, the results of the present study demonstrated that adventitial gene transfer of catalase significantly attenuated AngII‑induced vascular remodeling in rats via inhibition of adventitial p38MAPK phosphorylation.

  1. DNA methylation analysis of the angiotensin converting enzyme (ACE gene in major depression.

    Directory of Open Access Journals (Sweden)

    Peter Zill

    Full Text Available BACKGROUND: The angiotensin converting enzyme (ACE has been repeatedly discussed as susceptibility factor for major depression (MD and the bi-directional relation between MD and cardiovascular disorders (CVD. In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ~40%-50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood. MATERIALS AND METHODS: The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls. RESULTS: We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008 and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02. Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04. CONCLUSION: The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders.

  2. Association of polymorphisms in angiotensin-converting enzyme gene with gestational diabetes mellitus in Indian women

    Science.gov (United States)

    Aggarwal, Parul; Agarwal, Nutan; Das, Nibhriti; Dalal, Krishna

    2016-01-01

    Background: Numerous genes have been reported in relation with gestational diabetes mellitus (GDM), but the findings were not consistently replicated across populations, or there have been no detailed studies on them. Previous literatures suggested that, out of all angiotensin converting enzyme (ACE) gene polymorphisms, only ACE insertion/deletion (I/D) gene polymorphism has a strong association with GDM in Asian Indian women. Aim: This study was devoted to evaluate the association of four single nucleotide polymorphisms (SNPs) ACE A240T, C1237T, G2350A and I/D with GDM and Type 2 diabetes mellitus. Materials and Methods: This study recruited 105 GDM cases, 119 Type 2 diabetes mellitus subjects and 120 controls. PCR-RFLP was used for identifying genotypes of ACE A240T, C1237T and G2350A and PCR was performed in the case of ACE I/D. Results: Significant associations of ACE SNP's, C1237T, and G2350A with GDM were observed. Haplotype analysis revealed the remarkably significant evidence of association with SNP combination ACE A240T, C1237T, G2350A, and I/D with GDM patients (P = 0.024). Individuals possessing haplotype “TTAI” (frequency 30% in GDM and 0 in controls) derived from these SNPs had 185 fold increased risk of developing GDM (95% of confidence interval: 11.13–3102.15), which was highest when compared with other 15 haplotypes. Conclusion: Shorter-range haplotypes were also significant, but the only consistently associated alleles were found to be in ACE C1237T, G2350A, and I/D. These results suggested that the variant in close proximity to ACE C1237T, G2350A and/or I/D modulates susceptibility to GDM and noninsulin dependent diabetes mellitus in Indian women. PMID:26958520

  3. Cooperative effect of angiotensin AT(1) and endothelin ET(A) receptor antagonism limits the brain damage after ischemic stroke in rat

    DEFF Research Database (Denmark)

    Stenman, Emelie; Jamali, Roya; Henriksson, Marie;

    2007-01-01

    ) and endothelin ET(A) receptors however decreased the brain damage and improved the neurological scores (both Psmooth muscle cells......Cerebral ischemia results in enhanced expression of smooth muscle cell endothelin and angiotensin receptors in cerebral arteries. We hypothesise that this phenomenon may be detrimental and that acute treatment with a combined non-hypotensive dose of the angiotensin AT(1) receptor inhibitor.......05 mg/kg/day), ZD1611 (0.15 mg/kg/day), both combined or vehicle with start immediately after the occlusion. After 48 h the rats were sacrificed, the brains sliced and stained with 1% 2, 3, 5-triphenyltetrazolium chloride (TTC) and the volume of ischemic damage determined. The middle cerebral arteries...

  4. G16R single nucleotide polymorphism but not haplotypes of the ß2-adrenergic receptor gene alters cardiac output in humans

    DEFF Research Database (Denmark)

    Rokamp, Kim Z; Staalsø, Jonatan M; Gartmann, Martin;

    2013-01-01

    Variation in genes encoding the ß2-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) may influence Q¿ (cardiac output). The 46G>A (G16R) SNP (single nucleotide polymorphism) has been associated with ß2-mediated vasodilation, but the effect of ADRB2 haplotypes on Q¿ has not been ...

  5. Functional interaction between angiotensin II receptor type 1 and chemokine (C-C motif receptor 2 with implications for chronic kidney disease.

    Directory of Open Access Journals (Sweden)

    Mohammed Akli Ayoub

    Full Text Available Understanding functional interactions between G protein-coupled receptors is of great physiological and pathophysiological importance. Heteromerization provides one important potential mechanism for such interaction between different signalling pathways via macromolecular complex formation. Previous studies suggested a functional interplay between angiotensin II receptor type 1 (AT1 and Chemokine (C-C motif Receptor 2 (CCR2. However the molecular mechanisms are not understood. We investigated AT1-CCR2 functional interaction in vitro using bioluminescence resonance energy transfer in HEK293 cells and in vivo using subtotal-nephrectomized rats as a well-established model for chronic kidney disease. Our data revealed functional heteromers of these receptors resulting in CCR2-Gαi1 coupling being sensitive to AT1 activation, as well as apparent enhanced β-arrestin2 recruitment with agonist co-stimulation that is synergistically reversed by combined antagonist treatment. Moreover, we present in vivo findings where combined treatment with AT1- and CCR2-selective inhibitors was synergistically beneficial in terms of decreasing proteinuria, reducing podocyte loss and preventing renal injury independent of blood pressure in the subtotal-nephrectomized rat model. Our findings further support a role for G protein-coupled receptor functional heteromerization in pathophysiology and provide insights into previous observations indicating the importance of AT1-CCR2 functional interaction in inflammation, renal and hypertensive disorders.

  6. A RETROSPECTIVE STUDY ON THE POTENTIAL DRUG INTERACTION BETWEEN ANGIOTENSIN CONVERTING ENZYME INHIBITOR OR ANGIOTENSIN RECEPTOR ANTAGONIST AND OTHER DRUGS IN END-STAGE CHRONIC RENAL FAILURE PATIENTS

    Directory of Open Access Journals (Sweden)

    Honey Iskandar

    2012-10-01

    Full Text Available Increasing number of chronic renal failure (CRF patients had reflected an increase in the number of patients with diabetes and hypertension. Therefore, health practitioners would be faced with management of complicated medical problems for the patients of chronic renal disease. In this way, various complications of chronic renal failure would lead to polypharmacy, where the patients receive three to five drugs in a dose. Development of polypharmacy had made the potential of drug interaction greater. The objective was to determine whether CRF patients admitted to hospital with specific adverse drug reactions were likely to have been prescribed with interacting drugs. Retrospective study was designed. The study was conducted at the General Practice Rooms Floor 1 – Floor VI of Central Army Hospital Gatot Soebroto Jakarta. The study was conducted from December 2011 – February 2012. The data were collected in a retrospective way for a year (January – December 2011. End-stage CRF patients who were having hemodialysis therapy and receiving ACE Inhibitor drugs or Angiotensin II Receptor Antagonist (AIIRA and receiving treatment at the General Practice Rooms at Central Army Hospital Gatot Soebroto Jakarta. During the period of January – December 2011, 84 patients were treated with end-stage CRF at the Central Army Hospital and having routine hemodialysis and 44 patients were receiving therapy with ACE Inhibitor and AIIRA. Other drugs simultaneously given with ACE Inhibitor and AIIRA were captopril-spironolactone, captopril-aspirin, captopril-allopurinol, captopril-KSR, captopril-furosemide, lisinopril-furosemide and valsartan-mefenemic acid. An increase in adverse effects of the drugs was found based on the clinical evaluation and laboratory examination. The adverse effects included hyperkalemia (9,09%, decrease in anti-hypertension effect (6,8%, acute hypotension (40%, and declining renal function (11,36%. The study identifies drug interaction

  7. Changes in Angiotensin Receptor Distribution and in Aortic Morphology Are Associated with Blood Pressure Control in Aged Metabolic Syndrome Rats

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    Verónica Guarner-Lans

    2016-01-01

    Full Text Available The role of the renin-angiotensin system (RAS in blood pressure regulation in MS during aging is unknown. It participates in metabolic syndrome (MS and aging regulating vascular tone and remodeling. RAS might participate in a compensatory mechanism decreasing blood pressure and allowing MS rats to reach 18 months of age and it might form part of therapeutical procedures to ameliorate MS. We studied histological changes and distribution of RAS receptors in aortas of MS aged rats. Electron microscopy images showed premature aging in MS since the increased fibrosis, enlarged endothelium, and invasion of this layer by muscle cells that was present in control 18-month-old aortas were also found in 6-month-old aortas from MS rats. AT1, AT2, and Mas receptors mediate the effects of Ang II and Ang 1-7, respectively. Fluorescence from AT2 decreased with age in control and MS aortas, while fluorescence of AT1 increased in aortas from MS rats at 6 months and diminished during aging. Mas expression increased in MS rats and remained unchanged in control rats. In conclusion, there is premature aging in the aortas from MS rats and the elevated expression of Mas receptor might contribute to decrease blood pressure during aging in MS.

  8. Changes in Angiotensin Receptor Distribution and in Aortic Morphology Are Associated with Blood Pressure Control in Aged Metabolic Syndrome Rats

    Science.gov (United States)

    Guarner-Lans, Verónica; Soria-Castro, Elizabeth; Torrico-Lavayen, Rocío; Patrón-Soberano, Araceli; Carvajal-Aguilera, Karla G.; Castrejón-Tellez, Vicente; Rubio-Ruiz, María Esther

    2016-01-01

    The role of the renin-angiotensin system (RAS) in blood pressure regulation in MS during aging is unknown. It participates in metabolic syndrome (MS) and aging regulating vascular tone and remodeling. RAS might participate in a compensatory mechanism decreasing blood pressure and allowing MS rats to reach 18 months of age and it might form part of therapeutical procedures to ameliorate MS. We studied histological changes and distribution of RAS receptors in aortas of MS aged rats. Electron microscopy images showed premature aging in MS since the increased fibrosis, enlarged endothelium, and invasion of this layer by muscle cells that was present in control 18-month-old aortas were also found in 6-month-old aortas from MS rats. AT1, AT2, and Mas receptors mediate the effects of Ang II and Ang 1-7, respectively. Fluorescence from AT2 decreased with age in control and MS aortas, while fluorescence of AT1 increased in aortas from MS rats at 6 months and diminished during aging. Mas expression increased in MS rats and remained unchanged in control rats. In conclusion, there is premature aging in the aortas from MS rats and the elevated expression of Mas receptor might contribute to decrease blood pressure during aging in MS. PMID:27293881

  9. Activation of angiotensin II type 1 receptors in the median preoptic nucleus induces a diuretic and natriuretic response in rats

    Institute of Scientific and Technical Information of China (English)

    Yuan Gao; Lei Luo; Hong Liu

    2009-01-01

    Objective: To investigate the effect of activation of angiotensin II (AngII) type 1 (ATI) receptors in the median preoptic nucleus (MnPO) of rats on renal sodium excretion. Methods: After anesthesia, the rats were injected into the MnPO via an implanted cannula. Urine samples were collected via a bladder cannula, and the urine sodium concentration was assayed with flame spectrophotometry. The serum level of endogenous digitalis-like factor (EDLF) and Na+,K+-ATPase activity in the renal cortex tissue were assayed respectively with a radioimmunoassay and with an ammonium molybdophosphate-based kit. Results: Both the urinary volume and the sodium excretion peaked 60 min after Angll was administered into the MnPO. The responses were accompanied by an increase in serum EDLF and a decrease in Na+,K+-ATPase activity in the renal cortex. The responses of diuresis and natriuresis, as well as an increase in serum EDLF and a decrease in Na+,K+-ATPase activity in the renal cortex induced by MnPO adminstration with AngII were inhibited by pior treatment with the AngII receptor blocking agent losartan into the MnPO. Conclusion: These results suggest that activation of ATI receptors in the MnPO of rat induces diuretic and natriuretic responses. The responses are associated with an increase release of EDLF and with the inhibition of Na+,K+-ATPase activity in renal cortex tissue.

  10. Beneficial effects of the activation of the angiotensin-(1-7 MAS receptor in a murine model of adriamycin-induced nephropathy.

    Directory of Open Access Journals (Sweden)

    Kátia Daniela Silveira

    Full Text Available Angiotensin-(1-7 [Ang-(1-7] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II within the renin-angiotensin system (RAS. Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-β. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas(+/+ and Mas knockout (Mas (-/- mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas(+/+ , but not in Mas (-/- mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1-7/Mas axis may offer new therapeutic opportunities to treat human nephropathies.

  11. Angiotensin-converting enzyme and angiotensin II receptor subtype 2 genotypes in type 1 diabetes and severe hypoglycaemia requiring emergency treatment: a case cohort study

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Nielsen, Søren L; Akram, Kamran;

    2009-01-01

    AIMS: In type 1 diabetes, individual susceptibility to severe hypoglycaemia is likely to be influenced by genetic factors. We have previously reported an association of the deletion (D-) allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the A-allele of th...

  12. Relationship between angiotensin-converting enzyme gene polymorphism and cardio-brain complications in patients with NIDDM (type 2 diabetes mellitus)

    International Nuclear Information System (INIS)

    Objective: To investigate the relationship between angiotensin-converting enzyme gene polymorphism and cardio-brain complications in patients with NIDDM. Methods: The angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism in 174 patients with NIDDM and 62 controls were examined with PCR. Results: ACE gene I/D polymorphism was closely related to coronary heart disease (angina, cardiac infarction) and cerebral infarction in diabetic patients but not with hypertension. Plasma renin activity and plasma angiotensin II levels in complicated diabetic patients with ACE D/D gene were significantly higher than those in the controls (p < 0.01). Their aldosterone and endothelin contents were not significantly different. Conclusion: Examination of ACE gene I/D polymorphism was useful for the primary prevention of cardio-brain complications in diabetic patients and helpful in the early diagnosis and therapy of coronary heart disease and cerebral infarction

  13. Effect of angiotensin Ⅱ type Ⅰ receptor blocker losartan on bone deterioration in orchiectomized male hypertensive and normotensive rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Ya-feng; QIN Ling; Timothy CY Kwok; Benson HY Yeung; LI Guo-dong; LIU Fan

    2013-01-01

    Background Epidemiological study showed that the use of angiotensin-converting enzyme inhibitors was associated with higher bone mineral density (BMD) in older people,especially male subjects,which suggested that angiotensin Ⅱ may have a detrimental effect on bone.Therefore,blocking its effect may have a beneficial effect on bone health.Methods Six-month-old male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) were used.Animals of each model were randomly assigned to the following four groups:Group 1,SHAM operated+vehicle;Group 2,orchidectomy (ORX)+vehicle; Group 3,ORX+low-dose losartan (10 mg.kg-1·d-1); and Group 4,ORX+high-dose losartan (25 mg.kg-1.d-1).Blood pressure was recorded weekly.SHAM and ORX operations were performed,followed by daily losartan and vehicle treatment from day 4 after operation for 16 weeks.Serum and 24-hour urine samples were collected for measurement of bone turnover markers before euthanasia and then the left femur was collected for measurements of BMD and microarchitecture before mechanical test.Results Urine deoxypyridinoline/urine creatinine (DPD/Cr) ratio was significantly higher in SHR than in WKY.BMD and microarchitecture parameters also showed bone deterioration in SHR.After ORX,serum osteocalcin concentration decreased and urine DPD/Cr ratio increased significantly accompanied by a significant decrease in cortical and trabecular BMD and cortical bone thickness in both WKY and SHR.High-dose losartan significantly increased DPD in urine in both SHR and WKY.Apart from marginal favorable changes in bone architecture in WKY treated with high-dose losartan,losartan did not show significant effect on BMD,bone area,bone microarchitecture,and mechanical properties in both SHR and WKY.Conclusion Angiotensin Ⅱ type Ⅰ receptor blocker losartan was not able to demonstrate significant effect on ORX-induced bone deterioration in both hypertensive and normotensive rats.

  14. Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus.

    Science.gov (United States)

    Biancardi, Vinicia Campana; Stranahan, Alexis M; Krause, Eric G; de Kloet, Annette D; Stern, Javier E

    2016-02-01

    ANG II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (∼65% increase, P microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN.

  15. The role of AT1 and AT2 angiotensin receptors in the mechanism of apoptosis in renal tubular cells after physical exercise.

    Science.gov (United States)

    Podhorska-Okołów, M; Dziegiel, P; Gomułkiewicz, A; Dolińska-Krajewska, B; Murawska-Ciałowicz, E; Jethon, Z; Zabel, M

    2004-01-01

    Intensive physical exercise disturbs the entire homeostasis in the body and leads to changes in haemodynamic and metabolic alterations not only in skeletal muscles but also in many distant organs. In response to acute physical exercise, a decrease of the glomerular filtration may occur, followed by stimulation of the renin-angiotensin system (RAS). Recent studies have shown that both AT1 and AT2 angiotensin receptors may play a role in mediating the apoptotic process in the kidney. Our previous studies have demonstrated an occurrence of apoptosis in rat renal tubular cells after an excessive exercise. The aim of the present study was to determine the possible mechanism of exercise-induced apoptosis in rat kidney. The analysis was performed on kidneys of rats, subjected to treadmill running until exhaustion. Apoptosis was detected in paraffin sections by the TUNEL technique. The expression of AT1 and AT2 receptors in renal tubular cells was examined by immunohistochemistry and Western blot. Our results confirmed that apoptosis after physical exercise is present in renal distal tubular cells. Moreover, there was an increased expression of AT1 and AT2 receptors in distal tubular cells. These studies suggest that physical exercise may induce apoptosis by a mechanism, involving the activation of angiotensin AT1 and AT2 receptors. PMID:15638358

  16. The rat androgen receptor gene promoter

    NARCIS (Netherlands)

    W.M. Baarends (Willy); A.P.N. Themmen (Axel); L.J. Blok (Leen); P. Mackenbach (Petra); A.O. Brinkmann (Albert); D.N. Meijer (Dies); P.W. Faber; J. Trapman (Jan); J.A. Grootegoed (Anton)

    1990-01-01

    markdownabstractAbstract The androgen receptor (AR) is activated upon binding of testosterone or dihydrotestosterone and exerts regulatory effects on gene expression in androgen target cells. To study transcriptional regulation of the rat AR gene itself, the 5' genomic region of this gene was clon

  17. Angiotensin II type 2 receptor correlates with therapeutic effects of losartan in rats with adjuvant-induced arthritis.

    Science.gov (United States)

    Wang, Di; Hu, Shanshan; Zhu, Jie; Yuan, Jun; Wu, Jingjing; Zhou, Aiwu; Wu, Yujing; Zhao, Wendi; Huang, Qiong; Chang, Yan; Wang, Qingtong; Sun, Wuyi; Wei, Wei

    2013-12-01

    The angiotensin II type 1 receptor (AT1R) blocker losartan ameliorates rheumatoid arthritis (RA) in an experimental model. In RA, AT2R mainly opposes AT1R, but the mechanism by which this occurs still remains obscure. In the present study, we investigated the role of AT2R in the treatment of rats with adjuvant-induced arthritis (AIA) by losartan. Adjuvant-induced arthritis rats were treated with losartan (5, 10 and 15 mg/kg) and methotrexate (MTX; 0.5 mg/kg) in vivo from day 14 to day 28. Arthritis was evaluated by the arthritis index and histological examination. Angiotensin II, tumour necrosis factor-α, and VEGF levels were examined by ELISA. The expression of AT1R and AT2R was detected by western blot and immunohistochemistry analysis. After stimulation with interleukin-1β in vitro, the effects of the AT2R agonist CGP42112 (10(-8) -10(-5)  M) on the chemotaxis of monocytes induced by 10% foetal calf serum (FCS) were analysed by using Transwell assay. Subsequently, the therapeutic effects of CGP42112 (5, 10 and 20 μg/kg) were evaluated in vivo by intra-articular injection in AIA rats. After treatment with losartan, the down-regulation of AT1R expression and up-regulation of AT2R expression in the spleen and synovium of AIA rats correlated positively with reduction in the polyarthritis index. Treatment with CGP42112 inhibited the chemotaxis of AIA monocytes in vitro, possibly because of the up-regulation of AT2R expression. Intra-articular injection with CGP42112 (10 and 20 μg/kg) ameliorated the arthritis index and histological signs of arthritis. In summary, the present study strongly suggests that the up-regulation of AT2R might be an additional mechanism by which losartan exerts its therapeutic effects in AIA rats.

  18. 6β-Hydroxytestosterone, a Cytochrome P450 1B1-Testosterone-Metabolite, Mediates Angiotensin II-Induced Renal Dysfunction in Male Mice.

    Science.gov (United States)

    Pingili, Ajeeth K; Thirunavukkarasu, Shyamala; Kara, Mehmet; Brand, David D; Katsurada, Akemi; Majid, Dewan S A; Navar, L Gabriel; Gonzalez, Frank J; Malik, Kafait U

    2016-05-01

    6β-Hydroxytestosterone, a cytochrome P450 1B1-derived metabolite of testosterone, contributes to the development of angiotensin II-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the maintenance of renal homeostasis, development of hypertension, and end-organ damage, this study was conducted to determine the contribution of 6β-hydroxytestosterone to angiotensin II actions on water consumption and renal function in maleCyp1b1(+/+)andCyp1b1(-/-)mice. Castration ofCyp1b1(+/+)mice orCyp1b1(-/-)gene disruption minimized the angiotensin II-induced increase in water consumption, urine output, proteinuria, and sodium excretion and decreases in urine osmolality. 6β-Hydroxytestosterone did not alter angiotensin II-induced increases in water intake, urine output, proteinuria, and sodium excretion or decreases in osmolality inCyp1b1(+/+)mice, but restored these effects of angiotensin II inCyp1b1(-/-)or castratedCyp1b1(+/+)mice.Cyp1b1gene disruption or castration prevented angiotensin II-induced renal fibrosis, oxidative stress, inflammation, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, and angiotensin-converting enzyme. 6β-Hydroxytestosterone did not alter angiotensin II-induced renal fibrosis, inflammation, oxidative stress, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, or angiotensin-converting enzyme inCyp1b1(+/+)mice. However, inCyp1b1(-/-)or castratedCyp1b1(+/+)mice, it restored these effects of angiotensin II. These data indicate that 6β-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end-organ injury associated with angiotensin II-induced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in male mice. PMID:26928804

  19. Brain Angiotensin II Type 1 Receptor Blockade Improves Dairy Blood Pressure Variability via Sympathoinhibition in Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Takuya Kishi

    2015-01-01

    Full Text Available Abnormal blood pressure (BP elevation in early morning is known to cause cardiovascular events. Previous studies have suggested that one of the reasons in abnormal dairy BP variability is sympathoexcitation. We have demonstrated that brain angiotensin II type 1 receptor (AT1R causes sympathoexcitation. The aim of the present study was to investigate whether central AT1R blockade attenuates the excess BP elevation in rest-to-active phase in hypertensive rats or not. Stroke-prone spontaneously hypertensive rats (SHRSP were treated with intracerebroventricular infusion (ICV of AT1R receptor blocker (ARB, oral administration of hydralazine (HYD, or ICV of vehicle (VEH. Telemetric averaged mean BP (MBP was measured at early morning (EM, after morning (AM, and night (NT. At EM, MBP was significantly lower in ARB to a greater extent than in HYD compared to VEH, though MBP at AM was the same in ARB and HYD. At NT, MBP was also significantly lower in ARB than in HYD. These results in MBP were compatible to those in sympathoexcitation and suggest that central AT1R blockade attenuates excess BP elevation in early active phase and continuous BP elevation during rest phase independent of depressor response in hypertensive rats.

  20. Immunohistochemical Localization of AT1a, AT1b, and AT2 Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

    Directory of Open Access Journals (Sweden)

    Courtney Premer

    2013-01-01

    Full Text Available Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for the AT1a receptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus. AT1b and AT2, but not AT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells were AT1b positive while ovoid cells were AT2 positive. In the brain, neurons were AT1a, AT1b, and AT2 positive, but glia was only AT1b positive. Highest levels of AT1a, AT1b, and AT2 receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors.

  1. Increased expression of endothelin ET(B) and angiotensin AT(1) receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Ekelund, Ulf; Edvinsson, Marie-Louise;

    2009-01-01

    group. There were no significant differences in AT(2) and ET(A) receptor expression between the groups. The results indicate that the expression of arterial smooth muscle ET(B) and AT(1) receptors are increased in patients with suspected but ruled out ACS. These receptor changes could be important...... of arterial vasoconstrictor endothelin (ET) and angiotensin (AT) receptors. Our aim was to investigate if the arterial expressions of these receptors are changed in patients with suspected but ruled out acute coronary syndrome (ACS). Small subcutaneous arteries (diameter of 100 microm) were surgically removed....... The control group (controls) consisted of eight healthy volunteers matched for age and sex with no previous cardiac illness or medication. The susp ACS group had an increased expression of ET(B) (by 94%) and AT(1) (by 34%) receptors in the smooth muscle cells of resistance arteries as compared to the control...

  2. Beneficial effects of an angiotensin-II receptor blocker on structural atrial reverse-remodeling in a rat model of ischemic heart failure

    OpenAIRE

    Yoon, Namsik; Cho, Jeong Gwan; Kim, Kye Hun; Park, Keun Ho; Sim, Doo Sun; Yoon, Hyun Ju; Hong, Young Joon; Park, Hyung Wook; Kim, Ju Han; Ahn, Youngkeun; Jeong, Myung Ho; Park, Jong Chun

    2013-01-01

    The remodeling of gap junctions may affect their conduction properties and contribute to the maintenance of atrial fibrillation. The significance of the role of angiotensin-II receptor blockers (ARBs) in upstream therapy is not clear. This study was performed to investigate the effects of ARBs on atrial remodeling in a heart failure model. A model of heart failure was established or sham surgery performed in 24 Sprague-Dawley male rats. The rats were divided into sham, heart failure and heart...

  3. Inhibitory Effect of the Punica granatum Fruit Extract on Angiotensin-II Type I Receptor and Thromboxane B2 in Endothelial Cells Induced by Plasma from Preeclamptic Patients

    OpenAIRE

    Widya Kusumawati; Kusnarman Keman; Setyawati Soeharto

    2016-01-01

    This study aims to evaluate whether the Punica granatum fruit extract modulates the Angiotensin-II Type I receptor (AT1-R) and thromboxane B2 level in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluence, endothelial cells were divided into five groups, which included endothelial cells exposed to 2% plasma from normal pregnancy (NP), endothelial cells exposed to 2% plasma from preeclampti...

  4. Assessment of Effect of AngiotensinReceptor Antagonist Losartan on Aortic Distensibility in Patients With Essential Hypertension by Echocardiography

    Institute of Scientific and Technical Information of China (English)

    杨好意; 邓又斌; 黎春蕾; 毕小军; 潘敏; 常青

    2002-01-01

    Summary: The effects of angiotensinreceptor antagonist losartan on elastic properties of aorta in patients with mild to moderate essential hypertension were assessed. The ascending aortic distensibili-ty in 26 patients (48± 3 years) with mild to moderate essential hypertension before and after 12 weeks of treatment with losartan (50 mg/day) was evaluated by using two-dimensional echocardio graphy. M-mode measurements of aortic systolic (Ds) and diastolic diameter (Dd) were taken at a level approximately 3 cm above the aortic valve. Simultaneously, cuff brachial artery systolic (SBP)and diastolic(DBP) pressures were measured. Aortic pressure-strain elastic modulus (Ep) was calcu lated as Dd × (SBP-DBP)/(Ds-Dd) × 1333 and stiffness index beta (β) was defined as Dd × Ln (SBP/DBP)/(Ds-Dd). Blood pressure significantly decreased from 148±13/95±9 mmHg to 138± 12/88±8 mmHg (systolic blood pressure, P=0. 001; diastolic blood pressure, P=0. 003). Therewas no significant difference in pulse pressure before and after treatment with losartan (53±10 mmHg vs 50± 7 mmHg). The distensibility of ascending aorta increased significantly as showed by the significant decrease in pressure-strain elastic modulus from 4.42± 5.79 × 106 dynes/cm2 to 1.99 ± 1.49 × 106 dynes/cm2 (P=0. 02) and stiffness index beta from 27.4 ± 32.9 to 13.3 ± 9.9 (P = 0. 02). Although there was a weak correlation between the percent changes in pressure-strain elastic modulus and stiffness index beta and that in diastolic blood pressure after losartan treatment (r= 0. 40, P = 0. 04 and r = 0.55, P = 0. 004, respectively), no correlation was found between the percent changes in pressure-strain elastic modulus and stiffness index beta and that in systolic blood pressure (r = 0. 04, P = 0. 8 and r = 0. 24, P = 0. 2, respectively). Our study demonstrated that angiotensinreceptor antagonist losartan has a beneficial effect on aortic distensibility in patients with mild to moderate essential

  5. 受体成分蛋白在降钙素基因相关肽和血管紧张素Ⅱ对血管平滑肌细胞血管过氧化物酶1表达调控中的作用%Involvement of the receptor component protein in the regulation of vascular peroxidase-1 expression induced by calcitonin gene-related peptide and angiotensin Ⅱ in vascular smooth muscle cell

    Institute of Scientific and Technical Information of China (English)

    刘彦梅; 彭虹艳; 郭锋; 全海燕; 骆镜妃; 秦旭平

    2015-01-01

    血管紧张素Ⅱ (angiotensin Ⅱ,Ang Ⅱ)和降钙素基因相关肽(calcitonin gene-related peptide,CGRP)在血管的损伤和保护中起重要作用.为了探讨CGRP受体成分蛋白(receptor component protein,RCP)在CGRP和Ang Ⅱ对血管平滑肌细胞(vascularsmooth muscle cell,VSMC)血管过氧化物酶1(vascular peroxidase-1,VPO1)表达调控中的作用及机制,本研究采用体外培养鼠源性Al0血管平滑肌细胞株(A10VSMC),给予CGRP或/和Ang Ⅱ刺激,并用小干扰RNA (siRNA)干扰细胞RCP基因的表达,Western Blot检测RCP以及VPO1蛋白表达水平;RT-PCR检测RCP及VPO1 mRNA的表达水平.结果显示,在静止期野生型A10VSMC,CGRP和Ang Ⅱ能分别上调RCP和VPO1蛋白和mRNA表达(均P<0.05),但CGRP预孵育细胞后,Ang Ⅱ诱导的RCP和VPO1蛋白表达降低(均P<0.05);与野生型组比较,VPO1在所有RCP基因干扰组的表达均显著降低(均P<0.01).同时,在RCP基因干扰条件下,和对照组相比,CGRP处理组VPO1蛋白的表达显著增加,而Ang Ⅱ组没有明显变化;和Ang Ⅱ1组相比,CGRP与Ang Ⅱ联合作用显著增加VPOl蛋白表达,但这种作用能被抗氧化酶Catalase所抑制(P<0.05).以上结果提示,RCP可能参与CGRP或Ang Ⅱ诱导的VPO1蛋白表达;RCP可能在介导CGRP和Ang Ⅱ受体共同调控VPO1表达的信号转导整合中起一定作用.

  6. An angiotensin II type 1 receptor activation switch patch revealed through evolutionary trace analysis

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Yao, Rong; Ma, Jian-Nong;

    2010-01-01

    Seven transmembrane (7TM) or G protein-coupled receptors constitute a large superfamily of cell surface receptors sharing a structural motif of seven transmembrane spanning alpha helices. Their activation mechanism most likely involves concerted movements of the transmembrane helices, but remains...

  7. An Angiotensin II type 1 receptor activation switch patch revealed through Evolutionary Trace analysis

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Yao, Rong; Ma, Jian-Nong;

    2010-01-01

    Seven transmembrane (7TM) or G protein-coupled receptors constitute a large superfamily of cell surface receptors sharing a structural motif of seven transmembrane spanning alpha helices. Their activation mechanism most likely involves concerted movements of the transmembrane helices, but remains...

  8. Novel angiotensin type 2 (AT2) receptor agonists and uses thereof

    NARCIS (Netherlands)

    de Vries, L.; Nelemans, S.A.; Rink, R.; Roks, A.J.M.; Moll, G.N.

    2012-01-01

    The invention relates to novel pharmaceutically-useful peptides, in particular cyclic peptides that are agonists of the AngII type 2 receptor (AT2 receptor). The invention further relates to the use of such peptides as mecicaments, to pharmaceutical compositions containing them, and to their product

  9. The Role of Apelin on the Alleviative Effect of Angiotensin Receptor Blocker in Unilateral Ureteral Obstruction-Induced Renal Fibrosis

    Directory of Open Access Journals (Sweden)

    Masashi Nishida

    2012-03-01

    Full Text Available Background: Apelin is a selective endogenous ligand of the APJ receptor, which genetically has closest identity to the angiotensin II type 1 receptor (AT-1. The effects of the apelin/APJ system on renal fibrosis still remain unclear. Methods: We examined the effects of the apelin/APJ system on renal fibrosis during AT-1 blockade in a mouse unilateral ureteral obstruction (UUO model. Results: We obtained the following results: (1 At UUO day 7, mRNA expressions of apelin/APJ and phosphorylations of Akt/endothelial nitric oxide synthase (eNOS in the UUO kidney were increased compared to those in the nonobstructed kidney. (2 AT-1 blockade by the treatment with losartan resulted in a further increase of apelin mRNA as well as phosphorylations of Akt/eNOS proteins, and this was accompanied by alleviated renal interstitial fibrosis, decreased myofibroblast accumulation, and a decreased number of interstitial macrophages. (3 Blockade of the APJ receptor by the treatment with F13A during losartan administration completely abrogated the effects of losartan in the activation of the Akt/eNOS pathway and the amelioration of renal fibrosis. (4 Inhibition of NOS by the treatment with L-NAME also resulted in a further increase in renal fibrosis compared to the control group. Conclusion: These results suggest that increased nitric oxide production through the apelin/APJ/Akt/eNOS pathway may, at least in part, contribute to the alleviative effect of losartan in UUO-induced renal fibrosis.

  10. Expression of a naturally occurring angiotensin AT(1) receptor cleavage fragment elicits caspase-activation and apoptosis.

    Science.gov (United States)

    Cook, Julia L; Singh, Akannsha; DeHaro, Dawn; Alam, Jawed; Re, Richard N

    2011-11-01

    Several transmembrane receptors are documented to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. Our prior studies indicate that a population of the 7-transmembrane angiotensin type-1 receptor (AT(1)R) is cleaved in a ligand-augmented manner after which the cytoplasmic, carboxy-terminal cleavage fragment (CF) traffics to the nucleus. In the present report, we determine the precise cleavage site within the AT(1)R by mass spectrometry and Edman sequencing. Cleavage occurs between Leu(305) and Gly(306) at the junction of the seventh transmembrane domain and the intracellular cytoplasmic carboxy-terminal domain. To evaluate the function of the CF distinct from the holoreceptor, we generated a construct encoding the CF as an in-frame yellow fluorescent protein fusion. The CF accumulates in nuclei and induces apoptosis in CHO-K1 cells, rat aortic smooth muscle cells (RASMCs), MCF-7 human breast adenocarcinoma cells, and H9c2 rat cardiomyoblasts. All cell types show nuclear fragmentation and disintegration, as well as evidence for phosphotidylserine displacement in the plasma membrane and activated caspases. RASMCs specifically showed a 5.2-fold increase (P < 0.001) in CF-induced active caspases compared with control and a 7.2-fold increase (P < 0.001) in cleaved caspase-3 (Asp174). Poly(ADP-ribose)polymerase was upregulated 4.8-fold (P < 0.001) in CF expressing cardiomyoblasts and colocalized with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). CF expression also induces DNA laddering, the gold-standard for apoptosis in all cell types studied. CF-induced apoptosis, therefore, appears to be a general phenomenon as it is observed in multiple cell types including smooth muscle cells and cardiomyoblasts. PMID:21813711

  11. Expression of a naturally occurring angiotensin AT(1) receptor cleavage fragment elicits caspase-activation and apoptosis.

    Science.gov (United States)

    Cook, Julia L; Singh, Akannsha; DeHaro, Dawn; Alam, Jawed; Re, Richard N

    2011-11-01

    Several transmembrane receptors are documented to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. Our prior studies indicate that a population of the 7-transmembrane angiotensin type-1 receptor (AT(1)R) is cleaved in a ligand-augmented manner after which the cytoplasmic, carboxy-terminal cleavage fragment (CF) traffics to the nucleus. In the present report, we determine the precise cleavage site within the AT(1)R by mass spectrometry and Edman sequencing. Cleavage occurs between Leu(305) and Gly(306) at the junction of the seventh transmembrane domain and the intracellular cytoplasmic carboxy-terminal domain. To evaluate the function of the CF distinct from the holoreceptor, we generated a construct encoding the CF as an in-frame yellow fluorescent protein fusion. The CF accumulates in nuclei and induces apoptosis in CHO-K1 cells, rat aortic smooth muscle cells (RASMCs), MCF-7 human breast adenocarcinoma cells, and H9c2 rat cardiomyoblasts. All cell types show nuclear fragmentation and disintegration, as well as evidence for phosphotidylserine displacement in the plasma membrane and activated caspases. RASMCs specifically showed a 5.2-fold increase (P < 0.001) in CF-induced active caspases compared with control and a 7.2-fold increase (P < 0.001) in cleaved caspase-3 (Asp174). Poly(ADP-ribose)polymerase was upregulated 4.8-fold (P < 0.001) in CF expressing cardiomyoblasts and colocalized with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). CF expression also induces DNA laddering, the gold-standard for apoptosis in all cell types studied. CF-induced apoptosis, therefore, appears to be a general phenomenon as it is observed in multiple cell types including smooth muscle cells and cardiomyoblasts.

  12. Association of restriction fragment length polymorphism at the atrial natriuretic peptide gene locus with aldosterone responsiveness to angiotensin in aldosterone-producing adenoma.

    Science.gov (United States)

    Tunny, T J; Jonsson, J R; Klemm, S A; Ballantine, D M; Stowasser, M; Gordon, R D

    1994-11-15

    Primary aldosteronism is an important, potentially curable, form of hypertension. We examined the possible association between restriction fragment length polymorphisms in the atrial natriuretic peptide (ANP) gene and responsiveness of aldosterone to angiotensin II in 59 patients with primary aldosteronism due to aldosterone-producing adenoma (APA). Significant differences in the allelic frequencies of the BglI, TaqI and XhoI polymorphic sites at the ANP gene locus (chromosome 1; 1p36) between angiotensin II-unresponsive and angiotensin II-responsive tumors were observed. Variation in the ANP gene between the two groups may result in altered expression of ANP within the adrenal gland, and may contribute to the biochemical regulation of aldosterone production of these two subgroups of patients with APA.

  13. Interaction of signal transduction between angiotensin AT1 and AT2 receptor subtypes in rat senescent heart

    Institute of Scientific and Technical Information of China (English)

    SHI Shu-tian; LI Yan-fang

    2007-01-01

    Background Angiotensin Ⅱ (Ang Ⅱ) acting at angiotensin AT1 receptor (AT1R) has well documented effects on cardiovascular structure such as the promotion of cardiovascular hypertrophy and fibrosis, which are believed to be opposed by angiotensin AT2 receptor (AT2R) stimulation. The expressions of AT1R and AT2R are up-regulated in senescent hearts. The purpose of this study was to investigate the interaction of signal transduction between AT1R and AT2R, and to detect whether there is any difference in the interaction in rat hearts of different age.Methods In 3.5-, 12-, 18- and 24-month-old rats, the heart cell membrane activities of protein kinase C (PKC) andtyrosine kinase were measured when AT1R and AT2R were both activated by Ang Ⅱ or just the AT1R was activated by Ang Ⅱ and PD123319. The activities of cytosolic phospholipase A2 (cPLA2) and the levels of cGMP were investigated when AT1R and AT2R were both activated by Ang Ⅱ or just the AT2R was activated by Ang Ⅱ and Iosartan.Results When AT1R and AT2R were both activated compared to when the AT1R was activated, the activities of PKC were not different in hearts from 3.5- and 12-month-old rats, but decreased significantly in 18- and 24-month-old rats; the activities of tyrosine kinase were not different in 3.5-month-old rats but decreased significantly in 12-, 18- and 24-month-old rats. The activities of cPLA2 were all decreased significantly in rats of different age when AT1R and AT2R were both activated compared to when the AT2R was activated. Treatment with Ang Ⅱ alone compared to Ang Ⅱ and losartan decreased the levels of cGMP (fmol/mg) in rats of different age (102.7±12.7 versus 86.0±8.0 in 3.5-month-old rats, P<0.05; 81.0±9.4 versus 70.0±6.3 in 12-month-old rats, P<0.05; 69.8±5.6 versus 54.2±5.3 in 18-month-old rats,P<0.01; 57.7±8.0 versus 39.0±3.0 in 24-month-old rats, P<0.01).Conclusions The activation of AT1R inhibited the signal transduction of AT2R during the aging

  14. Deletion of angiotensin II type 2 receptor accelerates adipogenesis in murine mesenchymal stem cells via Wnt10b/beta-catenin signaling.

    Science.gov (United States)

    Matsushita, Kenichi; Wu, Yaojiong; Pratt, Richard E; Dzau, Victor J

    2016-08-01

    Recent evidence suggests that the renin-angiotensin system (RAS) has a vital role in adipocyte biology and the pathophysiology of metabolic syndrome. Obesity is the main culprit of metabolic syndrome; and mesenchymal stem cells (MSCs) have been forwarded as a major source of adipocyte generation. Previously, we reported that MSCs have a local RAS and that pharmacological blockade of angiotensin II type 2 receptor (AT2R) promotes adipogenesis in human MSCs. However, the definitive roles of AT2R and how AT2R functions in adipogenesis remains unknown. To this end, we employed AT2R-null murine MSCs to characterize how AT2R affects the differentiation of MSCs into adipocytes. Murine MSCs were isolated from AT2R-null mice and wild-type littermates, grown to confluency, and then differentiated into adipocytes. Adipogenesis was quantitated by assessing the lipid droplet accumulation. Using the lipophilic fluorescent dye, the AT2R-null cells showed significantly increased total fluorescence (261.6±49.6% vs littermate) on day 7. Oil red O staining followed by extraction of the absorbed dye and measurement of the absorbance on day 14 also exhibited significantly increased lipid droplet accumulation in the AT2R-null cells (202.7±14.1% vs littermate). We also examined the expression of adipogenic marker genes by quantitative RT-PCR. The AT2R-null group exhibited significantly increased expression of PPAR-gamma, fatty acid synthase, and adiponectin (vs littermate). We further examined the role of Wnt10b/beta-catenin signaling, which reportedly has an important inhibitory role in adipogenesis. The AT2R-null group exhibited significantly decreased Wnt10b expression accompanied by decreased beta-catenin (vs littermate). Our results thus revealed that the AT2R inhibits adipogenic differentiation in murine MSCs. Moreover, this inhibitory effect is associated with Wnt10b/beta-catenin signaling. These results provide important insights into the pathophysiology of obesity and obesity

  15. Genetic polymorphisms of angiotensin-2 type 1 receptor and angiotensinogen and risk of renal dysfunction and coronary heart disease in type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Hu Frank B

    2009-03-01

    Full Text Available Abstract Background Increased activation of the renin-angiotensin system (RAS may be important in promoting coronary heart disease (CHD and renal dysfunction, but limited data are available on associations between angiotensin type 1 receptor (AGT1R and angiotensinogen (AGT genotypes in type 2 diabetes. Methods Study participants were diabetics from the Health Professionals Follow-Up Study (HPFS and the Nurses' Health Study (NHS. We analyzed single nucleotide polymorphisms (SNPs associated with cardiovascular pathophysiology (including AGT1R T573C, AGT1R A1166C, and AGT M235T and presence of renal dysfunction (eGFR2 or history of CHD. Results The AGT1R 1166 C-allele was associated with eGFR2 (multivariable OR 1.63 [1.01, 2.65] in the HPFS men (n = 733 and in the combined dataset (n = 1566 (OR 1.42 [1.02, 1.98]. The AGT1R 1166 C-allele was also associated with CHD in men (OR 1.57 [1.10, 2.24]. In NHS women (n = 833, AGT 235T-allele was associated with CHD (OR 1.72 [1.20, 2.47]. Removal of hypertension from the fully adjusted models did not influence results, suggesting that the associations may not be mediated by hypertension. There were significant interactions between sex and AGT1R 1166 C-allele (p = 0.008 and AGT M235T (p = 0.03 in models for CHD. No significant associations were seen between AGT1R T573 C-allele and renal dysfunction or CHD. Conclusion Polymorphisms in AGT1R and AGT genes are associated with renal dysfunction and CHD in type 2 diabetes and further support the important role of the RAS in these complications. Sex may modify associations between AGT1R 1166 C-allele and AGT 235T and CHD in type 2 diabetes.

  16. Dietary NaC1 during pregnancy and lactation: effect on brain angiotensin II receptors and behavior.

    Science.gov (United States)

    Rowland, N E; Crews, E C; Young, S L; Speth, R C

    1999-10-01

    Female rats were fed diets containing either a basal (0.12%), mid- (1%) or high (3%) level of NaCl during pregnancy and lactation. Plasma aldosterone was elevated approximately 5- and 15-fold in dams fed basal compared with either the mid- or high-NaCl diets at the end of both pregnancy and lactation (Postnatal Day 21), respectively. Dams fed basal diet and killed at the end of lactation had a higher density of angiotensin II receptors in the organum vasculosum laminae terminalis, paraventricular hypothalamus, and median preoptic nucleus than did rats fed either mid- or high-NaCl diets. Other dams, treated identically, were returned to rodent chow (approximately 0.2% NaCl) at the end of lactation for intake tests during the next week. Dams that had received basal diet did not differ from mid-NaCl and high-NaCl groups in sodium appetite induced by either acute sodium depletion or mineralocorticoid administration but showed the lowest spontaneous intake of NaCl solution.

  17. Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

    Science.gov (United States)

    Hsiao, Hsiu-Ling; Langenickel, Thomas Heiko; Greeley, Michael; Roberts, John; Zhou, Wei; Pal, Parasar; Rebello, Sam; Rajman, Iris; Sunkara, Gangadhar

    2015-11-01

    LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies. PMID:27137712

  18. The Effect of an Angiotensin Receptor Blocker on Arterial Stiffness in Type 2 Diabetes Mellitus Patients with Hypertension

    Directory of Open Access Journals (Sweden)

    Ji Hyun Kim

    2011-06-01

    Full Text Available BackgroundHypertension and type 2 diabetes mellitus are major risk factors for cardiovascular disease. This study analyzed the changes in central aortic waveforms and pulse wave velocity as well as related parameters after treatment with valsartan, an angiotensin II type 1 receptor blocker, in patients with type 2 diabetes and hypertension.MethodsWe used pulse wave analysis to measure central aortic waveform in a total of 98 subjects. In 47 of these patients, pulse wave velocity measurements were obtained before and after 12 weeks of treatment with valsartan.ResultsIn the central aortic waveform analysis, the aortic pulse pressure and augmentation index were significantly decreased after valsartan treatment, as was the aortic pulse wave velocity. Factors contributing to the improvement in pulse wave velocity were the fasting blood glucose and haemoglobin A1c levels.ConclusionShort-term treatment with valsartan improves arterial stiffness in patients with type 2 diabetes and hypertension, and the glucose status at baseline was associated with this effect.

  19. Temporal Alterations in Vascular Angiotensin Receptors and Vasomotor Response in Offspring of Protein-restricted Rat Dams

    Science.gov (United States)

    SATHISHKUMAR, Kunju; BALAKRISHNAN, Meena; CHINNATHAMBI, Vijayakumar; GAO, Haijun; YALLAMPALLI, Chandra

    2012-01-01

    Objective Examine temporal alterations in vascular angiotensin II (ANG II) receptors (AT1R and AT2R) and determine vascular response to ANG II in growth-restricted offspring. Study design Offspring of pregnant rats fed low-protein (6%) and control (20%) diet were compared. Results Prenatal protein restriction reprogrammed AT1aR mRNA expression in males’ mesenteric arteries to cause 1.7- and 2.3-fold increases at 3 and 6 months of age associated with arterial pressure increases of 10 and 33 mmHg, respectively; however, in females, increased AT1aR expression (2-fold) and arterial pressure (15 mmHg) occurred only at 6 months. Prenatal protein restriction did not affect AT2R expression. Losartan abolished hypertension, suggesting that AT1aR plays a primary role in arterial pressure elevation. Vasoconstriction to ANG II was exaggerated in all protein-restricted offspring, with greater potency and efficacy in males. Conclusion Prenatal protein restriction increased vascular AT1R expression and vasoconstriction to ANG II, possibly contributing to programmed hypertension. PMID:22537420

  20. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure

    DEFF Research Database (Denmark)

    McMurray, John J V; Packer, Milton; Desai, Akshay S;

    2013-01-01

    AIMS: Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin-angiotensin-aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and n...... 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death. PERSPECTIVES: PARADIGM-HF will determine the place of the ARNI LCZ696...

  1. Heterogeneous Downregulation of Angiotensin II AT1-A and AT1-B Receptors in Arterioles in STZ-Induced Diabetic Rat Kidneys

    Directory of Open Access Journals (Sweden)

    Zsolt Razga

    2014-01-01

    Full Text Available Introduction. The renin granulation of kidney arterioles is enhanced in diabetes despite the fact that the level of angiotensin II in the diabetic kidney is elevated. Therefore, the number of angiotensin II AT1-A and AT1-B receptors in afferent and efferent arteriole’s renin-positive and renin-negative smooth muscle cells (SMC was estimated. Method. Immunohistochemistry at the electron microscopic level was combined with 3D stereological sampling techniques. Results. In diabetes the enhanced downregulation of AT1-B receptors in the renin-positive than in the renin-negative SMCs in both arterioles was resulted: the significant difference in the number of AT1 (AT1-A + AT1-B receptors between the two types of SMCs in the normal rats was further increased in diabetes and in contrast with the significant difference observed between the afferent and efferent arterioles in the normal animals, there was no such difference in diabetes. Conclusions. The enhanced downregulation of the AT1-B receptors in the renin-negative SMCs in the efferent arterioles demonstrates that the regulation of the glomerular filtration rate by the pre- and postglomerular arterioles is changed in diabetes. The enhanced downregulation of the AT1-B receptors in the renin-positive SMCs in the arterioles may result in an enhanced level of renin granulation in the arterioles.

  2. Exogenous angiotensin II does not facilitate norepinephrine release in the heart

    NARCIS (Netherlands)

    Th.W. Lameris (Thomas); P.A. de Zeeuw (Sandra); D.J.G.M. Duncker (Dirk); G. Alberts; F. Boomsma (Frans); P.D. Verdouw (Pieter); A.H. van den Meiracker (Anton)

    2002-01-01

    textabstractStudies on the effect of angiotensin II on norepinephrine release from sympathetic nerve terminals through stimulation of presynaptic angiotensin II type 1 receptors are equivocal. Furthermore, evidence that angiotensin II activates the cardiac sympathetic nervous syste

  3. A PROSPECTIVE STUDY OF EFFECT OF TELMISARTAN (ANGIOTENSIN II RECEPTOR BLOCKER ON METABOLIC PARAMETERS IN HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME

    Directory of Open Access Journals (Sweden)

    Somesekhar

    2016-04-01

    Full Text Available BACKGROUND The metabolic syndrome is currently a major worldwide epidemic. It strongly associates with obesity, insulin resistance, type 2 diabetes, and cardiovascular diseases, which are major pathologies contributing to mortality and morbidity worldwide. The effect of PPAR-y on metabolic syndrome is significant it is critical regulator of adipogenesis the gain in PPAR-y is resulted in obesity but loss of PPAR–y by mutation is associated with loss of weight and insulin resistance. Telmisartan is an orally active, long-acting, non-peptide angiotensin type 1 (ATI receptor blocker. In addition to this, it has been identified as partial agonist/selective modulator of the nuclear hormone receptor PPAR-y. MATERIAL AND METHOD This is a prospective, randomised and open labelled 16 weeks study conducted in the Dept. of General Medicine, Konaseema Institute of Medical Science, Amalapuram. Present study is designed to study the effect of telmisartan on various metabolic parameters in hypertensive patients who fulfilled the criteria of metabolic syndrome. RESULT There was statistically significant change in all parameters most important was lipid profile; LDL concentration was decreased from 139.2 mg/dL to 120.2 mg/dL. Baseline triglyceride concentration was 161.0 mg/dL which was changed 152.8 mg/dL Total cholesterol was decreased from 203.2 to 193.8 mg/dL. CONCLUSION In our study, we have also found that use of telmisartan is associated with decrease in lipid concentration in addition to its effect on blood pressure regulation. But a long term study with high dose required of this drug is required because safety profile of this drug is better than thiazolidinedione. Financial part of this study is our limitation.

  4. Angiotensin II receptor and postreceptor events in adrenal glomerulosa cells from streptozotocin-induced diabetic rats with hypoaldosteronism.

    Science.gov (United States)

    Azukizawa, S; Kaneko, M; Nakano, S; Kigoshi, T; Uchida, K; Morimoto, S

    1991-11-01

    Streptozotocin-induced chronic diabetic rats develop hyporeninemic hypoaldosteronism. The hypoaldosteronism is associated with selective unresponsiveness of aldosterone to angiotensin II (AII) and an atrophy of the zona glomerulosa. To assess the nature of the adrenal unresponsiveness to AII, we examined the [125I]monoiodoAII binding and the responses of pregnenolone formation and aldosterone production to AII using adrenal glomerulosa cells from diabetic rats 6 weeks after an injection of streptozotocin. Comparisons were made using the cells from control rats treated with vehicle. Diabetic rats had low levels of plasma renin activity, plasma 18-hydroxycorticosterone, and plasma aldosterone, and normal levels of plasma corticosterone and plasma potassium. The zona glomerulosa width was narrower in diabetic than in control rats. Scatchard analysis of the AII binding data demonstrated that the number and affinity of the receptors were similar in the cells from control and diabetic rats. When corrected to an uniform number of cells per group, baseline levels of pregnenolone formation and aldosterone production were similar in the cells from control and diabetic rats. However, cells from diabetic rats had a less sensitive and lower response of both pregnenolone formation and aldosterone production to AII. In contrast, the effect of ACTH on pregnenolone formation and aldosterone production was similar in the cells from control and diabetic rats. These results indicate that the main defect responsible for the hypoaldosteronism may be located on some step(s) mediating between AII receptors and conversion of cholesterol to pregnenolone, presumably on the calcium messenger system, with a disturbance downstream from AII binding.

  5. Angiotensin II modulates interleukin-1{beta}-induced inflammatory gene expression in vascular smooth muscle cells via interfering with ERK-NF-{kappa}B crosstalk

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Shanqin [Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (United States); Zhi, Hui [Cardiovascular Division, Department of Medicine, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States); Hou, Xiuyun [Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (United States); Jiang, Bingbing, E-mail: bjiang1@rics.bwh.harvard.edu [Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (United States); Cardiovascular Division, Department of Medicine, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States)

    2011-07-08

    Highlights: {yields} We examine how angiotensin II modulates ERK-NF-{kappa}B crosstalk and gene expression. {yields} Angiotensin II suppresses IL-1{beta}-induced prolonged ERK and NF-{kappa}B activation. {yields} ERK-RSK1 signaling is required for IL-1{beta}-induced prolonged NF-{kappa}B activation. {yields} Angiotensin II modulates NF-{kappa}B responsive genes via regulating ERK-NF-{kappa}B crosstalk. {yields} ERK-NF-{kappa}B crosstalk is a novel mechanism regulating inflammatory gene expression. -- Abstract: Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1. In cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1{beta}-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-{kappa}B, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1{beta}-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1{beta}, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE{sup -/-}) mice. VCAM-1 and iNOS expression were higher in ApoE{sup -/-} than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE{sup -/-} mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that angiotensin

  6. Direct stimulation of angiotensin II type 2 receptor enhances spatial memory

    DEFF Research Database (Denmark)

    Jing, Fei; Mogi, Masaki; Sakata, Akiko;

    2012-01-01

    evaluated by the Morris water maze test in C57BL6 mice, but this effect was not observed in AT(2) receptor-deficient mice. However, C21-induced cognitive enhancement in C57BL6 mice was attenuated by coadministration of icatibant, a bradykinin B(2) receptor antagonist. Administration of C21 dose dependently...... increased cerebral blood flow assessed by laser speckle flowmetry and hippocampal field-excitatory postsynaptic potential (f-EPSP) determined by electrophysiological techniques in C57BL6 mice. Furthermore, activation of the AT(2) receptor by C21 promoted neurite outgrowth of cultured hippocampal neurons...... prepared from fetal transgenic mice expressing green fluorescent protein. Finally, we investigated the pathologic relevance of C21 for spatial learning using an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid-β (1 to 40). We observed that treatment with C21 prevented...

  7. Reversible Fetal Renal Impairment following Angiotensin Receptor Blocking Treatment during Third Trimester of Pregnancy: Case Report and Review of the Literature.

    Science.gov (United States)

    Saar, Tal; Levitt, Lorinne; Amsalem, Hagai

    2016-01-01

    Background. Late pregnancy usage of angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) may cause severe oligohydramnios due to fetal renal impairment. Affected neonates will often suffer from fatal, renal, and respiratory failure. Case. A 39-year-old multigravida admitted due to anhydramnios secondary to valsartan (ARB) exposure at 30 weeks' gestation. Following secession of treatment amniotic fluid volume returned to normal. Delivery was induced at 34 weeks' gestation following premature rupture of membranes and maternal fever. During the two-year follow-up, no signs of renal insufficiency were noted. Conclusions. This description of reversible fetal renal damage due to ARB intake during pregnancy is the first to show no adverse renal function in a two-year follow-up period. This case may help clinicians counsel patients with pregnancies complicated by exposure to these drugs. PMID:27672462

  8. Reversible Fetal Renal Impairment following Angiotensin Receptor Blocking Treatment during Third Trimester of Pregnancy: Case Report and Review of the Literature

    Science.gov (United States)

    Saar, Tal; Levitt, Lorinne

    2016-01-01

    Background. Late pregnancy usage of angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) may cause severe oligohydramnios due to fetal renal impairment. Affected neonates will often suffer from fatal, renal, and respiratory failure. Case. A 39-year-old multigravida admitted due to anhydramnios secondary to valsartan (ARB) exposure at 30 weeks' gestation. Following secession of treatment amniotic fluid volume returned to normal. Delivery was induced at 34 weeks' gestation following premature rupture of membranes and maternal fever. During the two-year follow-up, no signs of renal insufficiency were noted. Conclusions. This description of reversible fetal renal damage due to ARB intake during pregnancy is the first to show no adverse renal function in a two-year follow-up period. This case may help clinicians counsel patients with pregnancies complicated by exposure to these drugs. PMID:27672462

  9. The bradykinin BK2 receptor mediates angiotensin II receptor type 2 stimulated rat duodenal mucosal alkaline secretion

    Directory of Open Access Journals (Sweden)

    Helander Herbert F

    2003-02-01

    Full Text Available Abstract Background This study investigates bradykinin and nitric oxide as potential mediators of AT2-receptor-stimulated duodenal mucosal alkaline secretion. Duodenal mucosal alkaline secretion was measured in methohexital- and α-chloralose-anaesthetised rats by means of in situ pH-stat titration. Immunohistochemistry and Western blot were used to identify the BK2 receptors. Results The AT2 receptor agonist CGP42112A (0.1 μg kg-1 min-1 administered intravenously increased the duodenal mucosal alkaline secretion by ~50 %. This increase was sensitive to the selective BK2 receptor blocker HOE140 (100 ng/kg iv, but not to luminal administration of the NOS blocker L-NAME (0.3 mM. Mean arterial pressure did not differ between groups during the procedures. Immunohistochemistry showed a distinct staining of the crypt epithelium and a moderate staining of basal cytoplasm in villus enterocytes. Conclusion The results suggest that the AT2-receptor-stimulated alkaline secretion is mediated via BK2 receptors located in the duodenal cryptal mucosal epithelium.

  10. Expression of angiotensin-converting enzyme mRNA gene in the kidneys of patients with glomerulonephrites

    Directory of Open Access Journals (Sweden)

    Alsayed Ahmed Alnahal

    2012-01-01

    Full Text Available A little is known about the behavior of the renin-angiotensin system (RAS in glomerulo-nephritis (GN, although it is activated in other models of injury. To study renal angiotensin-converting enzyme (ACE messenger ribonucleic acid (mRNA gene expression in patients with GN to determine its role in the disease process and other factors that may influence the course of the disease and the prognosis, e.g. treatment with ACE inhibitor (ACEI drugs, we studied 20 patients with GN allocated to two groups: ten patients received an ACEI drug and ten patients did not receive ACEI in addition to a control group of ten healthy subjects. Routine and special laboratory investigation, histopathological studies and quantitative polymerase chain reaction analysis for renal ACE mRNA were done for both the study and the control groups. There was a statistically significant increase in ACE mRNA gene expression in the GN groups than in control group, but no statistically significant difference in ACE mRNA gene expression between the patients group that received and the group that did not receive ACEI. A significant correlation was found between the ACE mRNA gene expression and the mean blood pressure, serum creatinine, blood urea nitrogen and 24-h urinary protein. In conclusion, a higher level of ACE mRNA gene expression in patients suffering from GN may suggest a role of the RAS in the process of GN, perhaps contributing to glomerular hypertrophy and matrix overproduction. The use of ACEI drugs possibly slows the rate of progression of renal failure and plays a role in controlling the pathophysiology.

  11. Expression of angiotensin-converting enzyme mRNA gene in the kidneys of patients with glomerulonephrites.

    Science.gov (United States)

    Alnahal, Alsayed Ahmed; Khalil, Usama Ahmed; Diab, Magada Alsayed; Zanaty, Ali Fahmy

    2012-09-01

    A little is known about the behavior of the renin-angiotensin system (RAS) in glomerulo-nephritis (GN), although it is activated in other models of injury. To study renal angiotensin-converting enzyme (ACE) messenger ribonucleic acid (mRNA) gene expression in patients with GN to determine its role in the disease process and other factors that may influence the course of the disease and the prognosis, e.g. treatment with ACE inhibitor (ACEI) drugs, we studied 20 patients with GN allocated to two groups: ten patients received an ACEI drug and ten patients did not receive ACEI in addition to a control group of ten healthy subjects. Routine and special laboratory investigation, histopathological studies and quantitative polymerase chain reaction analysis for renal ACE mRNA were done for both the study and the control groups. There was a statistically significant increase in ACE mRNA gene expression in the GN groups than in control group, but no statistically significant difference in ACE mRNA gene expression between the patients group that received and the group that did not receive ACEI. A significant correlation was found between the ACE mRNA gene expression and the mean blood pressure, serum creatinine, blood urea nitrogen and 24-h urinary protein. In conclusion, a higher level of ACE mRNA gene expression in patients suffering from GN may suggest a role of the RAS in the process of GN, perhaps contributing to glomerular hypertrophy and matrix overproduction. The use of ACEI drugs possibly slows the rate of progression of renal failure and plays a role in controlling the pathophysiology.

  12. Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: A role for angiotensin type 1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Yogi, Alvaro; Callera, Glaucia E. [Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario (Canada); Mecawi, André S. [Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP (Brazil); Batalhão, Marcelo E.; Carnio, Evelin C. [Department of General and Specialized Nursing, College of Nursing of Ribeirão Preto, USP, São Paulo (Brazil); Antunes-Rodrigues, José [Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP (Brazil); Queiroz, Regina H. [Department of Clinical, Toxicological and Food Science Analysis, Faculty of Pharmaceutical Sciences, USP, São Paulo (Brazil); Touyz, Rhian M. [Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ontario (Canada); Tirapelli, Carlos R., E-mail: crtirapelli@eerp.usp.br [Department of Psychiatric Nursing and Human Sciences, Laboratory of Pharmacology, College of Nursing of Ribeirão Preto, USP, Ribeirão Preto, SP (Brazil)

    2012-11-01

    Ethanol intake is associated with increase in blood pressure, through unknown mechanisms. We hypothesized that acute ethanol intake enhances vascular oxidative stress and induces vascular dysfunction through renin–angiotensin system (RAS) activation. Ethanol (1 g/kg; p.o. gavage) effects were assessed within 30 min in male Wistar rats. The transient decrease in blood pressure induced by ethanol was not affected by the previous administration of losartan (10 mg/kg; p.o. gavage), a selective AT{sub 1} receptor antagonist. Acute ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels. Ethanol induced systemic and vascular oxidative stress, evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels, NAD(P)H oxidase‐mediated vascular generation of superoxide anion and p47phox translocation (cytosol to membrane). These effects were prevented by losartan. Isolated aortas from ethanol-treated rats displayed increased p38MAPK and SAPK/JNK phosphorylation. Losartan inhibited ethanol-induced increase in the phosphorylation of these kinases. Ethanol intake decreased acetylcholine-induced relaxation and increased phenylephrine-induced contraction in endothelium-intact aortas. Ethanol significantly decreased plasma and aortic nitrate levels. These changes in vascular reactivity and in the end product of endogenous nitric oxide metabolism were not affected by losartan. Our study provides novel evidence that acute ethanol intake stimulates RAS activity and induces vascular oxidative stress and redox-signaling activation through AT{sub 1}-dependent mechanisms. These findings highlight the importance of RAS in acute ethanol-induced oxidative damage. -- Highlights: ► Acute ethanol intake stimulates RAS activity and vascular oxidative stress. ► RAS plays a role in acute ethanol-induced oxidative damage via AT{sub 1} receptor activation.

  13. Acute ethanol intake induces superoxide anion generation and mitogen-activated protein kinase phosphorylation in rat aorta: A role for angiotensin type 1 receptor

    International Nuclear Information System (INIS)

    Ethanol intake is associated with increase in blood pressure, through unknown mechanisms. We hypothesized that acute ethanol intake enhances vascular oxidative stress and induces vascular dysfunction through renin–angiotensin system (RAS) activation. Ethanol (1 g/kg; p.o. gavage) effects were assessed within 30 min in male Wistar rats. The transient decrease in blood pressure induced by ethanol was not affected by the previous administration of losartan (10 mg/kg; p.o. gavage), a selective AT1 receptor antagonist. Acute ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels. Ethanol induced systemic and vascular oxidative stress, evidenced by increased plasma thiobarbituric acid-reacting substances (TBARS) levels, NAD(P)H oxidase‐mediated vascular generation of superoxide anion and p47phox translocation (cytosol to membrane). These effects were prevented by losartan. Isolated aortas from ethanol-treated rats displayed increased p38MAPK and SAPK/JNK phosphorylation. Losartan inhibited ethanol-induced increase in the phosphorylation of these kinases. Ethanol intake decreased acetylcholine-induced relaxation and increased phenylephrine-induced contraction in endothelium-intact aortas. Ethanol significantly decreased plasma and aortic nitrate levels. These changes in vascular reactivity and in the end product of endogenous nitric oxide metabolism were not affected by losartan. Our study provides novel evidence that acute ethanol intake stimulates RAS activity and induces vascular oxidative stress and redox-signaling activation through AT1-dependent mechanisms. These findings highlight the importance of RAS in acute ethanol-induced oxidative damage. -- Highlights: ► Acute ethanol intake stimulates RAS activity and vascular oxidative stress. ► RAS plays a role in acute ethanol-induced oxidative damage via AT1 receptor activation. ► Translocation of p47

  14. Increased angiotensin II type 1 receptor expression in temporal arteries from patients with giant cell arteritis

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Malmsjö, Malin; Andersson, Christina;

    2009-01-01

    -AT(2) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries. MAIN OUTCOME MEASURES: AT(1) and AT(2) receptor immunostaining intensity was quantified. RESULTS: Hematoxylin-eosin-stained sections of temporal arteries from patients with GCA showed intimal hyperplasia...

  15. The Protective Arm of the Renin Angiotensin System (RAS)

    DEFF Research Database (Denmark)

    The Protective Arm of the Renin Angiotensin System: Functional Aspects and Therapeutic Implications is the first comprehensive publication to signal the protective role of a distinct part of the renin-angiotensin system (RAS), providing readers with early insight into a complex system which...... will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1-7) peptide with its receptor...... understanding of the protective side of the Renin Angiotensin System (RAS) involving angiotensin AT2 receptor, ACE2, and Ang(1-7)/Mas receptor Combines the knowledge of editors who pioneered research on the protective renin angiotensin system including; Dr. Thomas Unger, one of the founders of AT2 receptor...

  16. Interaction between angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin-converting enzyme inhibition on survival in hemodialyzed patients.

    Science.gov (United States)

    Kiss, István; Ambrus, Csaba; Kulcsár, Imre; Szegedi, János; Kerkovits, Lóránt; Tislér, András; Kiss, Zoltán

    2014-12-01

    The association between ACE (angiotensin-converting enzyme) gene insertion/deletion (I/D) polymorphism and mortality has been inconsistently observed in earlier studies in patients on maintenance hemodialysis. We hypothesized that the effect of ACE gene I/D polymorphism on mortality may be influenced by concurrent ACE inhibitor therapy in this population. In this prospective, multicenter cohort, observational study, data was collected from 716 prevalent chronic hemodialysis patients, blood samples were genotyped for I/D single nucleotide polymorphism. Patient mortality was assessed in tree genotype groups insertion/insertion, insertion/deletion and deletion/deletion (I/I, I/D, and D/D) using multivariate Cox proportional hazard models. The most frequent genotype was I/D (42.6%), followed by D/D (37.7%) and I/I (19.7%) genotypes. The mean age was 54.9±15.5 years, 53.2% of all patients were male and in the total group the prevalence of diabetes was 19.3%. ACE inhibitor therapy was prescribed for 47.9% of all patients. The median duration of dialysis before blood sampling was 23.8 months (IQR 11.2-47.1). Patients were followed for 10 years, the median follow-up time was 29.8 months (IQR 12.6-63.4). Patient characteristics were well balanced among the genotype groups. D/D genotype, was associated with inferior survival (I/I vs D/D: log-rank test: P=0.04) in patients not receiving ACE inhibitor therapy, and the presence of this therapy diminished this difference. There was no difference in survival among unselected patients with different genotypes. In multivariate Cox regression models, D/D genotype (compared to I/I) was a significant predictor of mortality only in patients without ACE inhibitor therapy (HR 0.67, 95% CI 0.46-0.97, P=0.03). Our data suggests that hemodialyzed patients with the deletion/deletion (D/D) genotype might have inferior outcome, and ACE inhibitor therapy may be associated with improved survival in this subgroup. PMID:25526485

  17. Angiotensin II Type 2-Receptor Agonist C21 Reduces Proteinuria and Oxidative Stress in Kidney of High-Salt-Fed Obese Zucker Rats.

    Science.gov (United States)

    Patel, Sanket N; Ali, Quaisar; Hussain, Tahir

    2016-05-01

    Oxidative and nitrosative stress have been implicated in high-sodium diet (HSD)-related hypertensive renal injury. In this study, we investigated angiotensin II type 2-receptor-mediated renoprotection in obese Zucker rats fed HSD. Obese Zucker rats were fed normal sodium diet or HSD 4%, for 14 days, with/without angiotensin II type 2-receptor agonist C21, delivered subcutaneously via osmotic pump, 1 mg/kg per day. Compared with normal sodium diet controls, HSD rats exhibited increase in cortical nicotinamide adenine dinucleotide phosphate oxidase activity, urinary H2O2, and 8-isoprostanes, which were associated with severe glomerulosclerosis, interstitial fibrosis, decline in estimated glomerular filtration rate, and an increase in urinary leak and activity ofN-acetyl-β-d-glucosaminidase, a lysosomal enzyme and a marker of tubular damage. These changes were improved by C21 treatment. Cortical expression of endothelial nitric oxide synthase, phospho-endothelial nitric oxide synthase (Ser(1177)), and plasma nitrites were reduced after HSD intake, whereas nitrosative stress (3-nitrotyrosine) and enzymatic defense (superoxide dismutase-to-catalase activity) remained unaltered. However, C21 preserved plasma nitrites in HSD-fed obese Zucker rat. C21 treatment reduced protein-to-creatinine, albumin-to-creatinine, as well as fractional excretion of protein and albumin in HSD-fed obese Zucker rat, which is independent of changes in protein recycling receptors, megalin, and cubilin. HSD intake also altered renal excretory and reabsorptive capacity as evident by elevated plasma urea nitrogen-to-creatinine and fractional excretion of urea nitrogen, and reduced urine-to-plasma creatinine, which were modestly, but insignificantly, improved by C21 treatment. Together results demonstrate that angiotensin II type 2-receptor activation protects against HSD-induced kidney damage in obesity plausibly by reducing nicotinamide adenine dinucleotide phosphate oxidase activity and

  18. Applications of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in the treatment of chronic heart failure%血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂在慢性心力衰竭治疗中的应用

    Institute of Scientific and Technical Information of China (English)

    居海宁; 卞金陵

    2011-01-01

    Heart failure is the ultimate cause of death in a variety of heart diseases. It has been discovered that the main strategy of slowing the progress of heart failure diseases is blocking the renin angiotensin aldosterone system (RAAS). Angiotensin converting enzyme inhibitors(ACEI) and angiotensin receptor blockers( ARB) are the most commonly used RAAS-blocking drugs. In this paper,the assessment of chronic heart failure and the applications of ACEI and ARB in the treatment of chronic heart failure are reviewed.%心力衰竭是多种心脏病的最终死亡原因,阻断肾素-血管紧张素-醛固酮系统(renin angiotensin aldosterone system,RAAS)是减慢心力衰竭病变进展的主要策略.血管紧张素转换酶抑制剂(angiotensin converting enzyme inhibitors,ACEI)和血管紧张素受体拮抗剂(angiotensin receptor blockers,ARB)是目前最常用的阻断RAAS的药物.本文对慢性心力衰竭评估,以及ACEI和ARB在慢性心力衰竭治疗中的应用进行综述.

  19. The renin-angiotensin system and its vasoactive metabolite angiotensin-(1-7) in the mechanism of the healing of preexisting gastric ulcers. The involvement of Mas receptors, nitric oxide, prostaglandins and proinflammatory cytokines.

    Science.gov (United States)

    Pawlik, M W; Kwiecien, S; Ptak-Belowska, A; Pajdo, R; Olszanecki, R; Suski, M; Madej, J; Targosz, A; Konturek, S J; Korbut, R; Brzozowski, T

    2016-02-01

    The inhibition of angiotensin-converting enzyme (ACE) or the blockade of angiotensin (Ang) AT-1 receptors affords protection against acute gastric mucosal injury, but whether the major metabolite of renin-angiotensin system (RAS), Ang-(1-7), accelerates the healing process of preexisting gastric ulcers remains unknown. Previous studies documented that Ang-(1-7) acting via its own Mas receptor exerts vascular responses opposing those of Ang II. We studied the effects of the Ang-(1-7)/Mas receptor axis on the healing rate of acetic-acid-induced gastric ulcers with or without the blockade of Mas receptors by A 779 and compared it with the effects of activation and blockade of the AT-1 receptor by the treatment with Ang II and losartan, respectively, the inhibition of ACE by lisinopril, the NO/cNOS inhibition by L-NAME and inhibition of prostaglandin/COX system by indomethacin in the presence of Ang-(1-7). Additionally, ex vivo metabolism of Ang I in gastric tissue was assessed by LC/MS method. At day 9 after ulcer induction, the area of these ulcers and the accompanying changes in total gastric blood flow (GBF) were determined as were gastric mucosal blood flow (GMBF) at ulcer margin and gastric oxygen uptake (GVO2). The gastric mucosal expression of mRNAs for constitutive nitric oxide synthase (cNOS), superoxide dismutase (SOD), and pro-inflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) and plasma level of both cytokines were determined by RT-PCR and ELISA. The 9 days treatment with Ang II dose-dependently increased the area of gastric ulcers and this effect was accompanied by a significant fall in the GBF, GVO2 and GMBF at ulcer margin. In contrast, treatment with Ang-(1-7) which produced a significant rise in the luminal content of NO significantly reduced the area of gastric ulcer and significantly increased the GBF, GVO2 and the GMBF at ulcer margin. Similar GMBF changes and significant reduction the area of gastric ulcer was

  20. Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID(2) ): an evidence-based mnemonic for the treatment of systolic heart failure.

    Science.gov (United States)

    Chia, N; Fulcher, J; Keech, A

    2016-06-01

    Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline-based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID (2) , standing for beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega-3 fatty acids, statins or anti-thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence-based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition.

  1. Orphan nuclear receptor small heterodimer partner inhibits angiotensin II-stimulated PAI-1 expression in vascular smooth muscle cells

    OpenAIRE

    Lee, Kyeong-Min; Seo, Hye-Young; Kim, Mi-Kyung; Min, Ae-Kyung; Ryu, Seong-Yeol; Kim, Yoon-Nyun; Park, Young Joo; Choi, Hueng-Sik; Lee, Ki-Up; Park, Wan-Ju; Park, Keun-Gyu; Lee, In-Kyu

    2009-01-01

    Angiotensin II is a major effector molecule in the development of cardiovascular disease. In vascular smooth muscle cells (VSMCs), angiotensin II promotes cellular proliferation and extracellular matrix accumulation through the upregulation of plasminogen activator inhibitor-1 (PAI-1) expression. Previously, we demonstrated that small heterodimer partner (SHP) represses PAI-1 expression in the liver through the inhibition of TGF-β signaling pathways. Here, we investigated whether SHP inhibite...

  2. Angiotensin II, a neuropeptide at the frontier between endocrinology and neuroscience: Is there a link between the angiotensin II type 2 receptor (AT2R and Alzheimer’s disease?

    Directory of Open Access Journals (Sweden)

    Nicole eGallo-Payet

    2011-08-01

    Full Text Available Amyloid-β peptide deposition, abnormal hyperphosphorylation of tau, as well as inflammation and vascular damage, are associated with the development of Alzheimer’s disease. Angiotensin II (Ang II is a peripheral hormone, as well as a neuropeptide, which binds two major receptors, namely the Ang II type-1 receptor (AT1R and the type-2 receptor (AT2R. Activation of the AT2R counteracts most of the AT1R-mediated actions, promoting vasodilation, decreasing the expression of pro-inflammatory cytokines, both in the brain and in the cardiovascular system. There is evidence that treatment with AT1R blockers (ARBs attenuates learning and memory deficits. Studies suggest that the therapeutic effects of ARBs may reflect this unopposed activation of the AT2R in addition to the inhibition of the AT1R. Within the context of Alzheimer’s disease (AD, modulation of AT2R signaling could improve cognitive performance not only through its action on blood flow/brain microcirculation but also through more specific effects on neurons. This review summarizes the current state of knowledge and potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2R activation by nonpeptide and highly selective agonists, acting on neuronal plasticity, could represent new pharmacological tools that may help improve impaired cognitive performance in Alzheimer’s disease and other neurological cognitive disorders.

  3. Lipid rafts are required for signal transduction by angiotensin II receptor type 1 in neonatal glomerular mesangial cells

    Energy Technology Data Exchange (ETDEWEB)

    Adebiyi, Adebowale, E-mail: aadebiyi@uthsc.edu; Soni, Hitesh; John, Theresa A.; Yang, Fen

    2014-05-15

    Angiotensin II (ANG-II) receptors (AGTRs) contribute to renal physiology and pathophysiology, but the underlying mechanisms that regulate AGTR function in glomerular mesangium are poorly understood. Here, we show that AGTR1 is the functional AGTR subtype expressed in neonatal pig glomerular mesangial cells (GMCs). Cyclodextrin (CDX)-mediated cholesterol depletion attenuated cell surface AGTR1 protein expression and ANG-II-induced intracellular Ca{sup 2+} ([Ca{sup 2+}]{sub i}) elevation in the cells. The COOH-terminus of porcine AGTR1 contains a caveolin (CAV)-binding motif. However, neonatal GMCs express CAV-1, but not CAV-2 and CAV-3. Colocalization and in situ proximity ligation assay detected an association between endogenous AGTR1 and CAV-1 in the cells. A synthetic peptide corresponding to the CAV-1 scaffolding domain (CSD) sequence also reduced ANG-II-induced [Ca{sup 2+}]{sub i} elevation in the cells. Real-time imaging of cell growth revealed that ANG-II stimulates neonatal GMC proliferation. ANG-II-induced GMC growth was attenuated by EMD 66684, an AGTR1 antagonist; BAPTA, a [Ca{sup 2+}]{sub i} chelator; KN-93, a Ca{sup 2+}/calmodulin-dependent protein kinase II inhibitor; CDX; and a CSD peptide, but not PD 123319, a selective AGTR2 antagonist. Collectively, our data demonstrate [Ca{sup 2+}]{sub i}-dependent proliferative effect of ANG-II and highlight a critical role for lipid raft microdomains in AGTR1-mediated signal transduction in neonatal GMCs. - Highlights: • AGTR1 is the functional AGTR subtype expressed in neonatal mesangial cells. • Endogenous AGTR1 associates with CAV-1 in neonatal mesangial cells. • Lipid raft disruption attenuates cell surface AGTR1 protein expression. • Lipid raft disruption reduces ANG-II-induced [Ca{sup 2+}]{sub i} elevation in neonatal mesangial cells. • Lipid raft disruption inhibits ANG-II-induced neonatal mesangial cell growth.

  4. Calcium channel blockers, more than diuretics, enhance vascular protective effects of angiotensin receptor blockers in salt-loaded hypertensive rats.

    Directory of Open Access Journals (Sweden)

    Eiichiro Yamamoto

    Full Text Available The combination therapy of an angiotensin receptor blocker (ARB with a calcium channel blocker (CCB or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP were divided into 6 groups, and they were orally administered (1 vehicle, (2 olmesartan, an ARB, (3 azelnidipine, a CCB, (4 hydrochlorothiazide, a diuretic, (5 olmesartan combined with azelnidipine, or (6 olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.

  5. Calcium Channel Blockers, More than Diuretics, Enhance Vascular Protective Effects of Angiotensin Receptor Blockers in Salt-Loaded Hypertensive Rats

    Science.gov (United States)

    Yamamoto, Eiichiro; Kataoka, Keiichiro; Dong, Yi-Fei; Koibuchi, Nobutaka; Toyama, Kensuke; Sueta, Daisuke; Katayama, Tetsuji; Yasuda, Osamu; Ogawa, Hisao; Kim-Mitsuyama, Shokei

    2012-01-01

    The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB. PMID:22720058

  6. Actin cytoskeleton-dependent Rab GTPase-regulated angiotensin type I receptor lysosomal degradation studied by fluorescence lifetime imaging microscopy

    Science.gov (United States)

    Li, Hewang; Yu, Peiying; Sun, Yuansheng; Felder, Robin A.; Periasamy, Ammasi; Jose, Pedro A.

    2010-09-01

    The dynamic regulation of the cellular trafficking of human angiotensin (Ang) type 1 receptor (AT1R) is not well understood. Therefore, we investigated the cellular trafficking of AT1R-enhanced green fluorescent protein (EGFP) (AT1R-EGFP) heterologously expressed in HEK293 cells by determining the change in donor lifetime (AT1R-EGFP) in the presence or absence of acceptor(s) using fluorescence lifetime imaging-fluorescence resonance energy transfer (FRET) microscopy. The average lifetime of AT1R-EGFP in our donor-alone samples was ~2.33 ns. The basal state lifetime was shortened slightly in the presence of Rab5 (2.01+/-0.10 ns) or Rab7 (2.11+/-0.11 ns) labeled with Alexa 555, as the acceptor fluorophore. A 5-min Ang II treatment markedly shortened the lifetime of AT1R-EGFP in the presence of Rab5-Alexa 555 (1.78+/-0.31 ns) but was affected minimally in the presence of Rab7-Alexa 555 (2.09+/-0.37 ns). A 30-min Ang II treatment further decreased the AT1R-EGFP lifetime in the presence of both Rab5- and Rab7-Alexa 555. Latrunculin A but not nocodazole pretreatment blocked the ability of Ang II to shorten the AT1R-EGFP lifetime. The occurrence of FRET between AT1R-EGFP (donor) and LAMP1-Alexa 555 (acceptor) with Ang II stimulation was impaired by photobleaching the acceptor. These studies demonstrate that Ang II-induced AT1R lysosomal degradation through its association with LAMP1 is regulated by Rab5/7 via mechanisms that are dependent on intact actin cytoskeletons.

  7. Effects of angiotensinreceptor antagonist, Losartan on the apoptosis, proliferation and migration of the human pancreatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    Wen-Bin Liu; Xing-Peng Wang; Kai Wu; Ru-Ling Zhang

    2005-01-01

    AIM: To investigate the effects of AT1 (Type 1 angiotensinreceptor) antagonist (Losartan) on the apoptosis,proliferation and migration of the human pancreaticstellate cells (hPSCs).METHODS: hPSCs were isolated from pancreatic sample of patients with pancreatic carcinoma using radioimmunoassay (RIA) technique to detect the concentration of AngⅡ in culture media and cell homogenate. Immunocytochemistry (ICC) and in situ hybridization (ISH) methods were utilized to test AT1 expression in hPSCs. Effects of Losartan on hPSCs proliferation, apoptosis and migration were investigated using BrdU incorporation, TUNEL, flow cytometry (FCM),and phase-contrast microscope separately when cells treated with Losartan. Immunofluorescence and Western blot were applied to quantify the expression of type Ⅰ collagen in hPSCs.RESULTS: There exists AT1 expression in hPSCs, while no AngⅡ was detected in culture media and cell homogenate. Losartan induces cell apoptosis in a doseand time-dependent manner (apparently at 10-5 mol/L),no pro-proliferative effect was observed in the same condition.Corresponding dosage of Losartan can also alleviate the motion capability and type Ⅰ collagen content of hPSCs compared with AngⅡ treatment and non-treatment control groups.CONCLUSION: These findings suggest that paracrine not autocrine functions of AngⅡ may have effects on hPSCs,which was mediated by AT1 expressed on cells, while Losartan may exert anti-fibrotic effects by inhibiting hPSCs motion and partly by inducing apoptosis.

  8. Interaction and Relationship Between Angiotensin Converting Enzyme Gene and Environmental Factors Predisposing to Essential Hypertension in Mongolian Population of China

    Institute of Scientific and Technical Information of China (English)

    QUN XU; HUA FENG; SHUANG-LIAN BAI; HAI-HUA PANG; GUI-RONG HUANG; MING-WU FANG; YONG-HONG ZHANG; ZHENG-LAI WU; CHANG-CHUN QIU; YAN-HUA WANG; WEI-JUN TONG; MING-LIANG GU; GANG WU; BATU BUREN; YONG-YUE LIU; JIAN WANG; YONG-SHAN LI

    2004-01-01

    Objective To investigate the association of specific functional gene ACE (I/D) variants of the renin-angiotensin system with essential hypertension (EH) and interaction between ACE (I/D) gene and risk factors for EH in a genetically homogenous Mongolia rural population of China. Methods Individuals (n=1099) were recruited from general population of Kezuohouqi Banner in Inner Mongolian Autonomous Region. Results The association was found between ACE genotype DD plus ID and EH, with an interaction between ACE genotype DD plus ID and cigarette smoking in an additive model. Cigarette smoking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 7.10 to 1.16. Interaction between ACE genotype DD plus ID and alcohol drinking on EH appeared an additive model. Alcohol drinking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 1.66 to 1.09. BMI and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 6.15 to 2.49. Interactions between ACE genotype and WHR on EH showed a multiplicative model. In a short, there was an interaction between ACE gene and cigarette smoking, alcohol drinking and BMI on EH, especially in a low dose-exposure effect. Conclusion It is important for individuals who carry ACE D allele gene to prevent EH, and furthermore, to prevent and control coronary heart disease, in a view of population-based prevention.

  9. Increased expression of endothelin ET(B) and angiotensin AT(1) receptors in peripheral resistance arteries of patients with suspected acute coronary syndrome

    DEFF Research Database (Denmark)

    Dimitrijevic, Ivan; Ekelund, Ulf; Edvinsson, Lars

    2009-01-01

    Patients who experience chest pain, in which ischemic heart disease has been ruled out, still have an increased risk of future ischemic cardiac events and premature death, possibly due to subclinical endothelial dysfunction. A feature of endothelial dysfunction is an increased expression...... of arterial vasoconstrictor endothelin (ET) and angiotensin (AT) receptors. Our aim was to investigate if the arterial expressions of these receptors are changed in patients with suspected but ruled out acute coronary syndrome (ACS). Small subcutaneous arteries (diameter of 100 microm) were surgically removed....... The control group (controls) consisted of eight healthy volunteers matched for age and sex with no previous cardiac illness or medication. The susp ACS group had an increased expression of ET(B) (by 94%) and AT(1) (by 34%) receptors in the smooth muscle cells of resistance arteries as compared to the control...

  10. Unique Expression of Angiotensin Type-2 Receptor in Sex-Specific Distribution of Myelinated Ah-Type Baroreceptor Neuron Contributing to Sex-Dimorphic Neurocontrol of Circulation.

    Science.gov (United States)

    Liu, Yang; Zhou, Jia-Ying; Zhou, Yu-Hong; Wu, Di; He, Jian-Li; Han, Li-Min; Liang, Xiao-Bo; Wang, Lu-Qi; Lu, Xiao-Long; Chen, Hanying; Qiao, Guo-Fen; Shou, Weinian; Li, Bai-Yan

    2016-04-01

    This study aims to understand the special expression patterns of angiotensin-II receptor (AT1R and AT2R) in nodose ganglia and nucleus of tractus solitary of baroreflex afferent pathway and their contribution in sex difference of neurocontrol of blood pressure regulation. In this regard, action potentials were recorded in baroreceptor neurons (BRNs) using whole-cell patch techniques; mRNA and protein expression of AT1R and AT2R in nodose ganglia and nucleus of tractus solitary were evaluated using real time-polymerase chain reaction, Western blot, and immunohistochemistry at both tissue and single-cell levels. The in vivo effects of 17β-estradiol on blood pressure and AT2R expression were also tested. The data showed that AT2R, rather than AT1R, expression was higher in female than age-matched male rats. Moreover, AT2R was downregulated in ovariectomized rats, which was restored by the administration of 17β-estradiol. Single-cell real time-polymerase chain reaction data indicated that AT2R was uniquely expressed in Ah-type BRNs. Functional study showed that long-term administration of 17β-estradiol significantly alleviated the blood pressure increase in ovariectomized rats. Electrophysiological recordings showed that angiotensin-II treatment increased the neuroexcitability more in Ah- than C-type BRNs, whereas no such effect was observed in A-types. In addition, angiotensin-II treatment prolonged action potential duration, which was not further changed by iberiotoxin. The density of angiotensin-II-sensitive K(+) currents recorded in Ah-types was equivalent with iberiotoxin-sensitive component. In summary, the unique, sex- and afferent-specific expression of AT2R was identified in Ah-type BRNs, and AT2R-mediated KCa1.1 inhibition in Ah-type BRNs may exert great impacts on baroreflex afferent function and blood pressure regulation in females. PMID:26883269

  11. Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor

    Science.gov (United States)

    Li, Ming; Tejada, Thor; Lambert, Jonathan P; Nicholson, Chad K; Yahiro, Eiji; Ambai, Vats T; Ali, Syeda F; Bradley, Eddie W; Graham, Robert M; Dell’Italia, Louis J; Calvert, John W; Naqvi, Nawazish

    2016-01-01

    Angiotensin II (Ang II) modulates blood pressure and atherosclerosis development through its vascular type-1 (AT1R) and type-2 (AT2R) receptors, which have opposing effects. AT2R activation produces hypotension, and is anti-atherogenic. Targeted overexpression of AT2Rs in vascular smooth muscle cells (VSMCs) indicates that these effects are due to increased nitric oxide (NO) generation. However, the role of endogenous VSMC AT2Rs in these events is unknown. Effect of 7-day low-dose Ang II-infusion (12 µg/kg/hr) on blood pressure was tested in 9-week-old apoE(-/-) mice fed a low or high cholesterol diet (LCD or HCD, respectively). Cardiac output was measured by echocardiography. Immunohistochemistry was performed to localize and quantify AT2Rs and p-Ser1177-endothelial nitric oxide synthase (eNOS) levels in the aortic arch. PD123319 and GW-9662 were used to selectively block the AT2R and peroxisome proliferator-activated receptor-γ (PPAR-γ), respectively. Ang II infusion decreased blood pressure by 12 mmHg (P LCD/apoE(-/-) mice without altering cardiac output; a response blocked by PD123319. Although, AT2R stimulation neither activated eNOS (p-Ser1177-eNOS) nor changed plasma NO metabolites, it caused an ~6-fold increase in VSMC PPAR-γ levels (P < 0.001) and the AT2R-mediated hypotension was abolished by GW-9662. AT2R-mediated hypotension was also inhibited by HCD, which selectively decreased VSMC AT2R expression by ~6-fold (P < 0.01). These findings suggest a novel pathway for the Ang II/AT2R-mediated hypotensive response that involves PPAR-γ, and is down regulated by a HCD. PMID:27679746

  12. Distinct properties of telmisartan on agonistic activities for peroxisome proliferator-activated receptor γ among clinically used angiotensin II receptor blockers: drug-target interaction analyses.

    Science.gov (United States)

    Kakuta, Hirotoshi; Kurosaki, Eiji; Niimi, Tatsuya; Gato, Katsuhiko; Kawasaki, Yuko; Suwa, Akira; Honbou, Kazuya; Yamaguchi, Tomohiko; Okumura, Hiroyuki; Sanagi, Masanao; Tomura, Yuichi; Orita, Masaya; Yonemoto, Takako; Masuzaki, Hiroaki

    2014-04-01

    A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement. PMID:24424487

  13. Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor-γ.

    Science.gov (United States)

    Li, Ming; Tejada, Thor; Lambert, Jonathan P; Nicholson, Chad K; Yahiro, Eiji; Ambai, Vats T; Ali, Syeda F; Bradley, Eddie W; Graham, Robert M; Dell'Italia, Louis J; Calvert, John W; Naqvi, Nawazish

    2016-01-01

    Angiotensin II (Ang II) modulates blood pressure and atherosclerosis development through its vascular type-1 (AT1R) and type-2 (AT2R) receptors, which have opposing effects. AT2R activation produces hypotension, and is anti-atherogenic. Targeted overexpression of AT2Rs in vascular smooth muscle cells (VSMCs) indicates that these effects are due to increased nitric oxide (NO) generation. However, the role of endogenous VSMC AT2Rs in these events is unknown. Effect of 7-day low-dose Ang II-infusion (12 µg/kg/hr) on blood pressure was tested in 9-week-old apoE((-/-)) mice fed a low or high cholesterol diet (LCD or HCD, respectively). Cardiac output was measured by echocardiography. Immunohistochemistry was performed to localize and quantify AT2Rs and p-Ser(1177)-endothelial nitric oxide synthase (eNOS) levels in the aortic arch. PD123319 and GW-9662 were used to selectively block the AT2R and peroxisome proliferator-activated receptor-γ (PPAR-γ), respectively. Ang II infusion decreased blood pressure by 12 mmHg (P < 0.001) in LCD/apoE((-/-)) mice without altering cardiac output; a response blocked by PD123319. Although, AT2R stimulation neither activated eNOS (p-Ser(1177)-eNOS) nor changed plasma NO metabolites, it caused an ~6-fold increase in VSMC PPAR-γ levels (P < 0.001) and the AT2R-mediated hypotension was abolished by GW-9662. AT2R-mediated hypotension was also inhibited by HCD, which selectively decreased VSMC AT2R expression by ~6-fold (P < 0.01). These findings suggest a novel pathway for the Ang II/AT2R-mediated hypotensive response that involves PPAR-γ, and is down regulated by a HCD. PMID:27679746

  14. The beta-arrestin pathway-selective type 1A angiotensin receptor (AT1A) agonist [Sar1,Ile4,Ile8]angiotensin II regulates a robust G protein-independent signaling network.

    Science.gov (United States)

    Kendall, Ryan T; Strungs, Erik G; Rachidi, Saleh M; Lee, Mi-Hye; El-Shewy, Hesham M; Luttrell, Deirdre K; Janech, Michael G; Luttrell, Louis M

    2011-06-01

    The angiotensin II peptide analog [Sar(1),Ile(4),Ile(8)]AngII (SII) is a biased AT(1A) receptor agonist that stimulates receptor phosphorylation, β-arrestin recruitment, receptor internalization, and β-arrestin-dependent ERK1/2 activation without activating heterotrimeric G-proteins. To determine the scope of G-protein-independent AT(1A) receptor signaling, we performed a gel-based phosphoproteomic analysis of AngII and SII-induced signaling in HEK cells stably expressing AT(1A) receptors. A total of 34 differentially phosphorylated proteins were detected, of which 16 were unique to SII and eight to AngII stimulation. MALDI-TOF/TOF mass fingerprinting was employed to identify 24 SII-sensitive phosphoprotein spots, of which three (two peptide inhibitors of protein phosphatase 2A (I1PP2A and I2PP2A) and prostaglandin E synthase 3 (PGES3)) were selected for validation and further study. We found that phosphorylation of I2PP2A was associated with rapid and transient inhibition of a β-arrestin 2-associated pool of protein phosphatase 2A, leading to activation of Akt and increased phosphorylation of glycogen synthase kinase 3β in an arrestin signalsome complex. SII-stimulated PGES3 phosphorylation coincided with an increase in β-arrestin 1-associated PGES3 and an arrestin-dependent increase in cyclooxygenase 1-dependent prostaglandin E(2) synthesis. These findings suggest that AT(1A) receptors regulate a robust G protein-independent signaling network that affects protein phosphorylation and autocrine/paracrine prostaglandin production and that these pathways can be selectively modulated by biased ligands that antagonize G protein activation.

  15. Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats

    OpenAIRE

    Shum, Michaël; Pinard, Sandra; Guimond, Marie-Odile; Labbé, Sébastien M.; Roberge, Claude; Baillargeon, Jean-Patrice; Langlois, Marie-France; Alterman, Mathias; Wallinder, Charlotta; Hallberg, Anders; Carpentier, André C; Gallo-Payet, Nicole

    2012-01-01

    This study was aimed at establishing whether specific activation of angiotensin II (ANG II) type 2 receptor (AT2R) modulates adipocyte differentiation and function. In primary cultures of subcutaneous (SC) and retroperitoneal (RET) preadipocytes, both AT2R and AT1R were expressed at the mRNA and protein level. Cells were stimulated with ANG II or the AT2R agonist C21/M24, alone or in the presence of the AT1R antagonist losartan or the AT2R antagonist PD123,319. During differentiation, C21/M24...

  16. Renin angiotensin system blockade reduces urinary levels of soluble urokinase plasminogen activator receptor (suPAR) in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Persson, Frederik; Theilade, Simone; Eugen-Olsen, Jesper;

    2016-01-01

    angiotensin system (RAS) single and dual blockade on suPAR levels in patients with type 2 diabetes and albuminuria. We conducted a post-hoc analysis of a randomized controlled crossover trial. Urine and plasma samples were analyzed for suPAR levels. The placebo period was considered reference and all......Soluble urokinase plasminogen activator receptor (suPAR) is associated with faster decline in kidney function and the pathogenesis of diabetic nephropathy. However, little is known about the impact of treatment on plasma and urinary levels of suPAR. We aimed to investigate the impact of renin...

  17. Combined blockade of angiotensin II and prorenin receptors ameliorates podocytic apoptosis induced by IgA-activated mesangial cells.

    Science.gov (United States)

    Leung, Joseph C K; Chan, Loretta Y Y; Saleem, M A; Mathieson, P W; Tang, Sydney C W; Lai, Kar Neng

    2015-07-01

    Glomerulo-podocytic communication plays an important role in the podocytic injury in IgA nephropathy (IgAN). In this study, we examine the role of podocytic angiotensin II receptor subtype 1 (AT1R) and prorenin receptor (PRR) in podocytic apoptosis in IgAN. Polymeric IgA (pIgA) was isolated from patients with IgAN and healthy controls. Conditioned media were prepared from growth arrested human mesangial cells (HMC) incubated with pIgA from patients with IgAN (IgA-HMC media) or healthy controls (Ctl-HMC media). A human podocyte cell line was used as a model to examine the regulation of the expression of AT1R, PRR, TNF-α and CTGF by IgA-HMC media. Podocytic nephrin expression, annexin V binding and caspase 3 activity were used as the functional readout of podocytic apoptosis. IgA-HMC media had no effect on AngII release by podocytes. IgA-HMC media significantly up-regulated the expression of AT1R and PRR, down-regulated nephrin expression and induced apoptosis in podocytes. Mono-blockade of AT1R, PRR, TNF-α or CTGF partially reduced podocytic apoptosis. IgA-HMC media activated NFκB, notch1 and HEY1 expression by podocytes and dual blockade of AT1R with PRR, or anti-TNF-α with anti-CTGF, effectively rescued the podocytic apoptosis induced by IgA-HMC media. Our data suggests that pIgA-activated HMC up-regulates the expression of AT1R and PRR expression by podocytes and the associated activation of NFκB and notch signalling pathways play an essential role in the podocytic apoptosis induced by glomerulo-podocytic communication in IgAN. Simultaneously targeting the AT1R and PRR could be a potential therapeutic option to reduce the podocytic injury in IgAN.

  18. The angiotensin-converting enzyme gene insertion–deletion polymorphism in a white British patient cohort with obstetric cholestasis

    Science.gov (United States)

    Müllenbach, Roman; Tetlow, Natasha; Bennett, Amanda; Pipkin, Fiona Broughton; Morgan, Linda; Williamson, Catherine

    2009-01-01

    The DD genotype of the angiotensin-converting enzyme (ACE) gene is over-represented in Finnish patients with obstetric cholestasis (OC). The purpose of this study was to establish whether this genotype is associated with cholestasis in UK cases. In a retrospective case-control study, we determined the ACE insertion/deletion frequencies in 166 British cases and 100 control women by polymerase chain reaction analysis. No significant difference in allele frequencies was found between these groups, but allele frequencies differed significantly between Finnish and UK OC cases (P = 0.0005). The prevalence of the DD genotype is lower in UK cases than in controls (χ2 [1 d.f.] = 4.32, P = 0.05) and the odds ratio for OC associated with the DD genotypeis 0.54, 95% confidence interval 0.30–0.97. In contrast to Finnish OC cases, the DD genotype of the ACE is not increased in UK cases.

  19. Pharmacological interventions into the renin-angiotensin system with ACE inhibitors and angiotensin II receptor antagonists: effects beyond blood pressure lowering.

    Science.gov (United States)

    Düsing, Rainer

    2016-06-01

    Hypertension is recognized as an important risk factor for cardiovascular morbidity and mortality. Lowering of blood pressure has been shown to minimize the risk of cardiovascular events, with the majority of antihypertensives demonstrating a similar ability to reduce coronary events and stroke for a given reduction in blood pressure. Agents that modify the activity of the renin-angiotensin system (RAS) have been proposed to exhibit additional effects that might go beyond simple blood pressure lowering. The RAS is a crucial system that regulates extracellular fluid volume and blood pressure. Proposed potential benefits of RAS blockade that go beyond blood pressure lowering include a reduction in platelet aggregation and thrombosis, blunting of cardiac and vascular remodeling, favorable metabolic effects and reno- and cerebro-protection. However, factors such as treatment adherence, duration of action of antihypertensive agents and differences in effects on central versus brachial blood pressure may also result in apparent differences in efficacy of different antihypertensives. The aim of this review article is to examine the available data from clinical studies of antihypertensive drugs for evidence of effects that might legitimately be claimed to go beyond simple blood pressure lowering. PMID:27122491

  20. Pharmacological interventions into the renin-angiotensin system with ACE inhibitors and angiotensin II receptor antagonists: effects beyond blood pressure lowering.

    Science.gov (United States)

    Düsing, Rainer

    2016-06-01

    Hypertension is recognized as an important risk factor for cardiovascular morbidity and mortality. Lowering of blood pressure has been shown to minimize the risk of cardiovascular events, with the majority of antihypertensives demonstrating a similar ability to reduce coronary events and stroke for a given reduction in blood pressure. Agents that modify the activity of the renin-angiotensin system (RAS) have been proposed to exhibit additional effects that might go beyond simple blood pressure lowering. The RAS is a crucial system that regulates extracellular fluid volume and blood pressure. Proposed potential benefits of RAS blockade that go beyond blood pressure lowering include a reduction in platelet aggregation and thrombosis, blunting of cardiac and vascular remodeling, favorable metabolic effects and reno- and cerebro-protection. However, factors such as treatment adherence, duration of action of antihypertensive agents and differences in effects on central versus brachial blood pressure may also result in apparent differences in efficacy of different antihypertensives. The aim of this review article is to examine the available data from clinical studies of antihypertensive drugs for evidence of effects that might legitimately be claimed to go beyond simple blood pressure lowering.

  1. The angiotensin II-AT1 receptor stimulates reactive oxygen species within the cell nucleus

    Energy Technology Data Exchange (ETDEWEB)

    Pendergrass, Karl D.; Gwathmey, TanYa M. [The Hypertension and Vascular Research Center, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States); Michalek, Ryan D.; Grayson, Jason M. [Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157 (United States); Chappell, Mark C., E-mail: mchappel@wfubmc.edu [The Hypertension and Vascular Research Center, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States)

    2009-06-26

    We and others have reported significant expression of the Ang II Type 1 receptor (AT1R) on renal nuclei; thus, the present study assessed the functional pathways and distribution of the intracellular AT1R on isolated nuclei. Ang II (1 nM) stimulated DCF fluorescence, an intranuclear indicator of reactive oxygen species (ROS), while the AT1R antagonist losartan or the NADPH oxidase (NOX) inhibitor DPI abolished the increase in ROS. Dual labeling of nuclei with antibodies against nucleoporin 62 (Nup62) and AT1R or the NADPH oxidase isoform NOX4 revealed complete overlap of the Nup62 and AT1R (99%) by flow cytometry, while NOX4 was present on 65% of nuclei. Treatment of nuclei with a PKC agonist increased ROS while the PKC inhibitor GF109203X or PI3 kinase inhibitor LY294002 abolished Ang II stimulation of ROS. We conclude that the Ang II-AT1R-PKC axis may directly influence nuclear function within the kidney through a redox sensitive pathway.

  2. Transcriptional up-regulation in expression of 5-hydroxytryptamine2A and transcriptional down-regulation of angiotensin II type 1 receptors during organ culture of rat mesenteric artery

    DEFF Research Database (Denmark)

    Luo, Guogang; Xu, Cang-Bao; Cao, Yong-Xiao;

    2004-01-01

    receptors (5-HT(2A)) and angiotensin II type 1 receptors (AT(1)) demonstrated that the contractions occurred via 5-HT(2A) and AT(1) receptors, respectively. Real-time PCR revealed that the 5-HT(2A) receptor mRNA was up-regulated in parallel with the contractile response while there was a down-regulation of...... AT(1) receptor mRNA. Transcriptional inhibitor actinomycin D and specific protein kinase C inhibitor Ro31-8220 demonstrated that it was a transcriptional mechanism with involvement of protein kinase C that regulated the enhanced expression of 5-HT(2A) receptors in the mesenteric artery....

  3. Neuroprotective Effect of Scutellarin on Ischemic Cerebral Injury by Down-Regulating the Expression of Angiotensin-Converting Enzyme and AT1 Receptor.

    Directory of Open Access Journals (Sweden)

    Wenjuan Wang

    Full Text Available Previous studies have demonstrated that angiotensin-converting enzyme (ACE is involved in brain ischemic injury. In the present study, we investigated whether Scutellarin (Scu exerts neuroprotective effects by down-regulating the Expression of Angiotensin-Converting Enzyme and AT1 receptor in a rat model of permanent focal cerebral ischemia.Adult Sprague-Dawley rats were administrated with different dosages of Scu by oral gavage for 7 days and underwent permanent middle cerebral artery occlusion (pMCAO. Blood pressure was measured 7 days after Scu administration and 24 h after pMCAO surgery by using a noninvasive tail cuff method. Cerebral blood flow (CBF was determined by Laser Doppler perfusion monitor and the neuronal dysfunction was evaluated by analysis of neurological deficits before being sacrificed at 24 h after pMCAO. Histopathological change, cell apoptosis and infarct area were respectively determined by hematoxylin-eosin staining, terminal deoxynucleotidyl transfer-mediated dUTP nick end labeling (TUNEL analysis and 2,3,5-triphenyltetrazolium chloride staining. Tissue angiotensin II (Ang II and ACE activity were detected by enzyme-linked immunosorbent assays. The expression levels of ACE, Ang II type 1 receptor (AT1R, tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, and interleukin-1β (IL-1β were measured by Western blot and real-time PCR. ACE inhibitory activity of Scu in vitro was detected by the photometric determination.Scu treatment dose-dependently decreased neurological deficit score, infarct area, cell apoptosis and morphological changes induced by pMCAO, which were associated with reductions of ACE and AT1R expression and the levels of Ang II, TNF-α, IL-6, and IL-1β in ischemic brains. Scu has a potent ACE inhibiting activity.Scu protects brain from acute ischemic injury probably through its inhibitory effect on the ACE/Ang II/AT1 axis, CBF preservation and proinflammation inhibition.

  4. Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-[gamma

    Energy Technology Data Exchange (ETDEWEB)

    Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan; Bigge, Christopher F.; Chen, Jing; Davis, Jo Ann; Dudley, Danette A.; Edmunds, Jeremy J.; Esmaeil, Nadia; Geyer, Andrew; Heemstra, Ronald J.; Jalaie, Mehran; Ohren, Jeffrey F.; Ostroski, Robert; Ellis, Teresa; Schaum, Robert P.; Stoner, Chad (Pfizer)

    2013-03-07

    Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partial PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

  5. Neuroprotective effect of an angiotensin receptor type 2 agonist following cerebral ischemia in vitro and in vivo

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    Lee Seyoung

    2012-08-01

    Full Text Available Abstract Background Intracerebral administration of the angiotensin II type 2 receptor (AT2R agonist, CGP42112, is neuroprotective in a rat model of ischemic stroke. To explore further its possible cellular target(s and therapeutic utility, we firstly examined whether CGP42112 may exert direct protective effects on primary neurons following glucose deprivation in vitro. Secondly, we tested whether CGP42112 is effective when administered systemically in a mouse model of cerebral ischemia. Methods Primary cortical neurons were cultured from E17 C57Bl6 mouse embryos for 9 d, exposed to glucose deprivation for 24 h alone or with drug treatments, and percent cell survival assessed using trypan blue exclusion. Ischemic stroke was induced in adult male C57Bl6 mice by middle cerebral artery occlusion for 30 min, followed by reperfusion for 23.5 h. Neurological assessment was performed and then mice were euthanized and infarct and edema volume were analysed. Results During glucose deprivation, CGP42112 (1x10-8 M and 1x10-7 M reduced cell death by ~30%, an effect that was prevented by the AT2R antagonist, PD123319 (1x10-6 M. Neuroprotection by CGP42112 was lost at a higher concentration (1x10-6 M but was unmasked by co-application with the AT1R antagonist, candesartan (1x10-7 M. By contrast, Compound 21 (1x10-8 M to 1x10-6 M, a second AT2R agonist, had no effect on neuronal survival. Mice treated with CGP42112 (1 mg/kg i.p. after cerebral ischemia had improved functional outcomes over vehicle-treated mice as well as reduced total and cortical infarct volumes. Conclusions These results indicate that CGP42112 can directly protect neurons from ischemia-like injury in vitro via activation of AT2Rs, an effect opposed by AT1R activation at high concentrations. Furthermore, systemic administration of CGP42112 can reduce functional deficits and infarct volume following cerebral ischemia in vivo.

  6. Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism and Small Vessel Cerebral Stroke in Indian Population

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    Puttachandra Prabhakar

    2014-01-01

    Full Text Available Background. Hypertension is an established risk factor for small-vessel cerebral stroke and the renin-angiotensin system plays an important role in the maintenance of blood pressure. We aimed at evaluating the contribution of the angiotensin-converting enzyme (ACE gene insertion/deletion (I/D polymorphism to the risk of small-vessel stroke in south Indian population. Materials and Methods. We investigated 128 patients diagnosed with small-vessel stroke and 236 age, and gender-matched healthy controls. ACE I/D polymorphism was detected by polymerase chain reaction. Results. Hypertension was significantly more prevalent in the patient group and was associated with 6-fold increase in risk for stroke. ACE genotypes were in Hardy-Weinberg equilibrium in both patients and controls. Prevalence of DD, ID, and II genotypes in cases (34.4%, 43.7%, and 28% did not differ significantly from controls (31.8%, 43.2%, and 25%. The polymorphism was not associated with small-vessel stroke (OR: 1.34; 95% CI: 0.52–1.55. However, diastolic blood pressure was associated with the ACE I/D genotypes in the patients. (DD; 90.2±14.2> ID; 86.2±11.9> II; 82.3±7.8 mm Hg,  P=0.047. Conclusion. Our study showed that hypertension, but not ACE I/D polymorphism, increased the risk of small-vessel stroke.

  7. POLYMORPHISM IN THE ANGIOTENSIN-CONVERTING ENZYME (ACE GENE AND ACE ACTIVITY IN TYPE 2 DIABETIC PATIENTS

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    A Nikzamir

    2008-08-01

    Full Text Available "nDiabetes mellitus is a multifactorial disease. It has recently been shown that an insertion (I/deletion (D polymorphism exists in the angiotensin-converting enzyme (ACE gene that can affect the serum ACE level. There are three genotypes: DD, DI, and II, with the ACE level being highest in DD, intermediate in DI, and lowest in II. In the present investigation, 170 patients with type 2 diabetes mellitus (T2DM and 144 control subjects were studied. The ACE I/D polymorphism was determined by polymerase chain reaction (PCR utilizing specific primers. ACE activity was determined spectrophotometrically. Distribution of ACE gene (I/D polymorphism and allele frequencies in patients with T2DM were significantly different from those in control (P < 0.001; D allele frequency was 51% in T2DM vs. 48% in controls. The level of ACE activity was significantly higher in the DD genotype (91.1 ± 23.18 than those in ID (60.6 ± 22.8 and in II genotypes (36.8 ± 6.9. There was a significant difference in genotype distribution between the two groups (P < 0.001. New normal ranges of serum ACE level were determined for each genotype. Moreover, we found test sensitivity to be 62.3%. Serum ACE activity was significantly associated with ACE (I/D gene polymorphism.

  8. Influence of angiotensin converting enzyme gene insertion/deletion polymorphism and β3-adrenergic receptor gene Trp64Arg polymorphism on fetal growth and neonatal insulin sensitivity%血管紧张素转化酶基因插入/缺失多态性及β3肾上腺素能受体基因Trp64Arg多态性对胎儿宫内发育及新生儿胰岛素敏感性的影响

    Institute of Scientific and Technical Information of China (English)

    崔蕴璞; 韩彤妍; 王新利; 叶鸿瑁

    2008-01-01

    Objective To understand the influence of angiotensin converting enzyme(ACE)gene insertion/deletion(I/D)polymorphism and β3-adrenergic receptor(β3-AR)gene Trp64Arg polymorphism on fetal growth and neonatal insulin sensitivity.Methods Totally 296 newborn infants were selected into our study and divided into 2 groups according to gestational age and birth weight:adequate-for-gestationalage(AGA)group(222 cases)and small-for-gestational-age(SGA)group(74 case).Serum glucose and insulin were examined in the morning of the 3rd day before milk.Insulin sensitivity was evaluated by homeostasis model assessment(HOMA)equation.β3-AR gene Trp64Arg polymorphism and ACE gene I/D polymorphism(202 cases)were analysed using polymerase chain reaction-restricted fragment length polymorphism(PCR-RFLP)technique.Gestational age,birth weight,birth weight percentage,serum glucose,insulin and HOMA-IR were compared among different genotype groups.Statistical analysis was performed with the SPSS 10.0 software.Results No significant difference was found between the sernm glucose level of SGA group(4.03±1.05 mmol/L)and AGA group(4.05±1.14 mmol/L),P=0.008. The serum insulin level(converted into Ln)of SGA group(2.262±0.746)was significantly higher than that of AGA group(1.757±0.805),P<0.001.The HOMA-IR(also convened into Ln)level of SGA group(0.217±0.367)was also significantly higher than that of AGA group(0.001±0.378),P<0.001. In the SGA group β3-AR gene Arg64 allele carriers had higher serum insulin and HOMA-IR level(botll changed to Ln,2.654±0.701,0.371±0.338)compared with noncarriers(2.074±0.698,0.143± O.360),P<0.05.The ACE gene DD genotype carriers had higher serum insulin and HOMA-IR level(both were converted into Ln,2.19 4-0.91,0.5l 4-1.01)compared with II(1.77 ±0.85,0.02 ±0.93) and ID genotype group(1.77 ±0.83,0.05 ±0.91),P<0.05.The ACE gene DD carriers had lower birth weight percentage compared with II and ID genotype group.P<0.05.When both genes'polymorphisms were taken

  9. Angiotensin Ⅱ induced upregulation of Gαq/11, phospholipase Cβ3 and extracellular signal-regulated kinase 1/2 via angiotensin Ⅱtype 1 receptor

    Institute of Scientific and Technical Information of China (English)

    白桦; 吴立玲; 邢东琦; 刘洁; 赵亚莉

    2004-01-01

    Background The role of the Gαq/11-mediated signal transduction pathway in angiotensin Ⅱ (Ang Ⅱ) induced cardiac hypertrophy remains unclear. This study was to investigate the role of the Gαq/11 signal transduction pathway in the development of cardiac hypertrophy in 2K1C hypertensive rats and in cultured neonatal rat ventricular myocytes (NRVMs) and to elucidate the effects of the pathway on Ang Ⅱ induced cardiac hypertrophy.Methods Renal hypertension was induced in 2K1C hypertensive rats by placing a silver clip around the left renal artery. At 8 weeks after operation, the systolic blood pressure, the ratio of left ventricular weight to body weight (LV/BW), and the concentration of AngⅡ in the heart were measured. The protein levels of Gαq/11 and extracellular signal-regulated kinase 1/2 (ERK1/2) were assayed by Western blot analysis, and the activity of phospholipase C (PLC) in the myocardium was detected using [3H]-PIP2 as a substrate. Changes in [3H]-leucine incorporation and in the protein levels of the signal molecules Gαq/11, PLCβ3, and ERK1/2 were measured after NRVMs were stimulated with 10-7mol/L AngⅡ. Results The protein levels of Gαq/11 and ERK1/2 in the hearts of 2K1C rats increased by 35.8% and 31.9%, respectively, compared with the sham group. The PLC activity in the 2K1C group was also significantly increased (P<0.05). The levels of Gαq/11, PLCβ3, and ERK1/2 increased significantly after NRVMs were stimulated by AngⅡ. The upregulation of Gαq/11, PLCβ3 and ERK1/2 in NRVMs occurred prior to [3H]-leucine incorporation increases, and could be inhibited with losartan. Conclusion AngⅡ can initiate cardiac hypertrophy and upregulate signal molecules in the Gαq/11-mediated signal transduction pathway, such as Gαq/11, PLCβ3 and ERK1/2, at both tissue and cellular levels.

  10. Effect of angiotensin converting enzyme gene I/D polymorphism in patients with metabolic syndrome in North Indian population

    Institute of Scientific and Technical Information of China (English)

    Gaurav Mittal; Vibhanshu Gupta; Shahzad F Haque; Anwer S Khan

    2011-01-01

    Background Numerous studies have investigated the effect of angiotensin converting enzyme (ACE) gene I/D polymorphism and various cardiovascular risk factors in different populations with varied results. Currently, the association of ACE gene polymorphism with metabolic syndrome has not been studied in North Indians. While studies assessing the effect with polymorphism on each of the components of metabolic syndrome separately are present, data regarding the metabolic syndrome per se are sparse. The present study evaluated the effect of ACE gene I/D polymorphism in patients with metabolic syndrome in North Indian population at a tertiary care centre.Methods Fifty subjects, with thirty cases of metabolic syndrome (NCEP/ATP Ⅲ guidelines, 2004) and twenty age and gender matched healthy controls were chosen. Detailed history was reviewed and clinical examination of the subjects was carried out. Relevant investigations including blood glucose (fasting and post prandial), blood urea, serum creatinine and serum lipids were done. DNA of cases and controls was analysed for I/D polymorphism using polymerase chain reaction.Results D/D genotype was more frequent in patients with metabolic syndrome as compared with healthy controls (P<0.05). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) was significantly higher in the D/D genotype than I/D and I/I genotypes (P <0.05). Our study also showed positive association between obesity, fasting blood glucose and ACE gene polymorphism while no association was found with triglycerides and high density lipoprotein cholesterol.The I/I group was significantly associated with waist circumference and fasting blood glucose (P <0.05).Conclusion Our study clearly showed that metabolic syndrome was associated with ACE gene polymorphism.However due to less number of subjects in the study further studies are needed to corroborate our results.

  11. Angiotensin Type 2 Receptor Stimulation Ameliorates Left Ventricular Fibrosis and Dysfunction via Regulation of Tissue Inhibitor of Matrix Metalloproteinase 1/Matrix Metalloproteinase 9 Axis and Transforming Growth Factor β1 in the Rat Heart

    DEFF Research Database (Denmark)

    Lauer, Dilyara; Slavic, Svetlana; Sommerfeld, Manuela;

    2014-01-01

    Left ventricular (LV) remodeling is the main reason for the development of progressive cardiac dysfunction after myocardial infarction (MI). This study investigated whether stimulation of the angiotensin type 2 receptor is able to ameliorate post-MI cardiac remodeling and what the underlying...

  12. Variations in angiotensin-converting enzyme gene insertion/deletion polymorphism in Indian populations of different ethnic origins

    Indian Academy of Sciences (India)

    M A Qadar Pasha; Amjad P Khan; Ratan Kumar; Rekh B Ram; Surinder K Grover; Kaushal K Srivastava; William Selvamurthy; Samir K Brahmachari

    2002-02-01

    The pattern of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in the Indian population is poorly known. In order to determine the status of the polymorphism, young unrelated male army recruits were screened. The population had cultural and linguistic differences and lived in an environment that varied significantly from one region to another. Analysis of the genotype, showed higher frequency of the insertion allele in four of the five groups i.e. I allele frequency was significantly higher ( < 0.05) in Dogras, Assamese and Kumaonese. The deletion allele frequency was comparatively higher in the fifth group that belonged to Punjab. A correlation was observed between the genotype and enzyme activity. Involvement of a single D allele in the genotype enhanced the activity up to 37.56 ± 3.13%. The results suggested ethnic heterogeneity with a significant gene cline with higher insertion allele frequency. Such population-based data on various polymorphisms can ultimately be exploited in pharmacogenomics.

  13. Association between the angiotensin Ⅱ type Ⅰ receptor gene A1166C polymorphism with the essential hypertension in chongqing%AT1R基因A1166C多态性与重庆地区高札压病的相关性研究

    Institute of Scientific and Technical Information of China (English)

    向林; 柳青; 雷寒

    2009-01-01

    目的:研究重庆地区人口血管紧张素Ⅱ的T型受体(Angiotensin Ⅱ type Ⅰ,AT1R)A1166C基因多态性与原发性高血压的关系方法:用多聚酶联反应(Polymerase chain reaction,PCR)结合限制性片段长度多态性(Restriction fragment length poly mor-phism,RFLP)方法对104例原发性高血压(Essentiac hypertension,EH)患者和100例健康体检者进行AT1R(A1166C)的基因多态性分析.结果:EH组AC基因型频率明显高于正常对照组(0.240 vs 0.005,P<0.05),EH组C1166等位基凶频率明显高于正常对照组(0.130 vs0.025,P<0.05);而EH组中的AA基因型频率明显低丁正常对照组(0.750 vs0.950,P<0.05);EH组中还发现了较罕见的CC纯合子基因型.结论:高血压组和正常对照组AT1R基因的AC、AA基因型频率有显著性差异,而其它指标无显著性差异.重庆地区原发性高血压与AT1R基因的A1166C多念性有密切的关系.

  14. Association of Angiotensin-Converting Enzyme (ACE Gene Polymorphism with Inflammation and Cellular Cytotoxicity in Vitiligo Patients.

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    Laila Rashed

    Full Text Available Vitiligo is a disorder with profound heterogeneity in its aetio-pathophysiology. Angiotensin converting enzyme (ACE plays an important role in the physiology of the vasculature, blood pressure and inflammation. An insertion/deletion (I/D polymorphism of the ACE gene was reported be associated with the development of vitiligo.Our aim was to evaluate the ACE I/D polymorphism in vitiligo patients and controls. Our second aim was to find a possible association between ACE gene polymorphism and inflammatory mediators (as interleukin (IL-6 and/or cellular cytotoxicity induced by serum nitrite (as a breakdown product of the cytotoxic nitric oxide in vitiligo patients.This case-control study included 74 vitiligo patients and 75 apparently healthy controls. The distribution of ACE gene I/D genotype was investigated using PCR. Serum ACE, IL-6 and nitrite were measured by colorimetric method, ELISA and Griess assay respectively.The ACE allele frequency was significantly different between vitiligo patients and healthy controls (P = 0.026. However there was no significant difference between the ACE genotyping frequency in both groups (P = 0.115. There were statistically significant higher VIDA score (P = 0.007, and serum IL-6 (P < 0.001 in patients with the DD genotype when compared to other genotypes. Serum nitrite in patients with the DD genotype was significantly higher (P = 0.007 when compared to patients with II genotype. Serum levels of ACE, IL-6 and nitrite in vitiligo patients were statistically significantly higher than those in controls.As a conclusion, ACE gene polymorphism might grant susceptibility to develop vitiligo. Serum IL-6 and nitrite levels might have an important role in the pathogenesis of vitiligo. Targeting these two factors might have an implication in the treatment of some resistant cases.

  15. Study of signal transduction mechanism of angiotensin 2 receptor by means of site-directed mutagenesis; Bui totsuzen hen'iho wo mochiita anjiotenshin 2 reseputa no joho dentatsu kiko no kaimei

    Energy Technology Data Exchange (ETDEWEB)

    Yamano, Yoshiaki [Tottori University, Tottori (Japan). Faculty of Agriculture

    1998-12-16

    The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure. In order to clarify the signaling mechanism mediated by angiotensin 2 receptor, Gq-protein binding amino acid residues of this receptor were clarified by site-directed mutagenesis study. Amino acid residues in the carboxyl tail region were changed by alanines, individually. These mutated receptors were expressed stably in CHO cells, and GTP effect and second messenger molecules were determined, and three residues (Y 312, F313 and L 314) in this region were determined to be concerned for the binding of Gq protein. The other signaling systems, Gi, MAP kinase, JAK-STAT mediated, were reported to be concerned for this receptor. Novel drags for high blood pressure therapy would be explored by clarifying these signaling mechanisms. (author)

  16. Systemic effects of angiotensin III in conscious dogs during acute double blockade of the renin-angiotensin-aldosterone-system

    DEFF Research Database (Denmark)

    Gammelgaard, Iben; Wamberg, Søren; Bie, Peter

    2006-01-01

    AIMS: The study was designed to determine (i) whether the effects of angiotensin III (AngIII) are similar to those of angiotensin II (AngII) at identical plasma concentrations and (ii) whether AngIII operates solely through AT1- receptors. METHODS: Angiotensin II (3 pmol kg(-1) min(-1)-3.1 ng kg(...

  17. Angiotensin II receptor blockade does not protect against progressive loss of residual renal function in hemodialysis patients: A randomized controlled trial (SAFIR study)

    DEFF Research Database (Denmark)

    Kjærgaard, Krista Dybtved; Peters, Christian Daugaard; Jespersen, Bente;

    Background: Glomerular filtration rate (GFR) declines during chronic dialysis treatment. In peritoneal dialysis, blockade of the renin-angiotensin-aldosterone system reduces GFR decline. Observational studies suggest that similar treatment may preserve renal function in hemodialysis (HD). Methods...... centers and randomized to placebo or the angiotensin II receptor blocker irbesartan 300 mg daily. Target systolic blood pressure (BP) was 140 mmHg. Outcomes were GFR measured as the mean of creatinine and urea renal clearance, urine volume and time to anuria. Results: Of the 82 patients randomized...... in both groups and BP did not differ significantly between groups over time. Adverse event rates were similar. GFR declined by 1.7 (1.2 to 2.3) (mean (95% CI)) mL/min/1.73m2/year in the placebo group and by 1.8 (1.1 to 2.4) mL/min/1.73m2/year in the irbesartan-treated group. Mean difference (baseline-12...

  18. High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

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    Tahereh Safari

    2015-01-01

    Full Text Available Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R- mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7±1.9% in estradiol-treated rats but only by 27.3±5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

  19. Angiotensin Ⅱ type Ⅰ receptor agonistic autoantibody-induced apoptosis in neonatal rat cardiomyocytes is dependent on the generation of tumor necrosis factor-α

    Institute of Scientific and Technical Information of China (English)

    Weiran Chai; Wenhui Zhang; Zhu Jin; Yiping Feng; Yanping Kuang; Jianming Zhi

    2012-01-01

    Angiotensin Ⅱ type Ⅰ receptor agonistic autoantibodies (AT1-AA) are related to pre-eclampsia and hypertension and have a direct effect of stimulating the production of tumor necrosis factor-alpha (TNF-α) in the placenta.TNF-α is a known mediator of apoptosis.However,few studies have reported the role of TNF-α and its relationship within AT1-AA-induced apoptosis of cardiomyocytes.In this study,neonatal rat cardiomyocytes were treated with various concentrations of AT1-AA.The apoptosis of neonatal rat cardiomyocytes was determined using TUNEL assay and flow cytometry.The level of secreted TNF-α was measured by enzyme-linked immunosorbent assay,and caspase-3 activity was measured by a fluorogenic protease assay kit.AT1 receptor blockade and TNF inhibitor were added to determine whether they could inhibit the apoptotic effect of AT1-AA.Results showed that AT1-AA induced the apoptosis of neonatal rat cardiomyocytes in a dose-dependent and time-dependent manner.AT1-AA increased TNF secretion and caspase-3activities.AT1 receptor blockade completely abrogated AT1-AA-induced TNF-α secretion,caspase-3 activation,and cardiomyocyte apoptosis.TNF-α receptor inhibitor significantly attenuated AT1-AA-induced neonatal rat cardiomyocyte apoptosis.AT1-AA in the plasma of preeclamptic patients promoted neonatal rat cardiomyocyte apoptosis through a TNF-caspase signaling pathway.

  20. Survival and Predictive Factors of Lethality in Hemodyalisis: D/I Polymorphism of The Angiotensin I-Converting Enzyme and of the Angiotensinogen M235T Genes

    Energy Technology Data Exchange (ETDEWEB)

    Alves, Mauro, E-mail: malves@cardiol.br; Silva, Nelson Albuquerque de Souza e; Salis, Lucia Helena Alvares; Pereira, Basilio de Bragança; Godoy, Paulo Henrique; Nascimento, Emília Matos do [Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ (Brazil); Oliveira, Jose Mario Franco [Universidade Federal Fluminense, Niterói, RJ (Brazil)

    2014-09-15

    End-stage kidney disease patients continue to have markedly increased cardiovascular disease morbidity and mortality. Analysis of genetic factors connected with the renin-angiotensin system that influences the survival of the patients with end-stage kidney disease supports the ongoing search for improved outcomes. To assess survival and its association with the polymorphism of renin-angiotensin system genes: angiotensin I-converting enzyme insertion/deletion and angiotensinogen M235T in patients undergoing hemodialysis. Our study was designed to examine the role of renin-angiotensin system genes. It was an observational study. We analyzed 473 chronic hemodialysis patients in four dialysis units in the state of Rio de Janeiro. Survival rates were calculated by the Kaplan-Meier method and the differences between the curves were evaluated by Tarone-Ware, Peto-Prentice, and log rank tests. We also used logistic regression analysis and the multinomial model. A p value ≤ 0.05 was considered to be statistically significant. The local medical ethics committee gave their approval to this study. The mean age of patients was 45.8 years old. The overall survival rate was 48% at 11 years. The major causes of death were cardiovascular diseases (34%) and infections (15%). Logistic regression analysis found statistical significance for the following variables: age (p = 0.000038), TT angiotensinogen (p = 0.08261), and family income greater than five times the minimum wage (p = 0.03089), the latter being a protective factor. The survival of hemodialysis patients is likely to be influenced by the TT of the angiotensinogen M235T gene.

  1. Survival and Predictive Factors of Lethality in Hemodyalisis: D/I Polymorphism of The Angiotensin I-Converting Enzyme and of the Angiotensinogen M235T Genes

    Directory of Open Access Journals (Sweden)

    Mauro Alves

    2014-09-01

    Full Text Available Background: End-stage kidney disease patients continue to have markedly increased cardiovascular disease morbidity and mortality. Analysis of genetic factors connected with the renin-angiotensin system that influences the survival of the patients with end-stage kidney disease supports the ongoing search for improved outcomes. Objective: To assess survival and its association with the polymorphism of renin-angiotensin system genes: angiotensin I-converting enzyme insertion/deletion and angiotensinogen M235T in patients undergoing hemodialysis. Methods: Our study was designed to examine the role of renin-angiotensin system genes. It was an observational study. We analyzed 473 chronic hemodialysis patients in four dialysis units in the state of Rio de Janeiro. Survival rates were calculated by the Kaplan-Meier method and the differences between the curves were evaluated by Tarone-Ware, Peto-Prentice, and log rank tests. We also used logistic regression analysis and the multinomial model. A p value ≤ 0.05 was considered to be statistically significant. The local medical ethics committee gave their approval to this study. Results: The mean age of patients was 45.8 years old. The overall survival rate was 48% at 11 years. The major causes of death were cardiovascular diseases (34% and infections (15%. Logistic regression analysis found statistical significance for the following variables: age (p = 0.000038, TT angiotensinogen (p = 0.08261, and family income greater than five times the minimum wage (p = 0.03089, the latter being a protective factor. Conclusions: The survival of hemodialysis patients is likely to be influenced by the TT of the angiotensinogen M235T gene.

  2. Upregulation of ERK1/2-eNOS via AT2 receptors decreases the contractile response to angiotensin II in resistance mesenteric arteries from obese rats.

    Directory of Open Access Journals (Sweden)

    Graziela N Hagihara

    Full Text Available It has been clearly established that mitogen-activated protein kinases (MAPKS are important mediators of angiotensin II (Ang II signaling via AT1 receptors in the vasculature. However, evidence for a role of these kinases in changes of Ang II-induced vasoconstriction in obesity is still lacking. Here we sought to determine whether vascular MAPKs are differentially activated by Ang II in obese animals. The role of AT2 receptors was also evaluated. Male monosodium glutamate-induced obese (obese and non-obese Wistar rats (control were used. The circulating concentrations of Ang I and Ang II, determined by HPLC, were increased in obese rats. Ang II-induced isometric contraction was decreased in endothelium-intact resistance mesenteric arteries from obese compared with control rats and exhibited a retarded AT1 receptor antagonist response. Blocking of AT2 receptors and inhibition of either endothelial nitric oxide synthase (eNOS or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2 restored Ang II-induced contraction in obese rats. Western blot analysis revealed increased protein expression of AT2 receptors in arteries from obese rats. Basal and Ang II-induced ERK1/2 phosphorylation was also increased in obese rats. Blockade of either AT1 or AT2 receptors corrected the increased ERK1/2 phosphorylation in arteries from obese rats to levels observed in control preparations. Phosphorylation of eNOS was increased in obese rats. Incubation with the ERK1/2 inhibitor before Ang II stimulation did not affect eNOS phosphorylation in control rats; however, it corrected the increased phosphorylation of eNOS in obese rats. These results clearly demonstrate that enhanced AT2 receptor and ERK1/2-induced, NO-mediated vasodilation reduces Ang II-induced contraction in an endothelium-dependent manner in obese rats.

  3. Common Promoter Elements in Odorant and Vomeronasal Receptor Genes

    OpenAIRE

    Jussara S Michaloski; Galante, Pedro A. F.; Nagai, Maíra H.; Lucia Armelin-Correa; Ming-Shan Chien; Hiroaki Matsunami; Bettina Malnic

    2011-01-01

    In mammals, odorants and pheromones are detected by hundreds of odorant receptors (ORs) and vomeronasal receptors (V1Rs and V2Rs) expressed by sensory neurons that are respectively located in the main olfactory epithelium and in the vomeronasal organ. Even though these two olfactory systems are functionally and anatomically separate, their sensory neurons show a common mechanism of receptor gene regulation: each neuron expresses a single receptor gene from a single allele. The mechanisms unde...

  4. Involvement of the Intrarenal Renin-Angiotensin System in Experimental Models of Glomerulonephritis

    Directory of Open Access Journals (Sweden)

    Maki Urushihara

    2012-01-01

    Full Text Available The intrarenal renin-angiotensin system (RAS has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN. Angiotensin II (Ang II is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1 receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN.

  5. Effect of angiotensin I-converting enzyme and α-actinin-3 gene polymorphisms on sport performance.

    Science.gov (United States)

    Gunel, Tuba; Gumusoglu, Ece; Hosseini, Mohammad Kazem; Yilmazyildirim, Eda; Dolekcap, Ismail; Aydinli, Kilic

    2014-04-01

    Genetic polymorphism is considered to be associated with human physical performance. The angiotensin I-converting enzyme insertion/deletion (ACE I/D) and the α-actinin-3 gene (ACTN3) R577X polymorphisms have been widely investigated for such associations, and functional ACE I/D and ACTN3 R577X polymorphisms have been associated with sprinter performance. The aim of this study was to determine the effect of these polymorphisms on sport performance among 37 elite athletes and 37 healthy controls. The ACE II genotype was identified in 32.43% of the control group and 8.11% of elite athletes, the DD genotype in 37.84% of the control group and 51.35% of the elite athletes, and the ID genotype in 29.73% of the control group and 40.54% of the elite athletes. With regard to the ACTN3 gene, the XX genotype, which confers an advantage for endurance activities, was identified in 10.81% of the control group and 35.14% of the elite athletes. The XX genotype was observed more frequently than the RR genotype (advantageous for sprinting), which was identified in 2.70% of the control group and 10.81% of elite athletes. The RX genotype (observed in 86.48% of the control group and in 54.05% of the elite athletes) was the most common genotype of the individuals in the present study. The study showed that ACTN3 and ACE gene polymorphisms have an effect on muscle power; however, larger studies are required.

  6. Polymorphisms of angiotensin-converting enzyme 2 gene confer a risk to lone atrial fibrillation in Chinese male patients

    Institute of Scientific and Technical Information of China (English)

    WANG Shu-xia; TAO Tao; FU Zhi-qing; XIE Xiang-zhu; WANG Hao; WANG Yu-tang

    2013-01-01

    Background Growing epidemiologic evidence has indicated that genetics can predispose individuals to the occurrence of lone atrial fibrillation (AF).The angiotensin-converting enzyme 2 (ACE2) gene has been established to be associated with hypertension and left ventricular hypertrophy.The objective of our study was to investigate the association of ACE2 gene polymorphisms with lone AF.Methods A total of 265 consecutive lone AF patients and 289 healthy controls were successfully investigated.The polymorphisms rs2106809 and rs2285666 were genotyped by polymerase chain reaction (PCR) and direct sequencing.A Logistic regression model was used to determine the odds ratio (OR) and 95% confidence intervals (CI) of variations of ACE2 for lone AF.Results The T allele of rs2106809 conferred an increased risk for lone AF (OR 1.24,95% CI 1.01-1.52,P=0.03) in males after adjustment for conventional risk factors.SNP at rs2285666 in males was not significantly different between AF patients and controls.No association was found between the two polymorphisms in the female population with lone AF.After (36.3±4.5) months of follow-up,the end point data were obtained:death (cardiac and noncardiac),ischemic stroke,and heart failure.In the male subgroup,the associations between rs2106809 T male carriers and combined end points including ischemic stroke,heart failure,and death in our study were of significance (OR 3.6,95% CI 1.0-13.1,P=0.04).Conclusions The results indicate that polymorphism at ACE2 gene is associated with male lone AF in a Chinese Han population.Lone AF males who carry the rs2106809 T allele are associated with adverse cardiac events.

  7. Intracellular Angiotensin II and cell growth of vascular smooth muscle cells

    NARCIS (Netherlands)

    Filipeanu, CM; Henning, RH; de Zeeuw, D; Nelemans, A

    2001-01-01

    1 We recently demonstrated that intracellular application of Angiotensin II (Angiotensin IIintr) induces rat aorta contraction independent of plasma membrane Angiotensin II receptors. In this study we investigated the effects of Angiotensin IIintr on cell growth in A7r5 smooth muscle cells. 2 DNA-sy

  8. The Androgen Receptor Gene Mutations Database.

    Science.gov (United States)

    Gottlieb, B; Lehvaslaiho, H; Beitel, L K; Lumbroso, R; Pinsky, L; Trifiro, M

    1998-01-01

    The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 272 to 309 in the past year. We have expanded the database: (i) by giving each entry an accession number; (ii) by adding information on the length of polymorphic polyglutamine (polyGln) and polyglycine (polyGly) tracts in exon 1; (iii) by adding information on large gene deletions; (iv) by providing a direct link with a completely searchable database (courtesy EMBL-European Bioinformatics Institute). The addition of the exon 1 polymorphisms is discussed in light of their possible relevance as markers for predisposition to prostate or breast cancer. The database is also available on the internet (http://www.mcgill. ca/androgendb/ ), from EMBL-European Bioinformatics Institute (ftp. ebi.ac.uk/pub/databases/androgen ), or as a Macintosh FilemakerPro or Word file (MC33@musica.mcgill.ca).

  9. The combination of amlodipine and angiotensin receptor blocker or diuretics in high-risk hypertensive patients: rationale, design and baseline characteristics

    Science.gov (United States)

    Wang, W; Ma, L; Zhang, Y; Deng, Q; Liu, M; Liu, L

    2011-01-01

    The Chinese Hypertension Intervention Efficacy Study (CHIEF) is a multi-centre randomized controlled clinical trial comparing the effects of amlodipine+angiotensin II receptor blocker and amlodipine+diuretics on the incidence of cardiovascular events, represented as a composite of non-fatal stroke, non-fatal myocardial infarction and cardiovascular death events in high-risk Chinese hypertensive patients. The study also evaluates the long-term effects of lipid-lowering treatment and lifestyle modification. From October 2007 to October 2008, 13 542 patients were enrolled into the study in 180 centres in China. Patients will be followed up for 4 years. There was no difference in baseline characteristics between the two blood pressure arms. PMID:20445570

  10. Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial: rationale, methods and design of a multicentre, randomised- and placebo-controlled clinical trial (NCT00120003)

    DEFF Research Database (Denmark)

    Sandset, Else Charlotte; Murray, Gordon; Boysen, Gudrun Margrethe;

    2010-01-01

    Elevated blood pressure following acute stroke is common, and yet early antihypertensive treatment is controversial. ACCESS suggested a beneficial effect of the angiotensin receptor blocker candesartan in the acute phase of stroke, but these findings need to be confirmed in new, large trials. AIM...... variables: Secondary effect variables include • the Barthel index (functional status) • EuroQol (quality of life) and • Mini-mental state examination (cognition) at 6-months • Health economic costs during the first 6-months......, Sweden, Denmark, Belgium, Germany, Poland, Lithuania, Estonia and Finland. STUDY OUTCOMES: There are two co-primary effect variables: • Functional status at 6-months, measured by the modified Rankin Scale, and • vascular death, myocardial infarction or stroke during the first 6-months. Secondary outcome...

  11. Insight into the structural requirement of substituted quinazolinone biphenyl acylsulfonamides derivatives as Angiotensin II AT1 receptor antagonist: 2D and 3D QSAR approach

    Directory of Open Access Journals (Sweden)

    Mukesh C. Sharma

    2014-01-01

    Full Text Available A series of 19 molecules substituted quinazolinone biphenyl acylsulfonamides derivatives displaying variable inhibition of Angiotensin II receptor AT1 activity were selected to develop models for establishing 2D and 3D QSAR. The compounds in the selected series were characterized by spatial, molecular and electro topological descriptors using QSAR module of Molecular Design Suite (VLife MDS™ 3.5. The best 2D QSAR model was selected, having correlation coefficient r2 (0.8056 and cross validated squared correlation coefficient q2 (0.6742 with external predictive ability of pred_r2 0.7583 coefficient of correlation of predicted data set (pred_r2se 0.2165. The results obtained from QSAR studies could be used in designing better Ang II activity among the congeners in future. The optimum QSAR model showed that the parameters SsssCHE index, SddCE-index, T_2_Cl_4, and SssNHE-index contributed in the model. 3D QSAR analysis by kNN-molecular field analysis approach developed based on principles of the k-nearest neighbor method combined with Genetic algorithms, stepwise forward variable selection approach; a leave-one-out cross-validated correlation coefficient (q2 of 0.6516 and a non-cross-validated correlation coefficient (r2 of 0.8316 and pred_r2 0.6954 were obtained. Contour maps using this approach showed that steric, electrostatic, and hydrophobic field effects dominantly determine binding affinities. The information rendered by 3D QSAR models may lead to a better understanding of structural requirements of Angiotensin II receptor and can help in the design of novel potent antihypertensive molecules.

  12. O polimorfismo A1166C do receptor tipo 1 da angiotensina II no infarto agudo do miocárdio The A1166C polymorphism of the angiotensin II type-1 receptor in acute myocardial infarction

    Directory of Open Access Journals (Sweden)

    Messias Antônio de Araújo

    2004-11-01

    Full Text Available RESUMO OBJETIVO:Avaliar a associação do polimorfismo A1166C do gene do receptor AT1 da angiotensina II (AT1R com o infarto agudo do miocárdio e a severidade da doença arterial coronariana. MÉTODOS: Estudo prospectivo, transversal de 110 pacientes com infarto agudo do miocárdio submetidos à angiografia coronariana com lesão significante (> 50% avaliada por três critérios de severidade: número de vasos lesados, morfologia da placa aterosclerótica e escore de risco coronariano. Sem lesões coronarianas 104 indivíduos controles. O polimorfismo A1166C do gene do AT1R foi determinado pela reação em cadeia da polimerase no DNA dos leucócitos do sangue periférico. Os fatores de risco coronariano clássicos foram analisados em todos os indivíduos. RESULTADOS: Na estratificação dos genótipos em relação aos fatores de risco apenas o tabagismo teve predominância nos heterozigotos AC (p = 0,02. A freqüência dos genótipos nos pacientes infartados foi de AA = 54,5%; AC = 35,5% e CC = 10%, sendo similar e não significativa em relação aos controles (p = 0,83. Não houve aumento do risco de infarto agudo do miocárdio nas comparações dos genótipos CC vs AA (OR = 1,35; IC-95% = 0,50 - 3,59, AC vs AA (OR = 1,03; IC-95% = 0,58 - 1,84 e AA+AC vs AA (OR = 1,33; IC-95% = 0,51 - 3,45. Nenhum dos critérios de severidade teve associação significativa com os genótipos. CONCLUSÃO: Os nossos resultados indicam não haver associação do polimorfismo A1166C do AT1R com o infarto agudo do miocárdio e nem com a severidade da doença arterial coronariana segundo nossos resultados.OBJECTIVE: To assess the association of the A1166C polymorphism of the angiotensin II type-1 receptor (AT1R gene with acute myocardial infarction and also with the severity of coronary artery disease. METHODS: A prospective, cross-sectional study was carried out with 110 patients with acute myocardial infarction, who, on coronary angiography, had significant

  13. Research progresses of Renin-angiotensin system receptors in breast cancer%肾素-血管紧张素系统相关受体在乳腺癌中的研究进展

    Institute of Scientific and Technical Information of China (English)

    王婷(综述); 陈雪松(审校)

    2016-01-01

    近期研究表明,肾素-血管紧张素系统( Renin-angiotensin system ,RAS)不仅在心血管系统方面起作用,而且在乳腺癌的发生和发展中也扮演着重要的角色。血管紧张素Ⅱ( Angiotensin Ⅱ, AngⅡ)和血管紧张素1-7(Angiotensin 1-7,Ang1-7)是RAS的主要效应分子,它们通过作用于RAS相关受体,可分别促进和抑制乳腺癌的发生和发展。本文就RAS在乳腺癌中的相关研究加以总结,并探讨RAS相关受体靶向治疗药物在乳腺癌临床治疗中的潜在用途。%Recent studies had demonstrated that Renin -angiotensin system ( RAS) plays an important role not only in the cardiovascular system ,but also in the occurrence and development of breast cancer .Associated with RAS receptor ,Angiotensin Ⅱ( Ang Ⅱ) and Angiotensin 1-7 ( Ang1-7 ) which are the major molecules of the RAS,respectively,promote or inhibit the occurrence and development of tumor .In this review,we summarize the current knowledge of the RAS in breast cancer ,and discuss the potential application of RAS related receptors targeted drugs in the clinical treatment of breast cancer .

  14. Effect of angiotensin Ⅰ-Ⅶ and angiotensin Ⅱ on expression of high density lipoprotein receptor in THP-1 macrophages%血管紧张素(1-7)与血管紧张素Ⅱ对THP-1巨噬细胞高密度脂蛋白受体表达的影响

    Institute of Scientific and Technical Information of China (English)

    柴婵娟; 杨志明; 李芳; 梁斌; 边云飞; 康玉明

    2012-01-01

    Objective To observe the effect of angiotensin I -Ⅶ and angiotensinll on expression of high density lipoprotein receptor l(SR-BI) in THP-1 macrophages. Methods THP-1 macropha-ges were divided into blank control group, angiotensin TJ group, angiotensin TJ + angiotensinI -\\H group, angiotensin TJ +angiotensin I -VI+A-779 group according to their effect on expression of SR-BI in THP-1 macrophages. Expression of SR-BI Mrna and protein in THP-1 macrophages was detected by RT-PCR and Western blot,respectively. Results The expression level of SR-BI Mrna and protein in THP-1 macrophages was significantly lower in 10 nmol/L-10' nmol/L angiotensin TJ group and 102 nmol angiotensin TJ + A-779 group than in blank control group and significantly higher in 10 nmol/L-104 nmol/L angiotensin I -Ⅶ group and angiotensinTJ +102 nmol/L-104 nmol/L angiotensin I -Ⅶ group than in angiotensin TJ group and blank control group(P<0. 05). Conclusion Angiotensin TJ down-regulates the expression of SR-BI in a dose-dependent manner and promotes the outflow of cholesterol, thus improving its inverted tranport.%目的 观察血管紧张素(1-7)[Ang(1-7)]及AngⅡ对THP-1巨噬细胞高密度脂蛋白受体I(SR-BI)表达的影响.方法 将THP-1巨噬细胞根据AngⅡ和Ang(1-7)对SR BI表达的影响分别分为:空白对照组及不同浓度AngⅡ组(10~104 nmol/L组);空白对照组及不同浓度Ang(1-7)组(10~104 nmol/L组);空白对照组、AngⅡ102nmol/L组、AngⅡ102 nmol/L+ Ang(1-7)组(102~104 nmol/L组)、AngⅡ+Ang(1-7)+A-779组.运用RT-PCR和Western blot法检测各组SR-BI mRNA及SR-BI蛋白表达的变化.结果 与空白对照组比较,AngⅡ10~104nmol/L组SR-BI mRNA及蛋白表达明显下调,呈浓度依赖性(P<0.05);而Ang(1-7)10~104 nmol/L组SR-BImRNA及蛋白表达明显上调,呈浓度依赖性(P<0.05);与空白对照组和AngⅡ组比较,AngⅡ102 nmol/L+Ang(1-7)组(102~104 nmol/L组)SR-BI表达明显上调,呈浓度依赖性(P<0.05).

  15. Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production.

    Directory of Open Access Journals (Sweden)

    Priscila R De Batista

    Full Text Available Hypertension is considered as a low-grade inflammatory disease, with adaptive immunity being an important mediator of this pathology. TLR4 may have a role in the development of several cardiovascular diseases; however, little is known about its participation in hypertension. We aimed to investigate whether TLR4 activation due to increased activity of the renin-angiotensin system (RAS contributes to hypertension and its associated endothelial dysfunction. For this, we used aortic segments from Wistar rats treated with a non-specific IgG (1 µg/day and SHRs treated with losartan (15 mg/kg·day, the non-specific IgG or the neutralizing antibody anti-TLR4 (1 µg/day, as well as cultured vascular smooth muscle cells (VSMC from Wistar and SHRs. TLR4 mRNA levels were greater in the VSMC and aortas from SHRs compared with Wistar rats; losartan treatment reduced those levels in the SHRs. Treatment of the SHRs with the anti-TLR4 antibody: 1 reduced the increased blood pressure, heart rate and phenylephrine-induced contraction while it improved the impaired acetylcholine-induced relaxation; 2 increased the potentiation of phenylephrine contraction after endothelium removal; and 3 abolished the inhibitory effects of tiron, apocynin and catalase on the phenylephrine-induced response as well as its enhancing effect of acetylcholine-induced relaxation. In SHR VSMCs, angiotensin II increased TLR4 mRNA levels, and losartan reduced that increase. CLI-095, a TLR4 inhibitor, mitigated the increases in NAD(PH oxidase activity, superoxide anion production, migration and proliferation that were induced by angiotensin II. In conclusion, TLR4 pathway activation due to increased RAS activity is involved in hypertension, and by inducing oxidative stress, this pathway contributes to the endothelial dysfunction associated with this pathology. These results suggest that TLR4 and innate immunity may play a role in hypertension and its associated end-organ damage.

  16. Identification of Significant Association and Gene-Gene Interaction of GABA Receptor Subunit Genes in Autism

    OpenAIRE

    Ma, D Q; Whitehead, P. L.; Menold, M M; Martin, E. R.; Ashley-Koch, A. E.; Mei, H; Ritchie, M. D.; Delong, G R; Abramson, R.K.; Wright, H. H.; Cuccaro, M. L.; Hussman, J. P.; Gilbert, J.R.; Pericak-Vance, M A

    2005-01-01

    Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied...

  17. Expression of the Components of the Renin–Angiotensin System in Venous Malformation

    OpenAIRE

    Siljee, Sam; Keane, Emily; Marsh, Reginald; Brasch, Helen D.; Tan, Swee T.; Itinteang, Tinte

    2016-01-01

    Background Venous malformation (VM) is the most common form of vascular malformation, consisting of a network of thin-walled ectatic venous channels with deficient or absent media. This study investigated the expression of the components of the renin–angiotensin system (RAS), namely, (pro)renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1), and angiotensin II receptor 2 (AIITR2) in subcutaneous (SC) and intramuscular (IM) VM. Materials and methods SC ...

  18. Androgen receptor gene polymorphism in zebra species

    Directory of Open Access Journals (Sweden)

    Hideyuki Ito

    2015-09-01

    Full Text Available Androgen receptor genes (AR have been found to have associations with reproductive development, behavioral traits, and disorders in humans. However, the influence of similar genetic effects on the behavior of other animals is scarce. We examined the loci AR glutamine repeat (ARQ in 44 Grevy's zebras, 23 plains zebras, and three mountain zebras, and compared them with those of domesticated horses. We observed polymorphism among zebra species and between zebra and horse. As androgens such as testosterone influence aggressiveness, AR polymorphism among equid species may be associated with differences in levels of aggression and tameness. Our findings indicate that it would be useful to conduct further studies focusing on the potential association between AR and personality traits, and to understand domestication of equid species.

  19. FGF receptor genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Agarwal, D; Pineda, S; Michailidou, K;

    2014-01-01

    Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying...... genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry......, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.Results:Little evidence of association with breast cancer risk...

  20. A Meta-analysis on the correlation between the polymorphism of angiotensin converting enzyme gene and hypertrophic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Ling CHEN

    2014-01-01

    Full Text Available Objective To systematically investigate the correlation between the polymorphism of angiotensin converting enzyme (ACE gene I/D and hypertrophic cardiomyopathy. Methods The databases, such as PubMed, Embase, OVID, Web of Science, Cochrane library, CNKI, WanFang Data and VIP, were searched to collect the studies on the correlation between ACE I/D polymorphism and hypertrophic cardiomyopathy susceptibility. Studies that met the inclusion criteria were Meta-analyzed using Stata 11.0 software. Results Fifteen articles were collected including 1114 cases and 1648 controls. The Meta-analysis indicated that there was significant correlation between the 4 models of ACE I/D polymorphism and hypertrophic cardiomyopathy susceptibility [D vs I: OR=1.49, 95%CI (1.20, 1.84; DD vs (ID+II: OR=1.56, 95%CI (1.17, 2.08; (DD+ID vs II: OR=1.76, 95%CI (1.30, 2.38; DD vs II: OR=2.20, 95%CI (1.44, 3.37]. In subgroup analysis, the significant difference existed in Asian population, but no significance was found in European population (P<0.05. Conclusions There is a positive correlation between hypertrophic cardiomyopathy and ACE I/D polymorphism in population, and D allele and DD genotype are likely to be the risk factors of hypertrophic cardiomyopathy. But such correlation does not exist in European population. DOI: 10.11855/j.issn.0577-7402.2013.12.07

  1. Risk conferred by FokI polymorphism of vitamin D receptor (VDR gene for essential hypertension

    Directory of Open Access Journals (Sweden)

    N Swapna

    2011-01-01

    Full Text Available Background : The vitamin D receptor (VDR gene serves as a good candidate gene for susceptibility to several diseases. The gene has a critical role in regulating the renin-angiotensin system (RAS influencing the regulation of blood pressure. Hence determining the association of VDR polymorphisms with essential hypertension is expected to help in the evaluation of risk for the condition. Aim : The aim of this study was to evaluate association between VDR Fok I polymorphism and genetic susceptibility to essential hypertension. Materials and Methods : Two hundred and eighty clinically diagnosed hypertensive patients and 200 normotensive healthy controls were analyzed for Fok I (T/C [rs2228570] polymorphism by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP analysis. Genotype distribution and allele frequencies in patients and controls, and odds ratios (ORs were calculated to predict the risk for developing hypertension by the individuals of different genotypes. Results : The genotype distribution and allele frequencies of Fok I (T/C [rs2228570] VDR polymorphism differed significantly between patients and controls (χ2 of 18.0; 2 degrees of freedom; P = 0.000. FF genotype and allele F were at significantly greater risk for developing hypertension and the risk was elevated for both the sexes, cases with positive family history and habit of smoking. Conclusions : Our data suggest that VDR gene Fok I polymorphism is associated with the risk of developing essential hypertension

  2. Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade

    NARCIS (Netherlands)

    B. Tom (Beril); R. de Vries (René); P.R. Saxena (Pramod Ranjan); A.H.J. Danser (Jan)

    2001-01-01

    textabstractACE inhibitors block B(2) receptor desensitization, thereby potentiating bradykinin beyond blocking its hydrolysis. Angiotensin (Ang)-(1-7) also acts as an ACE inhibitor and, in addition, may stimulate bradykinin release via angiotensin II type 2 receptors.

  3. Angiotensinreceptor blocker provides pancreatic β-cell protection independent of blood pressure lowering in diabetic db/db mice

    Institute of Scientific and Technical Information of China (English)

    Jia-qing SHAO; Noseki IWASHITA; Hong DU; Yang-tian WANG; Yan-yan WANG; Ming ZHAO; Jian WANG; Hirotaka WATADA; Ryuzo KAWAMORI

    2007-01-01

    Aim: Several epidemiological studies have suggested that treatment with angiotensin Ⅱ type 1 receptor blocker provided a risk reduction of developing type 2 diabetes. The aim of this study was to investigate whether and how chronic candesartan treatment can attenuate the deleterious influence of the hyperactive local intra-islet renin-angiotensin system in the diabetes state. Methods: Eight-week-old db/db mice were randomized to candesartan 1 mg/kg, candesartan 10mg/kg, manidipine 10 mg/kg, or placebo via gavage for 6 weeks. Their age-matched nondiabetic littermates db/m mice were treated with placebo and acted as nondia-betic controls. After 6 weeks' treatment, an intraperitoneal glucose tolerance test, immunohistochemical staining of oxidative stress markers, insulin, CD31, azan staining and an electron microscopy observation were performed. Results: Chronic candesartan treatment provided an improvement of glucose tolerance, and greatly rescued islet β-cell mass. Candesartan treatment also notably decreased staining intensity of oxidative stress markers, as well as attenuating intra-islet fibrosis and improving blood supply in the islet. In the electron microscopy observation, candesartan-treated animals exhibited improved granulation and less remarkable endoplasmic reticulum and Golgi bodies; furthermore, candesartan treatment greatly relieved the swelling of mitochondria to nearly normal. Both the benefits of reducing oxidative stress and ultra structure protection were in a dose-dependent and blood pressure-independent manner. Conclusion: After diabetes was initiated, candesartan treatment could not reverse the state of diabetes, but it effectively improved glucose tolerance and protected β-cell function by attenuating oxidative stress, islet fibrosis, sparsity of blood supply and ultrastructure disruption in a dose-dependent and blood pressure-independent manner.

  4. Genetic and Functional Analysis of Androgen Receptor Gene Mutations

    OpenAIRE

    Brüggenwirth, Hennie

    1998-01-01

    textabstractNuclear hormone receptors (NHRs) are intermediary factors through which extracellular signals regulate expression of genes that are involved in homeostasis, development, and differentiation (Beato et al. '995, Mangelsdorf and Evans 1995). These receptors are characterized by a modular structure, with domains involved in transcription activation, DNA binding. hormone binding, and dimerization. The nuclear receptor super-family comprises three subfamilies of receptors, which might h...

  5. Single nucleotide polymorphisms in the apolipoprotein B and low density lipoprotein receptor genes affect response to antihypertensive treatment

    Directory of Open Access Journals (Sweden)

    Kahan Thomas

    2004-09-01

    Full Text Available Abstract Background Dyslipidemia has been associated with hypertension. The present study explored if polymorphisms in genes encoding proteins in lipid metabolism could be used as predictors for the individual response to antihypertensive treatment. Methods Ten single nucleotide polymorphisms (SNP in genes related to lipid metabolism were analysed by a microarray based minisequencing system in DNA samples from ninety-seven hypertensive subjects randomised to treatment with either 150 mg of the angiotensin II type 1 receptor blocker irbesartan or 50 mg of the β1-adrenergic receptor blocker atenolol for twelve weeks. Results The reduction in blood pressure was similar in both treatment groups. The SNP C711T in the apolipoprotein B gene was associated with the blood pressure response to irbesartan with an average reduction of 19 mmHg in the individuals carrying the C-allele, but not to atenolol. The C16730T polymorphism in the low density lipoprotein receptor gene predicted the change in systolic blood pressure in the atenolol group with an average reduction of 14 mmHg in the individuals carrying the C-allele. Conclusions Polymorphisms in genes encoding proteins in the lipid metabolism are associated with the response to antihypertensive treatment in a drug specific pattern. These results highlight the potential use of pharmacogenetics as a guide for individualised antihypertensive treatment, and also the role of lipids in blood pressure control.

  6. Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system.

    Science.gov (United States)

    Ferrario, C M; Iyer, S N

    1998-11-30

    Accumulating evidence suggests that angiotensin-(1-7) [Ang-(1-7)] is an important component of the renin-angiotensin system. As the most pleiotropic metabolite of angiotensin I (Ang I) it manifest actions which are most often the opposite of those described for angiotensin II (Ang II). Ang-(1-7) is produced from Ang I bypassing the prerequisite formation of Ang II. The generation of Ang-(1-7) is under the control of at least three enzymes, which include neprilysin, thimet oligopeptidase, and prolyl oligopeptidase depending on the tissue compartment. Both neprilysin and thimet oligopeptidase are also involved in the metabolism of bradykinin and the atrial natriuretic peptide. Moreover, recent studies suggest that in addition to Ang I and bradykinin, Ang-(1-7) is an endogenous substrate for angiotensin converting enzyme. This suggests that there is a complex relationship between the enzymatic pathways forming angiotensin II and other various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. The antihypertensive actions of angiotensin-(1-7) are mediated by an angiotensin receptor that is distinct from the pharmacologically characterized AT1 or AT2 receptor subtypes. Ang-(1-7) mediates it antihypertensive effects by stimulating synthesis and release of vasodilator prostaglandins, and nitric oxide and potentiating the hypotensive effects of bradykinin.

  7. Differential extracellular signal-regulated kinases 1 and 2 activation by the angiotensin type 1 receptor supports distinct phenotypes of cardiac myocytes

    DEFF Research Database (Denmark)

    Aplin, Mark; Christensen, Gitte Lund; Schneider, Mikael;

    2007-01-01

    The angiotensin II (AngII) type 1 receptor (AT(1)R) is a seven-transmembrane receptor well established to activate extracellular signal-regulated kinases 1 and 2 (ERK1/2) by discrete G protein-dependent and beta-arrestin2-dependent pathways. The biological importance of this, however, remains...... obscure. Application of the modified analogue [Sar(1), Ile(4), Ile(8)]-AngII ([SII] AngII) allowed us to dissect the two pathways of ERK1/2 activation in native cardiac myocytes. Although cytosol-retained, the beta-arrestin2-bound pool of ERK1/2 represents an active signalling component...... that phosphorylates p90 Ribosomal S6 Kinase, a ubiquitous and versatile mediator of ERK1/2 signal transduction. Moreover, the beta-arrestin2-dependent ERK1/2 signal supports intact proliferation of cardiac myocytes. In contrast to G(q)-activated ERK1/2, and in keeping with its failure to translocate to the nucleus...

  8. Angiotensin type 2 receptor stimulation ameliorates left ventricular fibrosis and dysfunction via regulation of tissue inhibitor of matrix metalloproteinase 1/matrix metalloproteinase 9 axis and transforming growth factor β1 in the rat heart.

    Science.gov (United States)

    Lauer, Dilyara; Slavic, Svetlana; Sommerfeld, Manuela; Thöne-Reineke, Christa; Sharkovska, Yuliya; Hallberg, Anders; Dahlöf, Bjorn; Kintscher, Ulrich; Unger, Thomas; Steckelings, Ulrike Muscha; Kaschina, Elena

    2014-03-01

    Left ventricular (LV) remodeling is the main reason for the development of progressive cardiac dysfunction after myocardial infarction (MI). This study investigated whether stimulation of the angiotensin type 2 receptor is able to ameliorate post-MI cardiac remodeling and what the underlying mechanisms may be. MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with the angiotensin type 2 receptor agonist compound 21 (0.03 mg/kg) was started 6 hours post-MI and continued for 6 weeks. Hemodynamic parameters were measured by echocardiography and intracardiac catheter. Effects on proteolysis were studied in heart tissue and primary cardiac fibroblasts. Compound 21 significantly improved systolic and diastolic functions, resulting in improved ejection fraction (71.2±4.7% versus 53.4±7.0%; Pventricular filling velocities, and maximum and minimum rate of LV pressure rise (P<0.05). Compound 21 improved arterial stiffness parameters and reduced collagen content in peri-infarct myocardium. Tissue inhibitor of matrix metalloproteinase 1 was strongly upregulated, whereas matrix metalloproteinases 2 and 9 and transforming growth factor β1 were diminished in LV of treated animals. In cardiac fibroblasts, compound 21 initially induced tissue inhibitor of matrix metalloproteinase 1 expression followed by attenuated matrix metalloproteinase 9 and transforming growth factor β1 secretion. In conclusion, angiotensin type 2 receptor stimulation improves cardiac function and prevents cardiac remodeling in the late stage after MI, suggesting that angiotensin type 2 receptor agonists may be considered a future pharmacological approach for the improvement of post-MI cardiac dysfunction.

  9. Gene-load score of the renin-angiotensin-aldosterone system is associated with coronary heart disease in familial hypercholesterolaemia

    NARCIS (Netherlands)

    J.B. van der Net (Jeroen); J. van Etten (Jeroen); M. Yazdanpanah (Mojgan); G.M. Dallinga-Thie (Geesje); J.J.P. Kastelein (John); J.C. Defesche (Joep); R.P. Koopmans (Richard); E.W. Steyerberg (Ewout); E.J.G. Sijbrands (Eric)

    2008-01-01

    textabstractAims: Familial hypercholesterolaemia (FH) is characterized by premature coronary heart disease (CHD). However, the incidence of CHD varies considerably among FH patients. Genetic variation in the renin-angiotensin-aldosterone system (RAAS) and the adrenalin/noradrenalin system may be of

  10. Dopamine receptor-mediated regulation of neuronal "clock" gene expression.

    Science.gov (United States)

    Imbesi, M; Yildiz, S; Dirim Arslan, A; Sharma, R; Manev, H; Uz, T

    2009-01-23

    Using a transgenic mice model (i.e. "clock" knockouts), clock transcription factors have been suggested as critical regulators of dopaminergic behaviors induced by drugs of abuse. Moreover, it has been shown that systemic administration of psychostimulants, such as cocaine and methamphetamine regulates the striatal expression of clock genes. However, it is not known whether dopamine receptors mediate these regulatory effects of psychostimulants at the cellular level. Primary striatal neurons in culture express dopamine receptors as well as clock genes and have been successfully used in studying dopamine receptor functioning. Therefore, we investigated the role of dopamine receptors on neuronal clock gene expression in this model using specific receptor agonists. We found an inhibitory effect on the expression of mClock and mPer1 genes with the D2-class (i.e. D2/D3) receptor agonist quinpirole. We also found a generalized stimulatory effect on the expression of clock genes mPer1, mClock, mNPAS2 (neuronal PAS domain protein 2), and mBmal1 with the D1-class (i.e. D1) receptor agonist SKF38393. Further, we tested whether systemic administration of dopamine receptor agonists causes similar changes in striatal clock gene expression in vivo. We found quinpirole-induced alterations in mPER1 protein levels in the mouse striatum (i.e. rhythm shift). Collectively, our results indicate that the dopamine receptor system may mediate psychostimulant-induced changes in clock gene expression. Using striatal neurons in culture as a model, further research is needed to better understand how dopamine signaling modulates the expression dynamics of clock genes (i.e. intracellular signaling pathways) and thereby influences neuronal gene expression, neuronal transmission, and brain functioning. PMID:19017537

  11. Angiotensin II induces the production of MMP-3 and MMP-13 through the MAPK signaling pathways via the AT(1) receptor in osteoblasts.

    Science.gov (United States)

    Nakai, Kumiko; Kawato, Takayuki; Morita, Toyoko; Iinuma, Toshimitsu; Kamio, Noriaki; Zhao, Ning; Maeno, Masao

    2013-04-01

    Angiotensin II (Ang II) plays an important role in the maintenance of bone mass and integrity by activation of the mitogen-activated protein kinases (MAPKs) and by modulation of balance between resorption by osteoclasts and formation by osteoblasts. However, the role of Ang II in the turnover of extracellular matrix (ECM) in osteoid by osteoblasts remains unclear. Therefore, we examined the effect of Ang II on the expression of matrix metalloproteinases (MMPs), plasminogen activators (PAs), and their inhibitors [i.e., tissue inhibitors of metalloproteinases (TIMPs) and PA inhibitor-1 (PAI-1)] using osteoblastic ROS17/2.8 cells. Treatment with Ang II strikingly increased the expressions of MMP-3 and -13 and promoted cell proliferation associated with reduced alkaline phosphatase activity as well as enhanced phosphorylated expression of extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, and stress-activated protein kinases/c-jun N-terminal kinases (SAPK/JNK) in ROS17/2.8 cells. However, Ang II had no effect on the expression of MMP-2, -9, -14, urokinase-type PA, tissue-type PA, TIMP-1, -2, -3, and PAI-1 in cells. Losartan (AT1 receptor blocker) blocked Ang II-induced expression of MMP-3 and -13, whereas PD123319 (AT2 receptor blocker) did not completely block these responses. Losartan also blocked the Ang II-induced phosphorylation of ERK1/2, p38 MAPK, and SAPK/JNK. MAPK kinase 1/2 inhibitor PD98059 and JNK inhibitor SP600125 suppressed Ang II-induced expression of MMP-3 and -13. These results suggested that Ang II stimulated the degradation process that occurs during ECM turnover in osteoid by increasing the production of MMP-3 and -13 through MAPK signaling pathways via the AT1 receptor in osteoblasts. Furthermore, our findings suggest that Ang II does not influence the plasminogen/plasmin pathway in osteoblasts. PMID:23277113

  12. Vascular response to angiotensin II predicts long-term prognosis in patients undergoing coronary artery bypass grafting

    NARCIS (Netherlands)

    Harst, van der Pim; Volbeda, M.; Voors, Adriaan; Buikema, Hendrik; Wassmann, S.; Bohm, M.; Nickenig, G.; van Gilst, W.H.

    2004-01-01

    Persistent activation of the renin-angiotensin system leads to downregulation of the angiotensin type-1 receptor, and consequently, to a decreased response to exogenous angiotensin II. In the present study, we investigated the association of angiotensin II responsiveness to clinical outcome after co

  13. Recent advances in angiotensin II signaling

    Directory of Open Access Journals (Sweden)

    R.M. Touyz

    2002-09-01

    Full Text Available Angiotensin II (Ang II* is a multifunctional hormone that influences the function of cardiovascular cells through a complex series of intracellular signaling events initiated by the interaction of Ang II with AT1 and AT2 receptors. AT1 receptor activation leads to cell growth, vascular contraction, inflammatory responses and salt and water retention, whereas AT2 receptors induce apoptosis, vasodilation and natriuresis. These effects are mediated via complex, interacting signaling pathways involving stimulation of PLC and Ca2+ mobilization; activation of PLD, PLA2, PKC, MAP kinases and NAD(PH oxidase, and stimulation of gene transcription. In addition, Ang II activates many intracellular tyrosine kinases that play a role in growth signaling and inflammation, such as Src, Pyk2, p130Cas, FAK and JAK/STAT. These events may be direct or indirect via transactivation of tyrosine kinase receptors, including PDGFR, EGFR and IGFR. Ang II induces a multitude of actions in various tissues, and the signaling events following occupancy and activation of Ang receptors are tightly controlled and extremely complex. Alterations of these highly regulated signaling pathways may be pivotal in structural and functional abnormalities that underlie pathological processes in cardiovascular diseases such as cardiac hypertrophy, hypertension and atherosclerosis.

  14. Hemodynamic effect of angiotensin II receptor blockade in postmenopausal women on a high-sodium diet: A double-blind, randomized, placebo-controlled study

    Science.gov (United States)

    Pechère-Bertschi, Antoinette; Maillard, Marc; Bischof, Paul; Fathi, Marc; Burnier, Michel

    2008-01-01

    Background: Hypertension becomes increasingly prevalent after menopause. Postmenopausal women are more responsive to salt than premenopausal women, and they have been reported to develop marked renal vasoconstriction on a high-sodium diet. Objective: The aim of this study was to assess whether angiotensin II receptor blockade can restore a normal pattern of renal response to salt in postmenopausal women on a high-sodium diet. We also assessed segmental renal sodium handling in that population. Methods: Normotensive and hypertensive postmenopausal women not receiving hormone replacement therapy were enrolled in this prospective, double-blind, placebo-controlled, crossover study. They were assigned to receive irbesartan 150 mg or placebo for 6 weeks; the sequence in which they received irbesartan or placebo was randomized. During the last week of treatment, they received a high-sodium diet (250 mmol/d). Ambulatory blood pressure (ABP), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF) were measured using sinistrin and para-amino-hippurate clearances. Renal sodium handling was assessed by measuring endogenous lithium clearance on day 7 of the high-salt diet. Results: Nineteen women (mean age, 54.7 years; range, 43–72 years; 7 normotensive subjects [mean age, 53.4 years; range, 47–61 years] and 12 hypertensive subjects [mean age, 55.4 years; range, 43–72 years]) were included in the study. When the data for all 19 subjects were pooled, ABP was significantly lower with irbesartan than placebo both during the day (120 [3]/79 [2] vs 127 [3]/85 [2] mm Hg; both, P < 0.01) and at night (systolic BP, 107 [4] vs 111 [4] mm Hg [P < 0.01] and diastolic BP, 71 [2] vs 75 [2] mm Hg [P < 0.05]). Compared with placebo, irbesartan was not associated with a significant change in GFR in either the normotensive or the hypertensive women. When the data for all 19 subjects were pooled, irbesartan was associated with a significant increase in ERPF compared with

  15. Effects of angiotensinreceptor antagonist on expression of collagen Ⅲ, collagen Ⅴ, and transforming growth factor β1 in the airway walls of sensitized rats

    Institute of Scientific and Technical Information of China (English)

    杜永成; 许建英; 张韶君

    2004-01-01

    Background Repeated attacks of bronchial asthma lead to different degrees of airway remodeling, the mechanism of which is not yet clear. Some evidences indicate that it is related to the excessive expression of some growth promotion factors. Angiotensin Ⅱ is a polypeptide that may be involved in airway remodeling. To evaluate its role in airway remodeling in asthma, we observed the effects of an angiotensin Ⅱ type 1 receptor antagonist (valsartan) on the expression of collagen Ⅲ, collagen Ⅴ, and transforming growth factor β1 (TGF-β1) mRNA and protein in the airway walls of sensitized rats.Methods Forty Wistar rats were randomly divided into 5 groups: control group, sensitized group, and valsartan groups 1, 2, and 3. The rats in the sensitized group and in valsartan groups 1, 2, and 3 were sensitized and challenged with ovalbumin. Rats in control group were sensitized and challenged with 0.9% NaCl. Rats from valsartan groups 1, 2, and 3 were drenched with valsartan (10 μg, 20 μg, or 30 μg, respectively) at the time of the ovalbumin challenges. The expression of collagen Ⅲ, collagen Ⅴ, and TGF-β1 protein were detected using immunohistochemical method in combination with image analysis methods. The expression of TGF-β1 mRNA was detected by in situ hybridization. Results The expression in the airways of collagen Ⅲ and collagen Ⅴ was significantly higher in rats from the sensitized group (7.73±0.81, 1.34±0.28) and from valsartan groups 1, 2, and 3 (5.73±0.64, 1.13±0.15; 4.96±0.51, 0.98±0.08; 4.43±0.35, 0.93±0.06, respectively) than those in the control group (2.65±0.38, 0.67±0.08, P<0.05). In addition, collagen levels were significantly lower in valsartan groups 1, 2, and 3 than those from the sensitized group (P<0.05). The expression of TGF-β1 mRNA and protein in the airways was significantly higher in rats from the sensitized group (20.49%±3.46%, 29.73%±3.25%) and from valsartan groups 1, 2, and 3 (16.47%±1.94%, 19.41%±1.87%; 14

  16. A Critical Appraisal of the Intrinsic Pancreatic Angiotensin-Generating System

    Directory of Open Access Journals (Sweden)

    Sernia C

    2001-01-01

    Full Text Available The pancreas is a relative newcomer to the stable of tissues with an intrinsic angiotensin-generating system. The involvement of this system in pancreatic activity will be dependent on the angiotensin-generating paths present in the pancreas and their precise cellular location. Thus far, renin, angiotensin-converting enzyme (ACE, angiotensin II and AT1 and AT2 receptors have been found. These are components of the "classical" renin-angiotensin system. But there is uncertainty as to their location and site of action. Furthermore, it is not known which, if any, alternative enzymes to renin and ACE are present, which angiotensins in addition to angiotensin II are generated and whether or not there are receptors to angiotensin IV and angiotensin-(1-7. Future research should focus on these aspects in order to provide a mechanistic basis to pancreatic physiological functions and to pathological conditions of clinical relevance.

  17. Expression of the Components of the Renin-Angiotensin System in Venous Malformation

    Directory of Open Access Journals (Sweden)

    Sam eSiljee

    2016-05-01

    Full Text Available Background Venous malformation (VM is the most common form of vascular malformation, consisting of a network of thin-walled ectatic venous channels with deficient or absent media. This study investigated the expression of the components of the renin-angiotensin system (RAS, namely (prorenin receptor (PRR, angiotensin converting enzyme (ACE, angiotensin II receptor 1 (ATIIR1 and angiotensin II receptor 2 (AIITR2 in subcutaneous (SC and intramuscular (IM VM. Materials and Methods SC (n=7 and IM (n=7 VM were analyzed for the expression of PRR, ACE, ATIIR1, and ATIIR2 using 3,3-diaminobenzidine (DAB and immunofluorescent (IF immunohistochemical (IHC staining and NanoString gene expression analysis. Results IHC staining showed expression of PRR, ACE, ATIIR1 and faint expression of ATIIR2 in the endothelium of SC and IM VM. Furthermore, ATIIR2 was expressed by cells away from the endothelium in both SC and IM VM lesions examined. NanoString analysis demonstrated the presence of PRR, ACE and ATIIR1 but not ATIIR2.Conclusions The presence of PRR, ACE, ATIIR1 and potentially ATIIR2, in both SC and IM VM suggests a role for the RAS in the biology of VM. This novel finding may lead to a mechanism-based therapy for VM.

  18. Paracrine Effects of Adipose-Derived Stem Cells on Matrix Stiffness-Induced Cardiac Myofibroblast Differentiation via Angiotensin II Type 1 Receptor and Smad7

    Science.gov (United States)

    Yong, Kar Wey; Li, Yuhui; Liu, Fusheng; Bin Gao; Lu, Tian Jian; Wan Abas, Wan Abu Bakar; Wan Safwani, Wan Kamarul Zaman; Pingguan-Murphy, Belinda; Ma, Yufei; Xu, Feng; Huang, Guoyou

    2016-01-01

    Human mesenchymal stem cells (hMSCs) hold great promise in cardiac fibrosis therapy, due to their potential ability of inhibiting cardiac myofibroblast differentiation (a hallmark of cardiac fibrosis). However, the mechanism involved in their effects remains elusive. To explore this, it is necessary to develop an in vitro cardiac fibrosis model that incorporates pore size and native tissue-mimicking matrix stiffness, which may regulate cardiac myofibroblast differentiation. In the present study, collagen coated polyacrylamide hydrogel substrates were fabricated, in which the pore size was adjusted without altering the matrix stiffness. Stiffness is shown to regulate cardiac myofibroblast differentiation independently of pore size. Substrate at a stiffness of 30 kPa, which mimics the stiffness of native fibrotic cardiac tissue, was found to induce cardiac myofibroblast differentiation to create in vitro cardiac fibrosis model. Conditioned medium of hMSCs was applied to the model to determine its role and inhibitory mechanism on cardiac myofibroblast differentiation. It was found that hMSCs secrete hepatocyte growth factor (HGF) to inhibit cardiac myofibroblast differentiation via downregulation of angiotensin II type 1 receptor (AT1R) and upregulation of Smad7. These findings would aid in establishment of the therapeutic use of hMSCs in cardiac fibrosis therapy in future. PMID:27703175

  19. Inhibitory Effect of the Punica granatum Fruit Extract on Angiotensin-II Type I Receptor and Thromboxane B2 in Endothelial Cells Induced by Plasma from Preeclamptic Patients.

    Science.gov (United States)

    Kusumawati, Widya; Keman, Kusnarman; Soeharto, Setyawati

    2016-01-01

    This study aims to evaluate whether the Punica granatum fruit extract modulates the Angiotensin-II Type I receptor (AT1-R) and thromboxane B2 level in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluence, endothelial cells were divided into five groups, which included endothelial cells exposed to 2% plasma from normal pregnancy (NP), endothelial cells exposed to 2% plasma from preeclamptic patients (PP), and endothelial cells exposed to PP in the presence of ethanolic extract of Punica granatum (PP + PG) at the following three doses: 14; 28; and 56 ppm. The expression of AT1-R was observed by immunohistochemistry technique, and thromboxane B2 level was done by immunoassay technique. Plasma from PP significantly increased AT1-R expression and thromboxane B2 levels compared to cells treated by normal pregnancy plasma. The increasing of AT1-R expression significantly (P Punica granatum extract. Moreover, the increasing of thromboxane B2 levels significantly (P Punica granatum extract. We further concluded that Punica granatum fruit protects and inhibits the sensitivity of endothelial cells to plasma from preeclamptic patients due to inhibition of AT1-R expression (56 ppm) and reduced thromboxane B2 levels (14 ppm). PMID:26989513

  20. Depressor and Anti-Inflammatory Effects of Angiotensin II Receptor Blockers in Metabolic and/or Hypertensive Patients With Coronary Artery Disease: A Randomized, Prospective Study (DIAMOND Study)

    Science.gov (United States)

    Adachi, Sen; Miura, Shin-ichiro; Shiga, Yuhei; Arimura, Tadaaki; Kuwano, Takashi; Kitajima, Ken; Ike, Amane; Sugihara, Makoto; Iwata, Atsushi; Nishikawa, Hiroaki; Morito, Natsumi; Saku, Keijiro

    2016-01-01

    Background We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective, randomized clinical trial. Methods Forty-four hypertensive patients who had coronary artery disease (CAD) were enrolled. We randomly assigned patients to changeover from their prior angiotensin II receptor blockers (ARBs) to either azilsartan or olmesartan, and followed the patients for 12 weeks. Results Office systolic blood pressure (SBP) in the azilsartan group was significantly decreased after 12 weeks. SBP and diastolic blood pressure (DBP) after 12 weeks in the azilsartan group were significantly lower than those in the olmesartan group. The percentage of patients who reached the target BP at 12 weeks (78%) in the azilsartan group was significantly higher than that at 12 weeks (45%) in the olmesartan group. There were no significant changes in pentraxin-3, high-sensitively C-reactive protein or adiponectin in blood after 12 weeks in either group. Although serum levels of creatinine (Cr) in the azilsartan group significantly increased, these changes were within the respective normal range. Conclusion In conclusion, the ability of azilsartan to reduce BP may be superior to that of prior ARBs with equivalent safety in hypertensive patients with CAD.

  1. Genetic and Functional Analysis of Androgen Receptor Gene Mutations

    NARCIS (Netherlands)

    H.T. Brüggenwirth (Hennie)

    1998-01-01

    textabstractNuclear hormone receptors (NHRs) are intermediary factors through which extracellular signals regulate expression of genes that are involved in homeostasis, development, and differentiation (Beato et al. '995, Mangelsdorf and Evans 1995). These receptors are characterized by a modular st

  2. Effects related to gene-gene interactions of peroxisome proliferator-activated receptor on essential hypertension

    Institute of Scientific and Technical Information of China (English)

    俞浩

    2013-01-01

    Objective To explore the impact of the gene-gene interaction among the single nucleotide polymorphisms(SNPs) of peroxisome proliferator-activated receptorα/δ/γ on essential hypertension(EH).Methods

  3. Comparative genomics of natural killer cell receptor gene clusters.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Many receptors on natural killer (NK cells recognize major histocompatibility complex class I molecules in order to monitor unhealthy tissues, such as cells infected with viruses, and some tumors. Genes encoding families of NK receptors and related sequences are organized into two main clusters in humans: the natural killer complex on Chromosome 12p13.1, which encodes C-type lectin molecules, and the leukocyte receptor complex on Chromosome 19q13.4, which encodes immunoglobulin superfamily molecules. The composition of these gene clusters differs markedly between closely related species, providing evidence for rapid, lineage-specific expansions or contractions of sets of loci. The choice of NK receptor genes is polarized in the two species most studied, mouse and human. In mouse, the C-type lectin-related Ly49 gene family predominates. Conversely, the single Ly49 sequence is a pseudogene in humans, and the immunoglobulin superfamily KIR gene family is extensive. These different gene sets encode proteins that are comparable in function and genetic diversity, even though they have undergone species-specific expansions. Understanding the biological significance of this curious situation may be aided by studying which NK receptor genes are used in other vertebrates, especially in relation to species-specific differences in genes for major histocompatibility complex class I molecules.

  4. CRDB: Database of Chemosensory Receptor Gene Families in Vertebrate

    OpenAIRE

    Dong Dong; Ke Jin; Xiaoli Wu; Yang Zhong

    2012-01-01

    Chemosensory receptors (CR) are crucial for animals to sense the environmental changes and survive on earth. The emergence of whole-genome sequences provides us an opportunity to identify the entire CR gene repertoires. To completely gain more insight into the evolution of CR genes in vertebrates, we identified the nearly all CR genes in 25 vertebrates using homology-based approaches. Among these CR gene repertoires, nearly half of them were identified for the first time in those previously u...

  5. Reproduction and the renin-angiotensin system.

    Science.gov (United States)

    Ganong, W F

    1995-01-01

    A unique aspect of the circulating renin-angiotensin system and the many independent tissue renin-angiotensin systems is their interactions at multiple levels with reproduction. These interactions, which have received relatively little attention, include effects of estrogens and possibly androgens on hepatic and renal angiotensinogen mRNA; effects of androgens on the Ren-2 gene and salivary renin in mice; the prorenin surge that occurs with but outlasts the LH surge during the menstrual cycle; the inhibitory effects of estrogens on thirst and water intake; the tissue renin-angiotensin systems in the brain, the anterior pituitary, and the ovaries and testes, that is, in all the components of the hypothalamo-pituitary-gonadal axis; the presence of some components of the renin-angiotensin system in the uterus and the fetoplacental unit; and the possible relation of renin and angiotensin to ovulation and fetal well-being. These interactions are described and their significance considered in this short review.

  6. Reproduction and the renin-angiotensin system

    Science.gov (United States)

    Ganong, W. F.

    1995-01-01

    A unique aspect of the circulating renin-angiotensin system and the many independent tissue renin-angiotensin systems is their interactions at multiple levels with reproduction. These interactions, which have received relatively little attention, include effects of estrogens and possibly androgens on hepatic and renal angiotensinogen mRNA; effects of androgens on the Ren-2 gene and salivary renin in mice; the prorenin surge that occurs with but outlasts the LH surge during the menstrual cycle; the inhibitory effects of estrogens on thirst and water intake; the tissue renin-angiotensin systems in the brain, the anterior pituitary, and the ovaries and testes, that is, in all the components of the hypothalamo-pituitary-gonadal axis; the presence of some components of the renin-angiotensin system in the uterus and the fetoplacental unit; and the possible relation of renin and angiotensin to ovulation and fetal well-being. These interactions are described and their significance considered in this short review.

  7. Renoprotective effect of renal liver-type fatty acid binding protein and angiotensin II type 1a receptor loss in renal injury caused by RAS activation.

    Science.gov (United States)

    Ichikawa, Daisuke; Kamijo-Ikemori, Atsuko; Sugaya, Takeshi; Shibagaki, Yugo; Yasuda, Takashi; Katayama, Kimie; Hoshino, Seiko; Igarashi-Migitaka, Junko; Hirata, Kazuaki; Kimura, Kenjiro

    2014-03-15

    The aim of this study was to assess the renoprotective effect of renal human liver-type fatty acid binding protein (hL-FABP) and angiotensin II (ANG II) type 1A receptor (AT1a) loss in renal injury caused by renin-angiotensin system (RAS) activation. We established hL-FABP chromosomal transgenic mice (L-FABP(+/-)AT1a(+/+)), crossed the L-FABP(+/-)AT1a(+/+) with AT1a knockdown homo mice (L-FABP(-/-)AT1a(-/-)), and generated L-FABP(+/-)AT1a hetero mice (L-FABP(+/-)AT1a(+/-)). After the back-cross of these cubs, L-FABP(+/-)AT1a(-/-) were obtained. To activate the renal RAS, wild-type mice (L-FABP(-/-)AT1a(+/+)), L-FABP(+/-)AT1a(+/+), L-FABP(-/-)AT1a(+/-), L-FABP(+/-)AT1a(+/-), L-FABP(-/-)AT1a(-/-), and L-FABP(+/-)AT1a(-/-) were administered high-dose systemic ANG II infusion plus a high-salt diet for 28 days. In the L-FABP(-/-)AT1a(+/+), RAS activation (L-FABP(-/-)AT1a(+/+)RAS) caused hypertension and tubulointerstitial damage. In the L-FABP(+/-)AT1a(+/+)RAS, tubulointerstitial damage was significantly attenuated compared with L-FABP(-/-)AT1a(+/+)RAS. In the AT1a partial knockout (AT1a(+/-)) or complete knockout (AT1a(-/-)) mice, reduction of AT1a expression led to a significantly lower degree of renal injury compared with L-FABP(-/-)AT1a(+/+)RAS or L-FABP(+/-)AT1a(+/+)RAS mice. Renal injury in L-FABP(+/-)AT1a(+/-)RAS mice was significantly attenuated compared with L-FABP(-/-)AT1a(+/-)RAS mice. In both L-FABP(-/-)AT1a(-/-)RAS and L-FABP(+/-)AT1a(-/-)RAS mice, renal damage was rarely found. The degrees of renal hL-FABP expression and urinary hL-FABP levels increased by RAS activation and gradually decreased along with reduction of AT1a expression levels. In conclusion, in this mouse model, renal hL-FABP expression and a decrease in AT1a expression attenuated tubulointerstitial damage due to RAS activation.

  8. Effects of angiotensin converting enzyme inhibitor, angio- tensin II type I receptor blocker and their combination on postinfarcted ventricular remodeling in rats

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background Transforming growth factor (TGF) β1-Smads signal plays an important role in cardiac remodeling following myocardial infarction (MI). In addition, both angiotensin converting enzyme inhibitor (ACEI) and angiotensin II type I receptor blocker (ARB) can effectively prevent left ventricular remodeling. The current study focused on whether the combination of ACEI and ARB is more beneficial for preventing ventricular remodeling and whether Smad proteins mediate this beneficial effect.Results VW/BW significantly increased in the placebo groups compared with that in the control group (P<0.01). This increase was limited in ACEI, ARB, and combined groups (P<0.01 compared with placebo group). There was no significant difference among the three actively treated groups. Collagen was increased in placebo group (5.68±0.5)% compared with that in control group (P<0.01). ACEI, ARB and combined treatment attenuated this increase of collagen [(4.3±0.5)%, (3.5±0.5)%, (3.2±0.4)%] in comparison with that in placebo group (P<0.01 respectively). Combined treatment showed more significant effect on collagen deposition. EF and FS significantly decreased, LVDd and E/A significantly increased in placebo group compared with that in control group (P<0.01 respectively). ACEI, ARB and combined treatment ameliorated these indexes (P<0.01 compared with placebo group). The mRNA expression of TGFβ1, Smad 2, and Smad 3 (0.700±0.045, 0.959±0.037 and 0.850±0.051) increased in placebo group compared with that in control group (P<0.01). ACEI, ARB and combined treatment normalized the increase (P<0.01). Furthermore, ARB and combined treatment proved to be more effective in decreasing TGF β1 and Smad mRNA expression than ACEI treatment (P<0.01). The expression of Smad 2 and Smad 3 protein increased in placebo group compared with that in control group (P<0.01). ACEI, ARB and combined treatment normalized the increase (P<0.01). Furthermore, ARB and combined treatment proved to be more

  9. Regulation of gonadotropin receptor gene expression

    NARCIS (Netherlands)

    A.P.N. Themmen (Axel); R. Kraaij (Robert); J.A. Grootegoed (Anton)

    1994-01-01

    textabstractThe receptors for the gonadotropins differ from the other G protein-coupled receptors by having a large extracellular hormone-binding domain, encoded by nine or ten exons. Alternative splicing of the large pre-mRNA of approximately 100 kb can result in mRNA species that encode truncated

  10. Angiotensin II reduces cardiac AdipoR1 expression through AT1 receptor/ROS/ERK1/2/c-Myc pathway.

    Directory of Open Access Journals (Sweden)

    Li Li

    Full Text Available Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2 mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1 receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII.

  11. Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats

    DEFF Research Database (Denmark)

    Castoldi, Giovanna; di Gioia, Cira Rt; Bombardi, Camila;

    2014-01-01

    Aim of the study was to evaluate the effect of compound 21 (C21), selective AT2 receptor agonist, in diabetic nephropathy and the potential additive effect of C21, when associated to losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The ...

  12. Vitamin D receptor and estrogen receptor gene polymorphisms in postmenopausal Danish women

    DEFF Research Database (Denmark)

    Bagger, Y Z; Hassager, C; Heegaard, Anne-Marie;

    2000-01-01

    To investigate the polymorphisms of the vitamin D receptor (VDR) and estrogen receptor (ER) genes in relation to biochemical markers of bone turnover (serum osteocalcin and urinary collagen type I degradation products (CrossLaps), and to study ER genotypes in relation to serum lipoproteins, blood...

  13. Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide-High Angiotensin II-Induced Cardiovascular Injury.

    Science.gov (United States)

    Pojoga, Luminita H; Yao, Tham M; Opsasnick, Lauren A; Siddiqui, Waleed T; Reslan, Ossama M; Adler, Gail K; Williams, Gordon H; Khalil, Raouf A

    2015-10-01

    Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1-replete or -deficient states would alter vascular function in a mouse model of low nitric oxide (NO)-high angiotensin II (AngII)-induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1-0.2 mg/ml in drinking water at days 1-11) plus AngII (0.7-2.8 mg/kg per day via an osmotic minipump at days 8-11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1(-/-) mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1(-/-) mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1(-/-) mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1(-/-) versus WT mice, further increased with L-NAME + AngII, and not affected by EPL

  14. Association between insertion/deletion polymorphism in angiotensin-converting enzyme gene and acute lung injury/acute respiratory distress syndrome: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Matsuda Akihisa

    2012-08-01

    Full Text Available Abstract Background A previous meta-analysis reported a positive association between an insertion/deletion (I/D polymorphism in the angiotensin-converting enzyme gene (ACE and the risk of acute lung injury (ALI/acute respiratory distress syndrome (ARDS. Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality. Methods We searched electronic databases through October 2011 for the terms “angiotensin-converting enzyme gene”, “acute lung injury”, and “acute respiratory distress syndrome,” and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models. Results The ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects ( Pallele Pdominant = 0.001, Precessive = 0.002. This finding remained significant after correction for multiple comparisons. Conclusions There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.

  15. Characteristics of the mouse genomic histamine H1 receptor gene

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Isao; Taniuchi, Ichiro; Kitamura, Daisuke [Kyushu Univ., Fukuoka (Japan)] [and others

    1996-08-15

    We report here the molecular cloning of a mouse histamine H1 receptor gene. The protein deduced from the nucleotide sequence is composed of 488 amino acid residues with characteristic properties of GTP binding protein-coupled receptors. Our results suggest that the mouse histamine H1 receptor gene is a single locus, and no related sequences were detected. Interspecific backcross analysis indicated that the mouse histamine H1 receptor gene (Hrh1) is located in the central region of mouse Chromosome 6 linked to microphthalmia (Mitfmi), ras-related fibrosarcoma oncogene 1 (Raf1), and ret proto-oncogene (Ret) in a region of homology with human chromosome 3p. 12 refs., 3 figs.

  16. Increasing the doses of both diuretics and angiotensin receptor blockers is beneficial in subjects with uncontrolled systolic hypertension

    Science.gov (United States)

    Lacourcière, Yves; Poirier, Luc; Lefebvre, Jean; Ross, Stuart A; Leenen, Frans H

    2010-01-01

    BACKGROUND: Blood pressure (BP) control is frequently difficult to achieve in patients with predominantly elevated systolic BP. Consequently, these patients frequently require combination therapy including a thiazide diuretic such as hydrochlorothiazide (HCTZ) and an agent blocking the renin-angiotensin-aldosterone system. Current clinical practice usually limits the daily dose of HCTZ to 25 mg. This often leads to the necessity of using additional antihypertensive agents to control BP in a high proportion of patients. OBJECTIVES: To compare the efficacy of two doses of losartan (LOS)/HCTZ combinations in patients with uncontrolled ambulatory systolic hypertension after six weeks of treatment with LOS 100 mg/HCTZ 25 mg (LOS100/HCTZ25). METHODS: Following a two- to four-week washout period, subjects with a mean clinic sitting systolic BP of 160 mmHg or higher and a mean ambulatory daytime systolic BP (MDSBP) of 135 mmHg or higher on LOS100/HCTZ25 (n=105; 33 women and 72 men) were randomly assigned to receive LOS 150 mg/HCTZ 25 mg (group 1; n=53) or LOS 150 mg/HCTZ 37.5 mg (LOS150/HCTZ37.5, group 2; n=52). The primary end point was the difference in MDSBP reductions. RESULTS: At the end of the six-week treatment period, the respective additional decreases in MDSBP were 1.2 mmHg (P=0.335) on LOS 150 mg/HCTZ 25 mg and 5.6 mmHg (P<0.0001) on LOS150/HCTZ37.5 (difference of 4.4 mmHg; P=0.011). Daytime systolic ambulatory BP goal (lower than 130 mmHg) achievement tended to be higher (25% versus 17%; P=0.313) with LOS150/HCTZ37.5, while it was significantly higher (65% versus 43%; P=0.024) for mean daytime diastolic BP (lower than 80 mmHg). No deleterious metabolic changes were observed. CONCLUSIONS: In patients with uncontrolled systolic ambulatory hypertension receiving LOS100/HCTZ25, increasing both HCTZ and LOS dosages simultaneously to LOS150/HCTZ37.5 may be an effective strategy that does not affect metabolic parameters. PMID:20931100

  17. Cardioprotective Effect of AngiotensinReceptor Antagonist on Perfused Ischemic Reper-fusion Injury of Whole Isolated Rat Hearts

    Institute of Scientific and Technical Information of China (English)

    徐延敏; 黄体钢; 陈元禄; 李广平

    2003-01-01

    Objectives Investigated the cardioprotective and mechanisms of losartan onwhole isolated ischemic reperfused rat heart. Meth-ods Langendorff perfused systems was used to in-vestigate losartan effect on whole isolated rat hearts inCPK, LDH, MDA, SOD, ang Ⅱ and arrhythmia. Re-sults Losartan decreased incidence of arrhythmia,improved atrial ventricular block recovery in reperfu-sion period, during ischemic period, CPK and LDH inI/R group increased significantly compared with con-trol group, 51.33±27.02 vs 22.42±13.33, 31.80±4.56 vs 22.28 ± 15.96, respectively, but greatlydecreased in losartan group compared with I/R group,23.90±21.74 vs 51.33±27.02 and 11.50±13.20vs 31.80 ± 4. 56, respectively. During reperfusion pe-riod CPK, LDH increased significantly in I/R groupcompared with control group, 49.11 ± 20.63 vs 12.14±5.92 and 28.70±4.69 vs 23.10±21.38, re-spectively, but decreased greatly in losartan groupcompared with I/R group, 39.40 ± 9.60 vs 49.11 ±20.63 and 14.50±13.75 vs 28.70±4.69. Thecontent of MDA, ang Ⅱ in I/R group myocytes ishigher than control group's , 26. ±9. 25 vs 17.2 ±3.37 and 8.43±3.81 vs 4. 80±0.20. However thecontent of SOD in two groups has no significantlychange, 148. 20 ± 8. 72 vs 145.08±6.82. the con-tent of MDA in losartan group myocardial tissue ismuch lower than control group, 15.92±4.05 vs26.80± 9.25 and the content of ang Ⅱ in losartangroup myocardial tissue is much higher than I/Rgroup, 12.44 ± 6.09 vs 8.43 ± 3.21. The departmentof cardiology of second hospital of Tianjin medical u-niversity Tianjin 300211 However, SOD has nosignificant change in two groups, 143.47 ±7.91 vs145.08 ± 6.82. Conclusions Losartan against is-chemic-reperfusion injury of whole isolated rathearts, those beneficial effects are mediate primarily bythe inhibited of angiotensin Ⅱ binding with its receptorand inhibited oxygen free radical scavenging potential.

  18. [ANALYSIS OF THE ASSOCIATIONS BETWEEN ANGIOTENSIN-CONVERTING ENZYME GENE POLYMORPHISM AND ARTERIAL HYPOTENSION IN PREMATURE INFANTS WITH EARLY ONSET BACTERIAL INFECTIONS].

    Science.gov (United States)

    Kovaleva, E; Pokhylko, V; Chernyavskaya, Yu; Kalyuzka, E; Poltoropavlov, V

    2015-11-01

    The rate of neonatal sepsis is not reduced varying inversely proportional to the gestational age at birth, and may reach 60% in the most immature infants. The high mortality rate of this disease and adverse neurological effects are associated with the development of cardiovascular changes and shock. The main leadership role in the regulation of blood pressure and blood volume in the body plays a renin-angiotensin system. Synthesis of angiotensin-converting enzyme is regulated by the ACE gene. The aim of the study was to identify and analyze the associations between the development of arterial hypotension in premature infants and insertion-deletion (I/D) polymorphism of the ACE gene. We conducted a prospective cohort study, which included 118 prematurely born children with early onset bacterial infections (n=57 with clinical manifestations in the form of hypotension, n=61 without hypotension). Both groups were genotyped to determine the insertion-deletion polymorphism ACE gene. We compared the clinical, laboratory and instrumental parameters in premature infants with hypotension and II, ID, DD genotype of the ACE gene. Also an analysis of the associations between different genotypes of ACE gene and the development of arterial hypotension in prematurely born children was conducted. The distribution of neonates in relation to the three polymorphic variants of ACE gene with respect to I/D polymorphism was identical among the study groups. The study found that children with a variety of I/D polymorphic variants of ACE gene had no significant differences in hemodynamic parameters. The rate of hemodynamic support use did not differ in both groups. The study of the associations between the ACE gene polymorphism and major ultrasound, Doppler indices that characterized both systemic and organ hemodynamics, revealed no significant differences in mean values of all the criteria that have been studied. It can be concluded no effect of I/D polymorphism of ACE gene on the

  19. Association of Interleukin 23 Receptor Gene with Sarcoidosis

    Directory of Open Access Journals (Sweden)

    Hyun Soo Kim

    2011-01-01

    Full Text Available Interleukin 23 receptor (IL23R gene has been reported as a genetic factor strongly associated with inflammatory bowel disease, psoriasis, and ankylosing spondylitis. We investigated the association between IL23R gene single nucleotide polymorphisms (SNPs and susceptibility to sarcoidosis, including the clinical manifestation of uveitis.

  20. Interleukin 18 receptor 1 gene polymorphisms are associated with asthma

    DEFF Research Database (Denmark)

    Zhu, Guohua; Whyte, Moira K B; Vestbo, Jørgen;

    2008-01-01

    The interleukin 18 receptor (IL18R1) gene is a strong candidate gene for asthma. It has been implicated in the pathophysiology of asthma and maps to an asthma susceptibility locus on chromosome 2q12. The possibility of association between polymorphisms in IL18R1 and asthma was examined by genotyp...

  1. Prolactin receptor and signal transduction to milk protein genes

    Energy Technology Data Exchange (ETDEWEB)

    Djiane, J.; Daniel, N.; Bignon, C. [Unite d`Endocrinologie Moleculaire, Jouy en Josas (France)] [and others

    1994-06-01

    After cloning of the mammary gland prolactin (PRL) receptor cDNA, a functional assay was established using co-transfection of PRL receptor cDNA together with a milk protein promoter/chloramphenicol acetyl transferase (CAT) construct in Chinese hamster ovary (CHO) cells. Different mutants of the PRL receptor were tested in this CAT assay to delimit the domains in the receptor necessary for signal transduction to milk protein genes. In CHO cells stably transfected with PRL receptor cDNA, high numbers of PRL receptor are expressed. By metabolic labeling and immunoprecipitation, expressed PRL receptor was identified as a single species of 100 kDa. Using these cells, we analyzed the effects of PRL on intracellular free Ca{sup ++} concentration. PRL stimulates Ca{sup ++} entry and induces secondary Ca{sup ++} mobilization. The entry of Ca{sup ++} is a result of an increase in K{sup +} conductance that hyperpolarizes the membranes. We have also analyzed tyrosine phosphorylation induced by PRL. In CHO cells stably transfected with PRL receptor cDNA, PRL induced a very rapid and transient tyrosine phosphorylation of a 100-kDa protein which is most probably the PRL receptor. The same finding was obtained in mammary membranes after PRL injection to lactating rabbits. Whereas tyrosine kinase inhibitors genistein and lavendustin were without effect, PRL stimulation of milk protein gene promoters was partially inhibited by 2 {mu}M herbimycin in CHO cells co-transfected with PRL receptor cDNA and the {Beta} lactoglobulin CAT construct. Taken together these observations indicate that the cytoplasmic domain of the PRL receptor interacts with one or several tyrosine kinases, which may represent early postreceptor events necessary for PRL signal transduction to milk protein genes. 14 refs., 4 figs.

  2. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis.

    Science.gov (United States)

    Cao, Xi; Yang, Fangyuan; Shi, Tingting; Yuan, Mingxia; Xin, Zhong; Xie, Rongrong; Li, Sen; Li, Hongbing; Yang, Jin-Kui

    2016-01-01

    The classical axis of renin-angiotensin system (RAS), angiotensin (Ang)-converting enzyme (ACE)/Ang II/AT1, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, the role of bypass axis of RAS (Angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas) in hepatic steatosis is still unclear. Here we showed that deletion of ACE2 aggravates liver steatosis, which is correlated with the increased expression of hepatic lipogenic genes and the decreased expression of fatty acid oxidation-related genes in the liver of ACE2 knockout (ACE2(-/y)) mice. Meanwhile, oxidative stress and inflammation were also aggravated in ACE2(-/y) mice. On the contrary, overexpression of ACE2 improved fatty liver in db/db mice, and the mRNA levels of fatty acid oxidation-related genes were up-regulated. In vitro, Ang-(1-7)/ACE2 ameliorated hepatic steatosis, oxidative stress and inflammation in free fatty acid (FFA)-induced HepG2 cells, and what's more, Akt inhibitors reduced ACE2-mediated lipid metabolism. Furthermore, ACE2-mediated Akt activation could be attenuated by blockade of ATP/P2 receptor/Calmodulin (CaM) pathway. These results indicated that Ang-(1-7)/ACE2/Mas axis may reduce liver lipid accumulation partly by regulating lipid-metabolizing genes through ATP/P2 receptor/CaM signaling pathway. Our findings support the potential role of ACE2/Ang-(1-7)/Mas axis in prevention and treatment of hepatic lipid metabolism. PMID:26883384

  3. Cleavage of the angiotensin II type 1 receptor and nuclear accumulation of the cytoplasmic carboxy-terminal fragment.

    Science.gov (United States)

    Cook, Julia L; Mills, Sarah J; Naquin, Ryan T; Alam, Jawed; Re, Richard N

    2007-04-01

    Our published studies show that the distribution of the ANG II type 1 (AT(1)) receptor (AT(1)R), expressed as a enhanced yellow fluorescent fusion (YFP) protein (AT(1)R/EYFP), is altered upon cellular treatment with ANG II or coexpression with intracellular ANG II. AT(1)R accumulates in nuclei of cells only in the presence of ANG II. Several transmembrane receptors are known to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. The present study was designed to determine whether the AT(1)R is cleaved before nuclear transport. A plasmid encoding a rat AT(1)R labeled at the amino terminus with enhanced cyan fluorescent protein (CFP) and at the carboxy terminus with EYFP was employed. Image analyses of this protein in COS-7 cells, CCF-STTG1 glial cells, and A10 vascular smooth muscle cells show the two fluorescent moieties to be largely spatially colocalized in untreated cells. ANG II treatment, however, leads to a separation of the fluorescent moieties with yellow fluorescence accumulating in more than 30% of cellular nuclei. Immunoblot analyses of extracts and conditioned media from transfected cells indicate that the CFP domain fused to the extracellular amino-terminal AT(1)R domain is cleaved from the membrane and that the YFP domain, together with the intracellular cytoplasmic carboxy terminus of the AT(1)R, is also cleaved from the membrane-bound receptor. The carboxy terminus of the AT(1)R is essential for cleavage; cleavage does not occur in protein deleted with respect to this region. Overexpressed native AT(1)R (nonfusion) is also cleaved; the intracellular 6-kDa cytoplasmic domain product accumulates to a significantly higher level with ANG II treatment.

  4. Neuropeptide Y receptor gene y6: multiple deaths or resurrections?

    Science.gov (United States)

    Starbäck, P; Wraith, A; Eriksson, H; Larhammar, D

    2000-10-14

    The neuropeptide Y family of G-protein-coupled receptors consists of five cloned members in mammals. Four genes give rise to functional receptors in all mammals investigated. The y6 gene is a pseudogene in human and pig and is absent in rat, but generates a functional receptor in rabbit and mouse and probably in the collared peccary (Pecari tajacu), a distant relative of the pig family. We report here that the guinea pig y6 gene has a highly distorted nucleotide sequence with multiple frame-shift mutations. One evolutionary scenario may suggest that y6 was inactivated before the divergence of the mammalian orders and subsequently resurrected in some lineages. However, the pseudogene mutations seem to be distinct in human, pig, and guinea pig, arguing for separate inactivation events. In either case, the y6 gene has a quite unusual evolutionary history with multiple independent deaths or resurrections.

  5. Angiotensin type 1a receptors in the forebrain subfornical organ facilitate leptin-induced weight loss through brown adipose tissue thermogenesis

    Directory of Open Access Journals (Sweden)

    Colin N. Young

    2015-04-01

    Conclusions: These data identify a novel interaction between angiotensin-II and leptin in the control of BAT thermogenesis and body weight, and highlight a previously unrecognized role for the forebrain SFO in metabolic regulation.

  6. Comparative effect of angiotensin II type I receptor blockers and calcium channel blockers on laboratory parameters in hypertensive patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Nishida Yayoi

    2012-05-01

    Full Text Available Abstract Background Both angiotensin II type I receptor blockers (ARBs and calcium channel blockers (CCBs are widely used antihypertensive drugs. Many clinical studies have demonstrated and compared the organ-protection effects and adverse events of these drugs. However, few large-scale studies have focused on the effect of these drugs as monotherapy on laboratory parameters. We evaluated and compared the effects of ARB and CCB monotherapy on clinical laboratory parameters in patients with concomitant hypertension and type 2 diabetes mellitus. Methods We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2011, to identify cohorts of new ARB users (n = 601 and propensity-score matched new CCB users (n = 601, with concomitant mild to moderate hypertension and type 2 diabetes mellitus. We used a multivariate-adjusted regression model to adjust for differences between ARB and CCB users, and compared laboratory parameters including serum levels of triglyceride (TG, total cholesterol (TC, non-fasting blood glucose, hemoglobin A1c (HbA1c, sodium, potassium, creatinine, alanine aminotransferase (ALT, aspartate aminotransferase (AST, gamma-glutamyltransferase (GGT, hemoglobin and hematocrit, and white blood cell (WBC, red blood cell (RBC and platelet (PLT counts up to 12 months after the start of ARB or CCB monotherapy. Results We found a significant reduction of serum TC, HbA1c, hemoglobin and hematocrit and RBC count and a significant increase of serum potassium in ARB users, and a reduction of serum TC and hemoglobin in CCB users, from the baseline period to the exposure period. The reductions of RBC count, hemoglobin and hematocrit in ARB users were significantly greater than those in CCB users. The increase of serum potassium in ARB users was significantly greater than that in CCB users. Conclusions Our study suggested that hematological adverse effects and

  7. Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

    Science.gov (United States)

    Gan, Lu; Jiang, Xuemin; Mendonza, Anisha; Swan, Therese; Reynolds, Christine; Nguyen, Joanne; Pal, Parasar; Neelakantham, Srikanth; Dahlke, Marion; Langenickel, Thomas; Rajman, Iris; Akahori, Mizuki; Zhou, Wei; Rebello, Sam; Sunkara, Gangadhar

    2016-01-01

    LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions. PMID:27119576

  8. Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats.

    Science.gov (United States)

    Shum, Michaël; Pinard, Sandra; Guimond, Marie-Odile; Labbé, Sébastien M; Roberge, Claude; Baillargeon, Jean-Patrice; Langlois, Marie-France; Alterman, Mathias; Wallinder, Charlotta; Hallberg, Anders; Carpentier, André C; Gallo-Payet, Nicole

    2013-01-15

    This study was aimed at establishing whether specific activation of angiotensin II (ANG II) type 2 receptor (AT2R) modulates adipocyte differentiation and function. In primary cultures of subcutaneous (SC) and retroperitoneal (RET) preadipocytes, both AT2R and AT1R were expressed at the mRNA and protein level. Cells were stimulated with ANG II or the AT2R agonist C21/M24, alone or in the presence of the AT1R antagonist losartan or the AT2R antagonist PD123,319. During differentiation, C21/M24 increased PPARγ expression in both RET and SC preadipocytes while the number of small lipid droplets and lipid accumulation solely increased in SC preadipocytes. In mature adipocytes, C21/M24 decreased the mean size of large lipid droplets. Upon abolishment of AT2R expression using AT2R-targeted shRNAs, expressions of AT2R, aP2, and PPARγ remained very low, and cells were unable to differentiate. In Wistar rats fed a 6-wk high-fat/high-fructose (HFHF) diet, a significant shift toward larger adipocytes was observed in RET and SC adipose tissue depots. C21/M24 treatments for 6 wk restored normal adipocyte size distribution in both these tissue depots. Moreover, C21/M24 and losartan decreased hyperinsulinemia and improved insulin sensitivity impaired by HFHF diet. A strong correlation between adipocyte size area and glucose infusion rate during euglycemic-hyperinsulinemic clamp was observed. These results indicate that AT2R is involved in early adipocyte differentiation, while in mature adipocytes and in a model of insulin resistance AT2R activation restores normal adipocyte morphology and improves insulin sensitivity. PMID:23149621

  9. Androgen receptor gene mutations in 46, XY females

    Directory of Open Access Journals (Sweden)

    Mir Davood Omrani

    2006-12-01

    Full Text Available The androgen insensitivity syndrome is a heterogeneous disorder with a wide spectrum of phenotypic abnormalities, ranging from complete female to ambiguous forms that more closely resemble males. The primary abnormality is a defective androgen receptor protein due to a mutation of the androgen receptor gene. This prevents normal androgen action and thus leads to impaired virilization. A point mutation of the androgen receptor gene affecting two siblings with complete androgen insensitivity syndrome is described. On examination they both had normal external female genitalia. Genomic DNA was extracted from EDTA-preserved blood samples and isolated according to standard procedures. The androgen receptor gene was screened for mutations using an automated sequence analyzer (ABI Prism 310. Both girls possess one substitutions (G>A at position 2086 in exon 4, leading to D695N mutation. Mother was found to be a heterozygous carrier for this mutation. GTG banded karyotype of the girls showed they both have male karyotype (46, XY. In addition, the SRY gene screening showed they both have intact SRY gene. The labioscrotal folds contained palpable gonads measuring 1.5 cm in largest diameter. Ultrasound examination of the pelvis revealed absence of the uterus. Serum follicle stimulating hormone (FSH, luteinizing hormone (LH, and testosterone values were higher than normal range. To our knowledge this is the first confirmed instance of AIS due to an AR mutation occurring in familial cases in this country. Furthermore, the phenotype has complete association with this mutation. KEY WORDS: Androgen insensitivity syndrome, androgen receptor

  10. Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice.

    Science.gov (United States)

    Pati, Paramita; Fulton, David J R; Bagi, Zsolt; Chen, Feng; Wang, Yusi; Kitchens, Julia; Cassis, Lisa A; Stepp, David W; Rudic, R Daniel

    2016-03-01

    Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and period isoform knockout (KO) mice (Per2-KO, Per2, 3-KO, and Per1, 2, 3-KO/Per triple KO [TKO] mice). On a normal diet, administration of angiotensin II caused nondipping blood pressure and exacerbated vascular hypertrophy in the Period isoform KO mice relative to WT mice. To study the endogenous effects of angiotensin II stimulation, we then administered a low-salt diet to the mice, which does stimulate endogenous angiotensin II in addition to lowering blood pressure. A low-salt diet decreased blood pressure in wild-type mice. In contrast, Period isoform KO mice lost their circadian rhythm in blood pressure on a low-salt diet, because of an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic administration of low salt caused vascular hypertrophy in Period isoform KO mice, which also exhibited increased renin levels and altered angiotensin 1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension.

  11. A genome-wide search replicates evidence of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE unlinked to the ACE gene

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    Adeyemo Adebowale A

    2008-06-01

    Full Text Available Abstract Background Angiotensin I-converting enzyme (ACE plays an important role in cardiovascular homeostasis. There is evidence from different ethnic groups that circulating ACE levels are influenced by a quantitative trait locus (QTL at the ACE gene on chromosome 17. The finding of significant residual familial correlations in different ethnic groups, after accounting for this QTL, and the finding of support for linkage to a locus on chromosome 4 in Mexican-American families strongly suggest that there may well be QTLs for ACE unlinked to the ACE gene. Methods A genome-wide panel of microsatellite markers, and a panel of biallelic polymorphisms in the ACE gene were typed in Nigerian families. Single locus models with fixed parameters were used to test for linkage to circulating ACE with and without adjustment for the effects of the ACE gene polymorphisms. Results Strong evidence was found for D17S2193 (Zmax = 3.5; other nearby markers on chromosome 17 also showed modest support. After adjustment for the effects of the ACE gene locus, evidence of "suggestive linkage" to circulating ACE was found for D4S1629 (Zmax = 2.2; this marker is very close to a locus previously shown to be linked to circulating ACE levels in Mexican-American families. Conclusion In this report we have provided further support for the notion that there are QTLs for ACE unlinked to the ACE gene; our findings for chromosome 4, which appear to replicate the findings of a previous independent study, should be considered strong grounds for a more detailed examination of this region in the search for genes/variants which influence ACE levels. The poor yields, thus far, in defining the genetic determinants of hypertension risk suggest a need to look beyond simple relationships between genotypes and the ultimate phenotype. In addition to incorporating information on important environmental exposures, a better understanding of the factors which influence the building blocks of the

  12. Targeted gene delivery via N-acetylglucosamine receptor mediated endocytosis.

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    Singh, Bijay; Maharjan, Sushila; Kim, You-Kyoung; Jiang, Tai; Islam, Mohammad Ariful; Kang, Sang-Kee; Cho, Myung-Haing; Choi, Yun-Jaie; Cho, Chong-Su

    2014-11-01

    Receptor-mediated endocytosis is a promising approach of gene delivery into the target cells via receptor-ligand interaction. Vimentins at the cell surface are recently known to bind N-acetylglucosamine (GlcNAc) residue, therefore, the cell surfaces of vimentin-expressing cells could be targeted by using the GlcNAc residue as a specific ligand for receptor-mediated gene delivery. Here, we have developed polymeric gene delivery vectors, based on poly(ethylene oxide)(PEO) and poly(aspartamide), namely poly[(aspartamide)(diethylenetriamine)]-b-[PEO-(GlcNAc)] (PADPG) and poly[(aspartamide)(diethylenetriamine)]-b-[PEO] (PADP) to elucidate the efficiency of GlcNAc ligand for gene delivery through receptor mediated endocytosis. To determine the efficiency of these polymeric vectors for specific gene delivery, the DNA condensation ability of PADPG and PADP and the subsequent formation of polymeric nanoparticles were confirmed by gel retardation assay and transmission electron microscopy respectively. Both PADPG and PADP had lower cytotoxicity than polyethylenimine 25 K (PEI 25 K). However, their transfection efficiency was comparatively lower than PEI 25 K due to hydrophilic property of PEO in the vectors. To observe the stability of polymeric nanoparticles, the transfection of PADPG and PADP was carried out in the presence of serum. Favorably, the interfering effect of serum on the transfection efficiency of PADPG and PADP was also very low. Finally, when the cell specificity of these polymeric vectors was investigated, PADPG had high gene transfection in vimentin-expressing cells than vimentin-deficiency cells. The high transfection efficiency of PADPG was attributed to the GlcNAc in the polymeric vector which interact specifically with vimentin in the cells for the receptor-mediated endocytosis. The competitive inhibition assay further proved the receptor-mediated endocytosis of PADPG. Thus, this study demonstrates that conjugation of GlcNAc is an effective and rational

  13. The Mouse Solitary Odorant Receptor Gene Promoters as Models for the Study of Odorant Receptor Gene Choice.

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    Andrea Degl'Innocenti

    Full Text Available In vertebrates, several anatomical regions located within the nasal cavity mediate olfaction. Among these, the main olfactory epithelium detects most conventional odorants. Olfactory sensory neurons, provided with cilia exposed to the air, detect volatile chemicals via an extremely large family of seven-transmembrane chemoreceptors named odorant receptors. Their genes are expressed in a monogenic and monoallelic fashion: a single allele of a single odorant receptor gene is transcribed in a given mature neuron, through a still uncharacterized molecular mechanism known as odorant receptor gene choice.Odorant receptor genes are typically arranged in genomic clusters, but a few are isolated (we call them solitary from the others within a region broader than 1 Mb upstream and downstream with respect to their transcript's coordinates. The study of clustered genes is problematic, because of redundancy and ambiguities in their regulatory elements: we propose to use the solitary genes as simplified models to understand odorant receptor gene choice.Here we define number and identity of the solitary genes in the mouse genome (C57BL/6J, and assess the conservation of the solitary status in some mammalian orthologs. Furthermore, we locate their putative promoters, predict their homeodomain binding sites (commonly present in the promoters of odorant receptor genes and compare candidate promoter sequences with those of wild-caught mice. We also provide expression data from histological sections.In the mouse genome there are eight intact solitary genes: Olfr19 (M12, Olfr49, Olfr266, Olfr267, Olfr370, Olfr371, Olfr466, Olfr1402; five are conserved as solitary in rat. These genes are all expressed in the main olfactory epithelium of three-day-old mice. The C57BL/6J candidate promoter of Olfr370 has considerably varied compared to its wild-type counterpart. Within the putative promoter for Olfr266 a homeodomain binding site is predicted. As a whole, our findings

  14. Low sodium diet inhibits the local counter-regulator effect of angiotensin-(1-7) on angiotensin II

    NARCIS (Netherlands)

    Roks, AJM; Nijholt, J; van Buiten, A; van Gilst, WH; de Zeeuw, D; Henning, RH

    2004-01-01

    Objective The heptapeptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a versatile, endogenous inhibitor of the renin-angiotensin system (RAS). As the therapeutic response to exogenous RAS inhibitors, such as AT, receptor antagonists, is altered by changes in salt intake, we investigated th

  15. Low sodium diet inhibits the local counter-regulator effect of angiotensin-(1-7) on angiotensin II

    NARCIS (Netherlands)

    Roks, Anton J M; Nijholt, Jeroen; van Buiten, Azuwerus; van Gilst, Wiek H; de Zeeuw, Dick; Henning, Robert H

    2004-01-01

    OBJECTIVE: The heptapeptide angiotensin-(1-7) [Ang-(1-7)] has been identified as a versatile, endogenous inhibitor of the renin-angiotensin system (RAS). As the therapeutic response to exogenous RAS inhibitors, such as AT1 receptor antagonists, is altered by changes in salt intake, we investigated t

  16. Angiotensin-(1-7 and Its Effects in the Kidney

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    Marc Dilauro

    2009-01-01

    Full Text Available Angiotensin-(1-7 (Ang-[1-7] is a heptapeptide member of the renin-angiotensin system (RAS, and acts as a vasodilator and antagonist of angiotensin II (Ang II in the vasculature. The role of Ang-(1-7 in regulating kidney function is not well understood. Within the kidneys, Ang-(1-7 is generated by angiotensin-converting enzyme 2 (ACE2–mediated degradation of Ang II, sequential cleavage of the precursor angiotensin I (Ang I by ACE2 and ACE, or the actions of brush-border membrane peptidases on Ang I. Ang-(1-7 mediates its effects via binding to kidney Mas receptors, although some actions may occur via Ang II AT1 or AT2 receptors. In vitro studies suggest that Ang-(1-7 is an intrarenal vasodilator. Ang-(1-7 has been reported to induce either natriuresis/diuresis or sodium and water retention, via modulation of sodium transporters in the proximal tubule and loop of Henle, and collecting duct water transport. In the proximal tubule, Ang-(1-7 antagonizes growth-promoting signaling pathways via activation of a protein tyrosine phosphatase, whereas in mesangial cells, Ang-(1-7 stimulates cell growth via activation of mitogen-activated protein kinases. The phenotype of the Mas gene knockout mouse suggests that Ang-(1-7–signaling events exert cardiovascular protection by regulating blood pressure, and by limiting production of reactive oxygen species and extracellular matrix proteins. Ang-(1-7 also protects against renal injury in the renal wrap hypertension model, independent of effects on blood pressure. In diabetic nephropathy, however, the role of Ang-(1-7 on disease progression remains unclear. In summary, Ang-(1-7 and its receptor Mas have emerged as important components of the intrarenal RAS. The signaling and downstream effects of Ang-(1-7 in the kidney are complex and appear to be cell specific. The body of evidence suggests that Ang-(1-7 is protective against endothelial dysfunction or Ang II–stimulated proximal tubular injury, although

  17. Blood, pituitary, and brain renin-angiotensin systems and regulation of secretion of anterior pituitary gland.

    Science.gov (United States)

    Ganong, W F

    1993-07-01

    In addition to increasing blood pressure, stimulating aldosterone and vasopressin secretion, and increasing water intake, angiotensin II affects the secretion of anterior pituitary hormones. Some of these effects are direct. There are angiotensin II receptors on lactotropes and corticotropes in rats, and there may be receptors on thyrotropes and other secretory cells. Circulating angiotensin II reaches these receptors, but angiotensin II is almost certainly generated locally by the pituitary renin-angiotensin system as well. There are also indirect effects produced by the effects of brain angiotensin II on the secretion of hypophyseotropic hormones. In the anterior pituitary of the rat, the gonadotropes contain renin, angiotensin II, and some angiotensin-converting enzyme. There is debate about whether these cells also contain small amounts of angiotensinogen, but most of the angiotensinogen is produced by a separate population of cells and appears to pass in a paracrine fashion to the gonadotropes. An analogous situation exists in the brain. Neurons contain angiotensin II and probably renin, but most angiotensin-converting enzyme is located elsewhere and angiotensinogen is primarily if not solely produced by astrocytes. Angiotensin II causes secretion of prolactin and adrenocorticotropic hormone (ACTH) when added to pituitary cells in vitro. Paracrine regulation of prolactin secretion by angiotensin II from the gonadotropes may occur in vitro under certain circumstances, but the effects of peripheral angiotensin II on ACTH secretion appear to be mediated via the brain and corticotropin-releasing hormone (CRH). In the brain, there is good evidence that locally generated angiotensin II causes release of norepinephrine that in turn stimulates gonadotropin-releasing hormone-secreting neurons, increasing circulating luteinizing hormone. In addition, there is evidence that angiotensin II acts in the arcuate nuclei to increase the secretion of dopamine into the portal

  18. Genes involved in Drosophila glutamate receptor expression and localization

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    Featherstone David E

    2005-06-01

    Full Text Available Abstract Background A clear picture of the mechanisms controlling glutamate receptor expression, localization, and stability remains elusive, possibly due to an incomplete understanding of the proteins involved. We screened transposon mutants generated by the ongoing Drosophila Gene Disruption Project in an effort to identify the different types of genes required for glutamate receptor cluster development. Results To enrich for non-silent insertions with severe disruptions in glutamate receptor clustering, we identified and focused on homozygous lethal mutants in a collection of 2185 BG and KG transposon mutants generated by the BDGP Gene Disruption Project. 202 lethal mutant lines were individually dissected to expose glutamatergic neuromuscular junctions, stained using antibodies that recognize neuronal membrane and the glutamate receptor subunit GluRIIA, and viewed using laser-scanning confocal microscopy. We identified 57 mutants with qualitative differences in GluRIIA expression and/or localization. 84% of mutants showed loss of receptors and/or clusters; 16% of mutants showed an increase in receptors. Insertion loci encode a variety of protein types, including cytoskeleton proteins and regulators, kinases, phosphatases, ubiquitin ligases, mucins, cell adhesion proteins, transporters, proteins controlling gene expression and protein translation, and proteins of unknown/novel function. Expression pattern analyses and complementation tests, however, suggest that any single mutant – even if a mutant gene is uniquely tagged – must be interpreted with caution until the mutation is validated genetically and phenotypically. Conclusion Our study identified 57 transposon mutants with qualitative differences in glutamate receptor expression and localization. Despite transposon tagging of every insertion locus, extensive validation is needed before one can have confidence in the role of any individual gene. Alternatively, one can focus on the

  19. Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

    Energy Technology Data Exchange (ETDEWEB)

    Camelo, J.S. Jr. [Departamento de Puericultura e Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Martins, A.R. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Instituto de Ciências Biológicas, Universidade Federal do Triângulo Mineiro, Uberaba, MG (Brazil); Rosa, E. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Ramos, S.G. [Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SPBrasil (Brazil); Hehre, D.; Bancalari, E.; Suguihara, C. [Department of Pediatrics, Division of Neonatology, Neonatal Developmental Biology Laboratory, University of Miami Miller School of Medicine, Miami, FL (United States)

    2012-02-10

    The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT{sub 1} receptor (AT{sub 1}-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO{sub 2} = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT{sub 1}-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT{sub 1}-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT{sub 1}-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT{sub 1}-R staining, but C animals showed weak iNOS and AT{sub 1}-R staining. Macrophages of L and P animals showed moderate and weak AT{sub 2}-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT{sub 1}-R blockade. We suggest that AT{sub 1}-R blockade might act through AT{sub 2}-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

  20. Androgen receptor gene mutation, rearrangement, polymorphism.

    Science.gov (United States)

    Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E; Wang, Zhou

    2013-09-01

    Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents.

  1. Effects of angiotensinreceptor antagonist olmesartan on renal hemodynamic variables and vascular structural properties in streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    SONG Hui-fen; CHEN Jian-fei; SUN Ning-ling; LI Hong-wei

    2011-01-01

    Background Diabetic nephropathy is a major cause of renal failure in diabetes mellitus (DM). It has been known that renin-angiotensin system (RAS) blockers have a renal protective effect. This study aimed to investigate whether treatment with angiotensinreceptor blocker, olmesartan, could modify renal hemodynamic variables and vascular structural properties, then attenuate renal injury in streptozotocin (STZ)-induced DM rats.Methods DM was induced in male Wistar rats by intraperitoneal administration of STZ. The rats were then randomized to a DM group and an olmesartan treatment (OLM+DM) group. The normal group (non-DM) were administered only citrate buffer. At the end of the 14th week, blood glucose, kidney weight/body weight and urinary protein-to-creatinine ratio were determined. Further, the flow-pressure and pressure-glomerular filtration rate (GFR) relationships were determined for maximally vasodilated, perfused kidneys. From the relationship, 3 indices of vascular structural properties were estimated: slope of flow-pressure (minimal renal vascular resistance, reflecting overall luminal dimensions of preglomerular and postglomerular vasculature), slope of pressure-GFR (glomerular filtration capacity against pressure)and threshold pressure for beginning filtration at pressure-GFR (preglomerular to postglomerular vascular resistance ratio). Kidneys were then perfusion fixed for histological analysis. The renal histopathology was observed by light microscopy.Results The body weight of DM rats was lower than that of non-DM rats. Blood glucose, kidney weight/body weight,urinary protein-to-creatinine ratio were significantly greater in DM rats than in non-DM rats. The parameters such as kidney weight/body weight, urinary protein-to-creatinine ratio in OLM+DM rats had dramatically decreased compared with those in DM rats. However, the treatment with olmesartan had no effect on blood glucose levels. The slope of flow-pressure relationship was greater in DM rats

  2. A Coordination Model of Gene Sequences for SARS-CoV and its Receptor

    Institute of Scientific and Technical Information of China (English)

    SHAO Shi-huang; DAI Hua; GAO Lei; HUANG Ying-Song; HUANG Zhen-de; DING Yong-sheng

    2004-01-01

    A Z curve-based coordination model of genome sequences for the interaction of the SARS coronavirus (SARS-CoV) with its receptor, angiotensin-converting enzyme 2 (ACE2) is proposed. The model provides a novel, intuitive tool for visualizing and analyzing DNA sequences of SARS. It will be useful to the analysis of SARS-CoV in lab detection. Also, it can be used as a solution to other studies in bioinformatics field.

  3. Reversible renal impairment induced by treatment with the angiotensin II receptor antagonist candesartan in a patient with bilateral renal artery stenosis

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    Kjaer Andreas

    2001-05-01

    Full Text Available Abstract Background It is well established that ACE-inhibitors should be avoided in patients with renal artery stenosis. In recent years it has also been recommended that caution should be demonstrated when angiotensin II blockers are used in the same type of patients but the evidence is based only on few cases. Results We describe a case where use of the angiotensin II antagonist candesartan (Atacand induced renal failure in a patient with bilateral renal artery stenosis. The course of the case is enlighted by results from sequential renography, selective renal vein catheterisation for measurement of renin, and angiographic findings. Conclusions In patients with renal artery stenosis the angiotensin II antagonist candesartan should be avoided.

  4. Expression of serotonin receptor genes in cranial ganglia.

    Science.gov (United States)

    Maeda, Naohiro; Ohmoto, Makoto; Yamamoto, Kurumi; Kurokawa, Azusa; Narukawa, Masataka; Ishimaru, Yoshiro; Misaka, Takumi; Matsumoto, Ichiro; Abe, Keiko

    2016-03-23

    Taste cells release neurotransmitters to gustatory neurons to transmit chemical information they received. Sweet, umami, and bitter taste cells use ATP as a neurotransmitter. However, ATP release from sour taste cells has not been observed so far. Instead, they release serotonin when they are activated by sour/acid stimuli. Thus it is still controversial whether sour taste cells use ATP, serotonin, or both. By reverse transcription-polymerase chain reaction and subsequent in situ hybridization (ISH) analyses, we revealed that of 14 serotonin receptor genes only 5-HT3A and 5-HT3B showed significant/clear signals in a subset of neurons of cranial sensory ganglia in which gustatory neurons reside. Double-fluorescent labeling analyses of ISH for serotonin receptor genes with wheat germ agglutinin (WGA) in cranial sensory ganglia of pkd1l3-WGA mice whose sour neural pathway is visualized by the distribution of WGA originating from sour taste cells in the posterior region of the tongue revealed that WGA-positive cranial sensory neurons rarely express either of serotonin receptor gene. These results suggest that serotonin receptors expressed in cranial sensory neurons do not play any role as neurotransmitter receptor from sour taste cells. PMID:26854841

  5. Chemosensory receptor genes in the Oriental tobacco budworm Helicoverpa assulta.

    Science.gov (United States)

    Xu, W; Papanicolaou, A; Liu, N-Y; Dong, S-L; Anderson, A

    2015-04-01

    The Oriental tobacco budworm (Helicoverpa assulta) is a specialist herbivore moth and its larvae feed on Solanaceous plants. (Z)-9-hexadecenal (Z9-16: Ald) is the major sex pheromone component in H. assulta but the specific pheromone receptor (PR) against Z9-16: Ald has not yet been identified. In the present study, we integrated transcriptomic, bioinformatic and functional characterization approaches to investigate the chemosensory receptor genes of H. assulta. We identified seven potential PRs with 44 olfactory receptors, 18 gustatory receptors and 24 ionotropic receptors, which were further studied by in silico gene expression profile, phylogenetic analysis, reverse transcription PCR and calcium imaging assays. The candidate PR, HassOR13, showed a strong response to the minor sex pheromone component, (Z)-11-hexadecenal, but not the major component, Z9-16: Ald, in calcium imaging assays. This study provides the molecular basis for comparative studies of chemosensory receptors between H. assulta and other Helicoverpa species and will advance our understanding of the evolution and function of Lepidoptera insect chemosensation. PMID:25430896

  6. Molecular-genetic risk assessement of determining angiotensin-converting enzyme hyperactivity in hemorrhagic fever with renal syndrome

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    Ildar R. Minniakhmetov

    2012-09-01

    Full Text Available The present study was designed to investigate changes in angiotensin-converting enzyme (ACE blood activity and angiotensin II type 1 receptor gene polymorphism as a possible disease predictor in hemorrhagic fever with renal syndrome (HFRS. Four hundred and nine patients (346 males and 63 females with HFRS serologic confirmation were enrolled in the study. Their age ranged from 15 to 65 years. ACE blood activity was assessed kinetically using the Bühlmann (Switzerland kit. Peripheral blood genomic DNA was isolated by a phenol-chloroform extraction. The genotyping of DNA loci was done using a polymerase chain reaction of DNA synthesis. Statistically, ACE blood activity was significantly higher throughout the entire HFRS course with diverse severity apart from the feverish phase of moderate-to-severe uncomplicated disease forms. *A1166 and *C1166 alleles, *A1166/*A1166 and *C1166/*C1166 genotypes of angiotensin II type 1 receptor gene were not associated with HFRS severity. The results of this study indicate that high ACE activity has not adaptive characteristics due to abnormalities in angiotensin II reception. It is an adequate metabolic response of the body to endotheliotropic virus activity.

  7. Selection for Genes Encoding Secreted Proteins and Receptors

    Science.gov (United States)

    Klein, Robert D.; Gu, Qimin; Goddard, Audrey; Rosenthal, Arnon

    1996-07-01

    Extracellular proteins play an essential role in the formation, differentiation, and maintenance of multicellular organisms. Despite that, the systematic identification of genes encoding these proteins has not been possible. We describe here a highly efficient method to isolate genes encoding secreted and membrane-bound proteins by using a single-step selection in yeast. Application of this method, termed signal peptide selection, to various tissues yielded 559 clones that appear to encode known or novel extracellular proteins. These include members of the transforming growth factor and epidermal growth factor protein families, endocrine hormones, tyrosine kinase receptors, serine/threonine kinase receptors, seven transmembrane receptors, cell adhesion molecules, extracellular matrix proteins, plasma proteins, and ion channels. The eventual identification of most, or all, extracellular signaling molecules will advance our understanding of fundamental biological processes and our ability to intervene in disease states.

  8. Angiotensin II during experimentally simulated central hypovolemia

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    Theo Walther Jensen

    2016-03-01

    Full Text Available Abstract:Central hypovolemia, defined as diminished blood volume in the heart and pulmonary vascular bed, is still an unresolved problem from a therapeutic point of view. The development of pharmaceutical agents targeted at specific angiotensin II receptors, like the non-peptidergic AT2-receptor agonist compound 21, is yielding many opportunities to uncover more knowledge about angiotensin II receptor profiles and possible therapeutic use. Cardiovascular, anti-inflammatory and neuroprotective therapeutic use of compound 21 have been suggested. However, there has not yet been a focus on the use of these agents in a hypovolemic setting. We argue that the latest debates on the effect of angiotensin II during hypovolemia might guide for future studies investigating the effect of such agents during experimentally simulated central hypovolemia. The purpose of this review is to examine the role of angiotensin II during episodes of central hypovolemia.To examine this, we reviewed results from studies with three experimental models of simulated hypovolemia: head up tilt table test, lower body negative pressure, and hemorrhage of animals. A systemic literature search was made with the use of PubMed/MEDLINE for studies that measured variables of the renin-angiotensin system or its effect during simulated hypovolemia. 12 articles, using one of the three models, were included and showed a possible organ protective effect and an effect on the sympathetic system of angiotensin II during hypovolemia. The results support the possible organ protective vasodilatory role for the AT2-receptor during hypovolemia on both the kidney and the splanchnic tissue.

  9. Common promoter elements in odorant and vomeronasal receptor genes.

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    Jussara S Michaloski

    Full Text Available In mammals, odorants and pheromones are detected by hundreds of odorant receptors (ORs and vomeronasal receptors (V1Rs and V2Rs expressed by sensory neurons that are respectively located in the main olfactory epithelium and in the vomeronasal organ. Even though these two olfactory systems are functionally and anatomically separate, their sensory neurons show a common mechanism of receptor gene regulation: each neuron expresses a single receptor gene from a single allele. The mechanisms underlying OR and VR gene expression remain unclear. Here we investigated if OR and V1R genes share common sequences in their promoter regions.We conducted a comparative analysis of promoter regions of 39 mouse V1R genes and found motifs that are common to a large number of promoters. We then searched mouse OR promoter regions for motifs that resemble the ones found in the V1R promoters. We identified motifs that are present in both the V1R and OR promoter regions. Some of these motifs correspond to the known O/E like binding sites while others resemble binding sites for transcriptional repressors. We show that one of these motifs specifically interacts with proteins extracted from both nuclei from olfactory and vomeronasal neurons. Our study is the first to identify motifs that resemble binding sites for repressors in the promoters of OR and V1R genes. Analysis of these motifs and of the proteins that bind to these motifs should reveal important aspects of the mechanisms of OR/V1R gene regulation.

  10. The telmisartan renoprotective study from incipient nephropathy to overt nephropathy--rationale, study design, treatment plan and baseline characteristics of the incipient to overt: angiotensin II receptor blocker, telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) Study.

    Science.gov (United States)

    Makino, H; Haneda, M; Babazono, T; Moriya, T; Ito, S; Iwamoto, Y; Kawamori, R; Takeuchi, M; Katayama, S

    2005-01-01

    We planned the INNOVATION study to determine whether telmisartan, an angiotensin-2-receptor blocker, delays the progression of renal disease from incipient nephropathy to overt nephropathy in hypertensive or normotensive Japanese patients with type 2 diabetes mellitus. The INNOVATION study is a randomized, double-blind, placebo-controlled trial. Eligible patients must have incipient nephropathy (defined as a urinary albumin to creatinine ratio of 100-300 mg/g creatinine) and a serum creatinine concentration of 300 mg/g creatinine and 30% higher than the baseline on at least two consecutive visits). A total of 1855 patients have been enrolled from 160 study centres. In 527 randomized patients (28.4% of the enrolled patients), mean (SD) urinary albumin to creatinine ratio and serum creatinine concentration at baseline were 173.3 (47.2) mg/g creatinine and 0.78 (0.19) mg/dl. Sixty-eight per cent of the patients had hypertension at baseline. Mean (SD) systolic and diastolic blood pressures at baseline were 137.1 (14.6) and 77.5 (10.3) mmHg. The INNOVATION study will determine whether telmisartan, an angiotensin II receptor blocker, provides clinical benefits in hypertensive or normotensive patients with diabetes mellitus and diabetic nephropathy.

  11. Angiotensin II-induced Akt activation through the epidermal growth factor receptor in vascular smooth muscle cells is mediated by phospholipid metabolites derived by activation of phospholipase D.

    Science.gov (United States)

    Li, Fang; Malik, Kafait U

    2005-03-01

    Angiotensin II (Ang II) activates cytosolic Ca(2+)-dependent phospholipase A(2) (cPLA(2)), phospholipase D (PLD), p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR) and Akt in vascular smooth muscle cells (VSMC). This study was conducted to investigate the relationship between Akt activation by Ang II and other signaling molecules in rat VSMC. Ang II-induced Akt phosphorylation was significantly reduced by the PLD inhibitor 1-butanol, but not by its inactive analog 2-butanol, and by brefeldin A, an inhibitor of the PLD cofactor ADP-ribosylation factor, and in cells infected with retrovirus containing PLD(2) siRNA or transfected with PLD(2) antisense but not control LacZ or sense oligonucleotide. Diacylglycerol kinase inhibitor II diminished Ang II-induced and diC8-phosphatidic acid (PA)-increased Akt phosphorylation, suggesting that PLD-dependent Akt activation is mediated by PA. Ang II-induced EGFR phosphorylation was inhibited by 1-butanol and PLD(2) siRNA and also by cPLA(2) siRNA. In addition, the inhibitor of arachidonic acid (AA) metabolism 5,8,11,14-eicosatetraynoic acid (ETYA) reduced both Ang II- and AA-induced EGFR transactivation. Furthermore, ETYA, cPLA(2) antisense, and cPLA(2) siRNA attenuated Ang II-elicited PLD activation. p38 MAPK inhibitor SB202190 [4-(4-flurophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] reduced PLD activity and EGFR and Akt phosphorylation elicited by Ang II. Pyrrolidine-1, a cPLA(2) inhibitor, and cPLA(2) siRNA decreased p38 MAPK activity. These data indicate that Ang II-stimulated Akt activity is mediated by cPLA(2)-dependent, p38 MAPK regulated PLD(2) activation and EGFR transactivation. We propose the following scheme of the sequence of events leading to activation of Akt in VSMC by Ang II: Ang II-->cPLA(2)-->AA-->p38 MAPK-->PLD(2)-->PA-->EGFR-->Akt. PMID:15525798

  12. Angiotensin II-induced Akt activation through the epidermal growth factor receptor in vascular smooth muscle cells is mediated by phospholipid metabolites derived by activation of phospholipase D.

    Science.gov (United States)

    Li, Fang; Malik, Kafait U

    2005-03-01

    Angiotensin II (Ang II) activates cytosolic Ca(2+)-dependent phospholipase A(2) (cPLA(2)), phospholipase D (PLD), p38 mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR) and Akt in vascular smooth muscle cells (VSMC). This study was conducted to investigate the relationship between Akt activation by Ang II and other signaling molecules in rat VSMC. Ang II-induced Akt phosphorylation was significantly reduced by the PLD inhibitor 1-butanol, but not by its inactive analog 2-butanol, and by brefeldin A, an inhibitor of the PLD cofactor ADP-ribosylation factor, and in cells infected with retrovirus containing PLD(2) siRNA or transfected with PLD(2) antisense but not control LacZ or sense oligonucleotide. Diacylglycerol kinase inhibitor II diminished Ang II-induced and diC8-phosphatidic acid (PA)-increased Akt phosphorylation, suggesting that PLD-dependent Akt activation is mediated by PA. Ang II-induced EGFR phosphorylation was inhibited by 1-butanol and PLD(2) siRNA and also by cPLA(2) siRNA. In addition, the inhibitor of arachidonic acid (AA) metabolism 5,8,11,14-eicosatetraynoic acid (ETYA) reduced both Ang II- and AA-induced EGFR transactivation. Furthermore, ETYA, cPLA(2) antisense, and cPLA(2) siRNA attenuated Ang II-elicited PLD activation. p38 MAPK inhibitor SB202190 [4-(4-flurophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole] reduced PLD activity and EGFR and Akt phosphorylation elicited by Ang II. Pyrrolidine-1, a cPLA(2) inhibitor, and cPLA(2) siRNA decreased p38 MAPK activity. These data indicate that Ang II-stimulated Akt activity is mediated by cPLA(2)-dependent, p38 MAPK regulated PLD(2) activation and EGFR transactivation. We propose the following scheme of the sequence of events leading to activation of Akt in VSMC by Ang II: Ang II-->cPLA(2)-->AA-->p38 MAPK-->PLD(2)-->PA-->EGFR-->Akt.

  13. Endogenous hydrogen sulfide is associated with angiotensin II type 1 receptor in a rat model of carbon tetrachloride-induced hepatic fibrosis

    Science.gov (United States)

    FAN, HUI-NING; CHEN, NI-WEI; SHEN, WEI-LIN; ZHAO, XIANG-YUN; ZHANG, JING

    2015-01-01

    The present study aimed to investigate the effects of endogenous hydrogen sulfide (H2S) on the expression levels of angiotensin II type 1 receptor (AGTR1) in a rat model of carbon tetrachloride (CCl4)-induced hepatic fibrosis. A total of 56 Wistar rats were randomly divided into four groups: Normal control group, model group, sodium hydrosulfide (NaHS) group, and DL-propargylglycine (PAG) group. Hepatic fibrosis was induced by CCl4. The rats in the PAG group were intraperitoneally injected with PAG, an inhibitor of cystathionine-γ-lyase (CSE). The rats in the NaHS group were intraperitoneally injected with NaHS. An equal volume of saline solution was intraperitoneally injected into both the control and model groups. All rats were sacrificed at week three or four following treatment. The serum levels of hyaluronidase (HA), laminin protein (LN), procollagen III (PcIII), and collagen IV (cIV) were detected using ELISA. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and albumin (ALB) were detected using an automatic biochemical analyzer. The liver mRNA expression levels of CSE were detected by reverse transcription-quantitative polymerase chain reaction. The liver expression levels of AGTR1 and the plasma expression levels of H2S were detected using western blot analyses. The results indicated that the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly higher in the PAG group, as compared with the model group (P<0.05). Conversely, the expression levels of ALB were significantly lower in the PAG group, as compared with the model group. In addition, the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly lower in the NaHS group, as compared with

  14. EFFECT OF ANGIOTENSIN-II RECEPTOR ANTAGONIST LOSARTAN AND ITS COMBINATION WITH DIURETICS ON MYOCARDIAL MORPHO-FUNCTIONAL CONDITIONS IN HYPERTENSIVE PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY

    Directory of Open Access Journals (Sweden)

    S. N. Tolpygina

    2008-01-01

    Full Text Available Aim. To compare the effects of long-term therapy with angiotensin-II receptor antagonist losartan, alone or in combination with hydrochlorothiazide, and amlodipine treatment on left ventricular morpho-functional variables and blood pressure (BP in hypertensive patients.Material and methods. 25 women and 27 men (average age 52,7±1,2 y.o. with essential hypertension (1-2 grade and left ventricular hypertrophy (LVH were included into the study. After 3 week washout period the patients were randomized in 2:1 fashion to receive either losartan (n=34 or amlodipine (n=17. In 17 patients with insufficient response to losartan monotherapy (50-100mg/day hydrochlorothiazide (12,5mg was added to losartan (50mg 4 weeks later. The daily dose of amlodipine was increased from 5 to 10 mg in 10 patients. At baseline and after 24 weeks of treatment 24-h BP monitoring and echocardiography (with evaluation of cardiac chamber dimensions, inter-ventricular septal and posterior wall thickness, left ventricular mass index -LVMI were performed.Results. 4-week losartan treatment significantly decreased clinic BP (-14,1±2,2/8,2±1,4 mm Hg, p<0,01, mean daily systolic and diastolic BP (-15,1±2,4 mm Hg and -8,9±1,7 mm Hg , p<0,001, mean day-time and night-time BP and systolic and diastolic BP load in 34 patients. Addition of hydrochlorothiazide induced a further decrease of mean night-time BP, pulse BP, improved circadian rhythm and normalized BP in 75% of patients compared with 50% in losartan alone. Significant decrease of clinic BP (-24,1±3,6/15,2±2,3, p<0,01, mean daily systolic and diastolic BP and BP load were noticed at 24 week of amlodipine treatment. Circadian BP rhythm didn’t change; night-time decrease of BP was insufficient. Antihypertensive efficacy was similar in both groups. Losartan, alone or combined with hydrochlorothiazide, caused regression of LVH in all patients, normalized geometry of left ventricle in 33% of patients and improved left

  15. Effect of angiotensin receptor blockers in the prevention of type 2 diabetes and cardiovascular events: a meta-analysis of randomized trials

    Institute of Scientific and Technical Information of China (English)

    SONG Hui-fen; WANG Su; LI Hong-wei

    2012-01-01

    Background As the incidence of type 2 diabetes is rapidly increasing,prevention of the disease should be considered as a crucial objective in the near future.Several studies have shown angiotensin receptor blockers (ARBs) may contribute to the prevention of new-onset type 2 diabetes.This study was conducted to determine if ARBs as monotherapy or combination therapy may experience a decreased incidence of new-onset type 2 diabetes and prevent cardiovascular events.Methods Relevant experimental and clinical studies were identified by searching MEDLINE (1969 to May 30,2011) to extract a consensus of trial data involving the effect of ARBs on prevention of new-onset type 2 diabetes and cardiovascular events.Studies were included if they were randomized controlled trials versus placebo/routine therapy.A random-effects model was utilized.Subgroup and sensitivity analyses were conducted.Results Eleven trials were identified,including 82738 patients.ARBs prevented new-onset type 2 diabetes (odds ratio 0.8 (95% CI 0.76,0.85)).Regardless of indication for use,essential hypertension (seven trials),impaired glucose tolerance (one trial),cardiocerebrovascular disease (two trials) or heart failure (one trial),reductions in new-onset type 2 diabetes were maintained (0.75 (0.69,0.82),0.85 (0.78,0.92),0.80 (0.76,0.85) and 0.80 (0.64,0.99),respectively).No statistical heterogeneity was observed for any evaluation.However,ARBs did not significantly reduce the odds of all-cause mortality,myocardial infarction and heart failure versus control therapy among all of these studies.But ARBs did reduce the odds of cardiac death and heart failure among the heart failure study versus control therapy.Conclusion ARBs have significant ability to reduce risk of developing new-onset type 2 diabetes but does not improve cardiovascular outcomes over the study follow-up periods among all of included studies.

  16. Evidence for angiotensin II type 2 receptor–mediated cardiac myocyte enlargement during in vivo pressure overload

    OpenAIRE

    Senbonmatsu, Takaaki; Ichihara, Sahoko; Price, Edward; Gaffney, F.Andrew; Inagami, Tadashi

    2000-01-01

    The pathophysiological roles of the angiotensin II type 2 receptor (AT2) in cardiac hypertrophy remain unclear. By the targeted deletion of mouse AT2 we were able to prevent the left ventricular hypertrophy resulting from pressure overload, while cardiac contractile functions remained normal. This implies that AT2 is a mediator of cardiac hypertrophy in response to increased blood pressure. The effects of AT2 deletion were independent of activation of embryonic genes for cardiac hypertrophy. ...

  17. Gene specific actions of thyroid hormone receptor subtypes.

    Directory of Open Access Journals (Sweden)

    Jean Z Lin

    Full Text Available There are two homologous thyroid hormone (TH receptors (TRs α and β, which are members of the nuclear hormone receptor (NR family. While TRs regulate different processes in vivo and other highly related NRs regulate distinct gene sets, initial studies of TR action revealed near complete overlaps in their actions at the level of individual genes. Here, we assessed the extent that TRα and TRβ differ in target gene regulation by comparing effects of equal levels of stably expressed exogenous TRs +/- T(3 in two cell backgrounds (HepG2 and HeLa. We find that hundreds of genes respond to T(3 or to unliganded TRs in both cell types, but were not able to detect verifiable examples of completely TR subtype-specific gene regulation. TR actions are, however, far from identical and we detect TR subtype-specific effects on global T(3 response kinetics in HepG2 cells and many examples of TR subtype specificity at the level of individual genes, including effects on magnitude of response to TR +/- T(3, TR regulation patterns and T(3 dose response. Cycloheximide (CHX treatment confirms that at least some differential effects involve verifiable direct TR target genes. TR subtype/gene-specific effects emerge in the context of widespread variation in target gene response and we suggest that gene-selective effects on mechanism of TR action highlight differences in TR subtype function that emerge in the environment of specific genes. We propose that differential TR actions could influence physiologic and pharmacologic responses to THs and selective TR modulators (STRMs.

  18. Association of DD Genotype of Insertion/Deletion Polymorphism of Angiotensin-Converting Enzyme Gene with Systemic Lupus Erythematosus and Lupus Nephropathy

    Directory of Open Access Journals (Sweden)

    Saeedeh Salimi

    2013-10-01

    Full Text Available Background: Systemic lupus erythematosus (SLE is a multisystem disease with unknown etiology. We hypothesized that insertion/deletion (I/D polymorphism of angiotensin-converting enzyme (ACE gene may influence the development and/or progression of SLE and lupus nephritis. Materials and Methods: In a crass sectional case-control study, genomic DNA from 106 SLE patients and 103 healthy controls matched for sex, age, and ethnicity, were genotyped for the (I/D polymorphism of ACE gene by polymerase chain reaction (PCR. Comparison of quantitative variants between two groups was assessed by student t-test and association between qualitative variables was analyzed by the chi-square or Fisher exact tests. Results: The frequency of DD genotype in SLE patients was significantly higher than control group (25.5 % vs. 14 %, and the risk of SLE was 2.2 times greater in subjects with DD genotype than the individual by DI and II genotypes (OR, 2.2 [95% CI, 1.1 to 4.4]; p=0.023. The distribution of D allele in SLE patients was significantly higher (p=0.021 compare to controls (47 and 36.4, respectively. The Risk of nephropathy in SLE patients with DD genotype was three times more than other genotypes (OR, 3 [95% CI, 1.1 to 8]; p=0.027].Conclusion: This study demonstrated that ACE DD genotype acts as a risk factor on SLE and Lupus nephropathy in an Iranian population.

  19. The importance of short-term off-target effects in estimating the long-term renal and cardiovascular protection of angiotensin receptor blockers

    DEFF Research Database (Denmark)

    Smink, P A; Miao, Y; Eijkemans, M J C;

    2014-01-01

    . The score was used to predict renal/cardiovascular risk at baseline and at month 6 in the ARB treatment arm of the Reduction of Endpoints in NIDDM (noninsulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial. The net risk difference at these time points indicated...

  20. Gene Expression Control by Glucocorticoid Receptors during Innate Immune Responses

    Directory of Open Access Journals (Sweden)

    André M. Xavier

    2016-04-01

    Full Text Available Glucocorticoids (GCs are potent anti-inflammatory compounds that have been extensively used in clinical practice for several decades. GCs effects on inflammation are generally mediated through GC receptors (GRs. Signal transduction through these nuclear receptors leads to dramatic changes in gene expression programs in different cell types, typically due to GR binding to DNA or to transcription modulators. During the last decade the view of GCs as exclusive anti-inflammatory molecules has been challenged. GR negative interference in pro-inflammatory gene expression was a landmark in terms of molecular mechanisms that suppress immune activity. In fact, GR can induce varied inhibitory molecules, including a negative regulator of Toll-like receptors (TLRs pathway, or subject key transcription factors, such as NF-B and AP-1, to a repressor mechanism. In contrast, the expression of some acute-phase proteins (APPs and other players of innate immunity generally requires GR signaling. Consequently, GRs must operate context-dependent inhibitory, permissive or stimulatory effects on host defense signaling triggered by pathogens or tissue damage. This review aims to disclose how contradictory or comparable effects on inflammatory gene expression can depend on pharmacological approach (including selective glucocorticoid receptor modulators; SEGRMs, cell culture, animal treatment or transgenic strategies used as models. Although the current view of GR-signaling integrated many advances in the field, some answers to important questions remain elusive.