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Sample records for angiotensin ii-induced 12-lipoxygenase

  1. 12-Lipoxygenase Inhibition on Microalbuminuria in Type-1 and Type-2 Diabetes Is Associated with Changes of Glomerular Angiotensin II Type 1 Receptor Related to Insulin Resistance

    OpenAIRE

    Hong-Zhao Xu; Yan-Li Cheng; Wan-Ning Wang; Hao Wu; Yuan-Yuan Zhang; Chong-Sen Zang; Zhong-Gao Xu

    2016-01-01

    (1) Background: 12-lipoxygenase (12-LO) is involved in the development of diabetic nephropathy (DN). In the present study, we investigated whether 12-LO inhibition may ameliorate type-2 DN (T2DN) by interfering with insulin resistance (IR); (2) Methods: Rat glomerular mesangial cells, glomeruli and skeletal muscles were isolated and used in this study. Kidney histological changes were confirmed by periodic-acid Schiff staining; mRNA expression was detected by competitive reverse transcription...

  2. Angiotensin-(1–7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells

    International Nuclear Information System (INIS)

    Highlights: ► We for the first time found that Ang-(1–7) inhibits Ang II-induced VCAM-1 expression. ► The inhibitory effect of Ang-(1–7) on VCAM-1 is mediated by MAS receptor. ► The effect of Ang-(1–7) is due to the suppression of NF-kappaB translocation. -- Abstract: Angiotensin II (Ang II) and Angiotensin-(1–7) (Ang-(1–7)) are key effector peptides in the renin–angiotensin system. Increased circulatory Ang II level is associated with the development of hypertension and atherosclerosis, whereas Ang-(1–7) is a counter-regulatory mediator of Ang II which appears to be protective against cardiovascular disease. However, whether Ang-(1–7) regulates the action of Ang II on vascular endothelial cells (EC) remains unclear. We investigated the effects of Ang II and Ang-(1–7) in the context of atherogenesis, specifically endothelial cell VCAM-1 expression that is implicated in early plaque formation. The results show that Ang II increased VCAM-1 mRNA expression and protein displayed on EC surface, while Ang-(1–7) alone exerted no effects. However, Ang-(1–7) significantly suppressed Ang II-induced VCAM-1 expression. Ang-(1–7) also inhibited the Ang II-induced VCAM-1 promoter activity driven by transcription factor NF-KappaB. Furthermore, immunofluorescence assay and ELISA showed that Ang II facilitated the nuclear translocation of NF-kappaB in ECs, and this was attenuated by the presence of Ang-(1–7). The inhibitory effects of Ang-(1–7) on Ang II-induced VCAM-1 promoter activity and NF-kappaB nuclear translocation were all reversed by the competitive antagonist of Ang-(1–7) at the Mas receptor. Our results suggest that Ang-(1–7) mediates its affects on ECs through the Mas receptor, and negatively regulates Ang II-induced VCAM-1 expression by attenuating nuclear translocation of NF-kappaB.

  3. Angiotensin-(1-7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Feng [Department of Cardiology, Peking University People' s Hospital, Beijing (China); William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London (United Kingdom); Ren, Jingyi [Department of Cardiology, Peking University People' s Hospital, Beijing (China); Chan, Kenneth [William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London (United Kingdom); Chen, Hong, E-mail: chenhongbj@medmail.com.cn [Department of Cardiology, Peking University People' s Hospital, Beijing (China)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer We for the first time found that Ang-(1-7) inhibits Ang II-induced VCAM-1 expression. Black-Right-Pointing-Pointer The inhibitory effect of Ang-(1-7) on VCAM-1 is mediated by MAS receptor. Black-Right-Pointing-Pointer The effect of Ang-(1-7) is due to the suppression of NF-kappaB translocation. -- Abstract: Angiotensin II (Ang II) and Angiotensin-(1-7) (Ang-(1-7)) are key effector peptides in the renin-angiotensin system. Increased circulatory Ang II level is associated with the development of hypertension and atherosclerosis, whereas Ang-(1-7) is a counter-regulatory mediator of Ang II which appears to be protective against cardiovascular disease. However, whether Ang-(1-7) regulates the action of Ang II on vascular endothelial cells (EC) remains unclear. We investigated the effects of Ang II and Ang-(1-7) in the context of atherogenesis, specifically endothelial cell VCAM-1 expression that is implicated in early plaque formation. The results show that Ang II increased VCAM-1 mRNA expression and protein displayed on EC surface, while Ang-(1-7) alone exerted no effects. However, Ang-(1-7) significantly suppressed Ang II-induced VCAM-1 expression. Ang-(1-7) also inhibited the Ang II-induced VCAM-1 promoter activity driven by transcription factor NF-KappaB. Furthermore, immunofluorescence assay and ELISA showed that Ang II facilitated the nuclear translocation of NF-kappaB in ECs, and this was attenuated by the presence of Ang-(1-7). The inhibitory effects of Ang-(1-7) on Ang II-induced VCAM-1 promoter activity and NF-kappaB nuclear translocation were all reversed by the competitive antagonist of Ang-(1-7) at the Mas receptor. Our results suggest that Ang-(1-7) mediates its affects on ECs through the Mas receptor, and negatively regulates Ang II-induced VCAM-1 expression by attenuating nuclear translocation of NF-kappaB.

  4. Angiotensin II induced release of prostaglandins from rat uterus.

    Science.gov (United States)

    Campos, G A; Guerra, F A; Israel, E J

    1983-08-01

    The effect of Angiotensin II (A-II) on 6-keto-prostaglandin F1 (6-keto-PGF1 alpha) and prostaglandin F (PGF) production by the rat uterus was studied using a novel superfusion technique. The method of superfusion used allows prostaglandin synthesis in the myometrium and endometrium to be measured independently while their anatomical relationship is undisturbed. Prostaglandins were measured by radioimmunoassay. In uterine horns from castrated, estrogen treated rats, A-II (10(-6)M) stimulated the production rate of 6-keto-PGF1 alpha in the myometrium nd PGF in the endometrium. Sterile horns and pregnant horns coexisting in the same animals showed different responses when superfused with culture medium containing A-II (10(-6)M). In the sterile horns A-II failed to stimulate prostaglandin synthesis whereas in the pregnant horns there was a significant increase in the production rate of both 6-keto-PGF1 alpha and PGF in the decidua (endometrium) and of 6-keto-PGF1 alpha in the myometrium. Our results suggests that the effect of A-II on prostaglandin synthesis by the rat uterus appears to be dependent of the hormonal milieu of the experimental animal. Estrogen stimulated A-II induced PG synthesis. Progesterone inhibited the synthesis of PGs caused by A-II in non-decidualized uterus but stimulated the release of PG in the decidualized uterus. The apparent differential effect of A-II in stimulating prostaglandin synthesis in the whole uterus indicates that there are different pathways for prostaglandin production in both the endometrium and myometrium. PMID:6689628

  5. Immunosuppressive Treatment Protects Against Angiotensin II-Induced Renal Damage

    OpenAIRE

    Muller, Dominik N.; Shagdarsuren, Erdenechimeg; Park, Joon-Keun; Dechend, Ralf; Mervaala, Eero; Hampich, Franziska; Fiebeler, Anette; Ju, Xinsheng; Finckenberg, Piet; Theuer, Jürgen; Viedt, Christiane; Kreuzer, Joerg; Heidecke, Harald; Haller, Hermann; Zenke, Martin

    2002-01-01

    Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood p...

  6. TRPC6 enhances angiotensin II-induced albuminuria.

    LENUS (Irish Health Repository)

    Eckel, Jason

    2011-03-01

    Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6-deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell-membrane currents in primary cultures of podocytes from both wild-type and TRPC6-deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca(2+), suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease.

  7. INCREASED ANGIOTENSIN II INDUCED HYPERTENSION AND INFLAMMATORY CYTOKINES IN MICE LACKING ANGIOTENSIN CONVERTING ENZYME N DOMAIN ACTIVITY

    OpenAIRE

    Ong, Frank S.; Lin, Chentao X.; Campbell, Duncan J.; Okwan-Duodu, Derick; Chen, Xu; Blackwell, Wendell-Lamar B.; Shah, Kandarp H.; Gonzalez-Villalobos, Romer A.; Shen, Xiao Z.; Fuchs, Sebastien; Bernstein, Kenneth E.

    2011-01-01

    Angiotensin converting enzyme (ACE) is composed of the N- and C-terminal catalytic domains. To study the role of the ACE domains in the inflammatory response, N-KO and C-KO mice, models lacking one of the two ACE domains, were analyzed during angiotensin II-induced hypertension. At 2 weeks, N-KO mice have systolic blood pressures that averaged 173 ± 4.6 mm Hg, which is more than 25 mm Hg higher than the blood pressures observed in wild-type or C-KO mice (146 ± 3.2 and 147 ± 4.2 mm Hg). After ...

  8. Angiotensin II (AT1) Receptor Blockade Reduces Vascular Tissue Factor in Angiotensin II-Induced Cardiac Vasculopathy

    OpenAIRE

    Dominik N Müller; Mervaala, Eero M A; Dechend, Ralf; Fiebeler, Anette; Park, Joon-Keun; Schmidt, Folke; Theuer, Jürgen; Breu, Volker; Mackman, Nigel; Luther, Thomas; Schneider, Wolfgang; Gulba, Dietrich; Ganten, Detlev; Haller, Hermann; Luft, Friedrich C.

    2000-01-01

    Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT1 receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left...

  9. Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction

    OpenAIRE

    Murdoch, Colin E.; Alom-Ruiz, Sara P.; Wang, Minshu; Zhang, Min; Walker, Simon; Yu, Bin; Brewer, Alison; Shah, Ajay M.

    2011-01-01

    NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are known to be involved in angiotensin II-induced hypertension and endothelial dysfunction. Several Nox isoforms are expressed in the vessel wall, among which Nox2 is especially abundant in the endothelium. Endothelial Nox2 levels rise during hypertension but little is known about the cell-specific role of endothelial Nox2 in vivo. To address this question, we generated transgenic mice with endothelial-specific overexpression of Nox2 ...

  10. Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles

    Directory of Open Access Journals (Sweden)

    Siu-Lung eChan

    2013-06-01

    Full Text Available Angiotensin II is an important determinant of inward remodeling in cerebral arterioles. Many of the vascular effects of angiotensin II are mediated by reactive oxygen species generated from homologues of NADPH oxidase with Nox2 predominating in small arteries and arterioles. Therefore, we tested the hypothesis that superoxide generated by Nox2 plays a role in angiotensin II-induced cerebral arteriolar remodeling. We examined Nox2-deficient and wild-type mice in which a pressor or a non-pressor dose of angiotensin II (1000 or 200 ng/kg/day or saline was infused for 4 weeks via osmotic minipumps. Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of cerebral arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area (by histology and superoxide level (by hydroethidine staining of cerebral arterioles were determined ex vivo. The pressor, but not the non-pressor, dose of angiotensin II significantly increased systolic arterial pressure in both wild-type and Nox2-deficient mice. Both doses of angiotensin II increased superoxide levels and significantly reduced external diameter in maximally dilated cerebral arterioles in wild-type mice. Increased superoxide and inward remodeling were prevented in Nox2-deficient mice. Moreover, only the pressor dose of AngII increased cross-sectional area of arteriolar wall in wild-type mice and was prevented in Nox2-deficient mice. In conclusion, superoxide derived from Nox2-containing NADPH oxidase plays an important role in angiotensin II-mediated inward remodeling in cerebral arterioles. This effect appears to be independent of pressure and different from that of hypertrophy.

  11. Aldosterone and angiotensin II induced protein aggregation in renal proximal tubules

    DEFF Research Database (Denmark)

    Cheema, Muhammad Umar; Poulsen, Ebbe Toftgaard; Enghild, Jan J; Hoorn, Ewout; Fenton, Robert A; Praetorius, Jeppe

    2013-01-01

    systems in the kidney from control rats and rats receiving aldosterone or angiotensin II treatment for 7 days. Control rats formed both aggresomes and autophagosomes specifically in the proximal tubules, indicating a need for these structures even under baseline conditions. Fluorescence sorted aggresomes...... apparent change in the aggresome-autophagosome markers. Angiotensin II induced aggregation of RPL27 specifically in proximal tubules, again without apparent change in antiaggregating proteins or the aggresome-autophagosome markers. Albumin endocytosis was unaffected by the hormone administration. Taken...... together, we find that the renal proximal tubules display aggresome formation and autophagy. Despite an increase in aggregation-prone protein load in these tubules during hormone treatment, renal proximal tubules seem to have sufficient capacity for removing protein aggregates from the cells....

  12. Regulatory T cells in human and angiotensin II-induced mouse abdominal aortic aneurysms

    DEFF Research Database (Denmark)

    Zhou, Yi; Wu, Wenxue; Lindholt, Jes S;

    2015-01-01

    AIMS: Regulatory T cells (Tregs) protect mice from angiotensin II (Ang-II)-induced abdominal aortic aneurysms (AAA). This study tested whether AAA patients are Treg-insufficient and the Treg molecular mechanisms that control AAA pathogenesis. METHODS AND RESULTS: ELISA determined the Foxp3...... (r = -0.147, P = 0.007) and after (r = -0.153, P = 0.006) adjustment for AAA risk factors. AAA in apolipoprotein E-deficient (Apoe(-/-)) mice that received different doses of Ang-II exhibited a negative correlation of lesion Foxp3(+) Treg numbers with AAA size (r = -0.883, P < 0.0001). Adoptive...... transfer of Tregs from wild-type (WT) and IL10-deficient (Il10(-/-)) mice increased AAA lesion Treg content, but only WT mice Tregs reduced AAA size, AAA incidence, blood pressure, lesion macrophage and CD4(+) and CD8(+) T-cell accumulation, and angiogenesis with concurrent increase of lesion collagen...

  13. Role of Nox isoforms in angiotensin II-induced oxidative stress and endothelial dysfunction in brain

    Science.gov (United States)

    Chrissobolis, Sophocles; Banfi, Botond; Sobey, Christopher G.

    2012-01-01

    Angiotensin II (Ang II) promotes vascular disease through several mechanisms including by producing oxidative stress and endothelial dysfunction. Although multiple potential sources of reactive oxygen species exist, the relative importance of each is unclear, particularly in individual vascular beds. In these experiments, we examined the role of NADPH oxidase (Nox1 and Nox2) in Ang II-induced endothelial dysfunction in the cerebral circulation. Treatment with Ang II (1.4 mg·kg−1·day−1 for 7 days), but not vehicle, increased blood pressure in all groups. In wild-type (WT; C57Bl/6) mice, Ang II reduced dilation of the basilar artery to the endothelium-dependent agonist acetylcholine compared with vehicle but had no effect on responses in Nox2-deficient (Nox2−/y) mice. Ang II impaired responses to acetylcholine in Nox1 WT (Nox1+/y) and caused a small reduction in responses to acetylcholine in Nox1-deficient (Nox1−/y) mice. Ang II did not impair responses to the endothelium-independent agonists nitroprusside or papaverine in either group. In WT mice, Ang II increased basal and phorbol-dibutyrate-stimulated superoxide production in the cerebrovasculature, and these increases were abolished in Nox2−/y mice. Overall, these data suggest that Nox2 plays a relatively prominent role in mediating Ang II-induced oxidative stress and cerebral endothelial dysfunction, with a minor role for Nox1. PMID:22628375

  14. GLUTATHIONE PEROXIDASE-1 PLAYS A MAJOR ROLE IN PROTECTING AGAINST ANGIOTENSIN II-INDUCED VASCULAR DYSFUNCTION

    Science.gov (United States)

    Chrissobolis, Sophocles; Didion, Sean P.; Kinzenbaw, Dale A.; Schrader, Laura I.; Dayal, Sanjana; Lentz, Steven R.; Faraci, Frank M.

    2011-01-01

    Levels of reactive oxygen species, including hydrogen peroxide (H2O2), increase in blood vessels during hypertension and in response to angiotensin II (Ang II). Although glutathione peroxidases (GPx) are known to metabolize H2O2, the role of GPx during hypertension is poorly defined. We tested the hypothesis that GPx-1 protects against Ang II-induced endothelial dysfunction. Responses of carotid arteries from Gpx1-deficient (Gpx1 +/− and Gpx1 −/−) and Gpx1 transgenic (Tg) mice, and their respective littermate controls, were examined in vitro following overnight incubation with either vehicle or Ang II. Under control conditions, relaxation to acetylcholine (ACh, an endothelium-dependent agonist) was similar in control, Gpx1 +/−, and Gpx1 Tg mice, whereas in Gpx1 −/− mice, responses to ACh were impaired. In control mice, ACh-induced vasorelaxation was not affected by 1 nmol/L Ang II. In contrast, relaxation to ACh in arteries from Gpx1 +/− mice was inhibited by ~60% following treatment with 1 nmol/L Ang II, indicating Gpx1 haploinsufficiency markedly enhances Ang II-induced endothelial dysfunction. A higher concentration of Ang II (10 nmol/L) selectively impaired relaxation to ACh in arteries from control mice, and this effect was prevented in arteries from Gpx1 Tg mice, or arteries from control mice treated with PEG-catalase (which degrades H2O2). Thus, genetic and pharmacological evidence suggests a major role for GPx-1 and H2O2 in Ang II-induced effects on vascular function. PMID:18299484

  15. Clusterin/apolipoprotein J attenuates angiotensin II-induced renal fibrosis.

    Directory of Open Access Journals (Sweden)

    Gwon-Soo Jung

    Full Text Available The blockade of angiotensin II (Ang II is a major therapeutic strategy for diabetic nephropathy. The main roles of Ang II in renal disease are mediated via the Ang type 1 receptor (AT1R. Upregulation of clusterin/apolipoprotein J has been reported in nephropathy models, suggesting it has a protective role in nephropathogenesis. Here, we studied how clusterin acts against Ang II-induced renal fibrosis. Levels of AT1R and fibrotic markers in clusterin-/- mice and Ang II infused rats transfected with an adenovirus encoding clusterin were evaluated by immunoblot analysis, real time RT-PCR, and immunohistochemical staining. The effect of clusterin on renal fibrosis was evaluated in NRK-52E cells, a cultured renal tubular epithelial cell line, using immunoblot analysis and real time RT-PCR. Nuclear localization of NF-κB was evaluated using immunofluorecence and co-immunoprecipitation. Renal fibrosis and expression of AT1R was higher in the kidneys of clusterin-/- mice than in those of wild-type mice. Furthermore, loss of clusterin accelerated Ang II-stimulated renal fibrosis and AT1R expression. Overexpression of clusterin in proximal tubular epithelial cells decreased the levels of Ang II-stimulated fibrotic markers and AT1R. Moreover, intrarenal delivery of clusterin attenuated Ang II-mediated expression of fibrotic markers and AT1R in rats. Fluorescence microscopy and co-immunoprecipitation in conjunction with western blot revealed that clusterin inhibited Ang II-stimulated nuclear localization of p-NF-κB via a direct physical interaction and subsequently decreased the AT1R level in proximal tubular epithelial cells. These data suggest that clusterin attenuates Ang II-induced renal fibrosis by inhibition of NF-κB activation and subsequent downregulation of AT1R. This study raises the possibility that clusterin could be used as a therapeutic target for Ang II-induced renal diseases.

  16. 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

  17. Prolonged Subcutaneous Administration of Oxytocin Accelerates Angiotensin II-Induced Hypertension and Renal Damage in Male Rats.

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    James Phie

    Full Text Available Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h only, oxytocin only (20 or 100 ng/Kg/h, or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01. Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05 or both oxytocin and angiotensin II, compared to controls (P < 0.01. Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension.

  18. RAMP1 Augments Cerebrovascular Responses to CGRP And Inhibits Angiotensin II-Induced Vascular Dysfunction

    Science.gov (United States)

    Chrissobolis, Sophocles; Zhang, Zhongming; Kinzenbaw, Dale A.; Lynch, Cynthia M.; Russo, Andrew F.; Faraci, Frank M.

    2010-01-01

    Background and Purpose Receptors for calcitonin gene-related peptide (CGRP) are composed of the calcitonin-like receptor in association with receptor activity-modifying protein-1 (RAMP1). CGRP is an extremely potent vasodilator and may protect against vascular disease through other mechanisms. Methods We tested the hypothesis that overexpression of RAMP1 enhances vascular effects of CGRP using transgenic mice with ubiquitous expression of human RAMP1 (hRAMP1). Because angiotensin II (Ang II) is a key mediator of vascular disease, we also tested the hypothesis that RAMP1 protects against Ang II-induced vascular dysfunction. Results Responses to CGRP in carotid and basilar arteries in vitro as well as cerebral arterioles in vivo were selectively enhanced in hRAMP1 transgenic mice compared to littermate controls (P<0.05), and this effect was prevented by a CGRP receptor antagonist (P<0.05). Thus, vascular responses to CGRP are normally RAMP1-limited. Responses of carotid arteries were examined in vitro following overnight incubation with vehicle or Ang II. In arteries from control mice, Ang II selectively impaired responses to the endothelium-dependent agonist acetylcholine by ∼50% (P<0.05) via a superoxide-mediated mechanism. In contrast, Ang II did not impair responses to acetylcholine in hRAMP1 transgenic mice. Conclusions RAMP1 overexpression increases CGRP-induced vasodilation and protects against Ang II-induced endothelial dysfunction. These findings suggest that RAMP1 may be a new therapeutic target to regulate CGRP-mediated effects during disease including pathophysiological states where Ang II plays a major role. PMID:20814003

  19. Angiotensin II-induced arterial thickening, fibrosis and stiffening involves elevated arginase function.

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    Anil Bhatta

    Full Text Available Arterial stiffness (AS is an independent risk factor for cardiovascular morbidity/mortality. Smooth muscle cell (SMC proliferation and increased collagen synthesis are key features in development of AS. Arginase (ARG, an enzyme implicated in many cardiovascular diseases, can compete with nitric oxide (NO synthase for their common substrate, L-arginine. Increased arginase can also provide ornithine for synthesis of polyamines via ornithine decarboxylase (ODC and proline/collagen via ornithine aminotransferase (OAT, leading to vascular cell proliferation and collagen formation, respectively. We hypothesized that elevated arginase activity is involved in Ang II-induced arterial thickening, fibrosis, and stiffness and that limiting its activity can prevent these changes.We tested this by studies in mice lacking one copy of the ARG1 gene that were treated with angiotensin II (Ang II, 4 weeks. Studies were also performed in rat aortic Ang II-treated SMC. In WT mice treated with Ang II, we observed aortic stiffening (pulse wave velocity and aortic and coronary fibrosis and thickening that were associated with increases in ARG1 and ODC expression/activity, proliferating cell nuclear antigen, hydroxyproline levels, and collagen 1 protein expression. ARG1 deletion prevented each of these alterations. Furthermore, exposure of SMC to Ang II (1 μM, 48 hrs increased ARG1 expression, ARG activity, ODC mRNA and activity, cell proliferation, collagen 1 protein expression and hydroxyproline content. Treatment with ABH prevented these changes.Arginase 1 is crucially involved in Ang II-induced SMC proliferation and arterial fibrosis and stiffness and represents a promising therapeutic target.

  20. TRIF promotes angiotensin II-induced cross-talk between fibroblasts and macrophages in atrial fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiao-Qing; Zhang, Dao-Liang [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Zhang, Ming-Jian; Guo, Meng; Zhan, Yang-Yang; Liu, Fang [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Jiang, Wei-Feng; Zhou, Li [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Zhao, Liang, E-mail: zhaol_zg@163.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Wang, Quan-Xing, E-mail: wqxejd@126.com [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Liu, Xu, E-mail: liuxu_xk@163.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China)

    2015-08-14

    Aims: Atrial fibroblasts and macrophages have long been thought to participate in atrial fibrillation (AF). However, which specific mediator may regulate the interaction between them remains unclear. Methods and results: We provided the evidence for the involvement of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), an important inflammation-related molecule, in the pathophysiology of AF. Patients with AF showed higher levels of angiotensin II (AngII) and TRIF expression and larger number of macrophages infiltration in left atria appendage than individuals with sinus rhythm (SR). In the cell study, AngII induced chemokines expressions in mouse atrial fibroblasts and AngII-stimulated atrial fibroblasts induced the chemotaxis of macrophages, which were reduced by losartan and TRIF siRNA. Meanwhile, AngII-stimulated atrial fibroblasts proliferation was enhanced by macrophages. Conclusions: Our data demonstrated that TRIF may be a crucial factor promoting the interaction between atrial fibroblasts and macrophages, leading to atrial fibrosis. - Highlights: • Compared with SR, AF showed higher TRIF expression in left atrial appendage. • TRIF siRNA reversed macrophage chemotaxis induced by AngII-treated fibroblast. • TRIF siRNA reversed chemokines expressions induced by AngII in fibroblast. • AngII-stimulated atrial fibroblast proliferation was enhanced by macrophage.

  1. Rosiglitzone Suppresses Angiotensin II-Induced Production of KLF5 and Cell Proliferation in Rat Vascular Smooth Muscle Cells

    OpenAIRE

    Gao, Dengfeng; Hao, Guanghua; Meng, Zhe; Ning, Ning; Yang, Guang; Liu, Zhongwei; Dong, Xin; Niu, Xiaolin

    2015-01-01

    Krüppel-like factor (KLF) 5, which initiates vascular smooth muscle cell (VSMC) proliferation, also participates in Angiotensin (Ang) II-induced vascular remodeling. The protective effect of rosiglitazone on vascular remodeling may be due to their impact on VSMC proliferation. However, the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiproliferation effects of rosiglitazone are mediated by regulating Ang II/KLF5 response. We found that, i...

  2. Angiotensin II-Induced Production of Mitochondrial Reactive Oxygen Species: Potential Mechanisms and Relevance for Cardiovascular Disease

    OpenAIRE

    Dikalov, Sergey I.; Nazarewicz, Rafal R.

    2013-01-01

    Significance: The role of reactive oxygen species (ROS) in angiotensin II (AngII) induced endothelial dysfunction, cardiovascular and renal remodeling, inflammation, and fibrosis has been well documented. The molecular mechanisms of AngII pathophysiological activity involve the stimulation of NADPH oxidases, which produce superoxide and hydrogen peroxide. AngII also increases the production of mitochondrial ROS, while the inhibition of AngII improves mitochondrial function; however, the speci...

  3. Angiotensin II-induced mitochondrial Nox4 is a major endogenous source of oxidative stress in kidney tubular cells.

    Directory of Open Access Journals (Sweden)

    Su-Mi Kim

    Full Text Available Angiotensin II (Ang II-induced activation of nicotinamide adenine dinucleotide phosphate (NAD(PH oxidase leads to increased production of reactive oxygen species (ROS, an important intracellular second messenger in renal disease. Recent findings suggest that Ang II induces mitochondrial depolarization and further amplifies mitochondrial generation of ROS. We examined the hypothesis that ROS injury mediated by Ang II-induced mitochondrial Nox4 plays a pivotal role in mitochondrial dysfunction in tubular cells and is related to cell survival. In addition, we assessed whether angiotensin (1-7 peptide (Ang-(1-7 was able to counteract Ang II-induced ROS-mediated cellular injury. Cultured NRK-52E cells were stimulated with 10(-6 M Ang II for 24 h with or without Ang-(1-7 or apocynin. Ang II simulated mitochondrial Nox4 and resulted in the abrupt production of mitochondrial superoxide (O(2 (- and hydrogen peroxide (H(2O(2. Ang II also induced depolarization of the mitochondrial membrane potential, and cytosolic secretion of cytochrome C and apoptosis-inducing factor (AIF. Ang-(1-7 attenuated Ang II-induced mitochondrial Nox4 expression and apoptosis, and its effect was comparable to that of the NAD(PH oxidase inhibitor. These findings suggest that Ang II-induced activation of mitochondrial Nox4 is an important endogenous source of ROS, and is related to cell survival. The ACE2-Ang-(1-7-Mas receptor axis should be investigated further as a novel target of Ang II-mediated ROS injury.

  4. Polychlorinated biphenyl 77 augments angiotensin II-induced atherosclerosis and abdominal aortic aneurysms in male apolipoprotein E deficient mice

    International Nuclear Information System (INIS)

    Infusion of angiotensin II (AngII) to hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). Each of these AngII-induced vascular pathologies exhibit pronounced inflammation. Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote inflammation in endothelial cells and adipocytes, two cell types implicated in AngII-induced vascular pathologies. The purpose of this study was to test the hypothesis that administration of PCB77 to male apolipoprotein E (ApoE) −/− mice promotes AngII-induced atherosclerosis and AAA formation. Male ApoE−/− mice were administered vehicle or PCB77 (49 mg/kg, i.p.) during week 1 and 4 (2 divided doses/week) of AngII infusion. Body weights and total serum cholesterol concentrations were not influenced by administration of PCB77. Systolic blood pressure was increased in AngII-infused mice administered PCB77 compared to vehicle (156 ± 6 vs 137 ± 5 mmHg, respectively). The percentage of aortic arch covered by atherosclerotic lesions was increased in AngII-infused mice administered PCB77 compared to vehicle (2.0 ± 0.4 vs 0.9 ± 0.1%, respectively). Lumen diameters of abdominal aortas determined by in vivo ultrasound and external diameters of excised suprarenal aortas were increased in AngII-infused mice administered PCB77 compared to vehicle. In addition, AAA incidence increased from 47 to 85% in AngII-infused mice administered PCB77. Adipose tissue in close proximity to AAAs from mice administered PCB77 exhibited increased mRNA abundance of proinflammatory cytokines and elevated expression of components of the renin-angiotensin system (angiotensinogen, angiotensin type 1a receptor (AT1aR)). These results demonstrate that PCB77 augments AngII-induced atherosclerosis and AAA formation. -- Highlights: ► Polychlorinated biphenyl 77 (PCB77) promotes AngII-induced hypertension. ► PCB77 augments AngII-induced atherosclerosis. ► PCB77 promotes AngII-induced

  5. Polychlorinated biphenyl 77 augments angiotensin II-induced atherosclerosis and abdominal aortic aneurysms in male apolipoprotein E deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Arsenescu, Violeta [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Arsenescu, Razvan [Digestive Diseases and Nutrition, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Parulkar, Madhura; Karounos, Michael [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Zhang, Xuan [Graduate Center for Toxicology, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Baker, Nicki [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States); Cassis, Lisa A., E-mail: lcassis@uky.edu [Graduate Center for Nutritional Sciences, University of Kentucky, 800 Rose Street, Lexington, KY 40536-0200 (United States)

    2011-11-15

    Infusion of angiotensin II (AngII) to hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). Each of these AngII-induced vascular pathologies exhibit pronounced inflammation. Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote inflammation in endothelial cells and adipocytes, two cell types implicated in AngII-induced vascular pathologies. The purpose of this study was to test the hypothesis that administration of PCB77 to male apolipoprotein E (ApoE) -/- mice promotes AngII-induced atherosclerosis and AAA formation. Male ApoE-/- mice were administered vehicle or PCB77 (49 mg/kg, i.p.) during week 1 and 4 (2 divided doses/week) of AngII infusion. Body weights and total serum cholesterol concentrations were not influenced by administration of PCB77. Systolic blood pressure was increased in AngII-infused mice administered PCB77 compared to vehicle (156 {+-} 6 vs 137 {+-} 5 mmHg, respectively). The percentage of aortic arch covered by atherosclerotic lesions was increased in AngII-infused mice administered PCB77 compared to vehicle (2.0 {+-} 0.4 vs 0.9 {+-} 0.1%, respectively). Lumen diameters of abdominal aortas determined by in vivo ultrasound and external diameters of excised suprarenal aortas were increased in AngII-infused mice administered PCB77 compared to vehicle. In addition, AAA incidence increased from 47 to 85% in AngII-infused mice administered PCB77. Adipose tissue in close proximity to AAAs from mice administered PCB77 exhibited increased mRNA abundance of proinflammatory cytokines and elevated expression of components of the renin-angiotensin system (angiotensinogen, angiotensin type 1a receptor (AT1aR)). These results demonstrate that PCB77 augments AngII-induced atherosclerosis and AAA formation. -- Highlights: Black-Right-Pointing-Pointer Polychlorinated biphenyl 77 (PCB77) promotes AngII-induced hypertension. Black-Right-Pointing-Pointer PCB77 augments AngII-induced

  6. P-selectin increases angiotensin II-induced cardiac inflammation and fibrosis via platelet activation

    Science.gov (United States)

    LIU, GAIZHEN; LIANG, BIN; SONG, XIAOSU; BAI, RUI; QIN, WEIWEI; SUN, XU; LU, YAN; BIAN, YUNFEI; XIAO, CHUANSHI

    2016-01-01

    Platelet activation is important in hypertension-induced cardiac inflammation and fibrosis. P-selectin expression significantly (P<0.05) increases when platelets are activated during hypertension. Although P-selectin recruits leukocytes to sites of inflammation, the role of P-selectin in cardiac inflammation and fibrosis remains to be elucidated. The present study aimed to investigate whether platelet-derived P-selectin promotes hypertensive cardiac inflammation and fibrosis. P-selectin knockout (P-sel KO) mice and wild-type (WT) C57BL/6 littermates were infused with angiotensin II (Ang II) at 1,500 ng/kg/min for 7 days and then cross-transplanted with platelets originating from either WT or P-sel KO mice. P-selectin expression was increased in the myocardium and plasma of hypertensive mice, and the P-sel KO mice exhibited significantly (P<0.05) reduced cardiac fibrosis. The fibrotic areas were markedly smaller in the hearts of P-sel KO mice compared with WT mice, as assessed by Masson's trichrome staining. In addition, α-smooth muscle actin and transforming growth factor β1 (TGF-β1) expression levels were decreased in the P-sel KO mice, as assessed by immunohistochemistry. Following platelet transplantation into P-sel KO mice, the number of Mac-2 (galectin-3)- and TGF-β1-positive cells was increased in mice that received WT platelets compared with those that received P-sel KO platelets, and the mRNA expression levels of collagen I and TGF-β1 were also increased. The results from the present study suggest that activated platelets secrete P-selectin to promote cardiac inflammation and fibrosis in Ang II-induced hypertension. PMID:27121797

  7. 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

  8. Nitro-Arachidonic Acid Prevents Angiotensin II-Induced Mitochondrial Dysfunction in a Cell Line of Kidney Proximal Tubular Cells.

    Directory of Open Access Journals (Sweden)

    Beatriz Sánchez-Calvo

    Full Text Available Nitro-arachidonic acid (NO2-AA is a cell signaling nitroalkene that exerts anti-inflammatory activities during macrophage activation. While angiotensin II (ANG II produces an increase in reactive oxygen species (ROS production and mitochondrial dysfunction in renal tubular cells, little is known regarding the potential protective effects of NO2-AA in ANG II-mediated kidney injury. As such, this study examines the impact of NO2-AA on ANG II-induced mitochondrial dysfunction in an immortalized renal proximal tubule cell line (HK-2 cells. Treatment of HK-2 cells with ANG II increases the production of superoxide (O2●-, nitric oxide (●NO, inducible nitric oxide synthase (NOS2 expression, peroxynitrite (ONOO- and mitochondrial dysfunction. Using high-resolution respirometry, it was observed that the presence of NO2-AA prevented ANG II-mediated mitochondrial dysfunction. Attempting to address mechanism, we treated isolated rat kidney mitochondria with ONOO-, a key mediator of ANG II-induced mitochondrial damage, in the presence or absence of NO2-AA. Whereas the activity of succinate dehydrogenase (SDH and ATP synthase (ATPase were diminished upon exposure to ONOO-, they were restored by pre-incubating the mitochondria with NO2-AA. Moreover, NO2-AA prevents oxidation and nitration of mitochondrial proteins. Combined, these data demonstrate that ANG II-mediated oxidative damage and mitochondrial dysfunction is abrogated by NO2-AA, identifying this compound as a promising pharmacological tool to prevent ANG II-induced renal disease.

  9. Angiotensin II induces Fat1 expression/activation and vascular smooth muscle cell migration via Nox1-dependent reactive oxygen species generation

    OpenAIRE

    Bruder-Nascimento, T; Chinnasamy, P; Riascos-Bernal, DF; Cau, SB; Callera, GE; Touyz, RM; Tostes, RC; Sibinga, NES

    2014-01-01

    Fat1 is an atypical cadherin that controls vascular smooth muscle cell (VSMC) proliferation and migration. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (Nox1) is an important source of reactive oxygen species (ROS) in VSMCs. Angiotensin II (Ang II) induces the expression and/or activation of both Fat1 and Nox1 proteins. This study tested the hypothesis that Ang II-induced Fat1 activation and VSMC migration are mediated by Nox1-dependent ROS generation and redox signaling. Stu...

  10. Klotho inhibits angiotensin II-induced cardiomyocyte hypertrophy through suppression of the AT1R/beta catenin pathway.

    Science.gov (United States)

    Yu, Liangzhu; Meng, Wei; Ding, Jieqiong; Cheng, Menglin

    2016-04-29

    Myocardial hypertrophy is an independent risk factor for cardiac morbidity and mortality. The antiaging protein klotho reportedly possesses a protective role in cardiac diseases. However, the precise mechanisms underlying the cardioprotective effects of klotho remain unknown. This study was aimed to determine the effects of klotho on angiotensin II (Ang II)-induced hypertrophy in neonatal rat cardiomyocytes and the possible mechanism of actions. We found that klotho significantly inhibited Ang II-induced hypertrophic growth of neonatal cardiomyocytes, as evidenced by decreased [(3)H]-Leucine incorporation, cardiomyocyte surface area and β-myosin heavy chain (β-MHC) mRNA expression. Meanwhile, klotho inhibited Ang II-stimulated activation of the Wnt/β-catenin pathway in cardiomyocytes, as evidenced by decreased protein expression of active β-catenin, downregulated protein and mRNA expression of the β-catenin target genes c-myc and cyclin D1, and increased β-catenin phosphorylation. Inhibition of the Wnt/β-catenin pathway by the specific inhibitor XAV939 markedly attenuated Ang II-induced cardiomyocyte hypertrophy. The further study revealed that klotho treatment significantly downregulated protein expression of Ang II receptor type I (AT1R) but not type II (AT2R). The AT1R antagonist losartan inhibited Ang II-stimulated activation of the Wnt/β-catenin pathway and cardiomyocyte hypertrophy. Our findings suggest that klotho inhibits Ang II-induced cardiomyocyte hypertrophy through suppression of the AT1R/β-catenin signaling pathway, which may provide new insights into the mechanism underlying the protective effects of klotho in heart diseases, and raise the possibility that klotho may act as an endogenous antihypertrophic factor by inhibiting the Ang II signaling pathway. PMID:26970306

  11. Rosiglitzone suppresses angiotensin II-induced production of KLF5 and cell proliferation in rat vascular smooth muscle cells.

    Directory of Open Access Journals (Sweden)

    Dengfeng Gao

    Full Text Available Krüppel-like factor (KLF 5, which initiates vascular smooth muscle cell (VSMC proliferation, also participates in Angiotensin (Ang II-induced vascular remodeling. The protective effect of rosiglitazone on vascular remodeling may be due to their impact on VSMC proliferation. However, the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiproliferation effects of rosiglitazone are mediated by regulating Ang II/KLF5 response. We found that, in aortas of Ang II-infused rats, vascular remodeling and KLF5 expression were markedly increased, and its target gene cyclin D1 was overexpressed. Co-treatment with rosiglitazone diminished these changes. In growth-arrested VSMCs, PPAR-γ agonists (rosiglitazone and 15d-PGJ2 dose-dependently inhibited Ang II-induced cell proliferation and expression of KLF5 and cyclin D1. Moreover, these effects were attenuated by the PPAR-γ antagonists GW9662, bisphenol A diglycidyl ether and PPAR-γ specific siRNA. Furthermore, rosiglitazone inhibited Ang II-induced phosphorylation of protein kinase C (PKC ζ and extracellular signal-regulated kinase (ERK 1/2 and activation of early growth response protein (Egr. In conclusion, in Ang II-stimulated VSMCs, rosiglitazone might have an antiproliferative effect through mechanisms that include reducing KLF5 expression, and a crosstalk between PPAR-γ and PKCζ/ERK1/2/Egr may be involved in. These findings not only provide a previously unrecognized mechanism by which PPAR-γ agonists inhibit VSMC proliferation, but also document a novel evidence for the beneficial vascular effect of PPAR-γ activation.

  12. Rosiglitzone Suppresses Angiotensin II-Induced Production of KLF5 and Cell Proliferation in Rat Vascular Smooth Muscle Cells

    Science.gov (United States)

    Gao, Dengfeng; Hao, Guanghua; Meng, Zhe; Ning, Ning; Yang, Guang; Liu, Zhongwei; Dong, Xin; Niu, Xiaolin

    2015-01-01

    Krüppel-like factor (KLF) 5, which initiates vascular smooth muscle cell (VSMC) proliferation, also participates in Angiotensin (Ang) II-induced vascular remodeling. The protective effect of rosiglitazone on vascular remodeling may be due to their impact on VSMC proliferation. However, the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiproliferation effects of rosiglitazone are mediated by regulating Ang II/KLF5 response. We found that, in aortas of Ang II-infused rats, vascular remodeling and KLF5 expression were markedly increased, and its target gene cyclin D1 was overexpressed. Co-treatment with rosiglitazone diminished these changes. In growth-arrested VSMCs, PPAR-γ agonists (rosiglitazone and 15d-PGJ2) dose-dependently inhibited Ang II-induced cell proliferation and expression of KLF5 and cyclin D1. Moreover, these effects were attenuated by the PPAR-γ antagonists GW9662, bisphenol A diglycidyl ether and PPAR-γ specific siRNA. Furthermore, rosiglitazone inhibited Ang II-induced phosphorylation of protein kinase C (PKC) ζ and extracellular signal-regulated kinase (ERK) 1/2 and activation of early growth response protein (Egr). In conclusion, in Ang II-stimulated VSMCs, rosiglitazone might have an antiproliferative effect through mechanisms that include reducing KLF5 expression, and a crosstalk between PPAR-γ and PKCζ/ERK1/2/Egr may be involved in. These findings not only provide a previously unrecognized mechanism by which PPAR-γ agonists inhibit VSMC proliferation, but also document a novel evidence for the beneficial vascular effect of PPAR-γ activation. PMID:25874449

  13. Preventive effect of gomisin J from Schisandra chinensis on angiotensin II-induced hypertension via an increased nitric oxide bioavailability.

    Science.gov (United States)

    Ye, Byeong Hyeok; Lee, Seung Jin; Choi, Young Whan; Park, So Youn; Kim, Chi Dae

    2015-03-01

    Gomisin J (GJ) is a small molecular weight lignan found in Schisandra chinensis and has been demonstrated to have vasodilatory activity. In this study, the authors investigated the effect of GJ on blood pressure (BP) in angiotensin II (Ang II)-induced hypertensive mice. In addition, we determined the relative potencies of gomisin A (GA) and GJ with respect to vasodilatory activity and antihypertensive effects. C57/BL6 mice infused s.c. with Ang II (2 μg kg(-1) min(-1) for 2 weeks) showed an increase in BP and a decrease in plasma nitric oxide (NO) metabolites. In the thoracic aortas of Ang II-induced hypertensive mice, a decrease in vascular NO was accompanied by an increase in reactive oxygen species (ROS) production. Furthermore, these alterations in BP, plasma concentrations of NO metabolites and in the vascular productions of NO and ROS in Ang II-treated mice were reversed by the co-administration of GJ (1 and 3 μg kg(-1) min(-1)). In in vitro studies, Ang II decreased the cellular concentration of NO, which was accompanied by a reduction in phosphorylated endothelial nitric oxide synthase (eNOS) and an increase in ROS production. These eNOS phosphorylation and ROS production changes in Ang II-treated cells were also reversed by GJ pretreatment (0-3 μg ml(-1)). Interestingly, the vasodilatory and antihypertensive effects of GJ were more prominent than those of GA. Collectively, an increase in BP in mice treated with Ang II was markedly attenuated by GJ, which was attributed to the preservations of vascular NO bioavailability and eNOS function, and to the inhibition of ROS production in Ang II-induced hypertensive mice. PMID:25427681

  14. Arachidonate 12-lipoxygenases with reference to their selective inhibitors

    International Nuclear Information System (INIS)

    Lipoxygenase is a dioxygenase recognizing a 1-cis,4-cis-pentadiene of polyunsaturated fatty acids. The enzyme oxygenates various carbon atoms of arachidonic acid as a substrate and produces 5-, 8-, 12- or 15-hydroperoxy eicosatetraenoic acid with a conjugated diene chromophore. The enzyme is referred to as 5-, 8-, 12- or 15-lipoxygenase, respectively. Earlier we found two isoforms of 12-lipoxygenase, leukocyte- and platelet-type enzymes, which were distinguished by substrate specificity, catalytic activity, primary structure, gene intron size, and antigenicity. Recently, the epidermis-type enzyme was found as the third isoform. Attempts have been made to find isozyme-specific inhibitors of 12-lipoxygenase, and earlier we found hinokitol, a tropolone, as a potent inhibitor selective for the platelet-type 12-lipoxygenase. More recently, we tested various catechins of tea leaves and found that (-)-geotechnical gallate was a potent and selective inhibitor of human platelet 12-lipoxygenase with an IC5 of 0.14 μM. The compound was much less active with 12-lipoxygenase of leukocyte-type, 15-, 8-, and 5-lipoxygenases, and cyclo oxygenases-1 and -2

  15. The Murine Angiotensin II-Induced Abdominal Aortic Aneurysm Model: Rupture Risk and Inflammatory Progression Patterns

    OpenAIRE

    TimothySt. Amand

    2010-01-01

    An abdominal aortic aneurysm (AAA) is an enlargement of the greatest artery in the body defined as an increase in diameter of 1.5-fold. AAAs are common in the elderly population and thousands die each year from their complications. The most commonly used mouse model to study the pathogenesis of AAA is the angiotensin II (Ang II) infusion method delivered via osmotic mini-pump for 28 days. Here, we studied the site-specificity and onset of aortic rupture, characterized three-dimensional (3D) i...

  16. Reduced plasma noradrenaline during angiotensin II-induced acute hypertension in man

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Kastrup, J; Christensen, N J

    1985-01-01

    1. Plasma noradrenaline and adrenaline concentrations were measured in ten subjects before, during and after intravenous infusion of angiotensin II (ANG II) in order to determine the sympathoadrenal response of ANG II challenge in man. In five subjects ganglionic blockade was additionally performed...... by intravenous infusion of trimethaphan. 2. During ANG II infusion mean arterial blood pressure increased by 30% (P < 0.001), and plasma noradrenaline decreased by 25% (P < 0.001). Plasma adrenaline decreased less. 3. During ganglionic blockade plasma noradrenaline decreased significantly (P < 0...

  17. Crosstalk between AMPK activation and angiotensin II-induced hypertrophy in cardiomyocytes: the role of mitochondria

    OpenAIRE

    Hernández, Jessica Soto; Barreto-Torres, Giselle; Kuznetsov, Andrey V.; Khuchua, Zaza; Javadov, Sabzali

    2014-01-01

    AMP-kinase (AMPK) activation reduces cardiac hypertrophy, although underlying molecular mechanisms remain unclear. In this study, we elucidated the anti-hypertrophic action of metformin, specifically, the role of the AMPK/eNOS/p53 pathway. H9c2 rat cardiomyocytes were treated with angiotensin II (AngII) for 24 hrs in the presence or absence of metformin (AMPK agonist), losartan [AngII type 1 receptor (AT1R) blocker], Nω-nitro-L-arginine methyl ester (L-NAME, pan-NOS inhibitor), splitomicin (S...

  18. Propofol protects against angiotensin II-induced mouse hippocampal HT22 cells apoptosis via inhibition of p66Shc mitochondrial translocation.

    Science.gov (United States)

    Zhu, Minmin; Chen, Jiawei; Wen, Meilin; Sun, Zhirong; Sun, Xia; Wang, Jing; Miao, Changhong

    2014-12-01

    Hippocampal neuronal oxidative stress and apoptosis have been reported to be involved in cognitive impairment, and angiotensin II could induce hippocampal oxidative stress and apoptosis. Propofol is a widely used intravenous anesthetic agent in clinical practice, and it demonstrates significant neuroprotective activities. In this study, we investigated the mechanism how propofol protected mouse hippocampal HT22 cells against angiotensin II-induced oxidative stress and apoptosis. Cell viability was evaluated with CCK8 kit. Protein expressions of active caspase 3, cytochrome c, p66(Shc), p-p66(shc)-Ser(36), protein kinase C βII (PKCβII), Pin-1 and phosphatase A2 (PP2A) were measured by Western blot. Superoxide anion (O2(.-)) accumulation was measured with the reduction of ferricytochrome c. Compared with the control group, angiotensin II up-regulated expression of PKCβII, Pin-1 and PP2A, induced p66(Shc)-Ser(36) phosphorylation, and facilitated p66(Shc) mitochondrial translocation, resulting in O2(.-) accumulation, mitochondrial cytochrome c release, caspase 3 activation, and the inhibition of cell viability. Importantly, we found propofol inhibited angiotensin II-induced PKCβII and PP2A expression and improved p66(Shc) mitochondrial translocation, O2(.-) accumulation, mitochondrial cytochrome c release, caspase 3 activation, inhibition of cell viability. On the other hand, propofol had no effects on angiotensin II-induced Pin-1 expression and p66(Shc)-Ser(36) phosphorylation. Moreover, the protective effects of propofol on angiotensin II-induced HT22 apoptosis were similar with calyculin A, an inhibitor of PP2A and CGP53353, an inhibitor of PKCβII. However, the protective effect of propofol could be reversed by FTY720, an activator of PP2A, rather than PMA, an activator of PKCβII. Our data indicated that propofol down-regulated PP2A expression, inhibiting dephosphorylation of p66(Shc)-Ser(36) and p66(Shc) mitochondrial translocation, decreasing O2

  19. Roles of Caveolin-1 in Angiotensin II-Induced Hypertrophy and Inward Remodeling of Cerebral Pial Arterioles.

    Science.gov (United States)

    Umesalma, Shaikamjad; Houwen, Frederick Keith; Baumbach, Gary L; Chan, Siu-Lung

    2016-03-01

    Angiotensin II (Ang II) is a major determinant of inward remodeling and hypertrophy in pial arterioles that may have an important role in stroke during chronic hypertension. Previously, we found that epidermal growth factor receptor is critical in Ang II-mediated hypertrophy that may involve caveolin-1 (Cav-1). In this study, we examined the effects of Cav-1 and matrix metalloproteinase-9 (MMP9) on Ang II-mediated structural changes in pial arterioles. Cav-1-deficient (Cav-1(-/-)), MMP9-deficient (MMP9(-/-)), and wild-type mice were infused with either Ang II (1000 ng/kg per minute) or saline via osmotic minipumps for 28 days (n=6-8 per group). Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of pial arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area of the wall was determined histologically in pressurized fixed pial arterioles. Expression of Cav-1, MMP9, phosphorylated epidermal growth factor receptor, and Akt was determined by Western blotting and immunohistochemistry. Deficiency of Cav-1 or MMP9 did not affect Ang II-induced hypertension. Ang II increased the expression of Cav-1, phosphorylated epidermal growth factor receptor, and Akt in wild-type mice, which was attenuated in Cav-1(-/-) mice. Ang II-induced hypertrophy, inward remodeling, and increased MMP9 expression in pial arterioles were prevented in Cav-1(-/-) mice. Ang II-mediated increases in MMP9 expression and inward remodeling, but not hypertrophy, were prevented in MMP9(-/-) mice. In conclusion, Cav-1 is essential in Ang II-mediated inward remodeling and hypertrophy in pial arterioles. Cav-1-induced MMP9 is exclusively involved in inward remodeling, not hypertrophy. Further studies are needed to determine the role of Akt in Ang II-mediated hypertrophy. PMID:26831194

  20. An interaction of renin-angiotensin and kallikrein-kinin systems contributes to vascular hypertrophy in angiotensin II-induced hypertension: in vivo and in vitro studies.

    Directory of Open Access Journals (Sweden)

    Graziela S Ceravolo

    Full Text Available The kallikrein-kinin and renin-angiotensin systems interact at multiple levels. In the present study, we tested the hypothesis that the B1 kinin receptor (B1R contributes to vascular hypertrophy in angiotensin II (ANG II-induced hypertension, through a mechanism involving reactive oxygen species (ROS generation and extracellular signal-regulated kinase (ERK1/2 activation. Male Wistar rats were infused with vehicle (control rats, 400 ng/Kg/min ANG II (ANG II rats or 400 ng/Kg/min ANG II plus B1 receptor antagonist, 350 ng/Kg/min des-Arg(9-Leu(8-bradykinin (ANGII+DAL rats, via osmotic mini-pumps (14 days or received ANG II plus losartan (10 mg/Kg, 14 days, gavage - ANG II+LOS rats. After 14 days, ANG II rats exhibited increased systolic arterial pressure [(mmHg 184 ± 5.9 vs 115 ± 2.3], aortic hypertrophy; increased ROS generation [2-hydroxyethidium/dihydroethidium (EOH/DHE: 21.8 ± 2.7 vs 6.0 ± 1.8] and ERK1/2 phosphorylation (% of control: 218.3 ± 29.4 vs 100 ± 0.25]. B1R expression was increased in aortas from ANG II and ANG II+DAL rats than in aortas from the ANG II+LOS and control groups. B1R antagonism reduced aorta hypertrophy, prevented ROS generation (EOH/DHE: 9.17 ± 3.1 and ERK1/2 phosphorylation (137 ± 20.7% in ANG II rats. Cultured aortic vascular smooth muscle cells (VSMC stimulated with low concentrations (0.1 nM of ANG II plus B1R agonist exhibited increased ROS generation, ERK1/2 phosphorylation, proliferating-cell nuclear antigen expression and [H3]leucine incorporation. At this concentration, neither ANG II nor the B1R agonist produced any effects when tested individually. The ANG II/B1R agonist synergism was inhibited by losartan (AT1 blocker, 10 µM, B1R antagonist (10 µM and Tiron (superoxide anion scavenger, 10 mM. These data suggest that B1R activation contributes to ANG II-induced aortic hypertrophy. This is associated with activation of redox-regulated ERK1/2 pathway that controls aortic smooth muscle cells growth

  1. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Suo, Yu-Ping [Department of Obstetrics and Gynecology, Shanxi Provincial People' s Hospital, Taiyuan 030012 (China); Yue, Li-Ying [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China)

    2014-02-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  2. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    International Nuclear Information System (INIS)

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  3. The murine angiotensin II-induced abdominal aortic aneurysm model: rupture risk and inflammatory progression patterns

    Directory of Open Access Journals (Sweden)

    Richard Y Cao

    2010-07-01

    Full Text Available An abdominal aortic aneurysm (AAA is an enlargement of the greatest artery in the body defined as an increase in diameter of 1.5-fold. AAAs are common in the elderly population and thousands die each year from their complications. The most commonly used mouse model to study the pathogenesis of AAA is the angiotensin II (Ang II infusion method delivered via osmotic mini-pump for 28 days. Here, we studied the site-specificity and onset of aortic rupture, characterized three-dimensional (3D images and flow patterns in developing AAAs by ultrasound imaging, and examined macrophage infiltration in the Ang II model using 65 apolipoprotein E deficient mice. Aortic rupture occurred in 16 mice (25 % and was nearly as prevalent at the aortic arch (44 % as it was in the suprarenal region (56 % and was most common within the first seven days after Ang II infusion (12 of 16; 75 %. Longitudinal ultrasound screening was found to correlate nicely with histological analysis and AAA volume renderings showed a significant relationship with AAA severity index. Aortic dissection preceded altered flow patterns and macrophage infiltration was a prominent characteristic of developing AAAs. Targeting the inflammatory component of AAA disease with novel therapeutics will hopefully lead to new strategies to attenuate aneurysm growth and aortic rupture.

  4. Inhibition of angiotensin II-induced contraction by losartan in human coronary arteries

    DEFF Research Database (Denmark)

    Holmgren, A; Pantev, E; Erlinge, D;

    1998-01-01

    II on human coronary arteries and to study the effects of angiotensin II type 1 receptor blockade with losartan. The setting was contractile experiments with ring segments of coronary arteries. We observed that Ang II is a vasoconstrictor of human coronary arteries, with a pEC50 value of 9.26 +/- 0.......22 and Emax of 68.7 +/- 9.61% of potassium-induced contraction. Losartan (10-100 nM) shifted the concentration-response curve of Ang II to the right, with pEC50 values of 7.64 +/- 0.10 and 7.00 +/- 0.15, respectively (p = 0.001), demonstrating the antagonistic properties of losartan. We also noted a...... decreased maximal response to Ang II after incubation of losartan, with Emax of 51.1 +/- 7.08% and 41.9 +/- 4.70% (p = 0.05), respectively. In conclusion, this is the first report describing the contractile effect of Ang II and the antagonizing effects of losartan in isolated human coronary arteries....

  5. Effects of rutin from leaves and flowers of buckwheat (Fagopyrum esculentum Moench.) on angiotensin II-induced hypertrophy of cardiac myocytes and proliferation of fibroblasts

    OpenAIRE

    Han, Shu-ying; Chu, Jin-Xiu; Li, Guang-min; Zhu, Li-Sha; Shi, Rui-Fang

    2010-01-01

    Rutin was isolated from dried leaves and flowers of buckwheat (Fagopyrum esculentum Moench.). The effects of rutin on angiotensin II-induced hypertrophy of cultured cardiac myocytes and proliferation of cardiac fibroblasts of neonatal rats were evaluated by analyzing the cell surface area, measuring the protein synthesis rate through 3H-leucine incorporation, and the MTT method. Rutin (0.8 to 8.0 mg/l) exhibited a strong inhibition on the hypertrophy and proliferation. The results...

  6. Heparin inhibits Angiotensin II-induced vasoconstriction on isolated mouse mesenteric resistance arteries through Rho-A- and PKA-dependent pathways

    OpenAIRE

    Xie-Zukauskas, Hui; Das, Jharna; Short, Billie Lou; Gutkind, J Silvio; Ray, Patricio E.

    2012-01-01

    Heparin is commonly used to treat intravascular thrombosis in children undergoing extracorporeal membrane oxygenation or cardiopulmonary bypass. These clinical circumstances are associated with elevated plasma levels of angiotensin II (Ang II). However, the mechanisms by which heparin modulates vascular reactivity of Ang II remain unclear. We hypothesized that heparin may offset Ang II-induced vasoconstriction on mesenteric resistances arteries through modulating the Rho-A/Rho kinase pathway....

  7. Angiotensin II induced inflammation in the kidney and in the heart of double transgenic rats

    Directory of Open Access Journals (Sweden)

    Haller Hermann

    2002-01-01

    Full Text Available Abstract Background We are investigating a double transgenic rat (dTGR model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1 are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, iNOS and Tissue Factor expression. Furthermore we show evidence that Ang II causes the upregulation of NF-kB in our model. Methods We started PDTC-treatment on four weeks old dTGR (200 mg/kg sc and age-matched SD rats.. Blood-pressure- and albuminuria- measurements were monitored during the treatement period (four weeks. The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analsis. Results Chronic treatment with the antioxidant PDTC decreased blood pressure (162 ± 8 vs. 190 ± 7 mm Hg, p = 0.02. Cardiac hypertrophy index was significantly reduced (4.90 ± 0.1 vs. 5.77 ± 0.1 mg/g, p Conclusion Our data show that inhibition of NF-κB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-κB activation plays an important role in ANG II-induced end-organ damage.

  8. Impaired glutathione redox system paradoxically suppresses angiotensin II-induced vascular remodeling.

    Directory of Open Access Journals (Sweden)

    Kazuma Izawa

    Full Text Available BACKGROUND: Angiotensin II (AII plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH redox status in cardiovascular remodeling remains unknown. METHODS: In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs. RESULTS: BSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215 ± 4 mmHg by AII at 4 weeks (p<0.01, which was not affected by BSO. Superoxide production in vascular wall was increased by AII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52 ± 0.08, 2.50 ± 0.09 and 2.10 ± 0.07 mg/g respectively, p<0.05. Surprisingly, the co-treatment of BSO totally abolished these morphological changes. Although the vascular circumferential wall stress was well compensated in AII, significantly increased in AII+BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dose-dependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester. CONCLUSIONS: We demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical

  9. Gender Differences in Protection Against Angiotensin II-Induced Endothelial Dysfunction by MnSOD in the Cerebral Circulation

    Science.gov (United States)

    Chrissobolis, Sophocles; Faraci, Frank M.

    2010-01-01

    Angiotensin II (Ang II) produces oxidative stress and endothelial dysfunction in blood vessels. The vasculature from females may be protected against deleterious effects of Ang II. We tested the hypothesis that manganese superoxide dismutase (MnSOD) protects against Ang II-induced endothelial dysfunction. Experiments were performed in C57Bl/6, wild-type (MnSOD+/+) and MnSOD deficient (MnSOD+/−) mice treated systemically with vehicle or Ang II. Basilar arteries were isolated from C57Bl/6 mice treated for one week with a non-pressor dose of Ang II (0.28 mg/kg × day). Ang II treatment produced superoxide-mediated impairment of responses to the endothelium-dependent vasodilator acetylcholine (Ach)(P<0.05). In male, but not female MnSOD+/+ mice, Ang II modestly inhibited responses to ACh (P<0.05). In contrast, Ang II selectively impaired these responses by up to 70% in male MnSOD+/− mice (P<0.05) and this effect was reversed by tempol (P<0.05). Ang II had no effect on ACh responses in MnSOD+/− female mice. Vascular superoxide levels following treatment with an inhibitor of CuZn- and extracellular-SOD, were higher in Ang II-treated vs vehicle-treated MnSOD+/− mice. Thus, a non-pressor dose of Ang II produces endothelial dysfunction in male mice only, suggesting that the female vasculature is protected from Ang II. In male, but not female mice, MnSOD deficiency enhanced endothelial dysfunction, suggesting that MnSOD normally protects the vasculature during disease states in which Ang II contributes to vascular dysfunction. PMID:20194298

  10. Synergistic effect of atorvastatin and Cyanidin-3-glucoside on angiotensin II-induced inflammation in vascular smooth muscle cells.

    Science.gov (United States)

    Pantan, Rungusa; Tocharus, Jiraporn; Suksamrarn, Apichart; Tocharus, Chainarong

    2016-03-15

    Statins have often been used in atherosclerosis treatment because of its pleiotropic effects on inflammation. However, some adverse effects of high doses of statin show reverse effects after withdrawal. Cyanidin-3-glucoside (C3G) is a powerful anti-inflammation and antioxidant that has been of interest for use in combination with low doses of statin, which may be alternative treatment for atherosclerosis. The objective is to investigate the synergistic effect of atorvastatin and C3G in angiotensin II (Ang II)-induced inflammation in vascular smooth muscle cells. Human aortic smooth muscle cells (HASMCs) were exposed to Ang II with or without atorvastatin and C3G alone, or in combination. The results revealed that the combination of atorvastatin and C3G produces synergism against inflammation and oxidative stress. The mechanism of the combination of atorvastatin and C3G suppressed the translocation of the p65 subunit of NF-κB from cytosol to nucleus, and attenuated the expression of proteins including inducible nitric oxide synthase, intracellular adhesion molecule 1(ICAM-1), and vascular cell adhesion molecule 1(VCAM-1), in addition to nitric oxide (NO) production. Moreover, C3G exerts the antioxidative properties of atorvastatin through down-regulating NOX1 and promoting the activity of the Nrf2(-)ARE signaling pathway and downstream proteins including heme oxygenase (HO-1), NAD(P)H:quinoneoxidoreductase 1 (NQO-1), and glutamate-cysteine ligase catalytic subunit (γ-GCLC), besides increasing the activity of superoxide dismutase (SOD) enzymes. Taken together, these results suggest that a combination of low dose statins and C3G might serve as a potential regulator of the atherosclerosis process which is mediated by attenuating oxidative stress, thereby inhibiting NF-κB and activating Nrf2 signaling pathways induced by Ang II. PMID:26957227

  11. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia

    OpenAIRE

    Yoshida, Tadashi; Tabony, A. Michael; Galvez, Sarah; Mitch, William E.; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

    2013-01-01

    Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor tr...

  12. Adiponectin attenuates angiotensin II-induced vascular smooth muscle cell remodeling through nitric oxide and the RhoA/ROCK pathway.

    Directory of Open Access Journals (Sweden)

    Wared eNour-Eldine

    2016-04-01

    Full Text Available INTRODUCTION: Adiponectin (APN, an adipocytokine, exerts protective effects on cardiac remodeling, while angiotensin II (Ang II induces hypertension and vascular remodeling. The potential protective role of APN on the vasculature during hypertension has not been fully elucidated yet. Here, we evaluate the molecular mechanisms of the protective role of APN in the physiological response of the vascular wall to Ang II.METHODS AND RESULTS: Rat aortic tissues were used to investigate the effect of APN on Ang II-induced vascular remodeling and hypertrophy. We investigated whether nitric oxide (NO, the RhoA/ROCK pathway, actin cytoskeleton remodeling, and reactive oxygen species (ROS mediate the anti-hypertrophic effect of APN. Ang II-induced protein synthesis was attenuated by pre-treatment with APN, NO donor (SNAP, or cGMP. The hypertrophic response to Ang II was associated with a significant increase in RhoA activation and vascular force production, which were prevented by APN and SNAP. NO was also associated with inhibition of Ang II-induced phosphorylation of cofilin. In addition, immunohistochemistry revealed that 24 hr Ang II treatment increased the F- to G-actin ratio, an effect that was inhibited by SNAP. Ang II-induced ROS formation and upregulation of p22phox mRNA expression were inhibited by APN and NO. Both compounds failed to inhibit Nox1 and p47phox expression. CONCLUSIONS: Our results suggest that the anti-hypertrophic effects of APN are due, in part, to NO-dependent inhibition of the RhoA/ROCK pathway and ROS formation.

  13. 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

  14. Heparin inhibits Angiotensin II-induced vasoconstriction on isolated mouse mesenteric resistance arteries through Rho-A- and PKA-dependent pathways

    Science.gov (United States)

    Xie-Zukauskas, Hui; Das, Jharna; Short, Billie Lou; Gutkind, J. Silvio; Ray, Patricio E.

    2013-01-01

    Heparin is commonly used to treat intravascular thrombosis in children undergoing extracorporeal membrane oxygenation or cardiopulmonary bypass. These clinical circumstances are associated with elevated plasma levels of angiotensin II (Ang II). However, the mechanisms by which heparin modulates vascular reactivity of Ang II remain unclear. We hypothesized that heparin may offset Ang II-induced vasoconstriction on mesenteric resistances arteries through modulating the Rho-A/Rho kinase pathway. Vascular contractility was studied using pressurized, resistance-sized mesenteric arteries from mice. Rho-A activation was measured by pull-down assay, and myosin light chain or PKA phosphorylation by immunoblotting. We found that heparin significantly attenuated vasoconstriction induced by Ang II but not that by KCl. The combined effect of Ang II with heparin was almost abolished by a specific Rho kinase inhibitor Y27632. Ang II stimulated Rho-A activation and myosin light chain phosphorylation, both responses were antagonized by heparin. Moreover, the inhibitory effect of heparin on Ang II-induced vasoconstriction was reversed by Rp-cAMPS (cAMP-dependent PKA inhibitor), blunted by ODQ (soluble guanylate cyclase inhibitor), and mimicked by a cell-permeable cGMP analogue, 8-Br-cGMP, but not by a cAMP analogue. PKC and Src kinase were not involved. We conclude that heparin inhibits Ang II-induced vasoconstriction through Rho-A/Rho kinase- and cGMP/PKA-dependent pathways. PMID:23268358

  15. Angiotensin II induces secretion of plasminogen activator inhibitor 1 and a tissue metalloprotease inhibitor-related protein from rat brain astrocytes

    International Nuclear Information System (INIS)

    The present study investigates angiotensin (Ang) II effects on secretory protein synthesis in brain astrocytes cultured from neonatal and 21-day-old rats. Ang II-induced changes in the de novo synthesis of [35S]methionine-labeled secretory proteins were visualized using two-dimensional NaDodSO4/PAGE. Astrocytes from 21-day-old rat brain possess specific high-affinity receptors for Ang II. These cells express two Ang II-induced secretory proteins with Mr 55,000 (AISP-55K) and Mr 30,000 (AISP-30K), which were time- and dose-dependent (EC50, 1 nM). [Sar1, Ile8]Ang II (where Sar is sarcosine) inhibited Ang II-induced secretion of AISP-55K but not AISP-30K. N-terminal amino acid sequencing indicates that AISP-55K is identical to rat plasminogen activator inhibitor 1, whereas AISP-30K exhibits 72-81% identity to three closely related proteins: human tissue inhibitor of metalloproteases, a rat phorbol ester-induced protein, and the murine growth-responsive protein 16C8. Immunofluorescent staining with rat plasminogen activator inhibitor 1 antibody was induced in the majority of cells in culture after Ang II treatment of astrocytes from 21-day-old rat brains. Absence of this response to Ang II in astrocytes from neonatal rat brain provides evidence that this action of Ang II on astrocytes is developmentally regulated

  16. Early Endosomal Antigen 1 (EEA1) Is an Obligate Scaffold for Angiotensin II-induced, PKC-α-dependent Akt Activation in Endosomes*

    Science.gov (United States)

    Nazarewicz, Rafal Robert; Salazar, Gloria; Patrushev, Nikolay; Martin, Alejandra San; Hilenski, Lula; Xiong, Shiqin; Alexander, R. Wayne

    2011-01-01

    Akt/protein kinase B (PKB) activation/phosphorylation by angiotensin II (Ang II) is a critical signaling event in hypertrophy of vascular smooth muscle cells (VSMCs). Conventional wisdom asserts that Akt activation occurs mainly in plasma membrane domains. Recent evidence that Akt activation may take place within intracellular compartments challenges this dogma. The spatial identity and mechanistic features of these putative signaling domains have not been defined. Using cell fractionation and fluorescence methods, we demonstrate that the early endosomal antigen-1 (EEA1)-positive endosomes are a major site of Ang II-induced Akt activation. Akt moves to and is activated in EEA1 endosomes. The expression of EEA1 is required for phosphorylation of Akt at both Thr-308 and Ser-473 as well as for phosphorylation of its downstream targets mTOR and S6 kinase, but not for Erk1/2 activation. Both Akt and phosphorylated Akt (p-Akt) interact with EEA1. We also found that PKC-α is required for organizing Ang II-induced, EEA1-dependent Akt phosphorylation in VSMC early endosomes. EEA1 expression enables PKC-α phosphorylation, which in turn regulates Akt upstream signaling kinases, PDK1 and p38 MAPK. Our results indicate that PKC-α is a necessary regulator of EEA1-dependent Akt signaling in early endosomes. Finally, EEA1 down-regulation or expression of a dominant negative mutant of PKC-α blunts Ang II-induced leucine incorporation in VSMCs. Thus, EEA1 serves a novel function as an obligate scaffold for Ang II-induced Akt activation in early endosomes. PMID:21097843

  17. p120 catenin attenuates the angiotensin II-induced apoptosis of human umbilical vein endothelial cells by suppressing the mitochondrial pathway

    Science.gov (United States)

    ZHANG, YAN; ZOU, CHENSHUANG; YANG, SHUWEN; FU, JING

    2016-01-01

    Hypertension Hypertension impairs the morphological and functional integrity of circulation. Previous research has shown that the loss of endothelial cells (ECs) is a common event in many cardiovascular diseases. p120 catenin (p120ctn) plays an important role in the regulation of inflammatory responses in ECs. However, the functional significance of p120ctn in angiotensin II (AngII)-induced apoptosis of human umbilical vein endothelial cells (HUVECs) had not previously received much scholarly attention. In the present study, using western blot analysis and RT-PCR, we found that AngII-induced cell apoptosis was correlated with a significant decrease in p120ctn expression. The effect of AngII on cell viability was measured by CCK-8 assay. Knockdown of p120ctn with small hairpin RNA (shRNA) increased AngII-induced apoptosis of HUVECs, as demonstrated by Annexin V/PI staining and flow cytometric analysis. Knockdown of p120ctn with shRNA also increased cytochrome c release into the cytoplasm, and cleaved caspase-3 and -9 protein expression. These were accompanied by a decrease in the Bcl-2/Bax ratio (Bcl-2 and Bax protein expression were measured by western blot analysis), and in mitochondrial membrane potential, as measured using JC-1. Overexpression of p120ctn with adenovirus produced opposite effects. In the present study, we demonstrated that p120ctn attenuated AngII-induced apoptosis of HUVECs through the mitochondria-dependent pathway, suggesting that p120ctn plays a critical role in protecting ECs against apoptosis during hypertension. PMID:26848040

  18. 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

  19. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia.

    Science.gov (United States)

    Yoshida, Tadashi; Tabony, A Michael; Galvez, Sarah; Mitch, William E; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

    2013-10-01

    Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5' AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23769949

  20. Visualization of Complex Flow Patterns in Angiotensin II-Induced Dissecting Murine Abdominal Aortic Aneurysms with High Frequency Ultrasound

    OpenAIRE

    Schroeder, Hilary D.; Yrineo, Alexa A.; Bogucki, Amy E; Goergen, Craig J.

    2013-01-01

    Abdominal aortic aneurysm (AAA) rupture is a common cause of mortality in the United States. Current treatments are only employed once the risk of rupture outweighs the risks associated with surgery. Murine models have been developed to characterize AAA pathogenesis in the hope that new treatments will be developed. For this study, angiotensin II (AngII) was infused subcutaneously into apolipoprotein E-deficient (ApoE-/-) mice using an osmotic mini-pump over 28 days. ApoE-/- mice (16-week-old...

  1. Angiotensin II-Induced Migration of Vascular Smooth Muscle Cells Is Mediated by p38 Mitogen-Activated Protein Kinase-Activated c-Src Through Spleen Tyrosine Kinase and Epidermal Growth Factor Receptor Transactivation

    OpenAIRE

    Mugabe, Benon E.; Yaghini, Fariborz A.; Song, Chi Young; Buharalioglu, Cuneyt K.; Waters, Christopher M.; Malik, Kafait U.

    2010-01-01

    Angiotensin II (Ang II) stimulates protein synthesis by activating spleen tyrosine kinase (Syk) and DNA synthesis through epidermal growth factor receptor (EGFR) transactivation in vascular smooth muscle cells (VSMCs). This study was conducted to determine whether Syk mediates Ang II-induced migration of aortic VSMCs using a scratch wound approach. Treatment with Ang II (200 nM) for 24 h increased VSMC migration by 1.56 ± 0.14-fold. Ang II-induced VSMC migration and Syk phosphorylation as det...

  2. 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

  3. 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

  4. Angiotensin II-Induced Endothelial Dysfunction is Temporally Linked with Increases in Intereukin-6 and Vascular Macrophage Accumulation

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    Sean P Didion

    2014-10-01

    Full Text Available Angiotensin II (Ang II is associated with vascular hypertrophy, endothelial dysfunction and activation of a number of inflammatory molecules, however the linear events involved in the development of hypertension and endothelial dysfunction produced in response to Ang II are not well defined. The goal of this study was to examine the dose- and temporal-dependent development of endothelial dysfunction in response to Ang II. Blood pressure and responses of carotid arteries were examined in control (C57Bl/6 mice and in mice infused with 50, 100, 200, 400, or 1000 ng/kg/min Ang II for either 14 or 28 Days. Infusion of Ang II was associated with graded and marked increases in systolic blood pressure and plasma Ang II concentrations. While low doses of Ang II (ie, 50 and 100 ng/kg/min had little to no effect on blood pressure or endothelial function, high doses of Ang II (e.g., 1000 ng/kg/min were associated with large increases in arterial pressure and marked impairment of endothelial function. In contrast, intermediate doses of Ang II (200 and 400 ng/kg/min while initially having no effect on systolic blood pressure were associated with significant increases in pressure over time. Despite increasing blood pressure, 200 ng/kg/min had no effect on endothelial function, whereas 400 ng/kg/min produced modest impairment on Day 14 and marked impairment of endothelial function on Day 28. The degree of endothelial dysfunction produced by 400 and 1000 ng/kg/min Ang II was reflective of parallel increases in plasma IL-6 levels and vascular macrophage content, suggesting that increases in arterial blood pressure precede the development of endothelial dysfunction. These findings are important as they demonstrate that along with increases in arterial pressure that increases in IL-6 and vascular macrophage accumulation correlate with the impairment of endothelial function produced by Ang II.

  5. Ghrelin improves body weight loss and skeletal muscle catabolism associated with angiotensin II-induced cachexia in mice.

    Science.gov (United States)

    Sugiyama, Masako; Yamaki, Akira; Furuya, Mayumi; Inomata, Norio; Minamitake, Yoshiharu; Ohsuye, Kazuhiro; Kangawa, Kenji

    2012-10-10

    Ghrelin is a gastric peptide that regulates energy homeostasis. Angiotensin II (Ang II) is known to induce body weight loss and skeletal muscle catabolism through the ubiquitin-proteasome pathway. In this study, we investigated the effects of ghrelin on body weight and muscle catabolism in mice treated with Ang II. The continuous subcutaneous administration of Ang II to mice for 6 days resulted in cardiac hypertrophy and significant decreases in body weight gain, food intake, food efficiency, lean mass, and fat mass. In the gastrocnemius muscles of Ang II-treated mice, the levels of insulin-like growth factor 1 (IGF-1) were decreased, and the levels of mRNA expression of catabolic factors were increased. Although the repeated subcutaneous injections of ghrelin (1.0mg/kg, twice daily for 5 days) did not affect cardiac hypertrophy, they resulted in significant body weight gains and improved food efficiencies and tended to increase both lean and fat mass in Ang II-treated mice. Ghrelin also ameliorated the decreased IGF-1 levels and the increased mRNA expression levels of catabolic factors in the skeletal muscle. IGF-1 mRNA levels in the skeletal muscle significantly decreased 24h after Ang II infusion, and this was reversed by two subcutaneous injections of ghrelin. In C2C12-derived myocytes, the dexamethasone-induced mRNA expression of atrogin-1 was decreased by IGF-1 but not by ghrelin. In conclusion, we demonstrated that ghrelin improved body weight loss and skeletal muscle catabolism in mice treated with Ang II, possibly through the early restoration of IGF-1 mRNA in the skeletal muscle and the amelioration of nutritional status. PMID:22750276

  6. Over-Expression of Copper/Zinc Superoxide Dismutase in the Median Preoptic Nucleus Attenuates Chronic Angiotensin II-Induced Hypertension in the Rat

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    John P. Collister

    2014-12-01

    Full Text Available The brain senses circulating levels of angiotensin II (AngII via circumventricular organs, such as the subfornical organ (SFO, and is thought to adjust sympathetic nervous system output accordingly via this neuro-hormonal communication. However, the cellular signaling mechanisms involved in these communications remain to be fully understood. Previous lesion studies of either the SFO, or the downstream median preoptic nucleus (MnPO have shown a diminution of the hypertensive effects of chronic AngII, without providing a clear explanation as to the intracellular signaling pathway(s involved. Additional studies have reported that over-expressing copper/zinc superoxide dismutase (CuZnSOD, an intracellular superoxide (O2·− scavenging enzyme, in the SFO attenuates chronic AngII-induced hypertension. Herein, we tested the hypothesis that overproduction of O2·− in the MnPO is an underlying mechanism in the long-term hypertensive effects of chronic AngII. Adenoviral vectors encoding human CuZnSOD (AdCuZnSOD or control vector (AdEmpty were injected directly into the MnPO of rats implanted with aortic telemetric transmitters for recording of arterial pressure. After a 3 day control period of saline infusion, rats were intravenously infused with AngII (10 ng/kg/min for ten days. Rats over-expressing CuZnSOD (n = 7 in the MnPO had a blood pressure increase of only 6 ± 2 mmHg after ten days of AngII infusion while blood pressure increased 21 ± 4 mmHg in AdEmpty-infected rats (n = 9. These results support the hypothesis that production of O2·− in the MnPO contributes to the development of chronic AngII-dependent hypertension.

  7. Liberación de endotelina-1 por angiotensina ll en miocitos cardíacos aislados Angiotensin II-induced endothelin-1 release in cardiac myocytes

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    María C. Villa-Abrille

    2006-06-01

    + exchanger (NCX blockade or by ROS scavenging. Ang II 100 nM increases SS by 70.5±7.6% (p<0.05. This PIE was completely abolished by AT1 receptors blockade and were partially bocked by ET-1 receptors blockade, by NHE inhibition, by reverse mode NCX blockade or by ROS scavenging. Ang II increased preproET-1 mRNA, effect that was blunted by AT1 receptors blockade. We conclude that Ang II induces (through its AT1 receptor release/formation of ET-1, which acting in autocrine fashion on ET receptors of the isolated myocytes increases inotropism through NHE stimulation and NCX reverse mode activation. The participation of ROS is involved is this chain of events.

  8. Transcriptional up-regulation of antioxidant genes by PPARδ inhibits angiotensin II-induced premature senescence in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Research highlights: → Activation of PPARδ by GW501516 significantly inhibited Ang II-induced premature senescence in hVSMCs. → Agonist-activated PPARδ suppressed generation of Ang II-triggered ROS with a concomitant reduction in DNA damage. → GW501516 up-regulated expression of antioxidant genes, such as GPx1, Trx1, Mn-SOD and HO-1. → Knock-down of these antioxidant genes abolished the effects of GW501516 on ROS production and premature senescence. -- Abstract: This study evaluated peroxisome proliferator-activated receptor (PPAR) δ as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPARδ by GW501516, a specific agonist of PPARδ, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPARδ suppressed the generation of Ang II-triggered reactive oxygen species (ROS) with a concomitant reduction in DNA damage. Notably, GW501516 up-regulated the expression of antioxidant genes, such as glutathione peroxidase 1, thioredoxin 1, manganese superoxide dismutase and heme oxygenase 1. siRNA-mediated down-regulation of these antioxidant genes almost completely abolished the effects of GW501516 on ROS production and premature senescence in hVSMCs treated with Ang II. Taken together, the enhanced transcription of antioxidant genes is responsible for the PPARδ-mediated inhibition of premature senescence through sequestration of ROS in hVSMCs treated with Ang II.

  9. Vascular hyporeactivity to angiotensin II induced by Escherichia coli endotoxin is reversed by Nω-Nitro-L-Arginine, an inhibitor of nitric oxide synthase

    Directory of Open Access Journals (Sweden)

    L. A. RODRIGUES

    2009-01-01

    Full Text Available

    Septic shock or sepsis is reported to be one of the major causes of death when followed by systemic infectious trauma in humans and other mammals. Its development leads to a large drop in blood pressure and a reduction in vascular responsiveness to physiological vasoconstrictors which, if not contained, can lead to death. It is proposed that this vascular response is due to the action of bacterial cell wall products released into the bloodstream by the vascular endothelium and is considered a normal response of the body`s defenses against infection. A reduction in vascular reactivity to epinephrine and norepinephrine is observed under these conditions. In the present study in rats, the aim was to assess whether those effects of hypotension and hyporeactivity are also related to another endogenous vasoconstrictor, angiotensin II (AII. We evaluated the variation in the power of this vasoconstrictor over the mean arterial pressure in anesthetized rats, before and after the establishment of hypotension by Escherichia coli endotoxin (Etx. Our results show that in this model of septic shock, there is a reduction in vascular reactivity to AII and this reduction can be reversed by the inhibitor of nitric oxide synthase, Nω-Nitro-L-Arginine (NωNLA. Our results also suggest that other endogenous factors (not yet fully known are involved in the protection of rats against septic shock, in addition to the L-arginine NO pathway. Keywords: vascular hyporeactivity; NO; rat; angiotensin II; NωNLA Escherichia coli endotoxin.

  10. Angiotensin II-induced migration of vascular smooth muscle cells is mediated by p38 mitogen-activated protein kinase-activated c-Src through spleen tyrosine kinase and epidermal growth factor receptor transactivation.

    Science.gov (United States)

    Mugabe, Benon E; Yaghini, Fariborz A; Song, Chi Young; Buharalioglu, Cuneyt K; Waters, Christopher M; Malik, Kafait U

    2010-01-01

    Angiotensin II (Ang II) stimulates protein synthesis by activating spleen tyrosine kinase (Syk) and DNA synthesis through epidermal growth factor receptor (EGFR) transactivation in vascular smooth muscle cells (VSMCs). This study was conducted to determine whether Syk mediates Ang II-induced migration of aortic VSMCs using a scratch wound approach. Treatment with Ang II (200 nM) for 24 h increased VSMC migration by 1.56 +/- 0.14-fold. Ang II-induced VSMC migration and Syk phosphorylation as determined by Western blot analysis were minimized by the Syk inhibitor piceatannol (10 microM) and by transfecting VSMCs with dominant-negative but not wild-type Syk plasmid. Ang II-induced VSMC migration and Syk phosphorylation were attenuated by inhibitors of c-Src [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2)], p38 mitogen-activated protein kinase (MAPK) [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole (SB202190)], and extracellular signal-regulated kinase (ERK) 1/2 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene (U0126)]. SB202190 attenuated p38 MAPK and c-Src but not ERK1/2 phosphorylation, indicating that p38 MAPK acts upstream of c-Src and Syk. The c-Src inhibitor PP2 attenuated Syk and ERK1/2 phosphorylation, suggesting that c-Src acts upstream of Syk and ERK1/2. Ang II- and epidermal growth factor (EGF)-induced VSMC migration and EGFR phosphorylation were inhibited by the EGFR blocker 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) (2 microM). Neither the Syk inhibitor piceatannol nor the dominant-negative Syk mutant altered EGF-induced cell migration or Ang II- and EGF-induced EGFR phosphorylation. The c-Src inhibitor PP2 diminished EGF-induced VSMC migration and EGFR, ERK1/2, and p38 MAPK phosphorylation. The ERK1/2 inhibitor U0126 (10 microM) attenuated EGF-induced cell migration and ERK1/2 but not EGFR phosphorylation. These data suggest that Ang II stimulates VSMC migration via p38 MAPK-activated c

  11. The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension.

    Science.gov (United States)

    Weiss, Sebastian; Rosendahl, Alva; Czesla, Daniel; Meyer-Schwesinger, Catherine; Stahl, Rolf A K; Ehmke, Heimo; Kurts, Christian; Zipfel, Peter F; Köhl, Jörg; Wenzel, Ulrich O

    2016-06-01

    Adaptive and innate immune responses contribute to hypertension and hypertensive end-organ damage. Here, we determined the role of anaphylatoxin C5a, a major inflammatory effector of the innate immune system that is generated in response to complement activation, in hypertensive end-organ damage. For this purpose, we assessed the phenotype of C5a receptor 1 (C5aR1)-deficient mice in ANG II-induced renal and cardiac injury. Expression of C5aR1 on infiltrating and resident renal as well as cardiac cells was determined using a green fluorescent protein (GFP)-C5aR1 reporter knockin mouse. Flow cytometric analysis of leukocytes isolated from the kidney of GFP-C5aR1 reporter mice showed that 28% of CD45-positive cells expressed C5aR1. Dendritic cells were identified as the major C5aR1-expressing population (88.5%) followed by macrophages and neutrophils. Using confocal microscopy, we detected C5aR1 in the kidney mainly on infiltrating cells. In the heart, only infiltrating cells stained C5aR1 positive. To evaluate the role of C5aR1 deficiency in hypertensive injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of ANG II (1.5 ng·g(-1)·min(-1)) and salt in wild-type (n = 34) and C5aR1-deficient mice (n = 32). C5aR1-deficient mice exhibited less renal injury, as evidenced by significantly reduced albuminuria. In contrast, cardiac injury was accelerated with significantly increased cardiac fibrosis and heart weight in C5aR1-deficient mice after ANG II infusion. No effect was found on blood pressure. In summary, the C5a:C5aR1 axis drives end-organ damage in the kidney but protects from the development of cardiac fibrosis and hypertrophy in experimental ANG II-induced hypertension. PMID:27053686

  12. Angiopoietin-1 attenuates angiotensin II-induced ER stress in glomerular endothelial cells via a Tie2 receptor/ERK1/2-p38 MAPK-dependent mechanism.

    Science.gov (United States)

    Bi, Xiao; Niu, Jianying; Ding, Wei; Zhang, Minmin; Yang, Min; Gu, Yong

    2016-06-15

    Research has indicated that endoplasmic reticulum (ER) stress in endothelial cells affects vascular pathologies and induces cellular dysfunction and apoptosis. Angiopoietin1 (Angpt1) has been shown to have therapeutic potential in some vascular diseases, including chronic kidney disease. This study showed that Angpt1 is a powerful factor that attenuated ER stress-induced cellular dysfunction and apoptosis in glomerular endothelial cells (GEnCs). Furthermore, Angpt1 significantly decreased the angiotensin II (Ang II)-induced expression of the ER stress response proteins GRP78, GRP94, p-PERK and CHOP. These results suggest that the Angpt1-mediated cellular protection may occur downstream of the ER stress response. In addition, both specific inhibitors and siRNAs for Tie2 reversed these changes, implying the importance of Tie2 receptor activation in the signalling pathways that prevent ER stress. The protective effects of Angpt1 are related to the activation of two downstream signalling pathways, ERK1/2 and p38 MAPK. The inhibition of these pathways with specific inhibitors, PD98059 and SB203580, respectively, partially increased the expression of chaperones that assist in folding proteins in the ER and reduce the protective effects of Angpt1. In conclusion, Angpt1 attenuated ER stress-induced cellular dysfunction and apoptosis via the Tie2 receptor/ERK1/2-p38 MAPK pathways in GEnCs. This study may provide insights into a novel underlying mechanism and a strategy for alleviating ER stress-induced injury. PMID:27033326

  13. Prostaglandin E-prostanoid4 receptor mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla.

    Science.gov (United States)

    Wang, Fei; Lu, Xiaohan; Peng, Kexin; Du, Yaomin; Zhou, Shu-Feng; Zhang, Aihua; Yang, Tianxin

    2014-08-01

    Angiotensin II (Ang II) stimulates (pro)renin receptor (PRR) expression in the renal collecting duct, triggering the local renin response in the distal nephron. Our recent study provided evidence for involvement of cyclooxygenase-2-prostaglandin E2 pathway in Ang II-dependent stimulation of PRR expression in the collecting duct. Here, we tested the role of E-prostanoid (EP) subtypes acting downstream of cyclooxygenase-2 in this phenomenon. In primary rat inner medullary collecting duct cells, Ang II treatment for 12 hours induced a 1.8-fold increase in the full-length PRR protein expression. To assess the contribution of EP receptor, the cell was pretreated with specific EP receptor antagonists: SC-51382 (for EP1), L-798106 (for EP3), L-161982 (for EP4), and ONO-AE3-208 (ONO, a structurally distinct EP4 antagonist). The upregulation of PRR expression by Ang II was consistently abolished by L-161982 and ONO and partially suppressed by SC-51382 but was unaffected by L-798106. The PRR expression was also significantly elevated by the EP4 agonist CAY10598 in the absence of Ang II. Sprague-Dawley rats were subsequently infused for 1 or 2 weeks with vehicle, Ang II alone, or in combination with ONO. Ang II infusion induced parallel increases in renal medullary PRR protein and renal medullary and urinary renin activity and total renin content, all of which were blunted by ONO. Both tail cuff plethysmography and telemetry demonstrated attenuation of Ang II hypertension by ONO. Overall, these results have established a crucial role of the EP4 receptor in mediating the upregulation of renal medullary PRR expression and renin activity during Ang II hypertension. PMID:24866147

  14. Evaluation of 12-Lipoxygenase (12-LOX and Plasminogen Activator Inhibitor 1 (PAI-1 as Prognostic Markers in Prostate Cancer

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    Tomasz Gondek

    2014-01-01

    Full Text Available In carcinoma of prostate, a causative role of platelet 12-lipoxygenase (12-LOX and plasminogen activator inhibitor 1 (PAI-1 for tumor progression has been firmly established in tumor and/or adjacent tissue. Our goal was to investigate if 12-LOX and/or PAI-1 in patient’s plasma could be used to predict outcome of the disease. The study comprised 149 patients (age 70±9 divided into two groups: a study group with carcinoma confirmed by positive biopsy of prostate (n=116 and a reference group (n=33 with benign prostatic hyperplasia (BPH. The following parameters were determined by the laboratory test in plasma or platelet-rich plasma: protein level of 12-LOX, PAI-1, thromboglobulin (TGB, prostate specific antigen (PSA, C-reactive protein (CRP, hemoglobin (HGB, and hematocrit (HCT, as well as red (RBC and white blood cells (WBC, number of platelets (PLT, international normalized ratio of blood clotting (INR, and activated partial thromboplastin time (APTT. The only difference of significance was noticed in the concentration of 12-LOX in platelet rich plasma, which was lower in cancer than in BPH group. Standardization to TGB and platelet count increases the sensitivity of the test that might be used as a biomarker to assess risk for prostate cancer in periodically monitored patients.

  15. Two New Monoterpene Glycosides from Qing Shan Lu Shui Tea with Inhibitory Effects on Leukocyte-Type 12-Lipoxygenase Activity

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    Ding Zhi Fang

    2013-04-01

    Full Text Available We evaluated the inhibitory effect of 12 Chinese teas on leukocyte-type 12-lipoxygenase (LOX activity. Tea catechins such as epigallocatechin gallate have been known to exhibit leukocyte-type 12-LOX inhibition. Qing Shan Lu Shui, which contains lower catechin levels than the other tested teas, suppressed leukocyte-type 12-LOX activity. To characterize the bioactive components of Qing Shan Lu Shui, leukocyte-type 12-LOX inhibitory activity–guided fractionation of the aqueous ethanol extract of the tea was performed, resulting in the isolation of two new monoterpene glycosides: liguroside A (1 and B (2. The structures of compounds 1 and 2 were characterized as (2E,5E-7-hydroperoxy-3,7-dimethyl-2,5-octadienyl-O-(α-L-rhamnopyranosyl-(1″→3′-(4′″-O-trans-p-coumaroyl-β-D-glucopyranoside and (2E,5E-7-hydroperoxy-3,7-dimethyl-2,5-octa-dienyl- O-(α-L-rhamnopyranosyl-(1″→3′-(4′″-O-cis-p-coumaroyl-β-D-glucopyranoside, respectively, based on spectral and chemical evidence. Ligurosides A (1 and B (2 showed inhibitory effects on leukocyte-type 12-LOX activity, with IC50 values of 1.7 and 0.7 μM, respectively.

  16. Angiotensin converting enzyme inhibition does not affect the response to exogenous angiotensin II in the human forearm.

    OpenAIRE

    Lyons, D.; D. Stewart; Webster, J; Benjamin, N

    1994-01-01

    Suppression of endogenous levels of angiotensin II by angiotensin converting enzyme inhibition, may result in up-regulation of vascular AT1 receptors. We have evaluated the effects of orally administered enalapril on angiotensin II induced vasoconstriction in the human forearm. Subjects received in random order, enalapril (20 mg) or matched placebo daily for 2 weeks. Forearm blood flow response to increasing doses of angiotensin II was measured using venous occlusion plethysmography at the be...

  17. The Renin-Angiotensin System Modulates Inflammatory Processes in Atherosclerosis: Evidence from Basic Research and Clinical Studies

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    Fabrizio Montecucco

    2009-01-01

    Full Text Available Recent evidence shows that the renin-angiotensin system is a crucial player in atherosclerotic processes. The regulation of arterial blood pressure was considered from its first description of the main mechanism involved. Vasoconstriction (mediated by angiotensin II and salt and water retention (mainly due to aldosterone were classically considered as pivotal proatherosclerotic activities. However, basic research and animal studies strongly support angiotensin II as a proinflammatory mediator, which directly induces atherosclerotic plaque development and heart remodeling. Furthermore, angiotensin II induces proatherosclerotic cytokine and chemokine secretion and increases endothelial dysfunction. Accordingly, the pharmacological inhibition of the renin-angiotensin system improves prognosis of patients with cardiovascular disease even in settings of normal baseline blood pressure. In the present review, we focused on angiotensin-convertingenzyme (ACE inhibitors, angiotensin II receptor blockers (ARBs, and renin inhibitors to update the direct activities of the renin-angiotensin system in inflammatory processes governing atherosclerosis.

  18. Renin-angiotensin system in ventilator-induced diaphragmatic dysfunction: Potential protective role of Angiotensin (1-7).

    Science.gov (United States)

    Sigurta', Anna; Zambelli, Vanessa; Bellani, Giacomo

    2016-09-01

    Ventilator-induced diaphragmatic dysfunction is a feared complication of mechanical ventilation that adversely affects the outcome of intensive care patients. Human and animal studies demonstrate atrophy and ultrastructural alteration of diaphragmatic muscular fibers attributable to increased oxidative stress, depression of the anabolic pathway regulated by Insulin-like growing factor 1 and increased proteolysis. The renin-angiotensin system, through its main peptide Angiotensin II, plays a major role in skeletal muscle diseases, mainly increasing oxidative stress and inducing insulin resistance, atrophy and fibrosis. Conversely, its counter-regulatory peptide Angiotensin (1-7) has a protective role in these processes. Recent data on rodent models show that renin-angiotensin system is activated after mechanical ventilation and that infusion of Angiotensin II induces diaphragmatic skeletal muscle atrophy. Given: (A) common pathways shared by ventilator-induced diaphragmatic dysfunction and skeletal muscle pathology induced by renin-angiotensin system, (B) evidences of an involvement of renin-angiotensin system in diaphragm atrophy and dysfunction, we hypothesize that renin-angiotensin system plays an important role in ventilator-induced diaphragmatic dysfunction, while Angiotensin (1-7) can have a protective effect on this pathological process. The activation of renin-angiotensin system in ventilator-induced diaphragmatic dysfunction can be demonstrated by quantification of its main components in the diaphragm of ventilated humans or animals. The infusion of Angiotensin (1-7) in an established rodent model of ventilator-induced diaphragmatic dysfunction can be used to test its potential protective role, that can be further confirmed with the infusion of Angiotensin (1-7) antagonists like A-779. Verifying this hypothesis can help in understanding the processes involved in ventilator-induced diaphragmatic dysfunction pathophysiology and open new possibilities for its

  19. Angiotensin II stimulates melanogenesis via the protein kinase C pathway

    OpenAIRE

    Li-hong LIU; Fan, Xin; XIA, ZHI-KUAN; AN, XU-XI; Yang, Rong-Ya

    2015-01-01

    Melanogenesis is a physiological process that results in the synthesis of melanin pigments, which serve a crucial function in hyperpigmentation. The aim of the present study was to determine the effects of angiotensin II (Ang II) on melanogenesis and to elucidate the molecular events of Ang II-induced melanogenesis. Experiments were performed on human melanocytes to elucidate the pigmenting effect of Ang II and the underlying mechanisms. The elements involved in melanogenesis, including melan...

  20. Sirtuin3 Dysfunction Is the Key Determinant of Skeletal Muscle Insulin Resistance by Angiotensin II.

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    Daniela Macconi

    Full Text Available Angiotensin II promotes insulin resistance. The mechanism underlying this abnormality, however, is still poorly defined. In a different setting, skeletal muscle metabolism and insulin signaling are regulated by Sirtuin3.Here, we investigate whether angiotensin II-induced insulin resistance in skeletal muscle is associated with Sirtuin3 dysregulation and whether pharmacological manipulation of Sirtuin3 confers protection.Parental and GLUT4-myc L6 rat skeletal muscle cells exposed to angiotensin II are used as in vitro models of insulin resistance. GLUT4 translocation, glucose uptake, intracellular molecular signals such as mitochondrial reactive oxygen species, Sirtuin3 protein expression and activity, along with its downstream targets and upstream regulators, are analyzed both in the absence and presence of acetyl-L-carnitine. The role of Sirtuin3 in GLUT4 translocation and intracellular molecular signaling is also studied in Sirtuin3-silenced as well as over-expressing cells.Angiotensin II promotes insulin resistance in skeletal muscle cells via mitochondrial oxidative stress, resulting in a two-fold increase in superoxide generation. In this context, reactive oxygen species open the mitochondrial permeability transition pore and significantly lower Sirtuin3 levels and activity impairing the cell antioxidant defense. Angiotensin II-induced Sirtuin3 dysfunction leads to the impairment of AMP-activated protein kinase/nicotinamide phosphoribosyltransferase signaling. Acetyl-L-carnitine, by lowering angiotensin II-induced mitochondrial superoxide formation, prevents Sirtuin3 dysfunction. This phenomenon implies the restoration of manganese superoxide dismutase antioxidant activity and AMP-activated protein kinase activation. Acetyl-L-carnitine protection is abrogated by specific Sirtuin3 siRNA.Our data demonstrate that angiotensin II-induced insulin resistance fosters mitochondrial superoxide generation, in turn leading to Sirtuin3 dysfunction. The

  1. Angiotensin II-Induced Hypertension in Apolipoprotein E-Deficient Rats

    OpenAIRE

    Gorman, Sydney N; Goergen, Craig J.; Blaize, A Nicole

    2015-01-01

    Abdominal aortic aneurysms (AAAs) are characterized by a weakened vessel wall and a diameter 50% greater than normal. AAA are usually asymptomatic until they are near rupturing, which can be fatal if not treated immediately. Apolipoprotein E-deficient (ApoE) mice are commonly used as a model to study aneurysm growth. Our lab has created a similar model using rats, which are more similar to humans. This study focuses on the analysis of blood pressures collected from ApoE rats for comparison wi...

  2. Angiotensin II induced inflammation in the kidney and in the heart of double transgenic rats

    OpenAIRE

    Haller Hermann; Ganten Detlev; Barta Peter; Fiebeler Anette; Park Joon-Keun; Muller Dominik N; Dechend Ralf; Theuer Juergen; Dietz Rainer; Luft Friedrich C

    2002-01-01

    BACKGROUND: We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are ...

  3. Plasminogen activator inhibitor-1 deficient mice are protected from angiotensin II-induced fibrosis

    OpenAIRE

    Beier, Juliane I.; Kaiser, J. Phillip; Guo, Luping; Martínez-Maldonado, Manuel; Arteel, Gavin E.

    2011-01-01

    PAI-1 has been shown to be both profibrotic and antifibrotic in animal models of hepatic fibrosis. Although these models have similarities to human fibrotic liver disease, no rodent model completely recapitulates the clinical situation; indeed, transaminase values in most models of hepatic fibrosis are much higher than in chronic liver diseases in humans. Here, wild-type and PAI-1−/− mice were administered AngII (500 ng/kg/min) for 4 weeks. ECM accumulation was evaluated by Sirius red stainin...

  4. Angiotensin-converting enzyme

    DEFF Research Database (Denmark)

    Sørensen, P G; Rømer, F K; Cortes, D

    1984-01-01

    In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or radiolog......In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or...

  5. 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

    , 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<0.......05). Culture of coronary arteries for 48 h induced down-regulation of the angiotensin AT1 and AT2 receptor mRNA levels and also a less efficacious angiotensin II-induced vasoconstriction (Emax=103+/-2% before and 23+/-7% after artery culture, P<0.001). Artery culture may thus be a suitable method for studying...

  6. Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia.

    Science.gov (United States)

    Pereira, Priscila Cristina; Pernomian, Larissa; Côco, Hariane; Gomes, Mayara Santos; Franco, João José; Marchi, Kátia Colombo; Hipólito, Ulisses Vilela; Uyemura, Sergio Akira; Tirapelli, Carlos Renato; de Oliveira, Ana Maria

    2016-06-15

    Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions. PMID:27063446

  7. Can intradermal administration of angiotensin II influence human heat loss responses during whole body heat stress?

    Science.gov (United States)

    Fujii, Naoto; Meade, Robert D; Paull, Gabrielle; McGinn, Ryan; Foudil-bey, Imane; Akbari, Pegah; Kenny, Glen P

    2015-05-01

    It is unclear if angiotensin II, which can increase the production of reactive oxygen species (oxidative stress), modulates heat loss responses of cutaneous blood flow and sweating. We tested the hypothesis that angiotensin II-induced increases in oxidative stress impair cutaneous perfusion and sweating during rest and exercise in the heat. Eleven young (24 ± 4 yr) healthy adults performed two 30-min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35°C). The first and second exercises were followed by a 20- and 40-min recovery. Four microdialysis fibers were placed in the forearm skin for continuous administration of either: 1) lactated Ringer (control), 2) 10 μM angiotensin II, 3) 10 mM ascorbate (an antioxidant), or 4) a combination of 10 μM angiotensin II + 10 mM ascorbate. Cutaneous vascular conductance (CVC; laser-Doppler perfusion units/mean arterial pressure) and sweating (ventilated capsule) were evaluated at each skin site. Compared with control, angiotensin II reduced both CVC and sweating at baseline resting and during each recovery in the heat (all P 0.05). When ascorbate was coinfused with angiotensin II, the effect of angiotensin II on sweating was abolished (all P > 0.05); however, its effect on CVC at baseline resting and during each recovery remained intact (all P < 0.05). We show angiotensin II impairs cutaneous perfusion independent of oxidative stress, while it impairs sweating through increasing oxidative stress during exposure to an ambient heat stress before and following exercise. PMID:25767030

  8. 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.

  9. Sustained diacylglycerol formation from inositol phospholipids in angiotensin II-stimulated vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Griendling, K.K.; Rittenhouse, S.E.; Brock, T.A.; Ekstein, L.S.; Gimbrone, M.A. Jr.; Alexander, R.W.

    1986-05-05

    Angiotensin II acts on cultured rat aortic vascular smooth muscle cells to stimulate phospholipase C-mediated hydrolysis of membrane phosphoinositides and subsequent formation of diacylglycerol and inositol phosphates. In intact cells, angiotensin II induces a dose-dependent increase in diglyceride which is detectable after 5 s and sustained for at least 20 min. Angiotensin II (100 nM)-stimulated diglyceride formation is biphasic, peaking at 15 s (227 +/- 19% control) and at 5 min (303 +/- 23% control). Simultaneous analysis of labeled inositol phospholipids shows that at 15 s phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 4-phosphate (PIP) decline to 52 +/- 6% control and 63 +/- 5% control, respectively, while phosphatidylinositol (PI) remains unchanged. In contrast, at 5 min, PIP2 and PIP have returned toward control levels (92 +/- 2 and 82 +/- 4% control, respectively), while PI has decreased substantially (81 +/- 2% control). The calcium ionophore ionomycin (15 microM) stimulates diglyceride accumulation but does not cause PI hydrolysis. 4 beta-Phorbol 12-myristate 13-acetate, an activator of protein kinase C, inhibits early PIP and PIP2 breakdown and diglyceride formation, without inhibiting late-phase diglyceride accumulation. Thus, angiotensin II induces rapid transient breakdown of PIP and PIP2 and delayed hydrolysis of PI. The rapid attenuation of polyphosphoinositide breakdown is likely caused by a protein kinase C-mediated inhibition of PIP and PIP2 hydrolysis. While in vascular smooth muscle stimulated with angiotensin II inositol 1,4,5-trisphosphate formation is transient, diglyceride production is biphasic, suggesting that initial and sustained diglyceride formation from the phosphoinositides results from different biochemical and/or cellular processes.

  10. 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

  11. Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells

    International Nuclear Information System (INIS)

    Highlights: ► Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. ► Angiotensin II may enhance the DNA synthesis via induction of superoxide. ► Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. ► Angiotensin II enhanced differentiation into mesodermal progenitor cells. ► Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stem (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT1R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression. Treatment with Ang II enhanced the phosphorylation of p38 MAPK in Col IV- exposed iPS cells. These results suggest that the stimulation of

  12. Angiotensin II stimulates water and NaCl intake through separate cell signalling pathways

    OpenAIRE

    Daniels, Derek; Mietlicki, Elizabeth G.; Nowak, Erica L.; Fluharty, Steven J.

    2008-01-01

    Angiotensin II (AngII) stimulation of water and NaCl intake is a classic model of the behavioural effects of hormones. In vitro studies indicate that the AngII type 1 (AT1) receptor stimulates intracellular pathways that include PKC and MAP kinase activation. Previous studies support the hypotheses that PKC is involved in AngII-induced water, but not NaCl intake and that MAP kinase plays a role in NaCl consumption, but not water intake, after injection of AngII. The present experiments test t...

  13. Novel Roles for Peroxynitrite in Angiotensin II and CaMKII Signaling

    OpenAIRE

    Chaoming Zhou; Ramaswamy, Swarna S.; Johnson, Derrick E.; Vitturi, Dario A.; Schopfer, Franciso J.; Freeman, Bruce A.; Andy Hudmon; Levitan, Edwin S.

    2016-01-01

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) oxidation controls excitability and viability. While hydrogen peroxide (H2O2) affects Ca2+-activated CaMKII in vitro, Angiotensin II (Ang II)-induced CaMKIIδ signaling in cardiomyocytes is Ca2+ independent and requires NADPH oxidase-derived superoxide, but not its dismutation product H2O2. To better define the biological regulation of CaMKII activation and signaling by Ang II, we evaluated the potential for peroxynitrite (ONOO−) to mediate ...

  14. Over-expressed copper/zinc superoxide dismutase localizes to mitochondria in neurons inhibiting the angiotensin II-mediated increase in mitochondrial superoxide ☆

    OpenAIRE

    Shumin Li; Adam J. Case; Rui-Fang Yang; Schultz, Harold D.; Zimmerman, Matthew C

    2013-01-01

    Angiotensin II (AngII) is the main effector peptide of the renin–angiotensin system (RAS), and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2 •−). Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2 •−. We have previously reported...

  15. 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...

  16. Angiotensin II increases CTGF expression via MAPKs/TGF-{beta}1/TRAF6 pathway in atrial fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Gu, Jun [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China); Liu, Xu, E-mail: xkliuxu@yahoo.cn [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China); Wang, Quan-xing, E-mail: shmywqx@126.com [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Tan, Hong-wei [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China); Guo, Meng [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Jiang, Wei-feng; Zhou, Li [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of medicine, Shanghai (China)

    2012-10-01

    The activation of transforming growth factor-{beta}1(TGF-{beta}1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGF{beta}1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGF{beta}-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-{beta}1/non-Smad signaling pathways. In the present study, we explored the role of TGF-{beta}1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 {mu}M) provoked the activation of P38 mitogen activated protein kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 {mu}M) also promoted TGF{beta}1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGF{beta}1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGF{beta}1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis. -- Highlights: Black-Right-Pointing-Pointer MAPKs/TGF{beta}1/TRAF6 participates in AngII-induced CTGF expression in atrial fibroblasts. Black-Right-Pointing-Pointer TGF{beta}1/TRAF6 participates in AngII-induced atrial fibroblasts proliferation. Black-Right-Pointing-Pointer TRAF6 may represent a new target for reversing Ang II-induced atrial fibrosis.

  17. Interleukin-2/Anti-Interleukin-2 Immune Complex Expands Regulatory T Cells and Reduces Angiotensin II-Induced Aortic Stiffening

    OpenAIRE

    Beenish Majeed; Supannikar Tawinwung; Lance S. Eberson; SECOMB, TIMOTHY W.; Nicolas Larmonier; Larson, Douglas F.

    2014-01-01

    Adaptive immune function is implicated in the pathogenesis of vascular disease. Inhibition of T-lymphocyte function has been shown to reduce hypertension, target-organ damage, and vascular stiffness. To study the role of immune inhibitory cells, CD4+CD25+Foxp3+ regulatory T cells (Tregs), on vascular stiffness, we stimulated the proliferation of Treg lymphocytes in vivo using a novel cytokine immune complex of Interleukin-2 (IL-2) and anti-IL-2 monoclonal antibody clone JES6-1 (mAbCD25). Thre...

  18. Incomplete Restoration of Angiotensin II - Induced Renal Extracellular Matrix Deposition and Inflammation Despite Complete Functional Recovery in Rats

    NARCIS (Netherlands)

    Frenay, Anne-Roos S.; Yazdani, Saleh; Boersema, Miriam; van der Graaf, Anne Marijn; Waanders, Femke; van den Born, Jacob; Navis, Gerjan J.; van Goor, Harry

    2015-01-01

    Some diseases associated with a temporary deterioration in kidney function and/or development of proteinuria show an apparently complete functional remission once the initiating trigger is removed. While it was earlier thought that a transient impairment of kidney function is harmless, accumulating

  19. The microRNA-132/212 family fine-tunes multiple targets in Angiotensin II signalling in cardiac fibroblasts

    DEFF Research Database (Denmark)

    Eskildsen, Tilde V; Schneider, Mikael; Sandberg, Maria B; Skov, Vibe; Jensen, Hasse Brønnum; Thomassen, Mads; Kruse, Torben A; Andersen, Ditte Caroline; Sheikh, Søren P

    2015-01-01

    INTRODUCTION: MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular ...... pathways that fine-tuned by miR-132/212, suggesting a role for this miRNA family as master signalling switches in cardiac fibroblasts. Our data underscore the potential for miRNA tools to manipulate a large array of molecules and thereby control biological function....

  20. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Su, Qing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Wang, Fu-Xin [Department of Neurology, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002 (China); Ren, Jun [Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071 (United States); Li, Hong-Bao; Zhang, Meng; Yang, Qing; Miao, Yu-Wang; Yu, Xiao-Jing; Qi, Jie [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Zhiming [Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, The Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China)

    2014-04-15

    Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91{sup phox} (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91{sup phox}, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension.

  1. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

    International Nuclear Information System (INIS)

    Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91phox (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91phox, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension

  2. EPOXYEICOSATRIENOIC ACID ANALOG ATTENUATES ANGIOTENSIN II HYPERTENSION AND KIDNEY INJURY

    Directory of Open Access Journals (Sweden)

    Md. Abdul Hye Khan

    2014-09-01

    Full Text Available Epoxyeicosatrienoic acids (EETs contribute to blood pressure regulation leading to the concept that EETs can be therapeutically targeted for hypertension and the associated end-organ damage. In the present study, we investigated anti-hypertensive and kidney protective actions of an EET analog, EET-B in angiotensin II (ANG II-induced hypertension. EET-B was administered in drinking water for 14 days (10mg/kg/d and resulted in a decreased blood pressure elevation in ANG II hypertension. At the end of the two-week period, blood pressure was 30 mmHg lower in EET analog-treated ANG II hypertensive rats. The vasodilation of mesenteric resistance arteries to acetylcholine was impaired in ANG II hypertension; however, it was improved with EET-B treatment. Further, EET-B protected the kidney in ANG II hypertension as evidenced by a marked 90% decrease in albuminuria and 54% decrease in nephrinuria. Kidney histology demonstrated a decrease in renal tubular cast formation in EET analog-treated hypertensive rats. In ANG II hypertension, EET-B treatment markedly lowered renal inflammation. Urinary monocyte chemoattractant protein-1 excretion was decreased by 55% and kidney macrophage infiltration was reduced by 52% with EET-B treatment. Overall, our results demonstrate that EET-B has anti-hypertensive properties, improves vascular function, and decreases renal inflammation and injury in ANG II hypertension.

  3. Lipid rafts are required for signal transduction by angiotensin II receptor type 1 in neonatal glomerular mesangial cells

    International Nuclear Information System (INIS)

    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 Ca2+ ([Ca2+]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 [Ca2+]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 [Ca2+]i chelator; KN-93, a Ca2+/calmodulin-dependent protein kinase II inhibitor; CDX; and a CSD peptide, but not PD 123319, a selective AGTR2 antagonist. Collectively, our data demonstrate [Ca2+]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 [Ca2+]i elevation in neonatal mesangial cells. • Lipid raft disruption inhibits ANG-II-induced neonatal mesangial cell growth

  4. 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.

  5. Safflor yellow B suppresses angiotensin II-mediated human umbilical vein cell injury via regulation of Bcl-2/p22phox expression

    International Nuclear Information System (INIS)

    Intracellular reactive oxygen species (ROS) are derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Angiotensin II (Ang II) can cause endothelial dysfunction by promoting intracellular ROS generation. Safflor yellow B (SYB) effectively inhibits ROS generation by upregulating Bcl-2 expression. In this study, we examined the effects of SYB on Ang II-induced injury to human umbilical vein endothelial cells (HUVECs), and elucidated the roles of NADPH oxidase and Bcl-2. We treated cultured HUVECs with Ang II, SYB, and Bcl-2 siRNA, and determined NADPH oxidase activity and ROS levels. Furthermore, cellular and mitochondrial physiological states were evaluated, and the expression levels of target proteins were analyzed. Ang II significantly enhanced intracellular ROS levels, caused mitochondrial membrane dysfunction, and decreased cell viability, leading to apoptosis. This was associated with increased expression of AT1R and p22phox, increased NADPH oxidase activity, and an increased ratio of Bax/Bcl-2, leading to decreases in antioxidant enzyme activities, which were further strengthened after blocking Bcl-2. Compared to Ang II treatment alone, co-treatment with SYB significantly reversed HUVEC injury. Taken together, these results demonstrate that SYB could significantly protect endothelial cells from Ang II-induced cell damage, and that it does so by upregulating Bcl-2 expression and inhibiting ROS generation. - Highlights: • Angiotensin II depresses mitochondria physiological function. • Angiotensin II activates NADPH oxidase via up-regulating expresion of p22phox. • Bcl-2 plays a pivotal role in improving mitochondria function and regulates ROS level. • Inhibitor of Bcl-2 promotes angiotensin II mediated HUVEC injury. • SYB attenuates angiotensin II mediated HUVEC injury via up regulating Bcl-2 expression

  6. Safflor yellow B suppresses angiotensin II-mediated human umbilical vein cell injury via regulation of Bcl-2/p22{sup phox} expression

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chaoyun; He, Yanhao [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Department of Pharmacology, Xi' an Jiaotong University School of Medicine, Key Laboratory of Environment and Genes Related to Disease, Ministry of Education, Xi' an, Shaanxi 710061 (China); Yang, Ming; Sun, Hongliu; Zhang, Shuping [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Wang, Chunhua, E-mail: chunhuawang2012@163.com [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China)

    2013-11-15

    Intracellular reactive oxygen species (ROS) are derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Angiotensin II (Ang II) can cause endothelial dysfunction by promoting intracellular ROS generation. Safflor yellow B (SYB) effectively inhibits ROS generation by upregulating Bcl-2 expression. In this study, we examined the effects of SYB on Ang II-induced injury to human umbilical vein endothelial cells (HUVECs), and elucidated the roles of NADPH oxidase and Bcl-2. We treated cultured HUVECs with Ang II, SYB, and Bcl-2 siRNA, and determined NADPH oxidase activity and ROS levels. Furthermore, cellular and mitochondrial physiological states were evaluated, and the expression levels of target proteins were analyzed. Ang II significantly enhanced intracellular ROS levels, caused mitochondrial membrane dysfunction, and decreased cell viability, leading to apoptosis. This was associated with increased expression of AT1R and p22{sup phox}, increased NADPH oxidase activity, and an increased ratio of Bax/Bcl-2, leading to decreases in antioxidant enzyme activities, which were further strengthened after blocking Bcl-2. Compared to Ang II treatment alone, co-treatment with SYB significantly reversed HUVEC injury. Taken together, these results demonstrate that SYB could significantly protect endothelial cells from Ang II-induced cell damage, and that it does so by upregulating Bcl-2 expression and inhibiting ROS generation. - Highlights: • Angiotensin II depresses mitochondria physiological function. • Angiotensin II activates NADPH oxidase via up-regulating expresion of p22{sup phox}. • Bcl-2 plays a pivotal role in improving mitochondria function and regulates ROS level. • Inhibitor of Bcl-2 promotes angiotensin II mediated HUVEC injury. • SYB attenuates angiotensin II mediated HUVEC injury via up regulating Bcl-2 expression.

  7. AT2R autoantibodies block angiotensin II and AT1R autoantibody-induced vasoconstriction.

    Science.gov (United States)

    Liles, Campbell; Li, Hongliang; Veitla, Vineet; Liles, Jonathan T; Murphy, Taylor A; Cunningham, Madeleine W; Yu, Xichun; Kem, David C

    2015-10-01

    Activating autoantibodies to the angiotensin type 1 receptor (AT1R) are associated with hypertensive disorders. The angiotensin type 2 receptor (AT2R) is known to counter-regulate the actions of AT1R. We investigated whether AT2R autoantibodies produced in immunized rabbits will activate AT2R and suppress the vasopressor responses to angiotensin II and AT1R-activating autoantibodies. Five rabbits immunized with a peptide corresponding to the second extracellular loop of AT2R developed high AT2R antibody titers. Rabbit anti-AT2R sera failed to directly dilate isolated rat cremaster arterioles; however, when co-perfused with angiotensin II or AT1R-activating autoantibodies, the anti-AT2R sera significantly inhibited their contractile effects. Rabbit anti-AT2R sera recognized a predominant sequence near the N-terminus of the AT2R second extracellular loop. A decoy peptide based on this sequence effectively reversed the opposing effect of the anti-AT2R sera on angiotensin II-induced contraction of rat cremaster arterioles. A similar blockade of the anti-AT2R sera effect was observed with the AT2R antagonist PD 123319 and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Rabbit anti-AT2R sera reacted specifically with AT2R. No cross-reactivity with AT1R was observed. Blood pressure did not change in immunized animals. However, the pressor responses to incremental angiotensin II infusions were blunted in immunized animals. Thirteen subjects with primary aldosteronism demonstrated increased AT2R autoantibody levels compared with normal controls. In conclusion, AT2R autoantibodies produced in immunized rabbits have the ability to activate AT2R and counteract the AT1R-mediated vasoconstriction. These autoantibodies provide useful and selective tools for the study of their roles in blood pressure regulation and possible therapeutic intervention. PMID:26259590

  8. Nox2-Induced Production of Mitochondrial Superoxide in Angiotensin II-Mediated Endothelial Oxidative Stress and Hypertension

    Science.gov (United States)

    Dikalov, Sergey I.; Bikineyeva, Alfiya; Hilenski, Lula; Lassègue, Bernard; Griendling, Kathy K.; Harrison, David G.; Dikalova, Anna E.

    2014-01-01

    Abstract Aims: Angiotensin II (AngII)-induced superoxide (O2•−) production by the NADPH oxidases and mitochondria has been implicated in the pathogenesis of endothelial dysfunction and hypertension. In this work, we investigated the specific molecular mechanisms responsible for the stimulation of mitochondrial O2•− and its downstream targets using cultured human aortic endothelial cells and a mouse model of AngII-induced hypertension. Results: Western blot analysis showed that Nox2 and Nox4 were present in the cytoplasm but not in the mitochondria. Depletion of Nox2, but not Nox1, Nox4, or Nox5, using siRNA inhibits AngII-induced O2•− production in both mitochondria and cytoplasm. Nox2 depletion in gp91phox knockout mice inhibited AngII-induced cellular and mitochondrial O2•− and attenuated hypertension. Inhibition of mitochondrial reverse electron transfer with malonate, malate, or rotenone attenuated AngII-induced cytoplasmic and mitochondrial O2•− production. Inhibition of the mitochondrial ATP-sensitive potassium channel (mitoK+ATP) with 5-hydroxydecanoic acid or specific PKCɛ peptide antagonist (EAVSLKPT) reduced AngII-induced H2O2 in isolated mitochondria and diminished cytoplasmic O2•−. The mitoK+ATP agonist diazoxide increased mitochondrial O2•−, cytoplasmic c-Src phosphorylation and cytoplasmic O2•− suggesting feed-forward regulation of cellular O2•− by mitochondrial reactive oxygen species (ROS). Treatment of AngII-infused mice with malate reduced blood pressure and enhanced the antihypertensive effect of mitoTEMPO. Mitochondria-targeted H2O2 scavenger mitoEbselen attenuated redox-dependent c-Src and inhibited AngII-induced cellular O2•−, diminished aortic H2O2, and reduced blood pressure in hypertensive mice. Innovation and Conclusions: These studies show that Nox2 stimulates mitochondrial ROS by activating reverse electron transfer and both mitochondrial O2•− and reverse electron transfer may represent new

  9. Leptin Inhibits the Proliferation of Vascular Smooth Muscle Cells Induced by Angiotensin II through Nitric Oxide-Dependent Mechanisms

    Directory of Open Access Journals (Sweden)

    Amaia Rodríguez

    2010-01-01

    Full Text Available Objective. This study was designed to investigate whether leptin modifies angiotensin (Ang II-induced proliferation of aortic vascular smooth muscle cells (VSMCs from 10-week-old male Wistar and spontaneously hypertensive rats (SHR, and the possible role of nitric oxide (NO. Methods. NO and NO synthase (NOS activity were assessed by the Griess and 3H-arginine/citrulline conversion assays, respectively. Inducible NOS (iNOS and NADPH oxidase subutnit Nox2 expression was determined by Western-blot. The proliferative responses to Ang II were evaluated through enzymatic methods. Results. Leptin inhibited the Ang II-induced proliferative response of VSMCs from control rats. This inhibitory effect of leptin was abolished by NOS inhibitor, NMMA, and iNOS selective inhibitor, L-NIL, and was not observed in leptin receptor-deficient fa/fa rats. SHR showed increased serum leptin concentrations and lipid peroxidation. Despite a similar leptin-induced iNOS up-regulation, VSMCs from SHR showed an impaired NOS activity and NO production induced by leptin, and an increased basal Nox2 expression. The inhibitory effect of leptin on Ang II-induced VSMC proliferation was attenuated. Conclusion. Leptin blocks the proliferative response to Ang II through NO-dependent mechanisms. The attenuation of this inhibitory effect of leptin in spontaneous hypertension appears to be due to a reduced NO bioavailability in VSMCs.

  10. Estimation of urinary angiotensin II by radioimmunoassay

    International Nuclear Information System (INIS)

    Urine samples were collected from fasting subjects after maintaining posture for 2 hr in early morning. Urinary angiotensin II was extracted with SE-Sephadex. The extracts, after being dissolved in phosphate buffer, pH 7.5, were measured by radioimmunoassay. Recovery, sensitivity and accuracy were found to be satisfactory. The normal values obtained from 6 subjects were 52-280 pg/2 hr. The values were almost normal in essential hypertension and in chronic glomerulonephritis. They were high in 3 out of 6 cases with renovascular hypertension and subsequently dropped after surgery. In 6 cases with primary aldosteronism, very low levels were found. These increased after the removal of adrenal adenomas. No positive correlation between simultaneous plasma and urinary angiotensin samples was apparent. Also no positive correlation between urinary angiotensin and urine volume was found. In renovascular hypertention, during glucose infusion, lower values in urine volume and angiotensin excretion were observed on the stenotic side as compared to the intact side. Thus, the angiotensin excretion rate does not appear to be regulated by arterial angiotensin concentration, but rather by the angiotensin perfusion rate. (author)

  11. Angiotensin and insulin resistance: conspiracy theory.

    Science.gov (United States)

    Townsend, Raymond R

    2003-04-01

    Resistance to the metabolic effects of insulin is a contender for the short list of major cardiovascular risk factors. Since the elements of the syndrome of insulin resistance were first articulated together in 1988, numerous epidemiologic investigations and treatment endeavors have established a relationship between the metabolic disarray of impaired insulin action and cardiovascular disease. Angiotensin II, the primary effector of the renin-angiotensin system, has also achieved a place in the chronicles of cardiovascular risk factors. Conspiracy mechanisms by which angiotensin II and insulin resistance interact in the pathogenesis of cardiovascular disease are reviewed, with particular attention to recent developments in this engaging area of human research. PMID:12642009

  12. Angiotensin II and Renal Tubular Ion Transport

    Directory of Open Access Journals (Sweden)

    Patricia Valles

    2005-01-01

    Evidence for the regulation of H+-ATPase activity in vivo and in vitro by trafficking/exocytosis has been provided. An additional level of H+-ATPase regulation via protein synthesis may be important as well. Recently, we have shown that both aldosterone and angiotensin II provide such a mechanism of regulation in vivo at the level of the medullary collecting tubule. Interestingly, in this part of the nephron, the effects of aldosterone and angiotensin II are not sodium dependent, whereas in the cortical collecting duct, both aldosterone and angiotensin II, by contrast, affect H+ secretion by sodium-dependent mechanisms.

  13. Kelch-Like Protein 2 Mediates Angiotensin II-With No Lysine 3 Signaling in the Regulation of Vascular Tonus.

    Science.gov (United States)

    Zeniya, Moko; Morimoto, Nobuhisa; Takahashi, Daiei; Mori, Yutaro; Mori, Takayasu; Ando, Fumiaki; Araki, Yuya; Yoshizaki, Yuki; Inoue, Yuichi; Isobe, Kiyoshi; Nomura, Naohiro; Oi, Katsuyuki; Nishida, Hidenori; Sasaki, Sei; Sohara, Eisei; Rai, Tatemitsu; Uchida, Shinichi

    2015-09-01

    Recently, the kelch-like protein 3 (KLHL3)-Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease. However, the involvement of WNK kinase regulation by ubiquitination in situations other than PHAII has not been identified. Previously, we identified the WNK3-STE20/SPS1-related proline/alanine-rich kinase-Na/K/Cl cotransporter isoform 1 phosphorylation cascade in vascular smooth muscle cells and found that it constitutes an important mechanism of vascular constriction by angiotensin II (AngII). In this study, we investigated the involvement of KLHL proteins in AngII-induced WNK3 activation of vascular smooth muscle cells. In the mouse aorta and mouse vascular smooth muscle (MOVAS) cells, KLHL3 was not expressed, but KLHL2, the closest homolog of KLHL3, was expressed. Salt depletion and acute infusion of AngII decreased KLHL2 and increased WNK3 levels in the mouse aorta. Notably, the AngII-induced changes in KLHL2 and WNK3 expression occurred within minutes in MOVAS cells. Results of KLHL2 overexpression and knockdown experiments in MOVAS cells confirmed that KLHL2 is the major regulator of WNK3 protein abundance. The AngII-induced decrease in KLHL2 was not caused by decreased transcription but increased autophagy-mediated degradation. Furthermore, knockdown of sequestosome 1/p62 prevented the decrease in KLHL2, suggesting that the mechanism of KLHL2 autophagy could be selective autophagy mediated by sequestosome 1/p62. Thus, we identified a novel component of signal transduction in AngII-induced vascular contraction that could be a promising drug target. PMID:25556166

  14. Angiotensin Converting Enzyme Activity in Alopecia Areata

    OpenAIRE

    Mohammad Reza Namazi; Armaghan Ashraf; Farhad Handjani; Ebrahim Eftekhar; Amir Kalafi

    2014-01-01

    Background. Alopecia areata (AA) is a chronic inflammatory disease of the hair follicle. The exact pathogenesis of AA remains unknown, although recent studies support a T-cell mediated autoimmune process. On the other hand, some studies have proposed that the renin-angiotensin-aldosterone system (RAAS) may play a role in autoimmunity. Therefore, we assessed serum activity of angiotensin converting enzyme (ACE), a component of this system, in AA. Methods. ACE activity was measured in the sera ...

  15. Angiotensin II (de)sensitization: Fluid intake studies with implications for cardiovascular control.

    Science.gov (United States)

    Daniels, Derek

    2016-08-01

    Cardiovascular disease is the leading cause of death worldwide and hypertension is the most common risk factor for death. Although many anti-hypertensive pharmacotherapies are approved for use in the United States, rates of hypertension have increased over the past decade. This review article summarizes a presentation given at the 2015 meeting of the Society for the Study of Ingestive Behavior. The presentation described work performed in our laboratory that uses angiotensin II-induced drinking as a model system to study behavioral and cardiovascular effects of the renin-angiotensin system, a key component of blood pressure regulation, and a common target of anti-hypertensives. Angiotensin II (AngII) is a potent dipsogen, but the drinking response shows a rapid desensitization after repeated injections of AngII. This desensitization appears to be dependent upon the timing of the injections, requires activation of the AngII type 1 (AT1) receptor, requires activation of mitogen-activated protein (MAP) kinase family members, and involves the anteroventral third ventricle (AV3V) region as a critical site of action. Moreover, the response does not appear to be the result of a more general suppression of behavior, a sensitized pressor response to AngII, or an aversive state generated by the treatment. More recent studies suggest that the treatment regimen used to produce desensitization in our laboratory also prevents the sensitization that occurs after daily bolus injections of AngII. Our hope is that these findings can be used to support future basic research on the topic that could lead to new developments in treatments for hypertension. PMID:26801390

  16. Troglitazone stimulates β-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1A receptor

    International Nuclear Information System (INIS)

    Peroxisome proliferator-activated receptor γ (PPARγ) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPARγ-independent signaling events. Select angiotensin receptor blockers (ARBs) interact with and modulate PPARγ activity, thus we hypothesized that a PPARγ agonist may exert physiologic effects via the angiotensin II type 1A receptor (AT1AR). In AT1AR-overexpressing HEK 293 cells, both angiotensin II (Ang II) and the PPARγ agonist troglitazone (Trog) enhanced AT1AR internalization and recruitment of endogenous β-arrestin1/2 (βarr1/2) to the AT1AR. A fluorescence assay to measure diacylglycerol (DAG) accumulation showed that although Ang II induced AT1AR-Gq protein-mediated DAG accumulation, Trog had no impact on DAG generation. Trog-mediated recruitment of βarr1/2 was selective to AT1AR as the response was prevented by an ARB- and Trog-mediated βarr1/2 recruitment to β1-adrenergic receptor (β1AR) 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 βarr2-dependent, as cardiomyocytes isolated from βarr2-KO mice showed blunted contractile responses to Trog. These findings show for the first time that the PPARγ agonist Trog acts at the AT1AR to simultaneously block Gq protein activation and induce the recruitment of βarr1/2, which leads to an increase in cardiomyocyte contractility.

  17. Angiotensin converting enzyme 2 (ACE2) activity in fetal calf serum: implications for cell culture research

    OpenAIRE

    Lubel, J. S.; Herath, C. B.; Velkoska, E.; Casley, D. J.; Burrell, L. M.; Angus, P. W.

    2008-01-01

    Cell culture experiments often employ the use of culture media that contain fetal calf serum (FCS). The angiotensin peptides angiotensin II and angiotensin 1–7 have opposing effects with angiotensin converting enzyme 2 (ACE2) being the enzyme predominantly responsible for generating angiotensin 1–7 from angiotensin II. The effect of FCS on angiotensin peptides has not previously been described. We have shown that FCS has ACE2 enzyme activity capable of degrading angiotensin II and generating ...

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

    International Nuclear Information System (INIS)

    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 (p22phox, p47phox, p67phox, 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 H2O2. 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 fibroblast growth and collagen formation

  19. 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

  20. Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway.

    Science.gov (United States)

    Bautista-Pérez, Rocio; del Valle-Mondragón, Leonardo; Cano-Martínez, Agustina; Pérez-Méndez, Oscar; Escalante, Bruno; Franco, Martha

    2015-05-15

    The possibility that angiotensin II (ANG II) exerts its effects through the activation of neutral sphingomyelinase (nSMase) has not been tested in kidneys. The results of the present study provide evidence for the activity and expression of nSMase in rat kidneys. In isolated perfused rat kidney, ANG II-induced renal vasoconstriction was inhibited by GW4869, an inhibitor of nSMase. We used nSMase for investigating the signal transduction downstream of ceramide. nSMase constricted the renal vasculature. An inhibitor of ceramidase (CDase), N-oleoylethanolamine (OEA), enhanced either ANG II- or nSMase-induced renal vasoconstriction. To demonstrate the interaction between the nSMase and cytosolic phospholipase A2 (cPLA2) signal transduction pathways, we evaluated the response to nSMase in the presence and absence of inhibitors of arachidonic acid (AA) metabolism: arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor of cPLA2; 5,8,11,14-eicosatetraynoic acid (ETYA), an inhibitor of all AA pathways; indomethacin, an inhibitor of cyclooxygenase (COX); furegrelate, a thromboxane A2 (TxA2)-synthase inhibitor; and SQ29548, a TxA2-receptor antagonist. In these experiments, the nSMase-induced renal vasoconstriction decreased. ANG II or nSMase was associated with an increase in the release of thromboxane B2 (TxB2) in the renal perfusate of isolated perfused rat kidney. In addition, the coexpression of the ceramide with cPLA2, was found in the smooth muscle layer of intrarenal vessels. Our results suggest that ANG II stimulates ceramide formation via the activation of nSMase; thus ceramide may indirectly regulate vasoactive processes that modulate the activity of cPLA2 and the release of TxA2. PMID:25354938

  1. 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.

  2. 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

    II can differentially modulate inflammatory gene expression in aortic smooth muscle cells through influencing ERK-NF-{kappa}B crosstalk, which may contribute to angiotensin II-induced inflammatory disorders related to cardiovascular diseases.

  3. Angiotensin II during experimentally simulated central hypovolemia

    Directory of Open Access Journals (Sweden)

    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.

  4. Neurotrophins inhibit major histocompatibility class II inducibility of microglia: Involvement of the p75 neurotrophin receptor

    OpenAIRE

    Neumann, Harald; Misgeld, Thomas; Matsumuro, Kenji; Wekerle, Hartmut

    1998-01-01

    Major histocompatibility complex (MHC) molecules are rare in the healthy brain tissue, but are heavily expressed on microglial cells after inflammatory or neurodegenerative processes. We studied the conditions leading to the induction of MHC class II molecules in microglia by using explant cultures of neonatal rat hippocampus, a model of interacting neuronal networks. Interferon-γ (IFN-γ)-dependent MHC class II inducibility in microglia cells was very low, but strongly increased in the hippoc...

  5. Deficiency of Smad7 enhances cardiac remodeling induced by angiotensin II infusion in a mouse model of hypertension.

    Directory of Open Access Journals (Sweden)

    Li Hua Wei

    Full Text Available Smad7 has been shown to negatively regulate fibrosis and inflammation, but its role in angiotensin II (Ang II-induced hypertensive cardiac remodeling remains unknown. Therefore, the present study investigated the role of Smad7 in hypertensive cardiopathy induced by angiotensin II infusion. Hypertensive cardiac disease was induced in Smad7 gene knockout (KO and wild-type (WT mice by subcutaneous infusion of Ang II (1.46 mg/kg/day for 28 days. Although equal levels of high blood pressure were developed in both Smad7 KO and WT mice, Smad7 KO mice developed more severe cardiac injury as demonstrated by impairing cardiac function including a significant increase in left ventricular (LV mass (P<0.01,reduction of LV ejection fraction(P<0.001 and fractional shortening(P<0.001. Real-time PCR, Western blot and immunohistochemistry detected that deletion of Smad7 significantly enhanced Ang II-induced cardiac fibrosis and inflammation, including upregulation of collagen I, α-SMA, interleukin-1β, TNF-α, and infiltration of CD3(+ T cells and F4/80(+ macrophages. Further studies revealed that enhanced activation of the Sp1-TGFβ/Smad3-NF-κB pathways and downregulation of miR-29 were mechanisms though which deletion of Smad7 promoted Ang II-mediated cardiac remodeling. In conclusions, Smad7 plays a protective role in AngII-mediated cardiac remodeling via mechanisms involving the Sp1-TGF-β/Smad3-NF.κB-miR-29 regulatory network.

  6. 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.

  7. Over-expressed copper/zinc superoxide dismutase localizes to mitochondria in neurons inhibiting the angiotensin II-mediated increase in mitochondrial superoxide

    Directory of Open Access Journals (Sweden)

    Shumin Li

    2014-01-01

    Full Text Available Angiotensin II (AngII is the main effector peptide of the renin–angiotensin system (RAS, and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2·−. Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2·−. We have previously reported that over-expression of manganese superoxide dismutase (MnSOD, a mitochondrial matrix-localized O2·− scavenging enzyme, inhibits AngII intra-neuronal signaling. Interestingly, over-expression of copper/zinc superoxide dismutase (CuZnSOD, which is believed to be primarily localized to the cytoplasm, similarly inhibits AngII intra-neuronal signaling and provides protection against AngII-mediated neurogenic hypertension. Herein, we tested the hypothesis that CuZnSOD over-expression in central neurons localizes to mitochondria and inhibits AngII intra-neuronal signaling by scavenging mitochondrial O2·−. Using a neuronal cell culture model (CATH.a neurons, we demonstrate that both endogenous and adenovirus-mediated over-expressed CuZnSOD (AdCuZnSOD are present in mitochondria. Furthermore, we show that over-expression of CuZnSOD attenuates the AngII-mediated increase in mitochondrial O2·− levels and the AngII-induced inhibition of neuronal potassium current. Taken together, these data clearly show that over-expressed CuZnSOD in neurons localizes in mitochondria, scavenges AngII-induced mitochondrial O2·−, and inhibits AngII intra-neuronal signaling.

  8. Pneumonia Risk and Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

    OpenAIRE

    Liu, Chia-Lin; Shau, Wen-Yi; Chang, Chia-Hsuin; Wu, Chi-Shin; Lai, Mei-Shu

    2013-01-01

    Background Recent studies have shown that use of angiotensin-converting enzyme (ACE) inhibitors may decrease pneumonia risk in various populations. We investigated the effect of ACE inhibitors and angiotensin II receptor blockers (ARBs) on pneumonia hospitalization in the general population of Taiwan. Methods We conducted a case-crossover study using the Taiwan Longitudinal Health Insurance Database for the year 2005. Data from patients hospitalized for the first time for pneumonia during 199...

  9. 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 ...

  10. A Peroxisome Proliferator-Activated Receptor-α Activator Induces Renal CYP2C23 Activity and Protects from Angiotensin II-Induced Renal Injury

    OpenAIRE

    Muller, Dominik N.; Theuer, Juergen; Shagdarsuren, Erdenechimeg; Kaergel, Eva; Honeck, Horst; Park, Joon-Keun; Markovic , Marija; Barbosa-Sicard, Eduardo; Dechend, Ralf; Wellner, Maren; Kirsch, Torsten; Fiebeler, Anette; Rothe, Michael; Haller, Hermann; Luft, Friedrich C.

    2004-01-01

    Cytochrome P450 (CYP)-dependent arachidonic acid (AA) metabolites are involved in the regulation of renal vascular tone and salt excretion. The epoxygenation product 11,12-epoxyeicosatrienoic acid (EET) is anti-inflammatory and inhibits nuclear factor-κB activation. We tested the hypothesis that the peroxisome proliferator-activated receptor-α-activator fenofibrate (Feno) induces CYP isoforms, AA hydroxylation, and epoxygenation activity, and protects against inflammatory organ damage. Double...

  11. Upregulation of AT2 receptor and iNOS impairs angiotensin II-induced contraction without endothelium influence in young normotensive diabetic rats

    OpenAIRE

    Lee, Jin Hee; Xia, Shichao; Ragolia, Louis

    2008-01-01

    Diabetes and insulin resistance are associated with an increased risk of hypertension and cardiovascular disease. Recent evidence demonstrates that AT2 receptors (AT2R) play an important role in the hemodynamic control of hypertension by vasodilation. The quantitative significance of AT2R in the establishment of diabetic vascular dysfunction, however, is not well defined and needs further investigation. Goto-Kakizaki (GK) rats, a polygenic model of spontaneous normotensive type 2 diabetes, we...

  12. Liberación de endotelina-1 por angiotensina ll en miocitos cardíacos aislados Angiotensin II-induced endothelin-1 release in cardiac myocytes

    OpenAIRE

    María C. Villa-Abrille; Cingolani, Horacio E; Carolina D. Garciarena; Ennis, Irene L.; Aiello, Ernesto A.

    2006-01-01

    Muchos de los efectos de la angiotensina II (Ang II) son mediados en realidad por la acción de endotelina (ET) endógena liberada y/o producida en respuesta a la Ang II. En este trabajo evaluamos la interacción Ang II/ET-1, sus consecuencias en la contractilidad cardíaca y el papel de las especies reactivas del oxígeno (EROs). Se usaron cardiomiocitos aislados de gato. La Ang II, 1 nM, produjo un efecto inotrópico positivo (EIP) de 31.8±3.8% que fue cancelado por inhibición de los receptores A...

  13. Angiotensin converting enzyme inhibitor induced hyperkalaemic paralysis

    OpenAIRE

    Dutta., D; Fischler, M; McClung, A

    2001-01-01

    Secondary hyperkalaemic paralysis is a rare condition often mimicking the Guillain-Barré syndrome. There have been a few case reports of hyperkalaemia caused by renal failure, trauma, and drugs where the presentation has been with muscle weakness. A case of hyperkalaemic paralysis caused by an angiotensin converting enzyme inhibitor is reported.


Keywords: hyperkalaemia; paralysis; ACE inhibitors

  14. Antihypertensive effects of angiotensin-(1-7

    Directory of Open Access Journals (Sweden)

    M.C. Chappell

    1998-09-01

    Full Text Available Accumulating evidence suggests that angiotensin-(1-7 (Ang-(1-7 is an important component of the renin-angiotensin system and that the actions of the peptide may either contribute to or oppose those of Ang II. Ang-(1-7 can be converted directly from Ang I bypassing prerequisite formation of Ang II. Formation of Ang-(1-7 is under the control of at least three endopeptidases depending on the tissue compartment and include neprilysin, thimet oligopeptidase and prolyl oligopeptidase. 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. These enzymatic pathways may contribute to a complex relationship between the hypertensive actions of Ang II and various vasodepressor peptides from either the renin-angiotensin system or other peptide systems. Ang-(1-7 is devoid of the vasoconstrictor, central pressor, or thirst-stimulating actions associated with Ang II. In fact, new findings reveal depressor, vasodilator, and antihypertensive actions that may be more apparent in hypertensive animals or humans. Thus, Ang-(1-7 may oppose the actions of Ang II directly or as a result of increasing prostaglandins or nitric oxide. In this review, we examine the mechanisms by which Ang-(1-7 may contribute to cardiovascular regulation.

  15. Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules.

    Science.gov (United States)

    Aroor, Annayya; Zuberek, Marcin; Duta, Cornel; Meuth, Alex; Sowers, James R; Whaley-Connell, Adam; Nistala, Ravi

    2016-01-01

    Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT₁R) and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min) infusion in mice and Ang II (10(-8) M) treatment of T35OK-AT₁R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase (MEK) 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR) inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT₁R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression. PMID:27213360

  16. Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules

    Directory of Open Access Journals (Sweden)

    Annayya Aroor

    2016-05-01

    Full Text Available Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4. Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II signaling via the Ang II Type 1 receptor (AT1R and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min infusion in mice and Ang II (10−8 M treatment of T35OK-AT1R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK/extracellular regulated kinase (ERK kinase kinase (MEK 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT1R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression.

  17. Angiotensin II infusion induces marked diaphragmatic skeletal muscle atrophy.

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    Bashir M Rezk

    Full Text Available Advanced congestive heart failure (CHF and chronic kidney disease (CKD are characterized by increased angiotensin II (Ang II levels and are often accompanied by significant skeletal muscle wasting that negatively impacts mortality and morbidity. Both CHF and CKD patients have respiratory muscle dysfunction, however the potential effects of Ang II on respiratory muscles are unknown. We investigated the effects of Ang II on diaphragm muscle in FVB mice. Ang II induced significant diaphragm muscle wasting (18.7±1.6% decrease in weight at one week and reduction in fiber cross-sectional area. Expression of the E3 ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1 and of the pro-apoptotic factor BAX was increased after 24 h of Ang II infusion (4.4±0.3 fold, 3.1±0.5 fold and 1.6±0.2 fold, respectively, compared to sham infused control suggesting increased muscle protein degradation and apoptosis. In Ang II infused animals, there was significant regeneration of injured diaphragm muscles at 7 days as indicated by an increase in the number of myofibers with centralized nuclei and high expression of embryonic myosin heavy chain (E-MyHC, 11.2±3.3 fold increase and of the satellite cell marker M-cadherin (59.2±22.2% increase. Furthermore, there was an increase in expression of insulin-like growth factor-1 (IGF-1, 1.8±0.3 fold increase in Ang II infused diaphragm, suggesting the involvement of IGF-1 in diaphragm muscle regeneration. Bone-marrow transplantation experiments indicated that although there was recruitment of bone-marrow derived cells to the injured diaphragm in Ang II infused mice (267.0±74.6% increase, those cells did not express markers of muscle stem cells or regenerating myofibers. In conclusion, Ang II causes marked diaphragm muscle wasting, which may be important for the pathophysiology of respiratory muscle dysfunction and cachexia in conditions such as CHF and CKD.

  18. Pharmacological characterization of BR-A-657, a highly potent nonpeptide angiotensin II receptor antagonist

    International Nuclear Information System (INIS)

    The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3 - {[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl} - pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [125I][Sar1-Ile8]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats. (author)

  19. Urotensin II induces interleukin 8 expression in human umbilical vein endothelial cells.

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    Chung-Yi Lee

    Full Text Available BACKGROUND: Urotensin II (U-II, an 11-amino acid peptide, exerts a wide range of actions in cardiovascular systems. Interleukin-8 (IL-8 is secreted by endothelial cells, thereby enhancing endothelial cell survival, proliferation, and angiogenesis. However, the interrelationship between U-II and IL-8 as well as the detailed intracellular mechanism of U-II in vascular endothelial cells remain unclear. The aim of this study was to investigate the effect of U-II on IL-8 expression and to explore its intracellular mechanism in human umbilical vein endothelial cells. METHODS/PRINCIPAL FINDINGS: Primary human umbilical vein endothelial cells were used. Expression of IL-8 was determined by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and luciferase reporter assay. Western blot analyses and experiments with specific inhibitors were performed to reveal the downstream signaling pathways as concerned. U-II increased the mRNA/protein levels of IL-8 in human umbilical vein endothelial cells. The U-II effects were significantly inhibited by its receptor antagonist [Orn(5]-URP. Western blot analyses and experiments with specific inhibitors indicated the involvement of phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase in U-II-induced IL-8 expression. Luciferase reporter assay further revealed that U-II induces the transcriptional activity of IL-8. The site-directed mutagenesis indicated that the mutation of AP-1 and NF-kB binding sites reduced U-II-increased IL-8 promoter activities. Proliferation of human umbilical vein endothelial cells induced by U-II could be inhibited significantly by IL-8 RNA interference. CONCLUSION/SIGNIFICANCE: The results show that U-II induces IL-8 expression in human umbilical vein endothelial cells via p38 mitogen-activated protein kinase and extracellular signal-regulated kinase signaling pathways and IL-8 is involved in the U-II-induced

  20. Suppression of Carrageenan- and Collagen II-Induced Inflammation in Mice by Geranium Oil

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available To obtain experimental evidence on the therapeutic efficacy of essential oils in aromatherapy for inflammatory diseases, we examined the effects of geranium oil on carrageenan-induced and collagen II-induced inflammation in mice, to assess acute and chronic anti-inflammatory activities of the oil. Single intraperitoneal injection of 5μL of geranium oil clearly suppressed the carrageenan-induced footpaw edema and increase in tissue myeloperoxidase activity, and repeated administration of the oil suppressed collagen-induced arthritis. These results revealed that geranium oil suppressed both acute and chronic inflammatory responses in mice

  1. Suppression of Carrageenan- and Collagen II-Induced Inflammation in Mice by Geranium Oil

    Directory of Open Access Journals (Sweden)

    Naho Maruyama

    2006-01-01

    Full Text Available To obtain experimental evidence on the therapeutic efficacy of essential oils in aromatherapy for inflammatory diseases, we examined the effects of geranium oil on carrageenan-induced and collagen II-induced inflammation in mice, to assess acute and chronic anti-inflammatory activities of the oil. Single intraperitoneal injection of 5 μL of geranium oil clearly suppressed the carrageenan-induced footpaw edema and increase in tissue myeloperoxidase activity, and repeated administration of the oil suppressed collagen-induced arthritis. These results revealed that geranium oil suppressed both acute and chronic inflammatory responses in mice.

  2. Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system

    Czech Academy of Sciences Publication Activity Database

    Kurtz, T. W.; Pravenec, Michal

    2004-01-01

    Roč. 22, č. 12 (2004), s. 2253-2261. ISSN 0263-6352 R&D Projects: GA ČR GA301/03/0751 Grant ostatní: HHMI(US) HHMI55000331 Institutional research plan: CEZ:AV0Z5011922 Keywords : angiotensin II receptors * metabolic syndrome * peroxisome proliferator activated receptors Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.871, year: 2004

  3. The secretory phospholipase A2 group IIA: a missing link between inflammation, activated renin-angiotensin system, and atherogenesis?

    Directory of Open Access Journals (Sweden)

    Dimitar Divchev

    2008-06-01

    Full Text Available Dimitar Divchev, Bernhard SchiefferDepartment of Cardiology and Angiology, Medizinische Hochschule Hannover, GermanyAbstract: Inflammation, lipid peroxidation and chronic activation of the renin–angiotensin system (RAS are hallmarks of the development of atherosclerosis. Recent studies have suggested the involvement of the pro-inflammatory secretory phospholipase A2 (sPLA2-IIA in atherogenesis. This enzyme is produced by different cell types through stimulation by proinflammatory cytokines. It is detectable in the intima and in media smooth muscle cells, not only in atherosclerotic lesions but also in the very early stages of atherogenesis. sPLA2-IIA can hydrolyse the phospholipid monolayers of low density lipoproteins (LDL. Such modified LDL show increased affinity to proteoglycans. The modified particles have a greater tendency to aggregate and an enhanced ability to insert cholesterol into cells. This modification may promote macrophage LDL uptake leading to the formation of foam cells. Furthermore, sPLA2-IIA is not only a mediator for localized inflammation but may be also used as an independent predictor of adverse outcomes in patients with stable coronary artery disease or acute coronary syndromes. An interaction between activated RAS and phospholipases has been indicated by observations showing that inhibitors of sPLA2 decrease angiotensin (Ang II-induced macrophage lipid peroxidation. Meanwhile, various interactions between Ang II and oxLDL have been demonstrated suggesting a central role of sPLA2-IIA in these processes and offering a possible target for treatment. The role of sPLA2-IIA in the perpetuation of atherosclerosis appears to be the missing link between inflammation, activated RAS and lipidperoxidation.Keywords: secretory phospholipase A2, lipoproteins, renin-angiotensin system, inflammation, atherosclerosis

  4. 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.

  5. 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

  6. 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...

  7. Changes of Plasma Angiotensin-Converting Enzyme Activity during Hemodialysis *

    OpenAIRE

    Koo, Wan Suh; Lee, Yong Joon; Kim, Hye Su; Kim, Suk Young; Choi, Euy Jin; Chang, Yoon Sik; Yoon, Young Suk; Bang, Byung Kee

    1987-01-01

    Plasma angiotensin-converting enzyme activity was measured by spectrophotometer in normal subjects and in patients with end stage renal failure, serially during a routine hemodialysis. Patients on maintenance hemodialysis tended to be associated with elevated plasma angiotensin-converting enzyme activity versus normal subjects. Plasma angiotensin-converting enzyme activity was significantly elevated in patients with chronic renal failure after 5 hours of hemodialysis(p

  8. 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

  9. Cardiovascular actions of angiotensin-(1-7

    Directory of Open Access Journals (Sweden)

    Ferreira A.J.

    2005-01-01

    Full Text Available Angiotensin-(1-7 (Ang-(1-7 is now considered to be a biologically active member of the renin-angiotensin system. The functions of Ang-(1-7 are often opposite to those attributed to the main effector component of the renin-angiotensin system, Ang II. Chronic administration of angiotensin-converting enzyme inhibitors (ACEI increases 10- to 25-fold the plasma levels of this peptide, suggesting that part of the beneficial effects of ACEI could be mediated by Ang-(1-7. Ang-(1-7 can be formed from Ang II or directly from Ang I. Other enzymatic pathways for Ang-(1-7 generation have been recently described involving the novel ACE homologue ACE2. This enzyme can form Ang-(1-7 from Ang II or less efficiently by the hydrolysis of Ang I to Ang-(1-9 with subsequent Ang-(1-7 formation. The biological relevance of Ang-(1-7 has been recently reinforced by the identification of its receptor, the G-protein-coupled receptor Mas. Heart and blood vessels are important targets for the formation and actions of Ang-(1-7. In this review we will discuss recent findings concerning the biological role of Ang-(1-7 in the heart and blood vessels, taking into account aspects related to its formation and effects on these tissues. In addition, we will discuss the potential of Ang-(1-7 and its receptor as a target for the development of new cardiovascular drugs.

  10. 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...

  11. Serum angiotensin converting enzyme in pneumonias.

    OpenAIRE

    Kerttula, Y; Weber, T H

    1986-01-01

    Serum concentrations of angiotensin converting enzyme (ACE) were studied in pneumonias caused by different pathogens and in cases in which the aetiology could not be defined. In all aetiological groups, except in viral pneumonia, there was a significant increase in ACE during recovery (p less than 0.001). In several patients the lowest values during the acute phase of disease and the highest values during recovery were outside the reference limits. In cases with known aetiology the highest AC...

  12. Inhibitor and substrate binding by angiotensin-converting enzyme

    DEFF Research Database (Denmark)

    Wang, Xuemei; Wu, Shanshan; Xu, Dingguo;

    2011-01-01

    . In this work, we propose a model for an ACE Michaelis complex based on two known X-ray structures of inhibitor-enzyme complexes. Specifically, the human testis angiotensin-converting enzyme (tACE) complexed with two clinic drugs were first investigated using a combined quantum mechanical and molecular......Angiotensin-converting enzyme (ACE) is an important zinc-dependent hydrolase responsible for converting the inactive angiotensin I to the vasoconstrictor angiotensin II and for inactivating the vasodilator bradykinin. However, the substrate binding mode of ACE has not been completely understood...... computational protocol. Implications to ACE catalysis are discussed....

  13. Effect of RXR/PPAR interaction in angiotensin II-induced vascular inflammation and angiogenesis. Role of CXCL16/CXCR6 axis in angiotensin II or cigarette smoke-induced vascular inflammation

    OpenAIRE

    Escudero Diaz, Paula

    2016-01-01

    Aumentos en los niveles circulantes de mediadores, incluyendo angiotensina II (Ang-II) y citoquinas, han sido detectados en enfermedades cardiovasculares y cardiometabólicas como la hipertensión, la obesidad y la diabetes, y parecen ejercer efectos negativos sobre la función endotelial (Granger et al., 2004; Marinou et al., 2010). Estos agentes inician una cascada inflamatoria de señalización que promueve la generación de especies reactivas del oxígeno, aumento en la superficie celular de la ...

  14. 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...

  15. Reactive oxygen species and angiotensin II signaling in vascular cells: implications in cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Touyz R.M.

    2004-01-01

    Full Text Available Diseases such as hypertension, atherosclerosis, hyperlipidemia, and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many factors influence cellular changes, of which angiotensin II (Ang II appears to be amongst the most important. The physiological and pathophysiological actions of Ang II are mediated primarily via the Ang II type 1 receptor. Growing evidence indicates that Ang II induces its pleiotropic vascular effects through NADPH-driven generation of reactive oxygen species (ROS. ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, regulation of endothelial function, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca2+ concentration ([Ca2+]i, a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, these events play an important role in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review focuses on the biology of ROS in Ang II signaling in vascular cells and discusses how oxidative stress contributes to vascular damage in cardiovascular disease.

  16. Luteolin Inhibits Angiotensin II-Stimulated VSMC Proliferation and Migration through Downregulation of Akt Phosphorylation

    Directory of Open Access Journals (Sweden)

    Tongda Xu

    2015-01-01

    Full Text Available Luteolin is a naturally occurring flavonoid found in many plants that possesses cardioprotective properties. The purpose of this study was to elucidate the effect of luteolin on vascular smooth muscle cells (VSMCs proliferation and migration induced by Angiotensin II (Ang II and to investigate the mechanism(s of action of this compound. Rat VSMCs were cultured in vitro, and the proliferation and migration of these cells following Ang II stimulation were monitored. Different doses of luteolin were added to VSMC cultures, and the proliferation and migration rate were observed by MTT and Transwell chamber assays, respectively. In addition, the expressions of p-Akt (308, p-Akt (473, and proliferative cell nuclear antigen (PCNA in VSMCs were monitored by Western blotting. This study demonstrated that luteolin has an inhibitory effect on Ang II-induced VSMC proliferation and migration. Further, the levels of p-Akt (308, p-Akt (473, and PCNA were reduced in VSMCs treated with both Ang II and luteolin compared to VSMCs treated with only Ang II. These findings strongly suggest that luteolin inhibits Ang II-stimulated proliferation and migration of VSMCs, which is partially due to downregulation of the Akt signaling pathway.

  17. The Renin-Angiotensin System in the Endocrine Pancreas

    Directory of Open Access Journals (Sweden)

    Carlsson PO

    2001-01-01

    Full Text Available Experimental data suggest that a tissue renin-angiotensin system is present in the pancreatic islets of several species, including man. However, the physiological role for this local renin-angiotensin system remains largely unknown. In vitro findings argue against a direct effect of angiotensin II on alpha- and beta-cells. In contrast, when the influence of angiotensin II on the pancreatic islets has been evaluated in the presence of an intact vascular system either in vivo or in the perfused pancreas, a suppression of insulin release has been observed, also in man. These discrepancies may be explained by the profound effects of the renin-angiotensin system on pancreatic islet blood perfusion. Alterations in the systemic renin-angiotensin system and an increased vascular sensitivity for its components have been observed in diabetes mellitus and hypertension. Whether changes occur also in the pancreatic islet renin-angiotensin system during these conditions remains unknown. Future research may help to provide an answer to this question, and to elucidate to what extent the renin-angiotensin system may contribute to beta-cell dysfunction in these diseases.

  18. Angiotensin antagonists in the dog with chronic pericardial tamponade

    International Nuclear Information System (INIS)

    Assessing the role played by angiotensin in the pathogenesis and maintenance of the renal function and perfusion abnormalities dogs with chronic pericardial tamponade were used in the experiment as a stable model of chronic low output heart failure. The heptapeptide and octapeptide antagonist were used. The results of the experiments suggest that there is a role for angiotensin in the pathologenesis of congestive heart failure. The renin-angiotensin system was activated in the model. Plasma renin activity was elevated and increased further in response to angiotensin blockade. Under the experiment condition there was no evidence for a role for angiotensin in the maintenance of arterial blood pressure. But there was angiotensin-mediated renal vasoconstriction and a reduction in renal blood flow. Both analogues of angiotensin were able to antagonize this effect in similar fashion. Failure to achieve a natriuresis in response to angiotensin blockade may reflect the redistribution of blood flow that occured and suggests that additional factors are operative in this model. (APR)

  19. Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression

    DEFF Research Database (Denmark)

    Dhamrait, Sukhbir S; Maubaret, Cecilia; Pedersen-Bjergaard, Ulrik;

    2016-01-01

    Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial...

  20. Angiotensin processing activities in the venom of Thalassophryne nattereri.

    Science.gov (United States)

    Tenório, Humberto de Araújo; Marques, Maria Elizabeth da Costa; Machado, Sonia Salgueiro; Pereira, Hugo Juarez Vieira

    2015-05-01

    The venom of marine animals is a rich source of compounds with remarkable functional specificity and diversity. Thalassophryne nattereri is a small venomous fish inhabiting the northern and northeastern coast of Brazil, and represents a relatively frequent cause of injuries. Its venom causes severe inflammatory response followed frequently by the necrosis of the affected area. This venom presents characterized components such as proteases (Natterins 1-4) and a lectin (Nattectin) with complex effects on the human organism. A specific inhibitor of tissue kallikrein (TKI) reduces the nociception and the edema caused by the venom in mice. Our study sought to investigate the proteolytic activities against vasopeptides Angiotensin I, Angiotensin II, Angiotensin 1-9 and Bradykinin. The venom indicated angiotensin conversion against angiotensin I, as well as kininase against bradykinin. Captopril conducted the total inhibition of the converting activity, featuring the first report of ACE activity in fish venoms. PMID:25702959

  1. 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

  2. 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

  3. Nickel (II)-induced cytotoxicity and apoptosis in human proximal tubule cells through a ROS- and mitochondria-mediated pathway

    International Nuclear Information System (INIS)

    Nickel compounds are known to be toxic and carcinogenic in kidney and lung. In this present study, we investigated the roles of reactive oxygen species (ROS) and mitochondria in nickel (II) acetate-induced cytotoxicity and apoptosis in the HK-2 human renal cell line. The results showed that the cytotoxic effects of nickel (II) involved significant cell death and DNA damage. Nickel (II) increased the generation of ROS and induced a noticeable reduction of mitochondrial membrane potential (MMP). Analysis of the sub-G1 phase showed a significant increase in apoptosis in HK-2 cells after nickel (II) treatment. Pretreatment with N-acetylcysteine (NAC) not only inhibited nickel (II)-induced cell death and DNA damage, but also significantly prevented nickel (II)-induced loss of MMP and apoptosis. Cell apoptosis triggered by nickel (II) was characterized by the reduced protein expression of Bcl-2 and Bcl-xL and the induced the protein expression of Bad, Bcl-Xs, Bax, cytochrome c and caspases 9, 3 and 6. The regulation of the expression of Bcl-2-family proteins, the release of cytochrome c and the activation of caspases 9, 3 and 6 were inhibited in the presence of NAC. These results suggest that nickel (II) induces cytotoxicity and apoptosis in HK-2 cells via ROS generation and that the mitochondria-mediated apoptotic signaling pathway may be involved in the positive regulation of nickel (II)-induced renal cytotoxicity.

  4. Glial high-affinity binding site with specificity for angiotensin II not angiotensin III: a possible N-terminal-specific converting enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Printz, M.P.; Jennings, C.; Healy, D.P.; Kalter, V.

    1986-01-01

    Anomalous binding properties of angiotensin II to fetal rat brain primary cultures suggested a possible contribution from contaminating glia. To investigate this possibility, cultures of C6 glioma, a clonal rat cell line, were examined for the presence of angiotensin II receptors. A specific high-affinity site for (/sup 125/I)angiotensin II was measured both by traditional methodology using whole cells and by autoradiography. This site shared properties similar to that found with the brain cells, namely low ligand internalization and markedly decreased affinity for N-terminal sarcosine or arginine-angiotensin analogs. The competition rank order was angiotensin II much greater than (Sar1,Ile8)angiotensin II greater than or equal to des(Asp1,Arg2)angiotensin II. Angiotensin III did not compete for binding to the site. High-pressure liquid chromatography analysis indicated that the ligand either in the incubation or bound to the site was stable at 15 degrees C, but there was very rapid and extensive degradation by the C6 glioma cells at 37 degrees C. It is concluded that the site exhibits unusual N-terminal specificity for angiotensin with nanomolar affinity for angiotensin II. If angiotensin III is an active ligand in the brain, the site may have a converting enzyme function. Alternatively, it may form the des-Asp derivatives of angiotensin for subsequent degradation by other enzymatic pathways. Either way, it is proposed that the site may modulate the brain-angiotensin system.

  5. TGF-beta inhibits Ang II-induced MAPK p44/42 signaling in vascular smooth muscle cells by Ang II type 1 receptor downregulation.

    NARCIS (Netherlands)

    Meijering, B.D.; Wouden, E.A. van der; Pelgrom, V.; Henning, R.H.; Sharma, K.; Deelman, L.E.

    2009-01-01

    Vascular changes in diabetes are characterized by reduced vasoconstriction and vascular remodeling. Previously, we demonstrated that TGF-beta1 impairs Ang II-induced contraction through reduced calcium mobilization. However, the effect of TGF-beta1 on Ang II-induced vascular remodeling is unknown. T

  6. TGF-beta Inhibits Ang II-Induced MAPK p44/42 Signaling in Vascular Smooth Muscle Cells by Ang II Type 1 Receptor Downregulation

    NARCIS (Netherlands)

    Meijering, Bernadet D. M.; van der Wouden, Els A.; Pelgrom, Vincent; Henning, Robert H.; Sharma, Kumar; Deelman, Leo E.

    2009-01-01

    Vascular changes in diabetes are characterized by reduced vasoconstriction and vascular remodeling. Previously, we demonstrated that TGF-beta 1 impairs Ang II-induced contraction through reduced calcium mobilization. However, the effect of TGF-beta 1 on Ang II-induced vascular remodeling is unknown.

  7. Angiotensin II down-regulates nephrin–Akt signaling and induces podocyte injury: roleof c-Abl

    Science.gov (United States)

    Yang, Qian; Ma, Yiqiong; Liu, Yipeng; Liang, Wei; Chen, Xinghua; Ren, Zhilong; Wang, Huiming; Singhal, Pravin C.; Ding, Guohua

    2016-01-01

    Recent studies have shown that nephrin plays a vital role in angiotensin II (Ang II)–induced podocyte injury and thus contributes to the onset of proteinuria and the progression of renal diseases, but its specific mechanism remains unclear. c-Abl is an SH2/SH3 domain–containing nonreceptor tyrosine kinase that is involved in cell survival and regulation of the cytoskeleton. Phosphorylated nephrin is able to interact with molecules containing SH2/SH3 domains, suggesting that c-Abl may be a downstream molecule of nephrin signaling. Here we report that Ang II–infused rats developed proteinuria and podocyte damage accompanied by nephrin dephosphorylation and minimal interaction between nephrin and c-Abl. In vitro, Ang II induced podocyte injury and nephrin and Akt dephosphorylation, which occurred in tandem with minimal interaction between nephrin and c-Abl. Moreover, Ang II promoted c-Abl phosphorylation and interaction between c-Abl and SH2 domain–containing 5′-inositol phosphatase 2 (SHIP2). c-Abl small interfering RNA (siRNA) and STI571 (c-Abl inhibitor) provided protection against Ang II–induced podocyte injury, suppressed the Ang II-induced c-Abl–SHIP2 interaction and SHIP2 phosphorylation, and maintained a stable level of nephrin phosphorylation. These results indicate that c-Abl is a molecular chaperone of nephrin signaling and the SHIP2-Akt pathway and that the released c-Abl contributes to Ang II–induced podocyte injury. PMID:26510503

  8. 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...

  9. Exendin-4 Prevents Vascular Smooth Muscle Cell Proliferation and Migration by Angiotensin II via the Inhibition of ERK1/2 and JNK Signaling Pathways.

    Directory of Open Access Journals (Sweden)

    Kosuke Nagayama

    Full Text Available Angiotensin II (Ang II is a main pathophysiological culprit peptide for hypertension and atherosclerosis by causing vascular smooth muscle cell (VSMC proliferation and migration. Exendin-4, a glucagon-like peptide-1 (GLP-1 receptor agonist, is currently used for the treatment of type-2 diabetes, and is believed to have beneficial effects for cardiovascular diseases. However, the vascular protective mechanisms of GLP-1 receptor agonists remain largely unexplained. In the present study, we examined the effect of exendin-4 on Ang II-induced proliferation and migration of cultured rat aortic smooth muscle cells (RASMC. The major findings of the present study are as follows: (1 Ang II caused a phenotypic switch of RASMC from contractile type to synthetic proliferative type cells; (2 Ang II caused concentration-dependent RASMC proliferation, which was significantly inhibited by the pretreatment with exendin-4; (3 Ang II caused concentration-dependent RASMC migration, which was effectively inhibited by the pretreatment with exendin-4; (4 exendin-4 inhibited Ang II-induced phosphorylation of ERK1/2 and JNK in a pre-incubation time-dependent manner; and (5 U0126 (an ERK1/2 kinase inhibitor and SP600125 (a JNK inhibitor also inhibited both RASMC proliferation and migration induced by Ang II stimulation. These results suggest that exendin-4 prevented Ang II-induced VSMC proliferation and migration through the inhibition of ERK1/2 and JNK phosphorylation caused by Ang II stimulation. This indicates that GLP-1 receptor agonists should be considered for use in the treatment of cardiovascular diseases in addition to their current use in the treatment of diabetes mellitus.

  10. 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....

  11. The renin-angiotensin system and its blockers

    Directory of Open Access Journals (Sweden)

    Igić Rajko

    2014-01-01

    Full Text Available Research on the renin-angiotensin system (RAS has contributed significantly to advances in understanding cardiovascular and renal homeostasis and to the treatment of cardiovascular diseases. This review offers a brief history of the RAS with an overview of its major components and their functions, as well as blockers of the RAS, their clinical usage and current research that targets various components of the RAS. Because angiotensin-converting enzyme (ACE metabolizes two biologically active peptides, one in the kallikrein-kinin system (KKS and one in the RAS, it is the essential connection between the two systems. ACE releases very powerful hypertensive agent, angiotensin II and also inactivates strong hypotensive peptide, bradykinin. Inhibition of ACE thus has a dual effect, resulting in decreased angiotensin II and increased bradykinin. We described the KKS as well.

  12. Visceral Angioedema Induced by Angiotensin Converting Enzyme Inhibitor: Case Report

    Directory of Open Access Journals (Sweden)

    Beatriz Frutuoso

    2016-05-01

    Conclusion: The diagnosis of intestinal angioedema induced by angiotensin converting enzyme inhibitor can be challenging and time consuming due to its rarity and nonspecific symptoms, which may lead to underdiagnosis of this entity.

  13. Angiotensin-converting enzymes modulate aphid–plant interactions

    OpenAIRE

    Wei Wang; Lan Luo; Hong Lu; Shaoliang Chen; Le Kang; Feng Cui

    2015-01-01

    Angiotensin-converting enzymes (ACEs) are key components of the renin–angiotensin system in mammals. However, the function of ACE homologs in insect saliva is unclear. Aphids presumably deliver effector proteins via saliva into plant cells to maintain a compatible insect–plant interaction. In this study, we showed that ACE modulates aphid–plant interactions by affecting feeding behavior and survival of aphids on host plants. Three ACE genes were identified from the pea aphid Acyrthosiphon pis...

  14. Effects of prednisolone on angiotensin converting enzyme activity.

    OpenAIRE

    Roulston, J. E.; O'Malley, G I; Douglas, J G

    1984-01-01

    Plasma angiotensin converting enzyme was measured in 23 asthmatic subjects before and after administration of prednisolone, 20 mg daily, for seven days. Plasma specimens from seven patients with asthma, seven with sarcoidosis and 14 normal subjects were also assayed before and after the addition of prednisolone in vitro. A plasma free extract of normal lung was also prepared and assayed before and after prednisolone treatment. Mean angiotensin converting enzyme activity was significantly grea...

  15. 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.

  16. Activity of the renin-angiotensin system in acute severe asthma and the effect of angiotensin II on lung function.

    OpenAIRE

    Millar, E. A.; Angus, R. M.; Hulks, G.; Morton, J J; Connell, J M; Thomson, N C

    1994-01-01

    BACKGROUND--The activity of the renin-angiotensin system in asthma has not been studied previously and the effect of angiotensin II (AII) on bronchomotor tone in vivo is unknown. METHODS--Plasma levels of renin and AII levels were measured in 20 patients with acute severe asthma, nine with mild asthma, 10 with severe chronic asthma, and 16 normal volunteers. The effect of AII, given as an intravenous infusion, on bronchomotor tone was also investigated in eight mild asthmatic patients. RESULT...

  17. Angiotensin converting enzyme genotype in cardiovascular disease

    Energy Technology Data Exchange (ETDEWEB)

    Summers, K.M.; Huggard, P.R.; West, M.J. [Univ. of Queensland, Brisbane (Australia)] [and others

    1994-09-01

    Angiotensin converting enzyme (ACE) catalyses formation of angiotensin II and degradation of bradykinin, vasoactive peptides with opposing properties. The result of ACE action is to promote vasoconstriction and cell growth. PCR is used to detect a common polymorphism due to the insertion of an Alu repeat element of 287 bp into intron 16. ACE genotype has been implicated in risk for myocardial infarction (MI) and hypertension in humans. We have studied a group of 640 patients (61% male aged 64 {plus_minus} 11 years) with myocardial ischaemic syndromes, followed for 12 months after initial hospital admission. In this group, the frequency of the insertion (I) allele was 0.47 (N=1170 chromosomes), not significantly higher than the frequency of 0.46 in 112 local blood donors (50% male aged 59 {plus_minus}5 years). In the 300 patients with diagnosed MI, I allele frequency was 0.48. This is significantly higher ({chi}{sup 2}=5.78, P=0.015) than the frequency of 0.42 reported in a multi-centre study of ACE genotype in 600 male European patients with MI . There was a non-significant increase in the frequency of a cardiac event within 6 months of hospital admission in those of II genotype (N=464, 47 events to date). These results suggest that in our population, the I allele and/or II genotype may be associated with risk of MI. This contrasts with the study cited above, where the D (deletion) allele and DD genotype frequency were raised in patients compared with controls. Hypertension is associated with the ACE D allele, and does not explain the heart disease risk, which may be associated with the I allele, in this group of survivors of myocardial ischaemic disease. The difference between our results and the previous study may be due to ascertainment or ethnic differences or to problems amplifying the I allele in some heterozygotes. Clearly, the role of ACE genotype in these diseases is complex.

  18. G-protein coupled receptors of the renin-angiotensin system: new targets against breast cancer?

    OpenAIRE

    Rodrigues-Ferreira, Sylvie; Nahmias, Clara

    2015-01-01

    G-protein coupled receptors (GPCRs) constitute the largest family of membrane receptors, with high potential for drug discovery. These receptors can be activated by a panel of different ligands including ions, hormones, small molecules, and vasoactive peptides. Among those, angiotensins [angiotensin II (AngII) and angiotensin 1–7] are the major biologically active products of the classical and alternative renin-angiotensin system (RAS). These peptides bind and activate three different subtype...

  19. 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 ...

  20. 21 CFR 862.1090 - Angiotensin converting enzyme (A.C.E.) test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Angiotensin converting enzyme (A.C.E.) test system... Test Systems § 862.1090 Angiotensin converting enzyme (A.C.E.) test system. (a) Identification. An angiotensin converting enzyme (A.C.E.) test system is a device intended to measure the activity of...

  1. 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...

  2. 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

    Directory of Open Access Journals (Sweden)

    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.

  3. Tanshinone IIA Prevents Leu27IGF-II-Induced Cardiomyocyte Hypertrophy Mediated by Estrogen Receptor and Subsequent Akt Activation.

    Science.gov (United States)

    Weng, Yueh-Shan; Wang, Hsueh-Fang; Pai, Pei-Ying; Jong, Gwo-Ping; Lai, Chao-Hung; Chung, Li-Chin; Hsieh, Dennis Jine-Yuan; HsuanDay, Cecilia; Kuo, Wei-Wen; Huang, Chih-Yang

    2015-01-01

    IGF-IIR plays important roles as a key regulator in myocardial pathological hypertrophy and apoptosis, which subsequently lead to heart failure. Salvia miltiorrhiza Bunge (Danshen) is a traditional Chinese medicinal herb used to treat cardiovascular diseases. Tanshinone IIA is an active compound in Danshen and is structurally similar to 17[Formula: see text]-estradiol (E[Formula: see text]. However, whether tanshinone IIA improves cardiomyocyte survival in pathological hypertrophy through estrogen receptor (ER) regulation remains unclear. This study investigates the role of ER signaling in mediating the protective effects of tanshinone IIA on IGF-IIR-induced myocardial hypertrophy. Leu27IGF-II (IGF-II analog) was shown in this study to specifically activate IGF-IIR expression and ICI 182,780 (ICI), an ER antagonist used to investigate tanshinone IIA estrogenic activity. We demonstrated that tanshinone IIA significantly enhanced Akt phosphorylation through ER activation to inhibit Leu27IGF-II-induced calcineurin expression and subsequent NFATc3 nuclear translocation to suppress myocardial hypertrophy. Tanshinone IIA reduced the cell size and suppressed ANP and BNP, inhibiting antihypertrophic effects induced by Leu27IGF-II. The cardioprotective properties of tanshinone IIA that inhibit Leu27IGF-II-induced cell hypertrophy and promote cell survival were reversed by ICI. Furthermore, ICI significantly reduced phospho-Akt, Ly294002 (PI3K inhibitor), and PI3K siRNA significantly reduced the tanshinone IIA-induced protective effect. The above results suggest that tanshinone IIA inhibited cardiomyocyte hypertrophy, which was mediated through ER, by activating the PI3K/Akt pathway and inhibiting Leu27IGF-II-induced calcineurin and NFATC3. Tanshinone IIA exerted strong estrogenic activity and therefore represented a novel selective ER modulator that inhibits IGF-IIR signaling to block cardiac hypertrophy. PMID:26621443

  4. Die Behandlung der arteriellen Hypertonie mit Angiotensin-Rezeptorblockern

    Directory of Open Access Journals (Sweden)

    Wink K

    2007-01-01

    Full Text Available Angiotensin-II-Typ-1-Rezeptorantagonisten sind die neueste Gruppe zur Behandlung der arteriellen Hypertonie. Pharmakologisch ergeben sich bei den sieben zur Verfügung stehenden Angiotensin-Rezeptorblockern Unterschiede bezüglich der Halbwertszeit und der Rezeptorbindung. Die pharmakologischen Unterschiede bei der Behandlung der arteriellen Hypertonie sind hinsichtlich Blutdrucksenkung vernachlässigbar, hinsichtlich Mortalität und Morbidität sind aber nur Losartan und Valsartan in Vergleichsstudien mit Atenolol bzw. Amlodipin untersucht worden. Da vergleichbare Ergebnisse der Angiotensin-Rezeptorblocker mit den Vergleichssubstanzen vorliegen, kann aufgrund der in placebokontrollierten Studien nachgewiesenen mortalitäts- und morbiditätssenkenden Wirkung von Atenolol davon ausgegangen werden, daß diese Wirkungen auch bei Losartan erzielt werden und, da bei den placebokontrollierten Studien keine ausreichenden Hinweise für eine Mortalitätssenkung bestehen, der morbiditätssenkende Effekt von Amlodipin auch bei Valsartan besteht. Bei den übrigen Angiotensin-Rezeptorblockern wurden keine Mortalitäts- und Morbiditätsstudien durchgeführt, sodaß nur aufgrund des Verhaltens des Surrogatendpunktes Blutdrucksenkung auf einen günstigen Einfluß auf die Mortalität und Morbidität geschlossen werden kann. Hilfsweise kann noch hinzugezogen werden, daß bei den Angiotensin-Rezeptorblockern günstige Wirkungen auf die diabetische Nephropathie und eventuell auf die Entstehung eines Diabetes mellitus bestehen. Es gibt auch Hinweise darauf, daß Angiotensin-Rezeptorblocker bei Patienten nach zerebrovaskulären Ereignissen weiter kardio- und zerebrovaskuläre Ereignisse reduzieren.

  5. Angiotensin II facilitates breast cancer cell migration and metastasis.

    Directory of Open Access Journals (Sweden)

    Sylvie Rodrigues-Ferreira

    Full Text Available Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pre-treatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors.

  6. Vitamin K Prevents Oxidative Cell Death by Inhibiting Activation of 12-Lipoxygenase in Developing Oligodendrocytes

    OpenAIRE

    Li, Jianrong; Wang, Hong; Rosenberg, Paul A.

    2009-01-01

    Oxidative mechanisms of injury are important in many neurological disorders. Developing oligodendrocytes (pre-OLs) are particularly sensitive to oxidative stress-mediated injury. We previously demonstrated a novel function of phylloquinone (vitamin K1) and menaquinone 4 (MK-4; a major form of vitamin K2) in protecting pre-OLs and immature neurons against glutathione depletion-induced oxidative damage (Li et al. [2003] J. Neurosci. 23:5816–5826). Here we report that vitamin K at nanomolar conc...

  7. Complex pathologies of angiotensin Ⅱ-induced abdominal aortic aneurysms

    Institute of Scientific and Technical Information of China (English)

    Alan DAUGHERTY; Lisa A. CASSIS; Hong LU

    2011-01-01

    Angiotensin Ⅱ (Angll) is the primary bioactive peptide of the renin angiotensin system that plays a critical role in many cardiovascular diseases.Subcutaneous infusion of Angll into mice induces the development of abdominal aortic aneurysms (AAAs).Like human AAAs,Angll-induced AAA tissues exhibit progressive changes and considerable heterogeneity.This complex pathology provides an impediment to the quantification of aneurysmal tissue composition by biochemical and immunostaining techniques.Therefore,while the mouse model of Angll-induced AAAs provides a salutary approach to studying the mechanisms of the evolution of AAAs in humans,meaningful interpretation of mechanisms requires consideration of the heterogeneous nature of the diseased tissue.

  8. Vasopressin and angiotensin II stimulate oxygen uptake in the perfused rat hindlimb

    DEFF Research Database (Denmark)

    Colquhoun, E Q; Hettiarachchi, M; Ye, J M;

    1988-01-01

    Vasopressin and angiotensin II markedly stimulated oxygen uptake in the perfused rat hindlimb. The increase due to each agent approached 70% of the basal rate, and was greater than that produced by a maximal concentration of norepinephrine. Half-maximal stimulation occurred at 60 pM vasopressin, 0.......5 nM angiotensin II and 10 nM norepinephrine. Angiotensins I and III were less potent than angiotensin II. For each agent, the dose-dependent increase in oxygen uptake coincided with a dose-dependent increase in perfusion pressure. The effects of both vasopressin and angiotensin to increase oxygen...

  9. Ethanolic extract of Nigella sativa protects Fe(II) induced lipid peroxidation in rat's brain, kidney and liver homogenates.

    Science.gov (United States)

    Hassan, Waseem; Noreen, Hamsa; Khalil, ShafqatUllah; Hussain, Arshad; Rehman, Shakilla; Sajjad, Shagufta; Rahman, Ataur; da Rocha, Joao B T

    2016-01-01

    The study describes the effect of ethanolic extract of Nigella sativa against Fe(II) induced lipid peroxidation. Basal and Fe(II) induced thiobarbituric acid reactive species (TBARS) production was significantly inhibited by the ethanolic extract of Nigella sativa at 25-200 μg/ml. Our data revealed that the extract has high DPPH radical scavenging activity at highest tested concentrations. The extract significantly chelated Fe(II) and scavenged hydroxyl (OH) radical at 25-200μg/ml concentration. The nutritional analysis was performed and carbohydrate, fats, fiber, protein, moisture and ash content were measured in the studied extract. The phytochemical analysis confirmed the presence of alkaloid, carbohydrate & sugar, glycosides, phenolic compounds, flavonoids, protein and amino acid, phytosterols, tannins, gum and mucilage. The extract also showed significant antimicrobial activities against 10 bacterial strains i.e. Salmonella typhi, Bacillus subtilis, Bacillus cereus, Klebsiella pneumonia, Escheria coli, Xanthomonas, Salmonella heidelberg, Staphylococcus aureus, Clostridium and Escheria coli (human) and 5 fungal strains i.e. Aspergillus niger, Entomola, Aspergillus flavus, Alternaria alternata and Penicillium. This study confirms the potential antioxidant and antimicrobial activities of ethanolic extract of Nigella sativa which can be considered not only as a diet supplement but can be used against a variety of free radical induced damage diseases. PMID:26826815

  10. Comparative effects of contraction and angiotensin II on growth of adult feline cardiocytes in primary culture

    Science.gov (United States)

    Wada, H.; Zile, M. R.; Ivester, C. T.; Cooper, G. 4th; McDermott, P. J.

    1996-01-01

    The purposes of this study were 1) to determine whether angiotensin II causes growth of adult feline cardiocytes in long-term culture, 2) to compare the growth effects of angiotensin II with those resulting from electrically stimulated contraction, and 3) to determine whether the anabolic effects of contraction are exerted via the angiotensin type 1 receptor. Adult feline cardiocytes were cultured on laminin-coated trays in a serum-free medium. Cardiocytes were either electrically stimulated to contract (1 Hz, 5-ms pulse duration, alternating polarity) or were nonstimulated and quiescent. Quiescent cells were studied as controls and after treatment with angiotensin II (10(-8) M), losartan (10(-6) M; an angiotensin type 1-receptor antagonist), or angiotensin II plus losartan. Contracting cells were studied in the presence and absence of angiotensin II or losartan. In quiescent cardiocytes, angiotensin II treatment on day 7 significantly increased protein synthesis rates by 22% and protein content per cell by 17%. The effects of angiotensin II were completely blocked by losartan. Electrically stimulated contraction on days 4 and 7 in culture significantly increased protein synthesis rate by 18 and 38% and protein content per cell by 19 and 46%, respectively. Angiotensin II treatment did not further increase protein synthesis rate or protein content in contracting cardiocytes. Furthermore, losartan did not block the anabolic effects of contraction on protein synthesis rates or protein content. In conclusion, angiotensin II can exert a modest anabolic effect on adult feline cardiocytes in culture. In contracting feline cardiocytes, angiotensin II has no effect on growth. Growth caused by electrically stimulated contraction occurs more rapidly and is greater in magnitude than that caused by angiotensin II. Growth of contracting adult feline cardiocytes is not dependent on activation of the angiotensin receptor.

  11. 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...

  12. PGC-1α Serine 570 Phosphorylation and GCN5-mediated Acetylation by Angiotensin II Drive Catalase Down-regulation and Vascular Hypertrophy*

    Science.gov (United States)

    Xiong, Shiqin; Salazar, Gloria; San Martin, Alejandra; Ahmad, Mushtaq; Patrushev, Nikolay; Hilenski, Lula; Nazarewicz, Rafal Robert; Ma, Minhui; Ushio-Fukai, Masuko; Alexander, R. Wayne

    2010-01-01

    Angiotensin II (Ang II) is a pleuripotential hormone that is important in the pathophysiology of multiple conditions including aging, cardiovascular and renal diseases, and insulin resistance. Reactive oxygen species (ROS) are important mediators of Ang II-induced signaling generally and have a well defined role in vascular hypertrophy, which is inhibited by overexpression of catalase, inferring a specific role of H2O2. The molecular mechanisms are understood incompletely. The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a key regulator of energy metabolism and ROS-scavenging enzymes including catalase. We show that Ang II stimulates Akt-dependent PGC-1α serine 570 phosphorylation, which is required for the binding of the histone acetyltransferase GCN5 (general control nonderepressible 5) to PGC-1α and for its lysine acetylation. These sequential post-translational modifications suppress PGC-1α activity and prevent its binding to the catalase promoter through the forkhead box O1 transcription factor, thus decreasing catalase expression. We demonstrate that overexpression of the phosphorylation-defective mutant PGC-1α (S570A) prevents Ang II-induced increases in H2O2 levels and hypertrophy ([3H]leucine incorporation). Knockdown of PGC-1α by small interfering RNA promotes basal and Ang II-stimulated ROS and hypertrophy, which is reversed by polyethylene glycol-conjugated catalase. Thus, endogenous PGC-1α is a negative regulator of vascular hypertrophy by up-regulating catalase expression and thus reducing ROS levels. We provide novel mechanistic insights by which Ang II may mediate its ROS-dependent pathophysiologic effects on multiple cardiometabolic diseases. PMID:19940161

  13. Characteristics of renal sympathetic nerve single units in rabbits with angiotensin-induced hypertension.

    Science.gov (United States)

    Burke, Sandra L; Lukoshkova, Elena V; Head, Geoffrey A

    2016-01-01

    We examined the effect of chronic angiotensin (Ang II)-induced hypertension on activity of postganglionic renal sympathetic units to determine whether altered whole renal nerve activity is due to recruitment or changes in firing frequency. Rabbits were treated with a low (20 ng kg(-1) min(-1), 8 weeks) or high dose (50 ng kg(-1) min(-1), 4 weeks) of Ang II before the experiment under chloralose-urethane anaesthesia. Spontaneously active units were detected from multiunit recordings using an algorithm that separated units by action potential shape using templates that matched spikes within a prescribed standard deviation. Multiunit sympathetic nerve activity was 40% higher in rabbits treated with low-dose Ang II than in sham (P = 0.012) but not different in high-dose Ang II. Resting firing frequency was similar in sham rabbits (1.00 ± 0.09 spikes s(-1), n = 144) and in those treated with high-dose Ang II (1.10 ± 0.08 spikes s(-1), n = 112) but was lower with low-dose Ang II (0.65 ± 0.08 spikes s(-1), n = 149, P < 0.05). Unit firing rhythmicity was linked to the cardiac cycle and was similar in sham and low-dose Ang II groups but 29-32% lower in rabbits treated with high-dose Ang II (P < 0.001). Cardiac linkage followed a similar pattern during hypoxia. All units showed baroreceptor dependency. Baroreflex gain and range were reduced and curves shifted to the right in Ang II groups. Firing frequency during hypoxia increased by +39% in low-dose Ang II and +82% in shams, but the greatest increase was in the high-dose Ang II group (+103%, P(dose) = 0.001). Responses to hypercapnia were similar in all groups. Increases in sympathetic outflow in hypertension caused by low-dose chronic Ang II administration are due to recruitment of neurons, but high-dose Ang II increases firing frequency in response to chemoreceptor stimuli independently of the arterial baroreceptors. PMID:26467849

  14. 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...

  15. ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause.

    Science.gov (United States)

    Pollow, Dennis P; Romero-Aleshire, Melissa J; Sanchez, Jessica N; Konhilas, John P; Brooks, Heddwen L

    2015-12-15

    Premenopausal females are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease onset and severity. However, it is unknown how a fluctuating ovarian hormone environment during the transition from perimenopause to menopause impacts the onset of hypertension, and whether interventions during perimenopause prevent disease onset after menopause. A gradual transition to menopause was induced by repeated daily injections of 4-vinylcyclohexene diepoxide (VCD). ANG II (800 ng·kg(-1)·min(-1)) was infused into perimenopausal and menopausal female mice for 14 days. A separate cohort of mice received 17β-estradiol replacement during perimenopause. ANG II infusion produced significantly higher mean arterial pressure (MAP) in menopausal vs. cycling females, and 17β-estradiol replacement prevented this increase. In contrast, MAP was not significantly different when ANG II was infused into perimenopausal and cycling females, suggesting that female resistance to ANG II-induced hypertension is intact during perimenopause. ANG II infusion caused a significant glomerular hypertrophy, and hypertrophy was not impacted by hormonal status. Expression levels of aquaporin-2 (AQP2), a collecting duct protein, have been suggested to reflect blood pressure. AQP2 protein expression was significantly downregulated in the renal cortex of the ANG II-infused menopause group, where blood pressure was increased. AQP2 expression levels were restored to control levels with 17β-estradiol replacement. This study indicates that the changing hormonal environment in the VCD model of menopause impacts the severity of ANG II-induced hypertension. These data highlight the utility of the ovary-intact VCD model of menopause as a clinically relevant model to investigate the physiological mechanisms of hypertension that occur in women during the transition into menopause. PMID:26491098

  16. Evaluation of aldosterone-and cortisol levels in blood plasma in normal conditions of ingestion of sodium and potassium, after saline-increase and depletion, in regard to position, and after stimulation with ACTH and angiotensin II

    International Nuclear Information System (INIS)

    Methods for the determination of plasma aldosterone and cortisol, by radioimmunoassay, were performed utilizing highly specific antisera. With this methodology it was possible to evaluate cortisol and aldosterone secretion, in six normal subjects, submitted to a basal rice diet on standing and recumbent positions, the effects of exogenous cortrosyn (β1-24 ACTH) and angiotensin II and the same manoevres with progressively increased Na+ content of the diet. Aldosterone basal levels decreased with the increase of Na+ content in the diet. However, there were no significant differences between the relative increments observed on the recumbent position, at the three levels of sodium intake. The relative increase of plasma aldosterone after ACTH was similar for each basal level of aldosterone induced by different sodium intakes. The responsiveness of aldosterone secretion to cortrosyn and standing position was similar, with no relation to the sodium intake. The infusion of angiotensin II induced an increase in plasma aldosterone, and the relative increment in the levels of the hormone were higher with high sodium than on the rice diet. The average basal cortisol value at the different levels of sodium intake was significantly different being greater on the basal, rice diet, and there was a decrease in cortisol level after recumbency, with the theree diets. The injection of ACTH induced similar cortisol secretion with no relation to the sodium intake. The infusion of non-hypertensive doses of angiotensin II resulted in an anomalous fall in cortisol level, probably because of 'shunt' of substrates to biosynthesis with the added effect of cortisol diurnal rhythmycity. (Author)

  17. Inhibition of the renin-angiotensin system for lowering coronary artery disease risk.

    Science.gov (United States)

    Sheppard, Richard J; Schiffrin, Ernesto L

    2013-04-01

    The renin-angiotensin system when activated exerts proliferative and pro-inflammatory actions and thereby contributes to progression of atherosclerosis, including that occurring in the coronary arteries. It thus contributes as well to coronary artery disease (CAD). Several clinical trials have examined effects of renin-angiotensin system inhibition for primary and secondary prevention of coronary heart disease. These include important trials such as HOPE, EUROPA and PEACE using angiotensin converting enzyme inhibitors, VALIANT, OPTIMAAL and TRANSCEND using angiotensin receptor blockers, and the ongoing TOPCAT study in patients with preserved ejection fraction heart failure, many of who also have coronary artery disease. Data are unavailable as yet of effects of either direct renin inhibitors or the new angiotensin receptor/neprilysin inhibitor agents. Today, inhibition of the renin-angiotensin system is standard-of-care therapy for lowering cardiovascular risk in secondary prevention in high cardiovascular risk subjects. PMID:23523606

  18. Role of EGFR transactivation in angiotensin II signaling to extracellular regulated kinase in preglomerular smooth muscle cells.

    Science.gov (United States)

    Andresen, Bradley T; Linnoila, Jenny J; Jackson, Edwin K; Romero, Guillermo G

    2003-03-01

    Angiotensin (Ang) II promotes the phosphorylation of extracellular regulated kinase (ERK); however, the mechanisms leading to Ang II-induced ERK phosphorylation are debated. The currently accepted theory involves transactivation of epidermal growth factor receptor (EGFR). We have shown that generation of phosphatidic acid (PA) is required for the recruitment of Raf to membranes and the activation of ERK by multiple agonists, including Ang II. In the present report, we confirm that phospholipase D-dependent generation of PA is required for Ang II-mediated phosphorylation of ERK in Wistar-Kyoto and spontaneously hypertensive rat preglomerular smooth muscle cells (PGSMCs). However, EGF stimulation does not activate phospholipase D or generate PA. These observations indicate that EGF recruits Raf to membranes via a mechanism that does not involve PA, and thus, Ang II-mediated phosphorylation of ERK is partially independent of EGFR-mediated signaling cascades. We hypothesized that phosphoinositide-3-kinase (PI3K) can also act to recruit Raf to membranes; therefore, inhibition of PI3K should inhibit EGF signaling to ERK. Wortmannin, a PI3K inhibitor, inhibited EGF-mediated phosphorylation of ERK (IC50, approximately 14 nmol/L). To examine the role of the EGFR in Ang II-mediated phosphorylation of ERK we utilized 100 nmol/L wortmannin to inhibit EGFR signaling to ERK and T19N RhoA to block Ang II-mediated ERK phosphorylation. Wortmannin treatment inhibited EGF-mediated but not Ang II-mediated phosphorylation of ERK. Furthermore, T19N RhoA inhibited Ang II-mediated ERK phosphorylation, whereas T19N RhoA had significantly less effect on EGF-mediated ERK phosphorylation. We conclude that transactivation of the EGFR is not primarily responsible for Ang II-mediated activation of ERK in PGSMCs. PMID:12623996

  19. Demonstration of extrapulmonary activity of angiotensin converting enzyme in intact tissue preparations.

    OpenAIRE

    Lembeck, F.; Griesbacher, T; Eckhardt, M.

    1990-01-01

    1. The activity of angiotensin converting enzyme (ACE) has been studied on functional parameters of intact isolated preparations of extrapulmonary tissues. The conversion of angiotensin I (A I) to angiotensin II (A II) and the cleavage of bradykinin (BK) were used as indicators of ACE activity. Captopril was employed as a specific inhibitor of ACE. 2. Captopril augmented the BK-induced contractions of the rat isolated uterus, the BK- and substance P-induced contractions of the guinea-pig ileu...

  20. A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

    OpenAIRE

    Bernstein, Kenneth E.; Ong, Frank S.; Blackwell, Wendell-Lamar B.; Shah, Kandarp H.; Giani, Jorge F.; Gonzalez-Villalobos, Romer A.; Shen, Xiao Z.; Fuchs, Sebastien

    2013-01-01

    Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of...

  1. Discovery and Characterization of Alamandine, a Novel Component of the Renin-Angiotensin System

    DEFF Research Database (Denmark)

    Lautner, Roberto Q.; Villela, Daniel C; Fraga-Silva, Rodrigo A;

    2013-01-01

    Rationale: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte and water balance. Here we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of ACE2 angiotensin A, or directly from angiotensin-(1......, provides new insights for the understanding of the physiological and pathophysiological role of the RAS, and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders....

  2. The Pancreatic Renin-Angiotensin System: Does It Play a Role in Endocrine Oncology?

    OpenAIRE

    Lam KY

    2001-01-01

    The characterization of a local renin-angiotensin system in the pancreas has attracted much attention because of its potential clinical applications. A pancreatic renin-angiotensin system may be present in humans and may interact with islet cells. Nevertheless, our knowledge of the renin-angiotensin system in the human pancreas is still in its infancy, especially in the field of endocrine oncology. Much of our knowledge stems from the study of the pancreas and pancreatic endocrine tumors of r...

  3. Advances in the Renin-Angiotensin-Aldosterone System: Relevance to Diabetic Nephropathy

    OpenAIRE

    Audrey Koitka; Christos Tikellis

    2008-01-01

    Hypertension is now recognized as a key contributory factor to the development and progression of kidney disease in both type 1 and type 2 diabetes. The renin angiotensin system (RAS) and its effector molecule angiotensin II, in particular, have a range of hemodynamic and nonhemodynamic effects that contribute not only to the development of hypertension, but also to renal disease. As a result, therapeutic inhibition of the RAS with angiotensin-converting enzyme inhibitors and/or selective ang...

  4. Local Bone Marrow Renin-Angiotensin System and Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Yavuz Beyazit

    2011-01-01

    Full Text Available Local hematopoietic bone marrow (BM renin-angiotensin system (RAS affects the growth, production, proliferation differentiation, and function of hematopoietic cells. Angiotensin II (Ang II, the dominant effector peptide of the RAS, regulates cellular growth in a wide variety of tissues in pathobiological states. RAS, especially Ang II and Ang II type 1 receptor (AT1R, has considerable proinflammatory and proatherogenic effects on the vessel wall, causing progression of atherosclerosis. Recent investigations, by analyzing several BM chimeric mice whose BM cells were positive or negative for AT1R, disclosed that AT1R in BM cells participates in the pathogenesis of atherosclerosis. Therefore, AT1R blocking not only in vascular cells but also in the BM could be an important therapeutic approach to prevent atherosclerosis. The aim of this paper is to review the function of local BM RAS in the pathogenesis of atherosclerosis.

  5. Hyperinsulinemic rats are normotensive but sensitized to angiotensin II

    DEFF Research Database (Denmark)

    Johansson, Maria E; Andersson, Irene J; Alexanderson, Camilla; Skøtt, Ole; Holmang, Agneta; Bergstrom, Goran

    2008-01-01

    rats received insulin (2 IU/day, INS, n=12) or insulin combined with losartan (30 mg/kg/day, INS-LOS, n=10), the angiotensin II receptor antagonist, for six weeks. Losartan-treated (LOS, n=10) and untreated rats served as controls (C, n=11). We used telemetry to measure BP and heart rate (HR), and......The effect of insulin on blood pressure is debated and an involvement of an activated renin-angiotensin aldosterone system (RAAS) has been suggested. We studied the effect of chronic insulin infusion on telemetry BP and assessed sympathetic activity and dependence of the RAAS. Female Sprague Dawley...... acute ganglion blockade and air-jet stress to investigate possible control of BP by the sympathetic nervous system. In addition, we used myograph technique to study vascular function ex vivo. INS and INS-LOS developed euglycemic hyperinsulinemia. Insulin did not affect BP but increased HR (27 beats...

  6. Lipids, inflammation, and the Renin-Angiotensin System

    OpenAIRE

    van der Harst, Pim

    2006-01-01

    Summary and Future Perspectives Impaired endothelial function is recognized as one of the earliest events of atherogenesis.1, 2 In Part I, chapter 1, we discussed the clinical value of the different techniques to evaluate endothelium-dependent vasomotor function. We also reviewed the efficacy of both angiotensin converting enzyme inhibitors and the HMG-CoA reductase inhibitors on improving vascular function. Despite the extensive experimental evidence and some clinical trials studies using qu...

  7. Silica Exposure and Serum Angiotensin Converting Enzyme Activity

    OpenAIRE

    YK Sharma; AB Karnik; RR Tiwari

    2010-01-01

    Background: Silicosis is known in industrial workers for centuries. Till recently, the mainstay of its diagnosis and progress was clinical examination of the respiratory system, pulmonary function test and chest radiography. Several biomarkers such as serum angiotensin converting enzyme (ACE) activity have been examined to determine the extent of silicosis. Objective: To elucidate the effect of age, gender, duration of exposure to silica dust, smoking habit, and pulmonary function status on t...

  8. African Americans, hypertension and the renin angiotensin system.

    OpenAIRE

    Williams, SF; Nicholas, SB; Vaziri, ND; Norris, KC

    2014-01-01

    African Americans have exceptionally high rates of hypertension and hypertension related complications. It is commonly reported that the blood pressure lowering efficacy of renin angiotensin system (RAS) inhibitors is attenuated in African Americans due to a greater likelihood of having a low renin profile. Therefore these agents are often not recommended as initial therapy in African Americans with hypertension. However, the high prevalence of comorbid conditions, such as diabetes, cardiovas...

  9. Elevated serum angiotensin converting enzyme levels in metastatic ovarian dysgerminoma.

    LENUS (Irish Health Repository)

    Cotter, T P

    2012-02-03

    A case of a 32-year-old XY genotype female is described, presenting with mediastinal and abdominal lymphadenopathy and associated with an elevated serum angiotensin I converting enzyme (SACE) level. Lymph node histology showed a malignant dysgerminoma of ovarian origin. Combined chemotherapy led to a radiological regression of the lymphadenopathy and coincided with a decrease in SACE concentration. The authors suggest that SACE may be a marker for disseminated germinoma tumours and may be useful for monitoring treatment.

  10. Visceral Angioedema Induced by Angiotensin Converting Enzyme Inhibitor: Case Report

    OpenAIRE

    Beatriz Frutuoso; Joana Esteves; Mafalda Silva; Pedro Gil; Ana Cristina Carneiro; Sílvio Vale

    2016-01-01

    Introduction: Intestinal angioedema is a rare adverse effect of angiotensin converting enzyme inhibitors. Clinical case: A 42-year old woman presented to the Emergency Department complaining of diffuse abdominal pain, predominantly in the right quadrants, with no other associated symptoms. She had been started on perindopril plus indapamide 72 h before the admission for arterial hypertension. There was no other relevant background. Physical examination suggested peritoneal irritation...

  11. Rate of angiotensin II generation within the human pulmonary vascular bed

    DEFF Research Database (Denmark)

    Giese, Jacob; Kappelgaard, A M; Tønnesen, K H;

    1980-01-01

    concentration in mixed venous blood and in systemic arterial blood. The pulmonary angiotensin II production rate was measured in fourteen patients. This parameter was linearly correlated with plasma renin concentration in systemic arterial blood. The plasma clearance of angiotensin II across the systemic......Plasma angiotensin II concentration gradients across the pulmonary vascular bed were measured during diagnostic renal venous/right heart catheterization in twenty-seven hypertensive patients with renal or renovascular disease. There was a linear correlation between the plasma angiotensin II...

  12. Angiotensin II prevents hypoxic pulmonary hypertension and vascular changes in rat

    International Nuclear Information System (INIS)

    Angiotensin II, a vasoconstrictor, has been previously demonstrated to produce a secondary vasodilatation due to release of prostaglandins. Because of this effect, the authors investigated whether infusion of exogenous angiotensin II via miniosmopumps in rats during a 1-wk exposure to chronic hypobaric hypoxia might prevent pulmonary hypertension, right ventricular hypertrophy, and vascular changes. They instrumented the rats with indwelling cardiovascular catheters and compared the hemodynamic and structural response in animals given angiotensin II, indomethacin in addition to angiotensin II (to block prostaglandin production), or saline with or without indomethacin. They then determine whether angiotensin II infusion also prevents acute hypoxic pulmonary vasoconstriction. They observed that exogenous angiotensin II infusion abolished the rise in pulmonary artery pressure, the right ventricular hypertrophy, and the vascular changes induced during chronic hypoxia in control saline-infused rats with or without indomethacin. The protective effects of angiotensin II was lost when indomethacin was given to block prostaglandin synthesis. During acute hypoxia, both antiotensin II and prostacyclin infusion similarly prevented the rise in pulmonary artery pressure observed in saline-infused rats and in rats given indomethacin or saralasin in addition to angiotensin II. Thus exogenous angiotensin II infusion prevents chronic hypoxic pulmonary hypertension, associated right ventricular hypertrophy, and vascular changes and blocks acute hypoxic pulmonary hypertension, and this is likely related to its ability to release vasodilator prostaglandins

  13. Renin angiotensin system: A novel target for migraine prophylaxis

    Directory of Open Access Journals (Sweden)

    Ruchika Nandha

    2012-01-01

    Full Text Available Migraine constitutes 16% of primary headaches affecting 10-20% of general population according to International Headache Society. Till now nonsteroidalanti-inflammatory drugs (NSAIDS, opioids and triptans are the drugs being used for acute attack of migraine. Substances with proven efficacy for prevention include β-blockers, calcium channel blockers, antiepileptic drugs and antidepressants. All the already available drugs have certain limitations. Either they are unable to produce complete relief or 30-40% patients are no responders or drugs produce adverse effects. This necessitates the search for more efficacious and well-tolerated drugs. A new class of drugs like angiotensin-converting enzyme inhibitors (ACE inhibitors and angiotensin II receptor antagonists have recently been studied for their off label use in prophylaxis of migraine. Studies, done so far, have shown results in favour of their clinical use because of the ability to reduce number of days with headache, number of days with migraine, hours with migraine, headache severity index, level of disability, improved Quality of life and decrease in consumption of specific or nonspecific analgesics. This article reviews the available evidence on the efficacy and safety of these drugs in prophylaxis of migraine and can give physician a direction to use these drugs for chronic migraineurs. Searches of pubmed, Cochrane database, Medscape, Google and clinicaltrial.org were made using terms like ACE inhibitors, angiotensin II receptor antagonists and migraine. Relevant journal articles were chosen to provide necessary information.

  14. 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

  15. NEW INSIGHTS INTO THE GENERATION OF THE ANGIOTENSIN PEPTIDES

    Directory of Open Access Journals (Sweden)

    Ion Raducu Popescu

    2012-06-01

    Full Text Available The classical concept of Ang II as main pressor angiotensin peptide has undergone experiencedsubstantial changes in the past few years. Many experimental research have revealed novel aspects of the circulating andtissue RAS. After a brief introduction concerning the two distinct forms of the angiotensin converting enzyme andproangiotensin – 12 as a new potential precursor for the formation of bioactive angiotensin peptides, the generation andactions of the main bioactive fragments of Ang II are also presented. Among them are mentioned the pathways offormation and biological effects of Ang (1-7, Ang III, Ang IV and Ang V involved in the modulation of the Ang II, themost active multifunctional hormone of RAS. The inhibitory properties of the ACE2–Ang (1-7–Mas axis are interpretedas a counterbalancing mechanism against the eventual deleterious actions of Ang II. As described here, these counter-regulatory properties provide the self-regulation of RAS, as a unitary and integrated hormone system.

  16. Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease.

    Science.gov (United States)

    Lin, Mei; Gao, Ping; Zhao, Tianya; He, Lei; Li, Mengshi; Li, Yaoyao; Shui, Hua; Wu, Xiaoyan

    2016-05-01

    To investigate the effects of calcitriol on angiotensin-converting enzyme (ACE) and ACE2 in diabetic nephropathy. Streptozotocin (STZ) induced diabetic rats were treated with calcitriol for 16 weeks. ACE/ACE2 and mitogen activated protein kinase (MAPK) enzymes were measured in the kidneys of diabetic rats and rat renal tubular epithelial cells exposed to high glucose. Calcitriol reduced proteinuria in diabetic rats without affecting calcium-phosphorus metabolism. ACE and ACE2 levels were significantly elevated in diabetic rats compared to those in control rats. The increase in ACE levels was greater than that of ACE2, leading to an elevated ACE/ACE2 ratio. Calcitriol reduced ACE levels and ACE/ACE2 ratio and increased ACE2 levels in diabetic rats. Similarly, high glucose up-regulated ACE expression in NRK-52E cells, which was blocked by the p38 MAPK inhibitor SB203580, but not the extracellular signal-regulated kinase (ERK) inhibitor FR180204 or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. High glucose down-regulated ACE2 expression, which was blocked by FR180204, but not SB203580 or SP600125. Incubation of cells with calcitriol significantly inhibited p38 MAPK and ERK phosphorylation, but not JNK phosphorylation, and effectively attenuated ACE up-regulation and ACE2 down-regulation in high glucose conditions. The renoprotective effects of calcitriol in diabetic nephropathy were related to the regulation of tubular levels of ACE and ACE2, possibly by p38 MAPK or ERK, but not JNK pathways. PMID:26968558

  17. The Adipose Renin-Angiotensin System Modulates Systemic Markers of Insulin Sensitivity and Activates the Intrarenal Renin-Angiotensin System

    OpenAIRE

    Suyeon Kim; Morvarid Soltani-Bejnood; Annie Quignard-Boulange; Florence Massiera; Michele Teboul; Gerard Ailhaud; Jung Han Kim; Naima Moustaid-Moussa; Voy, Brynn H.

    2006-01-01

    Background. The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results. A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO), mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO), and mice overexpressing Agt in adipose tissue (aP2-Agt) was studied. Total body weight, epididymal fat pad weight, and circulating...

  18. Relationship between angiotensin-(1-7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis

    Science.gov (United States)

    Vilas-Boas, Walkíria Wingester; Ribeiro-Oliveira Jr, Antônio; Pereira, Regina Maria; da Cunha Ribeiro, Renata; Almeida, Jerusa; Nadu, Ana Paula; Simões e Silva, Ana Cristina; dos Santos, Robson Augusto Souza

    2009-01-01

    AIM: To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system (RAS) components and hemodynamic changes. METHODS: Patients were allocated into 4 groups: mild-to-moderate liver disease (MLD), advanced liver disease (ALD), patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity (PRA), angiotensin (Ang) I, Ang II, and Ang-(1-7) levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components. RESULTS: PRA and angiotensins were elevated in ALD when compared to MLD and controls (P < 0.05). In contrast, Ang II was significantly reduced in MLD. Ang-(1-7)/Ang II ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang II levels were lower and Ang-(1-7)/Ang II ratios were higher in the splanchnic circulation than in the peripheral circulation (0.52 ± 0.08 vs 0.38 ± 0.04, P < 0.02), whereas the peripheral circulating Ang II/Ang I ratio was elevated in comparison to splanchnic levels (0.18 ± 0.02 vs 0.13 ± 0.02, P < 0.04). Ang-(1-7)/Ang II ratios positively correlated with cardiac output (r = 0.66) and negatively correlated with systemic vascular resistance (r = -0.70). CONCLUSION: Our findings suggest that the relationship between Ang-(1-7) and Ang II may play a role in the hemodynamic changes of human cirrhosis. PMID:19469002

  19. 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.

  20. Role of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in hypertension of chronic kidney disease and renoprotection. Study results

    OpenAIRE

    Baltatzi, M; Savopoulos, Ch; Hatzitolios, A

    2011-01-01

    Chronic kidney disease (CKD) is a global health problem associated with considerable morbidity and mortality and despite advances in the treatment of end stage renal disease (ESRD) mechanisms to prevent and delay its progression are still being sought. The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in many of the pathophysiologic changes that lead to progression of renal disease. Traditionally RAAS was considered as an endocrine system and its principal role was to maint...

  1. 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.

  2. Anti-atherosclerotic effects of an angiotensin converting enzyme inhibitor and an angiotensin II antagonist in Cynomolgus monkeys fed a high-cholesterol diet

    OpenAIRE

    Miyazaki, Mizuo; Sakonjo, Hiroshi; Takai, Shinji

    1999-01-01

    We investigated the relationship between angiotensin II formation and the development of atherosclerotic lesions in the aorta of monkeys (Macaca fascicularis) fed a high-cholesterol (4% cholesterol and 6% corn oil) diet for 6 months, and studied the effects of an angiotensin converting enzyme (ACE) inhibitor, trandolapril (10 mg kg−1 per day, p.o.), and an angiotensin II type 1 receptor antagonist, 2-butyl-4-(methylthio)-1-[[2′[[[(propylamino)carbonyl]amino]sulfonyl](1,1′-biphenyl)-4-yl]methy...

  3. Renal effects of angiotensin II in the newborn period: role of type 1 and type 2 receptors

    OpenAIRE

    Vinturache, Angela E.; Francine G. Smith

    2016-01-01

    Background Evidence suggests a critical role for the renin-angiotensin system in regulating renal function during postnatal development. However, the physiological relevance of a highly elevated renin-angiotensin system early in life is not well understood, nor which angiotensin receptors might be involved. This study was designed to investigate the roles of angiotensin receptors type 1 (AT1R) and type 2 (AT2R) in regulating glomerular and tubular function during postnatal development. Method...

  4. Angiotensin II Differentially Induces Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 Production and Disturbs MMP/TIMP Balance

    OpenAIRE

    Yaghooti, Hamid; Firoozrai, Mohsen; Fallah, Soudabeh; Khorramizadeh, Mohammad Reza

    2010-01-01

    Angiotensin II, the main component of the renin-angiotensin system, is associated with cardiovascular diseases such as hypertension, vascular remodeling and inflammation. Remodeling process results from dysregulation of Matrix Metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). MMPs are considered as important target genes for angiotensin II. The aim of this study was to determine the effects of angiotensin II on MMP-9 and TIMP-1 production and MMP/TIMP balance in a monocytic cell ...

  5. Between-patient differences in the renal response to renin-angiotensin system intervention: clue to optimising renoprotective therapy?

    NARCIS (Netherlands)

    Laverman, Ger Jan; Navis, Ger Jan; de Zeeuw, Dick

    2002-01-01

    Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II (Ang II), AT(1)-receptor blockers (ARB) is the cornerstone of renoprotective therapy. Still, the number of patients with end-stage renal disease is increasing worldwide, promp

  6. Between-patient differences in the renal response to renin-angiotensin system intervention : clue to optimising renoprotective therapy?

    NARCIS (Netherlands)

    Laverman, GD; de Zeeuw, D; Navis, G

    2002-01-01

    Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II (Ang II), AT(1)-receptor blockers (ARB) is the cornerstone of renoprotective therapy. Still, the number of patients with end-stage renal disease is increasing worldwide, promp

  7. Interaction of red pepper (Capsicum annum, Tepin) polyphenols with Fe(II)-induced lipid peroxidation in brain and liver

    International Nuclear Information System (INIS)

    Polyphenols exhibit a wide range of biological effects because of their antioxidant properties. Several types of polyphenols (phenolic acids, hydrolyzable tannins, and flavonoids) show anticarcinogenic and antimutagenic effects. Comparative studies were carried on the protective ability of free and bound polyphenol extracts of red Capsicum annuum Tepin (CAT) on brain and liver - In vitro. Free polyphenols of red Capsicum annuum Tepin (CAT) were extracted with 80% acetone, while the bound polyphenols were extracted with ethyl acetate from acid and alkaline hydrolysis of the pepper residue from free polyphenols extract. The phenol content, Fe (II) chelating ability, OH radical scavenging ability and protective ability of the extract against Fe (II)-induced lipid peroxidation in brain and liver was subsequently determined. The results of the study revealed that the free polyphenols (218.2mg/100g) content of the pepper were significantly higher than the bound polyphenols (42.5mg/100g). Furthermore, the free polyphenol extract had a significantly higher (2+ induced lipid peroxidation, and this is probably due to the higher Fe (II) chelating ability and OH radical scavenging ability of the free polyphenols from the pepper. (author)

  8. SARTANS AND ANGIOTENSIN CONVERTING ENZYME INHIBITORS: A DUEL BETWEEN TWO LEADERS OF PHARMACOTHERAPY OF CARDIOVASCULAR DISEASES

    OpenAIRE

    K. A. Gyamdzhyan; M. L. Maksimov

    2015-01-01

    Topical issues of cardiovascular disease pharmacotherapy influencing function of the renin-angiotensin-aldosterone system are discussed. Efficacy and safety of two major cardiovascular drug classes, angiotensin converting enzyme inhibitors and sartans, are compared. Data from evidence base of the both drug classes are presented.

  9. Use of angiotensin-converting enzyme inhibitors and cardiovascular outcomes following primary vascular surgery

    DEFF Research Database (Denmark)

    Høgh, Annette Langager; Lindholt, Jes S; Nielsen, Henrik;

    2012-01-01

    To examine the association between angiotensin-converting enzyme (ACE) inhibitor use and clinical outcome after primary vascular reconstruction in a population-based follow-up study.......To examine the association between angiotensin-converting enzyme (ACE) inhibitor use and clinical outcome after primary vascular reconstruction in a population-based follow-up study....

  10. Systemic vascular resistance during brief withdrawal of angiotensin converting enzyme inhibition in heart failure

    DEFF Research Database (Denmark)

    Gabrielsen, A; Bie, P; Christensen, N J;

    2002-01-01

    We tested the hypothesis that moderate increases in endogenous angiotensin II (Ang II) concentrations, induced by withdrawal of angiotensin converting enzyme inhibition (ACE-I) in patients with compensated heart failure (HF) on chronic medical therapy, do not increase or impair control of systemi...

  11. Does angiotensin (1-7) contribute to the anti-proteinuric effect of ACE-inhibitors

    NARCIS (Netherlands)

    van der Wouden, Els A; Henning, Robert H; Deelman, Leo E; Roks, Anton J M; Boomsma, Frans; de Zeeuw, Dick

    2005-01-01

    Angiotensin-converting enzyme inhibitors (ACE-I) reduce proteinuria and protect the kidney in proteinuric renal disease. During ACE-I therapy, circulating levels of angiotensin (1-7) [Ang (1-7)] are increased. As cardiac and renal protective effects of Ang (1-7) have been reported, we questioned whe

  12. SARTANS AND ANGIOTENSIN CONVERTING ENZYME INHIBITORS: A DUEL BETWEEN TWO LEADERS OF PHARMACOTHERAPY OF CARDIOVASCULAR DISEASES

    Directory of Open Access Journals (Sweden)

    K. A. Gyamdzhyan

    2015-12-01

    Full Text Available Topical issues of cardiovascular disease pharmacotherapy influencing function of the renin-angiotensin-aldosterone system are discussed. Efficacy and safety of two major cardiovascular drug classes, angiotensin converting enzyme inhibitors and sartans, are compared. Data from evidence base of the both drug classes are presented.

  13. 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...

  14. Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

    DEFF Research Database (Denmark)

    Hilliard, Lucinda M; Chow, Charis L E; Mirabito, Katrina M; Steckelings, Ulrike Muscha; Unger, Thomas; Widdop, Robert E; Denton, Kate M

    2014-01-01

    Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT2R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT2R stimul...

  15. Local Angiotensin Pathways in Human Carotid Atheroma: Towards a Systems Biology Approach

    OpenAIRE

    Bricca, Giampiero; Legedz, Liliana; Nehme, Ali; Ayari, Hanène; Paultre, Christian; Hodroj, Wassim; Li, Jacques-Yuan; Randon, Jacques; Lohez, Olivier; Dhaouadi, Nedra; Gustin, Marie Paule; Cerutti, Catherine

    2015-01-01

    We will summarize the data we have obtained in human carotid artery concerning the organization of an extended local renin angiotensin aldosterone system and its variations at different stages of atheroma. In a system view, we propose a model where concomitant increase in angiotensin and glucocorticoid signaling is induced and amplified in VSMC while vascular smooth muscle cells transdifferentiate toward a lipid storing phenotype.

  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. 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; Rissler, Pehr; Edvinsson, Lars

    2009-01-01

    peptide involved in vessel inflammation during atherosclerosis, and angiotensin II receptor inhibitors are effective in preventing atherosclerosis. The present study was performed to elucidate the role of angiotensin type 1 (AT(1)) and type 2 (AT(2)) receptors in GCA. DESIGN: Experimental retrospective...

  18. 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

  19. 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...... group). INTERPRETATION: Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors. Although the drug had no significant effect on the primary outcome of this study, which included hospitalisations for heart failure, it modestly reduced the risk of the composite outcome...

  20. Intrarenal Distributions and Changes of Angiotensin-Converting Enzyme and Angiotensin-Converting Enzyme 2 in Feline and Canine Chronic Kidney Disease

    OpenAIRE

    MITANI, Sawane; Yabuki, Akira; Sawa, Mariko; Chang, Hye-Sook; YAMATO, Osamu

    2013-01-01

    ABSTRACT Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system (RAS). ACE2 is a newly identified member of the RAS. The present immunohistochemical study focused on changes in intrarenal ACE and ACE2 immunoreactivity in feline and canine chronic kidney disease (CKD). ACE immunoreactivity was predominantly observed in the brush border of the proximal tubules in dogs and cats. ACE immunoreactivity was lower in CKD kidneys than in normal kidneys, and quantitative an...

  1. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis

    Institute of Scientific and Technical Information of China (English)

    Kazim; Husain; Wilfredo; Hernandez; Rais; A; Ansari; Leon; Ferder

    2015-01-01

    Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin Ⅱ(Ang Ⅱ) and a decrease in nitric oxide. The renin-angiotensin system(RAS), and its primary mediator Ang Ⅱ, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors(angiotensin-converting enzyme inhibitors)], Ang Ⅱ receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in Apo E-deficient atherosclerotic mice.

  2. 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

  3. Renin angiotensin system and gender differences in dopaminergic degeneration

    Directory of Open Access Journals (Sweden)

    Rodriguez-Perez Ana I

    2011-08-01

    Full Text Available Abstract Background There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson's disease (PD. It has been shown that the local renin angiotensin system (RAS plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1 receptors. Results In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen. However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen. Conclusions The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen.

  4. Hypertensive retinopathy in a transgenic angiotensin-based model.

    Science.gov (United States)

    Reichhart, Nadine; Haase, Nadine; Crespo-Garcia, Sergio; Skosyrski, Sergej; Herrspiegel, Christina; Kociok, Norbert; Fuchshofer, Rudolf; Dillinger, Andrea; Poglitsch, Marco; Müller, Dominik N; Joussen, Antonia M; Luft, Friedrich C; Dechend, Ralf; Strauß, Olaf

    2016-07-01

    Severe hypertension destroys eyesight. The RAS (renin-angiotensin system) may contribute to this. This study relied on an established angiotensin, AngII (angiotensin II)-elevated dTGR (double-transgenic rat) model and same-background SD (Sprague-Dawley) rat controls. In dTGRs, plasma levels of AngII were increased. We determined the general retinal phenotype and observed degeneration of ganglion cells that we defined as vascular degeneration. We also inspected relevant gene expression and lastly observed alterations in the outer blood-retinal barrier. We found that both scotopic a-wave and b-wave as well as oscillatory potential amplitude were significantly decreased in dTGRs, compared with SD rat controls. However, the b/a-wave ratio remained unchanged. Fluorescence angiography of the peripheral retina indicated that exudates, or fluorescein leakage, from peripheral vessels were increased in dTGRs compared with controls. Immunohistological analysis of blood vessels in retina whole-mount preparations showed structural alterations in the retina of dTGRs. We then determined the general retinal phenotype. We observed the degeneration of ganglion cells, defined vascular degenerations and finally found differential expression of RAS-related genes and angiogenic genes. We found the expression of both human angiotensinogen and human renin in the hypertensive retina. Although the renin gene expression was not altered, the AngII levels in the retina were increased 4-fold in the dTGR retina compared with that in SD rats, a finding with mechanistic implications. We suggest that alterations in the outer blood-retinal barrier could foster an area of visual-related research based on our findings. Finally, we introduce the dTGR model of retinal disease. PMID:27026533

  5. Effects of angiotensin II on visual neurons in the superficial laminae of the hamster's superior colliculus.

    Science.gov (United States)

    Mooney, R D; Zhang, Y; Rhoades, R W

    1994-01-01

    Superficial layer superior colliculus (SC) neurons were recorded extracellularly with multibarreled recording/ejecting micropipettes. Angiotensin II was delivered via micropressure ejection during visual stimulation (n = 215 cells), or during electrical stimulation of either the optic chiasm (OX; n = 150 cells) or visual cortex (CTX; n = 42 cells). Application of angiotensin II decreased visual responses of SC cells to 43.8% +/- 30.7% (mean +/- S.D.) and reduced responses to electrical stimulation of the OX and CTX to 58.6% +/- 34.1% and 43.8% +/- 30.7% of control values, respectively. Angiotensin II enhanced responses by at least 30% in only 6 cells (1.5%). Of the 35 neurons tested with both OX and CTX stimulation, the correlation of evoked response suppression by angiotensin II was highly significant (r = 0.69; P iontophoresis of glutamate and then tested with angiotensin II. Angiotensin II reduced the glutamate-evoked responses to an average 29.1% +/- 21.1% of control values (n = 9 cells). This suggest that the site of action of angiotensin II is most likely postsynaptic. To identify which receptors were involved in these effects, angiotensin II was ejected concurrently with the AT1 antagonist Losartan (DUP753) or with either of two AT2 antagonists, CGP42112A or PD123177. Losartan antagonized the action of angiotensin II in 65.6% of the cells tested (n = 99) and CGP42112A and PD123177 had antagonistic effects in 58% (n = 65) and 60% (n = 5), respectively. Both classes of antagonists were tested in 29 cells; and there was no significant correlation between their effectiveness. These results suggest that both AT1 and AT2 receptors may independently mediate the suppressive effects of angiotensin II, and that collicular neurons may have either or both receptor subtypes. PMID:7841124

  6. Activation of the Renin-Angiotensin System Promotes Colitis Development

    OpenAIRE

    Yongyan Shi; Tianjing Liu; Lei He; Urszula Dougherty; Li Chen; Sarbani Adhikari; Lindsay Alpert; Guolin Zhou; Weicheng Liu; Jiaolong Wang; Deb, Dilip K.; John Hart; Liu, Shu Q.; John Kwon; Joel Pekow

    2016-01-01

    The renin-angiotensin system (RAS) plays pathogenic roles in renal and cardiovascular disorders, but whether it is involved in colitis is unclear. Here we show that RenTgMK mice that overexpress active renin from the liver developed more severe colitis than wild-type controls. More than 50% RenTgMK mice died whereas all wild-type mice recovered. RenTgMK mice exhibited more robust mucosal TH17 and TH1/TH17 responses and more profound colonic epithelial cell apoptosis compared to wild-type cont...

  7. 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...

  8. Angiotensin Converting Enzyme-induced Angioedema - A Dangerous New Epidemic

    DEFF Research Database (Denmark)

    Rasmussen, Eva Rye; Mey, Kristianna; Bygum, Anette

    2013-01-01

    Angioedema is a sudden localised and often asymmetric swelling of the skin or mucous membranes caused by transient increased endothelial permeability causing plasma extravasation. In the last decades the incidence of severe angioedema involving the upper airways and even fatal outcome due to...... asphyxia has increased. This is mainly due to pharmaceuticals such as angiotensin converting enzyme-inhibitors, which are extensively used worldwide. Some aspects of the pathophysiology have been elucidated and the vasoactive molecule bradykinin is shown to be one of the main causative agents. The...

  9. Lung angiotensin converting enzyme activity in rats with pulmonary hypertension.

    OpenAIRE

    Keane, P. M.; Kay, J M; Suyama, K L; Gauthier, D.; Andrew, K

    1982-01-01

    We have studied serum and lung tissue angiotensin converting enzyme (ACE) activity in female Wistar rats with pulmonary hypertension induced by two different methods. Chronic pulmonary hypertension was produced in one group of 10 rats (CH) by confinement in a hypobaric chamber (380 mmHg) for three weeks, and in another group fo 10 rats (M) by a single subcutaneous injection of monocrotaline (60 mg/kg body weight). In these two groups of tests rats and in 20 untreated controls (C), we evaluate...

  10. Lung angiotensin converting enzyme activity in chronically hypoxic rats.

    OpenAIRE

    Kay, J M; Keane, P. M.; Suyama, K L; Gauthier, D.

    1985-01-01

    A study was carried out to test the hypothesis that the reduced lung angiotensin converting enzyme (ACE) activity which occurs in chronic hypoxia is related to the development of pulmonary hypertension rather than to hypoxia per se. Right ventricular mean systolic pressure (Prvs, mm Hg) and ACE activity (nmol/mg protein/min) in lung tissue homogenates were measured in seven groups of four rats placed in a hypobaric chamber (380 mm Hg; 51 kPa) for two to 24 days. Identical measurements were ma...

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

    Science.gov (United States)

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

    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 conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, −51.0%, −11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, −37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial. PMID:19926893

  12. 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

  13. Angiotensin II receptor alterations during pregnancy in rabbits

    International Nuclear Information System (INIS)

    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 125I-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

  14. Brain renin angiotensin system in cardiac hypertrophy and failure

    Directory of Open Access Journals (Sweden)

    MichaelBader

    2012-01-01

    Full Text Available Brain renin-angiotensin system (RAS is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the development of cardiac hypertrophy and fibrosis through sympathetic activation. Inhibition of sympathetic hyperactivity after myocardial infarction through suppression of the brain RAS appears beneficial. The brain RAS is involved in the modulation of circadian rhythms of arterial pressure, contributing to nondipping hypertension. We conclude that the brain RAS in pathophysiological states interacts synergistically with the chronically overactive RAS through a positive biofeedback in order to maintain a state of alert diseased conditions, such as cardiac hypertrophy and failure. Therefore, targeting brain RAS with drugs such as angiotensin converting inhibitors or receptor blockers having increased brain penetrability could be of advantage. These RAS-targeting drugs are first-line therapy for all heart failure patients. Since the RAS has both endocrine and local tissue components, RAS drugs are being developed to attain increased tissue penetrability and volume of distribution and consequently an efficient inhibition of both RAS components.

  15. 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.

  16. 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

  17. The adipose renin-angiotensin system modulates sysemic markers of insulin sensitivity activates the intrarenal renin-angiotensin system

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Suyeon [University of Tennessee, Knoxville (UTK); Soltani-Bejnood, Morvarid [University of Tennessee, Knoxville (UTK); Quignard-Boulange, Annie [Centre Biomedical des Cordeliers, Paris, France; Massiera, Florence [Centre de Biochimie, Nice, France; Teboul, Michele [Centre de Biochimie, Nice, France; Ailhaud, Gerard [Centre de Biochimie, Nice, France; Kim, Jung [University of Tennessee, Knoxville (UTK); Moustaid-Moussa, Naima [University of Tennessee, Knoxville (UTK); Voy, Brynn H [ORNL

    2006-07-01

    BACKGROUND: A growing body of data provides increasing evidence that the adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass. Beyond its paracrine actions within adipose tissue, adipocyte-derived angiotensin II (Ang II) may also impact systemic functions such as blood pressure and metabolism. METHODS AND RESULTS: We used a genetic approach to manipulate adipose RAS activity in mice and then study the consequences on metabolic parameters and on feedback regulation of the RAS. The models included deletion of the angiotensinogen (Agt) gene (Agt-KO), its expression solely in adipose tissue under the control of an adipocyte-specific promoter (aP2-Agt/ Agt-KO), and overexpression in adipose tissue of wild type mice (aP2-Agt). Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. Overexpression of Agt in adipose tissue resulted in increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also markedly elevated in kidney of aP2-Agt mice, suggesting that hypertension in these animals may be in part due to stimulation of the intrarenal RAS. CONCLUSIONS: Taken together, the results from this study demonstrate that alterations in adipose RAS activity significantly alter both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.

  18. Hypertension and Angiotensin II Hypersensitivity in Aminopeptidase A–deficient Mice

    OpenAIRE

    MITSUI, Takashi; NOMURA, Seiji; Okada, Mayumi; Ohno, Yasumasa; Kobayashi, Honami; Nakashima,Yutaka; Murata, Yasutaka; Takeuchi, Mikihito; Kuno, Naohiko; Nagasaka, Tetsuo; O-Wang, Jiyang; Cooper, Max D.; Mizutani, Shigehiko

    2003-01-01

    Local concentrations of the vasopressor peptide, angiotensin II (AngII), depend upon the balance between synthesis and degradation. Previous studies of blood pressure (BP) regulation have focused primarily on the generation of AngII and its receptors, and less attention has been devoted to angiotensin degradation. Aminopeptidase A (APA, EC 3.4.11.7) is responsible for the N-terminal cleavage of AngII, a hydrolytic event that serves as a rate-limiting step in angiotensin degradation. To evalua...

  19. 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...

  20. 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.

  1. African Americans,hypertension and the renin angiotensin system

    Institute of Scientific and Technical Information of China (English)

    Sandra; F; Williams; Susanne; B; Nicholas; Nosratola; D; Vaziri; Keith; C; Norris

    2014-01-01

    African Americans have exceptionally high rates of hypertension and hypertension related complications. It is commonly reported that the blood pressure lowering efficacy of renin angiotensin system(RAS) inhibitors is attenuated in African Americans due to a greater likelihood of having a low renin profile. Therefore these agents are often not recommended as initial therapy in African Americans with hypertension. However, the high prevalence of comorbid conditions, such as diabetes, cardiovascular and chronic kidney disease makes treatment with RAS inhibitors more compelling. Despite lower circulating renin levels and a less significant fall in blood pressure in response to RAS inhibitors in African Americans, numerous clinical trials support the efficacy of RAS inhibitors to improve clinical outcomes in this population, especially in those with hypertension and risk factors for cardiovascular and related diseases. Here, we discuss the rationale of RAS blockade as part of a comprehensive approach to attenuate the high rates of premature morbidity and mortality associated with hypertension among African Americans.

  2. 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...

  3. 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...

  4. Angiotensin-I-converting enzyme and gallium scan in noninvasive evaluation of sarcoidosis

    Energy Technology Data Exchange (ETDEWEB)

    Nosal, A. (Harbor General Hospital, Torrance, CA); Schleissner, L.A.; Mishkin, F.S.; Lieberman, J.

    1979-03-01

    Angiotensin-converting enzyme assays and gallium-scan results were obtained from 27 patients with biopsy-proven, clinically active sarcoidosis. Twenty-three of these patients had elevated converting enzyme levels, and 22 had positive gallium-scan results. Three of four patients with normal or borderline-elevated levels of angiotensin-converting enzyme also had positive gallium-scan results. Of 156 nonsarcoid patients (pulmonary and other diseases), 27 were found to have elevated serum converting enzyme levels, and 25 of these had negative gallium-scan results. These results indicate that the combination of an assay of angiotensin-converting enzyme and gallium scan increases diagnostic specificity from 83% to 99% without sacrificing sensitivity. It was concluded that the concurrent use of angiotensin-converting enzyme assay and gallium scan is of value in the diagnosis of sarcoidosis.

  5. Angiotensin-I-converting enzyme and gallium scan in noninvasive evaluation of sarcoidosis

    International Nuclear Information System (INIS)

    Angiotensin-converting enzyme assays and gallium-scan results were obtained from 27 patients with biopsy-proven, clinically active sarcoidosis. Twenty-three of these patients had elevated converting enzyme levels, and 22 had positive gallium-scan results. Three of four patients with normal or borderline-elevated levels of angiotensin-converting enzyme also had positive gallium-scan results. Of 156 nonsarcoid patients (pulmonary and other diseases), 27 were found to have elevated serum converting enzyme levels, and 25 of these had negative gallium-scan results. These results indicate that the combination of an assay of angiotensin-converting enzyme and gallium scan increases diagnostic specificity from 83% to 99% without sacrificing sensitivity. It was concluded that the concurrent use of angiotensin-converting enzyme assay and gallium scan is of value in the diagnosis of sarcoidosis

  6. Effects of angiotensin converting enzyme inhibitor: ramipril on different biochemical parameters in essential hypertensive patients

    Directory of Open Access Journals (Sweden)

    Pratibha S. Salve

    2016-06-01

    Conclusions: Ramipril has beneficial effects on RAS (Renin angiotensin system and kinin system or both may contribute to the improvement in different biochemical parameters by ramipril. [Int J Res Med Sci 2016; 4(6.000: 2288-2291

  7. Local generation and action of angiotensin II in dog iris sphincter muscle.

    Science.gov (United States)

    Okamura, T; Wang, Y; Toda, N

    1992-10-01

    Existence of the renin-angiotensin system was pharmacologically investigated in the dog isolated iris sphincter muscle. The sphincter muscle contracted in response to tetradecapeptide, a synthetic renin substrate, angiotensin (ANG) I and ANG II dose-dependently. The contractions induced by these peptides were suppressed by treatment with saralasin, indomethacin and aspirin. Contractile responses to tetradecapeptide and ANG I were also reduced by KRI-1314, a renin inhibitor, and captopril, respectively. ANG II stimulated the release of prostaglandin (PG) F2 alpha from the sphincter muscle. Angiotensin-converting enzyme activity was measurable in the sphincter muscle. Miosis was observed by intracameral injection of ANG I and ANG II into the anterior chamber. These results strongly suggest that angiotensin generating enzymes function in the sphincter muscle and ANG II produced by these enzymes contracts the sphincter muscle via the formation of PG (s), possibly PG F2 alpha. PMID:1336465

  8. 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.

  9. 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

  10. Effect of selective angiotensin antagonists on the antidiuresis produced by angiotensin-(1-7 in water-loaded rats

    Directory of Open Access Journals (Sweden)

    Baracho N.C.V.

    1998-01-01

    Full Text Available In the present study we evaluated the nature of angiotensin receptors involved in the antidiuretic effect of angiotensin-(1-7 (Ang-(1-7 in water-loaded rats. Water diuresis was induced in male Wistar rats weighing 280 to 320 g by water load (5 ml/100 g body weight by gavage. Immediately after water load the rats were treated subcutaneously with (doses are per 100 g body weight: 1 vehicle (0.05 ml 0.9% NaCl; 2 graded doses of 20, 40 or 80 pmol Ang-(1-7; 3 200 nmol Losartan; 4 200 nmol Losartan combined with 40 pmol Ang-(1-7; 5 1.1 or 4.4 nmol A-779; 6 1.1 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7; 7 4.4 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7; 8 95 nmol CGP 42112A, or 9 95 nmol CGP 42112A combined with 40 pmol Ang-(1-7. The antidiuretic effect of Ang-(1-7 was associated with an increase in urinary Na+ concentration, an increase in urinary osmolality and a reduction in creatinine clearance (CCr: 0.65 ± 0.04 ml/min vs 1.45 ± 0.18 ml/min in vehicle-treated rats, P<0.05. A-779 and Losartan completely blocked the effect of Ang-(1-7 on water diuresis (2.93 ± 0.34 ml/60 min and 3.39 ± 0.58 ml/60 min, respectively. CGP 42112A, at the dose used, did not modify the antidiuretic effect of Ang-(1-7. The blockade produced by Losartan was associated with an increase in CCr and with an increase in sodium and water excretion as compared with Ang-(1-7-treated rats. When Ang-(1-7 was combined with A-779 there was an increase in CCr and natriuresis and a reduction in urine osmolality compared with rats treated with Ang-(1-7 alone. The observation that both A-779, which does not bind to AT1 receptors, and Losartan blocked the effect of Ang-(1-7 suggests that the kidney effects of Ang-(1-7 are mediated by a non-AT1 angiotensin receptor that is recognized by Losartan.

  11. Effect of Angiotensin(1-7) on Heart Function in an Experimental Rat Model of Obesity

    Science.gov (United States)

    Blanke, Katja; Schlegel, Franziska; Raasch, Walter; Bader, Michael; Dähnert, Ingo; Dhein, Stefan; Salameh, Aida

    2015-01-01

    Aim: Obesity is a risk factor for the development of cardiovascular diseases. Recently it was shown that overexpression of the Mas-receptor antagonist angiotensin(1-7) could prevent from diet-induced obesity. However, it remained unclear whether diet-induced obesity and angiotensin(1-7) overexpression might also have effects on the cardiovascular system in these rats. Methods:Twenty three male Sprague Dawley rats were fed with standard chow (SD+chow, n = 5) or a cafeteria diet (SD+CD, n = 6) for 5 months. To investigate the effect of angiotensin(1-7) transgenic rats, expressing an angiotensin(1-7)-producing fusion protein in testis were used. These transgenic rats also received a 5 month's feeding period with either chow (TGR+chow, n = 6) or cafeteria diet (TGR+CD, n = 6), respectively. Hemodynamic measurements (pressure-volume loops) were carried out to assess cardiac function and blood pressure. Subsequently, hearts were explanted and investigated according to the Langendorff technique. Furthermore, cardiac remodeling in these animals was investigated histologically. Results:After 5 months cafeteria diet feeding rats showed a significantly increased body weight, which could be prevented in transgenic rats. However, there was no effect on cardiac performance after cafeteria diet in non-transgenic and transgenic rats. Moreover, overexpression of angiotensin(1-7) deteriorated cardiac contractility as indicated by impaired dp/dt. Furthermore, histological analysis revealed that cafeteria diet led to myocardial fibrosis in both, control and transgenic rats and this was not inhibited by an overproduction of angiotensin(1-7). Conclusion:These results indicate that an overexpression of circulating angiotensin(1-7) prevents a cafeteria diet-induced increase in body weight, but does not affect cardiac performance in this experimental rat model of obesity. Furthermore, overexpression of angiotensin(1-7) alone resulted in an impairment of cardiac function. PMID:26733884

  12. A role for the angiotensin type-2 receptor in experimental radiation nephropathy

    International Nuclear Information System (INIS)

    Full text: Irradiation of the kidneys is followed by a well-defined sequence of changes that eventually lead to renal failure. In the rat, blockade of angiotensin II type-1 receptors diminishes and delays the structural and functional changes that occur after kidney irradiation. It has been hypothesized that some of the effects of angiotensin II type-1 blockers are caused by a rise in angiotensin II that stimulates the angiotensin II type-2 receptor. If this hypothesis were applicable to experimental radiation nephropathy, one would expect that blockade of the type-2 receptor by itself would exacerbate radiation nephropathy; and/or that blockade of the type-2 receptor would counteract some or all of the beneficial effects of type-1 receptor blockade. Experiments in the rat radiation nephropathy model failed to support this hypothesis. To the contrary, a type-2 blocker produced a temporary delay in the development of radiation nephropathy when used alone, and it substantially enhanced the prophylactic efficacy of the type-1 blocker. These results imply that both type-1 and type-2 angiotensin receptors need to be blocked to achieve the maximum level of prophylaxis of radiation nephropathy. It is possible that the increased efficacy of the combined blockers is due simply to increased molar levels of angiotensin blockers, so we are determining whether increasing the dose of the type-1 blocker will increase its efficacy. We are also assessing the possibility that the efficacy of angiotensin II blockade can be explained by radiation-induced up-regulation of angiotensin II receptors (type-1, type-2 or total)

  13. Regulation of peripheral vascular tone in patients with heart failure: contribution of angiotensin II

    OpenAIRE

    NEWBY, D.; Goodfield, N; Flapan, A; Boon, N.; Fox, K.; Webb, D

    1998-01-01

    Objective—To determine directly the contribution of angiotensin II to basal and sympathetically stimulated peripheral arteriolar tone in patients with heart failure.
Design—Parallel group comparison.
Subjects—Nine patients with New York Heart Association grade II-IV chronic heart failure, and age and sex matched controls.
Interventions—Forearm plethysmography, lower body negative pressure, local intra-arterial administration of losartan, angiotensin II, and noradrenaline, and estimation of pl...

  14. The effect of angiotensin II on endogenous noradrenaline release in man.

    OpenAIRE

    Seidelin, P H; Coutie, W J; Struthers, A.D.

    1987-01-01

    1. Considerable data from animal studies suggest that angiotensin II exerts a facilitatory effect on noradrenaline release. We sought evidence for such an effect in man by examining how a subpressor dose of angiotensin II (1.5 ng kg-1 min-1) influences the haemodynamic and plasma noradrenaline responses to physiological stimulation of the sympathetic nervous system. 2. The physiological stimuli investigated were a cold pressor test, the response to standing from lying, bicycle exercise and fo...

  15. Charakterisierung der Wirkung von Angiotensin II auf die elektrophysiologischen Eigenschaften reninsezernierenden Zellen der Rattenniere

    OpenAIRE

    Stehle, Alexander

    2006-01-01

    Das Renin-Angiotensin-Aldosteron System (RAAS) ist ein rückgekoppeltes Hormonsystem zur Aufrechterhaltung und Regulation von Plasmavolumen, Plasmaosmolarität und Blutdruck. Die Aspartylprotease Renin wird aus reninsezernierenden Zellen (RSZ) der Vasa afferentia der Nieren freigesetzt. Die Sekretion wird gesteuert durch den Sympathikus, den Blutdruck in den Vasa afferentia, die NaCl-Konzentration an der Macula densa und zirkulierende Hormone, insbesondere Angiotensin II (ANGII). Diese Faktoren...

  16. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study

    OpenAIRE

    Chawla, Lakhmir S.; Busse, Laurence; Brasha-Mitchell, Ermira; Davison, Danielle; Honiq, Jacqueline; Alotaibi, Ziyad; Seneff, Michael G

    2014-01-01

    Introduction Patients with distributive shock who require high dose vasopressors have a high mortality. Angiotensin II (ATII) may prove useful in patients who remain hypotensive despite catecholamine and vasopressin therapy. The appropriate dose of parenteral angiotensin II for shock is unknown. Methods In total, 20 patients with distributive shock and a cardiovascular Sequential Organ Failure Assessment score of 4 were randomized to either ATII infusion (N =10) or placebo (N =10) plus standa...

  17. Effect of angiotensin receptor blockade on endothelial function: focus on olmesartan medoxomil

    OpenAIRE

    Carlos Ferrario

    2009-01-01

    Carlos FerrarioHypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC, USAAbstract: Endothelial dysfunction is the common link between cardiovascular disease risk factors and the earliest event in the cascade of incidents that results in target organ damage. Angiotensin II, the terminal pressor effector arm of the renin-angiotensin-aldosterone system, increases blood pressure (BP) by vasoconstriction and sodium and fluid retention, and has a pro...

  18. Prevention of atrial fibrillation by Renin-Angiotensin system inhibition a meta-analysis

    DEFF Research Database (Denmark)

    Schneider, Markus; Hua, Tsushung A; Böhm, Michael;

    2010-01-01

    The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective.......The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective....

  19. 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

  20. Angiotensin-Receptor Blocker, Angiotensin-Converting Enzyme Inhibitor, and Risks of Atrial Fibrillation: A Nationwide Cohort Study.

    Science.gov (United States)

    Hsieh, Yu-Cheng; Hung, Chen-Ying; Li, Cheng-Hung; Liao, Ying-Chieh; Huang, Jin-Long; Lin, Ching-Heng; Wu, Tsu-Juey

    2016-05-01

    Both angiotensin-receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) have protective effects against atrial fibrillation (AF). The differences between ARB and ACEI in their effects on the primary prevention of AF remain unclear. This study compared ARB and ACEI in combined antihypertensive medications for reducing the risk of AF in patients with hypertension, and determined which was better for AF prevention in a nationwide cohort study.Patients aged ≥55 years and with a history of hypertension were identified from Taiwan National Health Insurance Research Database. Medical records of 25,075 patients were obtained, and included 6205 who used ARB, 8034 who used ACEI, and 10,836 nonusers (no ARB or ACEI) in their antihypertensive regimen. Cox regression models were applied to estimate the hazard ratio (HR) for new-onset AF.During an average of 7.7 years' follow-up, 1619 patients developed new-onset AF. Both ARB (adjusted HR: 0.51, 95% CI 0.44-0.58, P reduced the risk of AF compared to nonusers. Subgroup analysis showed that ARB and ACEI were equally effective in preventing new-onset AF regardless of age, gender, the presence of heart failure, diabetes, and vascular disease, except for those with prior stroke or transient ischemic attack (TIA). ARB prevents new-onset AF better than ACEI in patients with a history of stroke or TIA (log-rank P = 0.012).Both ARB and ACEI reduce new-onset AF in patients with hypertension. ARB prevents AF better than ACEI in patients with a history of prior stroke or TIA. PMID:27196491

  1. 20-Hydroxyeicosatetraenoic acid contributes to the inhibition of K+ channel activity and vasoconstrictor response to angiotensin II in rat renal microvessels.

    Directory of Open Access Journals (Sweden)

    Fan Fan

    Full Text Available The present study examined whether 20-hydroxyeicosatetraenoic acid (HETE contributes to the vasoconstrictor effect of angiotensin II (ANG II in renal microvessels by preventing activation of the large conductance Ca(2+-activated K(+ channel (KCa in vascular smooth muscle (VSM cells. ANG II increased the production of 20-HETE in rat renal microvessels. This response was attenuated by the 20-HETE synthesis inhibitors, 17-ODYA and HET0016, a phospholipase A2 inhibitor AACOF3, and the AT1 receptor blocker, Losartan, but not by the AT2 receptor blocker, PD123319. ANG II (10(-11 to 10(-6 M dose-dependently decreased the diameter of renal microvessels by 41 ± 5%. This effect was blocked by 17-ODYA. ANG II (10(-7 M did not alter KCa channel activity recorded from cell-attached patches on renal VSM cells under control conditions. However, it did reduce the NPo of the KCa channel by 93.4 ± 3.1% after the channels were activated by increasing intracellular calcium levels with ionomycin. The inhibitory effect of ANG II on KCa channel activity in the presence of ionomycin was attenuated by 17-ODYA, AACOF3, and the phospholipase C (PLC inhibitor U-73122. ANG II induced a peak followed by a steady-state increase in intracellular calcium concentration in renal VSM cells. 17-ODYA (10(-5 M had no effect on the peak response, but it blocked the steady-state increase. These results indicate that ANG II stimulates the formation of 20-HETE in rat renal microvessels via the AT1 receptor activation and that 20-HETE contributes to the vasoconstrictor response to ANG II by blocking activation of KCa channel and facilitating calcium entry.

  2. 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...... natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor...

  3. 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

  4. The Impact of Age-Related Dysregulation of the Angiotensin System on Mitochondrial Redox Balance

    Directory of Open Access Journals (Sweden)

    Ramya eVajapey

    2014-11-01

    Full Text Available Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS. A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II by angiotensin-converting enzyme (ACE. Ang II binds with equal affinity to two main angiotensin receptors—type 1 (AT1R and type 2 (AT2R. The binding of Ang II to AT1R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS. This Ang II-AT1R–NADPH-ROS signal triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell.AT2R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT2R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b discuss the effect of age-related activation of RAS on generation of free radicals.

  5. 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...

  6. Renin-angiotensin-aldosterone responsiveness to low sodium and blood pressure reactivity to angiotensin-II are unrelated to cholesteryl ester transfer protein mass in healthy subjects

    NARCIS (Netherlands)

    Krikken, Jan A.; Dallinga-Thie, Geesje M.; Navis, Gerjan; Dullaart, Robin P. F.

    2008-01-01

    Background: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin-angiotensin-aldosterone system (RAAS) may be related to variation in the pla

  7. 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...

  8. Association of the Serum Angiotensin II Level with Disease Severity in Severe Fever with Thrombocytopenia Syndrome Patients.

    Science.gov (United States)

    Cheng, Jiamei; Li, Huiyu; Jie, Shenghua

    2016-01-01

    Objective Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel Bunyavirus. Recent data suggest that the physiological balance of multiple proinflammatory cytokines is substantially changed in cases of severe fever with thrombocytopenia syndrome virus (SFTSV) infection, and the inflammatory response probably plays an important role in disease progression. Angiotensin II is an important active substance of the renin-angiotensin system, and studies have demonstrated that angiotensin II is involved in key events in the inflammatory process and can regulate inflammatory cell responses. Methods In order to elucidate the role of angiotensin II in the pathogenesis of SFTS, we collected serum samples from SFTS patients in the acute or convalescent phase and tested the angiotensin II levels using an enzyme-linked immunosorbent assay as well as SFTSV viral RNA with real-time reverse-transcriptase polymerase chain reaction. Furthermore, we explored possible correlations between the angiotensin II levels and clinical parameters in SFTS patients. Results Our data showed that the serum level of angiotensin II was significantly increased in the acute phase compared with that seen in the convalescent phase and the healthy controls, while there were no significant differences between the convalescent cases and healthy controls (p>0.05). A correlation analysis demonstrated that the level of angiotensin II positively correlated with the SFTS viral RNA load. The angiotensin II levels were also found to be correlated with clinical parameters indicating impairments in organ functions. Moreover, we also found that the angiotensin II levels were significantly increased in the severe cases versus the non-severe cases (p<0.001). Conclusion The serum angiotensin II levels in SFTS patients may be used to stratify the disease severity and are possibly predictive of disease outcomes. PMID:27086801

  9. 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

  10. Angiotensin II activates different calcium signaling pathways in adipocytes.

    Science.gov (United States)

    Dolgacheva, Lyudmila P; Turovskaya, Maria V; Dynnik, Vladimir V; Zinchenko, Valery P; Goncharov, Nikolay V; Davletov, Bazbek; Turovsky, Egor A

    2016-03-01

    Angiotensin II (Ang II) is an important mammalian neurohormone involved in reninangiotensin system. Ang II is produced both constitutively and locally by RAS systems, including white fat adipocytes. The influence of Ang II on adipocytes is complex, affecting different systems of signal transduction from early Са(2+) responses to cell proliferation and differentiation, triglyceride accumulation, expression of adipokine-encoding genes and adipokine secretion. It is known that white fat adipocytes express all RAS components and Ang II receptors (АТ1 and АТ2). The current work was carried out with the primary white adipocytes culture, and Са(2+) signaling pathways activated by Ang II were investigated using fluorescent microscopy. Са(2+)-oscillations and transient responses of differentiated adipocytes to Ang II were registered in cells with both small and multiple lipid inclusions. Using inhibitory analysis and selective antagonists, we now show that Ang II initiates periodic Са(2+)-oscillations and transient responses by activating АТ1 and АТ2 receptors and involving branched signaling cascades:In these cascades, AT1 receptors play the leading role. The results of the present work open a perspective of using Ang II for correction of signal resistance of adipocytes often observed during obesity and type 2diabetes. PMID:26850364

  11. Quantum Chemistry Calculation of Angiotensin Converting Enzyme Inhibitors

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Angiotensin Converting-Enzyme (ACE) inhibitors are potential drugs for hypertension.There are three requirements to be necessary for successful inhibition of ACE:1) a functional group capable of binding to zine in the active site (i.e.carboxylate,phosphonate,or sulfhydryl);2) a carbonyl oxygen capable of accepting a hydryogen bond from some donor residue functional groups and 3) an ionizable C-terminal carboxylate moiety which interacts with positively charged residue〔1〕. We reported active conformers of some ACE inhibitor molecules,which were derived by Distance Comparison〔2〕.In this paper,the electronic structure of the lowest energy conformers and active conformers of the ACE inhibitor molecules (Figure 1) were calculated through ab initio calculation by using Gaussian94 package.The Density Functional Theory (DFT) method and 6-31G** basis set were used 〔3〕.The calculation results were listed in Table 1.The total energies、HOMO energies and the charges of the marked atoms of all active conformers were higher than that of the correspondent lowest energy conformers.They were useful clues for designing novel analogs to inhibit the activity of ACE.

  12. Norepinephrine metabolism in neuronal cultures is increased by angiotensin II

    International Nuclear Information System (INIS)

    In this study the authors have examined the actions of angiotensin II (ANG II) on catecholamine metabolism in neuronal brain cell cultures prepared from the hypothalamus and brain stem. Neuronal cultures prepared from the brains of 1-day-old Sprague-Dawley rats exhibit specific neuronal uptake mechanisms for both norepinephrine (NE) and dopamine (DA), and also monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) activity. Separate neuronal uptake sites for NE and DA were identified by using specific neuronal uptake inhibitors for each amine. In previous studies, they determined that ANG II (10 nM-1 μM) stimulates increased neuronal [3H]NE uptake by acting as specific receptors. They have confirmed these results here and in addition have shown that ANG II has not significant effects on neuronal [3H]DA uptake. These results suggest that the actions of ANG II are restricted to the NE transporter in neuronal cultures. It is possible that ANG II stimulates the intraneuronal metabolism of at least part of the NE that is taken up, because the peptide stimulates MAO activity, an effect mediated by specific ANG II receptors. ANG II had no effect on COMT activity in neuronal cultures. Therefore, the use of neuronal cultures of hypothalamus and brain stem they have determined that ANG II can specifically alter NE metabolism in these areas, while apparently not altering DA metabolism

  13. Angiotensin I converting enzyme inhibitory peptide extracted from freshwater zooplankton.

    Science.gov (United States)

    Lee, Jung Kwon; Lee, Min-Su; Park, Heum Gi; Kim, Se-Kwon; Byun, Hee-Guk

    2010-04-01

    In this study, hydrolysates obtained from the freshwater rotifer Brachionus calyciflonus were investigated for angiotensin I converting enzyme (ACE) inhibitory peptides. Freshwater rotifer protein was hydrolyzed using six separate enzymes in a batch reactor. The peptic hydrolysate had the highest ACE inhibitory activity compared to the other hydrolysates. The highest ACE inhibitory peptide was separated using Sephadex G-25 column chromatography and high-performance liquid chromatography on a C18 column. The 50% inhibitory concentration (IC(50)) value of purified ACE inhibitory peptide was 40.01 microg/mL. ACE inhibitory peptide was identified as being seven amino acid residues of Ala-Gln-Gly-Glu-Arg-His-Arg by N-terminal amino acid sequence analysis. The IC(50) value of purified ACE inhibitory peptide was 47.1 microM, and Lineweaver-Burk plots suggested that the peptide purified from rotifer protein acts as a competitive inhibitor against ACE. The results of this study suggest that peptides derived from freshwater rotifers may be beneficial as antihypertension compounds in functional foods or as pharmaceuticals. PMID:20170338

  14. Angiotensin-converting enzyme kinetics in an endothelial cell column

    International Nuclear Information System (INIS)

    The kinetics of saturable endothelial metabolic functions have been assessed in vivo by transient (indicator-dilution) measurements and in culture by steady-state measurements, but comparisons between the two are difficult. Therefore, we used indicator-dilution methods to assess the kinetics of angiotensin-converting enzyme (ACE) activity in cultured endothelium. Bovine fetal aortic endothelial cells were grown to confluence on microcarrier beads. Cell-covered beads were poured into polypropylene columns and perfused with serum-free culture medium. Six injections, containing [3H]benzol-Phe-Ala-Pro [( 3H]BPAP, an ACE substrate) and varying amounts of unlabeled BPAP, were applied to each column and effluent was collected in serial samples. The apparent kinetics of BPAP metabolism were determined by four models used previously to determine pulmonary endothelial ACE kinetics in vivo, the most useful model incorporating transit time heterogeneity. The Km averaged 5 microM, which is close to values determined previously in vivo and in vitro. The Amax (Vmax.reaction volume) and Amax/Km averaged 6 nmol/min and 1.5 ml/min, respectively, which are lower than estimates in vivo. In conclusion, we have developed a new method for investigating saturable metabolic activity in cultured endothelium, which after further exploration should also enable better comparisons of endothelial metabolic functions in vivo and in culture

  15. Angiotensin-converting enzyme inhibitors in veterinary medicine.

    Science.gov (United States)

    Lefebvre, H P; Brown, S A; Chetboul, V; King, J N; Pouchelon, J-L; Toutain, P L

    2007-01-01

    Angiotensin-converting enzyme (ACE) inhibitors represent one of the most commonly used categories of drugs in canine and feline medicine. ACE inhibitors currently approved for use in veterinary medicine are benazepril, enalapril, imidapril and ramipril. They are all pro-drugs administered by oral route. A physiologically based model taking into account the saturable binding to ACE has been developed for pharmacokinetic analysis. The bioavailability of the active compounds from their respective pro-drug is low. The active metabolites are eliminated by renal, hepatorenal or biliary excretion, according to the drug. The elimination half-life of the free fraction of the active compounds is very short (ranging from approximately 10 min to 2 h). ACE inhibitors are generally well tolerated. Benazepril, enalapril, imidapril and ramipril are approved for dogs with chronic heart failure (CHF). The efficacy of ACE inhibitors has been convincingly demonstrated in dogs with CHF, especially in those with chronic valvular disease. In such clinical settings, ACE inhibitors improve hemodynamics and clinical signs, and increase survival time. In cats with cardiovascular disease, little information is available except for reports of some benefit in cats with hypertrophic cardiomyopathy in two non-controlled investigations. ACE inhibitors have also a mild to moderate hypotensive effect. There is also evidence to recommend ACE inhibitors in dogs and cats with chronic renal failure (CRF). They decrease the glomerular capillary pressure, have antiproteinuric effects, tend to delay the progression of CRF and to limit the extent of renal lesions. PMID:17506720

  16. Norepinephrine uptake by rat jejunum: Modulation by angiotensin II

    International Nuclear Information System (INIS)

    Angiotensin II (ANG II) is believed to stimulate sodium and water absorption from the small intestine by enhancing sympathetic nerve transmission. This study is designed to determine whether ANG II can enhance sympathetic neurotransmission within the small intestine by inhibition norepinephrine (NE) uptake. Intracellular NE accumulation by rat jejunum was concentration dependent and resolved into high- and low-affinity components. The high-affinity component (uptake 1) exhibited a Michaelis constant (Km) of 1.72 μM and a maximum velocity (Vmax) of 1.19 nmol · g-1 · 10 min-1. The low-affinity component (uptake 2) exhibited a Km of 111.1 μM and a Vmax of 37.1 nmol · g-1 · 10 min-1. Cocaine, an inhibitor of neuronal uptake, inhibited the intracellular accumulation of label by 80%. Treatment of animals with 6-hydroxydopamine, which depletes norepinephrine from sympathetic terminals, also attenuated NE uptake by 60%. Thus accumulation within sympathetic nerves constitutes the major form of [3H]NE uptake into rat jejunum. ANG II inhibited intracellular [3H]NE uptake in a concentration-dependent manner. At a dose of 1 mM, ANG II inhibited intracellular [3H]NE accumulation by 60%. Cocaine failed to potentiate the inhibition of [3H]NE uptake produced by ANG II. Thus ANG II appears to prevent [3H]NE accumulation within rat jejunum by inhibiting neuronal uptake

  17. New perspectives in the renin-angiotensin-aldosterone system (RAAS I: endogenous angiotensin converting enzyme (ACE inhibition.

    Directory of Open Access Journals (Sweden)

    Miklós Fagyas

    Full Text Available Angiotensin-converting enzyme (ACE inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected enzyme activities significantly increased by dilution of human serum samples (23.2 ± 0.7 U/L at 4-fold dilution, 51.4 ± 0.3 U/L at 32-fold dilution, n = 3, p = 0.001, suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655 ± 145 U/L, 605 ± 42 U/L, n = 3, p = 0.715, respectively. FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4 ± 2.4 U/L, n = 4, control: 26.4 ± 0.7 U/L, n = 4, p<0.001. Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity

  18. Incidence and influencing factors of aldosterone breakthrough during therapy with angiotensin Ⅱ receptor 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 angiotensin Ⅱ receptor blockers(ARB) alone,or combined with angiotensin-converting enzyme inhibitors(ACEI) in Chinese patients with non-diabetic

  19. Hydrosmotic effect of angiotensin II in the toad skin: role of cyclic AMP.

    Science.gov (United States)

    Coviello, A; Brauckmann, E S; de Atenor, M S; Apud, J A; Causarano, J

    1975-01-01

    The mechanism of action of the hydrosmotic response of the isolated skin of the toad Bufo arenarum Hensel to angiotensin II was studied by means of an indirect pharmacological approach. Angiotensin II (2.10(-10) M), vasopressin (2.10(-13) M) and theophylline (10(-4) and 10(-3) M) in subliminal doses produced a significant increase on water permeability when added in different paired combinations. Angiotensin II (2.10(-7) M) and vasopressin (2.10(-8) M) in doses producing significant effects on water permeability increased the response to submaximal doses of epinephrine (10(-6) M) but not to higher doses (10(-5) M). Acid pH (6.4) and prostaglandin E1 (2.10(-7) M) reduced significantly the hydrosmotic response to angiotensin II, but in contrast with the toad bladder, the effect was not completely abolished. Present results support the view that the hydrosmotic effect of angiotensin II in toad skin is mediated by the adenylate cyclase - cyclic AMP system. PMID:189568

  20. Drug discovery in renin-angiotensin system intervention: past and future.

    Science.gov (United States)

    Williams, Bryan

    2016-06-01

    The renin-angiotensin system (RAS) plays a central role in the control of blood pressure in the body and the way this interacts with other systems is widely recognized. This has not always been the case and this review summarizes how our knowledge has evolved from the initial discovery of renin by Tigerstedt and Berman in 1898. This includes the identification of angiotensin in the 1950s to the proposed relationship between this system, hypertension and ultimately cardiovascular disease. While the RAS is far more complex than originally thought, much is now known about this system and the wide ranging effects of angiotensin in the body. This has enabled the development of therapies that target the various proteins in this pathway and hence are implicated in disease. The first of these treatments was the angiotensin converting enzyme inhibitors (ACE-Is), followed by the angiotensin receptor blockers (ARBs), and more recently the direct renin inhibitors (DRIs). Clinical outcome trials have shown these drugs to be effective, but as they act at contrasting points in the RAS, there are differences in their efficacy and safety profiles. RAS blockade is the foundation of modern combination therapy with a calcium channel blocker and/or a diuretic given to reduce blood pressure and limit the impact of RAS activation. Other options that complement these treatments may be available in the future and will offer more choice to clinicians. PMID:27126389

  1. Spiral CT during pharmacoangiography with angiotensin II in patients with pancreatic disease. Technique and diagnostic efficacy

    Energy Technology Data Exchange (ETDEWEB)

    Kuroda, C.; Mihara, N.; Hosomi, N.; Inoue, E.; Fujita, M. [Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan). Dept. of Diagnostic Radiology; Ohigashi, H.; Ishikawa, O. [Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan). Dept. of Surgery; Nakaizumi, A. [Osaka Medical Center for Cancer and Cardiovascular Deseases (Japan). Dept. of Internal Medicine; Ishiguro, S. [Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan). Dept. of Pathology

    1998-03-01

    Purpose: To compare the diagnostic efficacy of pancreatic pharmacoangiographic CT using angiotensin II with conventional angiographic CT. Material and Methods: Eighteen patients with space-occupying pancreatic disease were examined in this study. Pharmacoangiographic CT was performed with a 1-3-{mu}/6-ml solution of angiotensin II injected through a catheter into the celiac artery during spiral CT. Results: In 17 of the 18 (94%) patients, the area of pancreatic parenchymal enhancement was the same or larger at pharmacoangiographic CT than at conventional angiographic CT. The attenuation value of the pancreatic parenchyma was significantly increased at pharmacoangiographic CT (p=0.0010). Although the attenuation value of tumors was also increased on images obtained after the injection of angiotensin II, the tumor-to-pancreas contrast was significantly greater at pharmacoangiographic CT (p=0.0479). The mean differences in attenuation between tumor and pancreas at angiographic CT with and without angiotensin II were respectively 182 HU and 115 HU. Conclusion: Pharmacoangiographic CT with angiotensin II proved superior to conventional angiographic CT in the diagnosis of pancreatic disease. We therefore recommend it as a supplementary technique at the angiographic examination of patients with suspected pancreatic tumor. (orig.).

  2. Perioperative changes of serum cortisol and plasma angiotensin II levels in patients undergoing thoracotomy for malignancy

    International Nuclear Information System (INIS)

    Objective: To investigate the perioperative changes of serum stress hormones cortisol and plasma angiotensin II in patients undergoing thoracotomy for malignancy. Methods: Serum cortisol and plasma angiotensin II levels were measured with RIA repeatedly in 35 thoracotomy patients operated for malignancy before operation, 1 h after starting operation, at the end of operation, and one day later, Heart rate and blood pressure were constantly monitored during operation. Results: The serum levels of cortisol and plasma angiotensin-II rose gradually during operation with significant differences among the measurements (P < 0. 001 -0.05), No age-difference for the measurements was observed except for a higher systolic pressure in patients over 60. Heart rates at 1 h were positively correlated with 1 h angiotensin-II levels. Heart rates at the end of operation were positively correlated with the cortisol and angiotensin-II levels at that time. Conclusion: The serum levels of these stress hormones rose significantly during the operation. Stress responses in older patients were adequate, yet the higher levels of stress hormones might bring more adverse effect in elderly people, especially cognition impairment. Smooth anaesthesia and adequate post-operative analgesia would lessen the stress effect, providing more ideal recovery, especially for the older patients. (authors)

  3. Effect of Angiotensin II on Blood Flow in Acute and Chronically Inflamed Knee Joints of Rabbits: The Role of Nitric Oxide

    Directory of Open Access Journals (Sweden)

    Hamid Najafipour

    2009-03-01

    Full Text Available Background: Angiotensin converting enzyme (ACE upregulationin stromal cells of joints affected by rheumatoid arthritismay lead to higher tissue angiotensin II that is a vasoconstrictorand mitogen factor. To date, the role of angiotensin II onregulating blood flow in inflamed joints has not been studied.Methods: Acute and chronic joint inflammation was inducedin rabbits by intra-articular injection of carrageenan and antigen-induced arthritis method, respectively. The ACE level ofsynovial fluid and the response of joint blood flow to angiotensinII, angiotensin II receptor antagonist, and the role ofnitric oxide (NO in modulation of the effects of angiotensin IIon joint blood vessels were examined.Results: The synovial fluid level of ACE was significantly increasedduring the process of inflammation and angiotensin IIincreased joint vascular resistance dose-dependently in both acuteand chronically inflamed joints. The angiotensin 1 receptor antagonistlosartan completely blocked the vasoconstrictor effect ofangiotensin II on joint blood vessels and induced vasodilatation.Nitric oxide synthase inhibitor N-omega -nitro L- argininemethyl ester (L-NAME increased joint vascular resistance andaugmented vascular response of inflamed joints to angiotensin II.Conclusion: Angiotensin II receptors in joint blood vesselsare angiotensin -1 subtype, and inflammation significantlyincreases the activity of synovial fluid ACE. Nitric oxide playsa significant role on regulating joint blood flow and in modulationof angiotensin 1 receptor-mediated vasoconstriction ofinflamed joint blood vessels.

  4. Loss of collectrin, an angiotensin-converting enzyme 2 homolog, uncouples endothelial nitric oxide synthase and causes hypertension and vascular dysfunction

    DEFF Research Database (Denmark)

    Cechova, Sylvia; Zeng, Qing; Billaud, Marie;

    2013-01-01

    Collectrin is an orphan member of the renin-angiotensin system and is a homolog of angiotensin-converting enzyme 2, sharing ≈50% sequence identity. Unlike angiotensin-converting enzyme 2, collectrin lacks any catalytic domain. Collectrin has been shown to function as a chaperone of amino acid...

  5. Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles

    Energy Technology Data Exchange (ETDEWEB)

    Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio, E-mail: toshio_n@cc.tuat.ac.jp

    2013-12-06

    Highlights: •Angiotensin converting enzyme (ACE) increases in UVB-irradiated skin. •Administration of an ACE inhibitor improved UVB-induced skin wrinkle. •ACE inhibitor improved UVB-induced epidermal hypertrophy. •ACE inhibitor improved transepidermal water loss in the UVB-irradiated skin. -- Abstract: Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin.

  6. 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...

  7. The effect of an angiotensin converting enzyme inhibitor, ramipril, on bronchial responses to inhaled histamine and bradykinin in asthmatic subjects.

    OpenAIRE

    Dixon, C M; Fuller, R W; Barnes, P J

    1987-01-01

    The effect of a potent inhibitor of angiotensin-converting enzyme, ramipril, was studied on both inhaled histamine and bradykinin-induced bronchoconstriction in six male, normotensive, mild asthmatic subjects. Oral administration of 10 mg ramipril caused no change in lung function or airway reactivity to inhaled histamine or bradykinin despite achieving adequate reduction in angiotensin-converting enzyme activity.

  8. The Adipose Renin-Angiotensin System Modulates Systemic Markers of Insulin Sensitivity and Activates the Intrarenal Renin-Angiotensin System

    Directory of Open Access Journals (Sweden)

    Suyeon Kim

    2006-01-01

    Full Text Available Background. The adipose tissue renin-angiotensin system (RAS contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results. A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO, mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO, and mice overexpressing Agt in adipose tissue (aP2-Agt was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. aP2-Agt mice exhibited increased adiposity and plasma leptin and insulin levels compared to wild type (WT controls. Angiotensinogen and type I Ang II receptor protein levels were also elevated in kidney of aP2-Agt mice. Conclusion. These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity.

  9. Severe hypoglycaemia in type 1 diabetes: impact of the renin-angiotensin system and other risk factors

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik

    2009-01-01

    renin-angiotensin system activity as a novel predictor of risk of severe hypoglycaemia in type 1 diabetes with potential clinical significance. Thus, three sequential renin-angiotensin system-related risk factors were associated with severe hypoglycaemia, and by including these factors in a common model...... which, however, must await additional independent confirmation, include prediction and possibly some prevention of severe hypoglycaemia. An evaluation of renin-angiotensin system activity may - together with assessment of other risk factors - contribute to rational individualized setting of glycaemic...... needs to be confirmed by case-control studies. We identified elevated renin-angiotensin system activity as a novel predictor of risk of severe hypoglycaemia in type 1 diabetes with potential clinical significance. Thus, three sequential renin-angiotensin system-related risk factors were associated with...

  10. Pharmacogenetic risk stratification in angiotensin-converting enzyme inhibitor-treated patients with congestive heart failure

    DEFF Research Database (Denmark)

    Nelveg-Kristensen, Karl Emil; Busk Madsen, Majbritt; Torp-Pedersen, Christian;

    2015-01-01

    SNPs of the angiotensin-converting enzyme gene (rs4343) and ABO blood group genes (rs495828 and rs8176746). METHODS: Danish patients with CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were included. Subjects were genotyped and categorized according to pharmacogenetic......BACKGROUND: Evidence for pharmacogenetic risk stratification of angiotensin-converting enzyme inhibitor (ACEI) treatment is limited. Therefore, in a cohort of ACEI-treated patients with congestive heart failure (CHF), we investigated the predictive value of two pharmacogenetic scores that...... previously were found to predict ACEI efficacy in patients with ischemic heart disease and hypertension, respectively. Score A combined single nucleotide polymorphisms (SNPs) of the angiotensin II receptor type 1 gene (rs275651 and rs5182) and the bradykinin receptor B1 gene (rs12050217). Score B combined...

  11. The Pancreatic Renin-Angiotensin System: Does It Play a Role in Endocrine Oncology?

    Directory of Open Access Journals (Sweden)

    Lam KY

    2001-01-01

    Full Text Available The characterization of a local renin-angiotensin system in the pancreas has attracted much attention because of its potential clinical applications. A pancreatic renin-angiotensin system may be present in humans and may interact with islet cells. Nevertheless, our knowledge of the renin-angiotensin system in the human pancreas is still in its infancy, especially in the field of endocrine oncology. Much of our knowledge stems from the study of the pancreas and pancreatic endocrine tumors of rodents. Thus, the direction of future research should be based on in-depth and collaborative efforts between researchers in the various disciplines in order to apply the newly acquired scientific knowledge to the patient.

  12. Possible Involvement of the Local Renin-Angiotensin System in Exocrine Pancreas Responses to Food Components

    Directory of Open Access Journals (Sweden)

    Grant G

    2001-01-01

    Full Text Available The functioning of the exocrine and endocrine pancreas is strictly co-ordinated through an interdependent array of neural and endocrine, paracrine and autocrine hormonal factors. The responses of the exocrine pancreas to food are primarily initiated via hormones secreted by neuroendocrine cells in the gut. No role for the pancreatic renin-angiotensin system in these mechanisms has so far been established. However, because of its distribution throughout the pancreas, the renin-angiotensin system could have a function in fine-tuning of secretory responses or in integrating some of the actions of the endocrine and exocrine pancreas. In the normal diet, we are exposed to an array of bioactive (lectins, protease inhibitors, hormone-mimics, tannins, etc. Some can profoundly alter pancreas metabolism both in a beneficial or detrimental manner. Others could have beneficial effects on the pancreas renin-angiotensin system. The effects of these compounds need to be evaluated.

  13. Angiotensin-I-Converting Enzyme (ACE Inhibitors from Marine Resources: Prospects in the Pharmaceutical Industry

    Directory of Open Access Journals (Sweden)

    Isuru Wijesekara

    2010-03-01

    Full Text Available Hypertension or high blood pressure is one of the major independent risk factors for cardiovascular diseases. Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE plays an important physiological role in regulation of blood pressure by converting angiotensin I to angiotensin II, a potent vasoconstrictor. Therefore, the inhibition of ACE activity is a major target in the prevention of hypertension. Recently, the search for natural ACE inhibitors as alternatives to synthetic drugs is of great interest to prevent several side effects and a number of novel compounds such as bioactive peptides, chitooligosaccharide derivatives (COS and phlorotannins have been derived from marine organisms as potential ACE inhibitors. These inhibitory derivatives can be developed as nutraceuticals and pharmaceuticals with potential to prevent hypertension. Hence, the aim of this review is to discuss the marine-derived ACE inhibitors and their future prospects as novel therapeutic drug candidates for treat hypertension.

  14. Intrarenal alterations of the angiotensin-converting enzyme type 2/angiotensin 1-7 complex of the renin-angiotensin system do not alter the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats.

    Science.gov (United States)

    Husková, Zuzana; Kopkan, Libor; Červenková, Lenka; Doleželová, Šárka; Vaňourková, Zdeňka; Škaroupková, Petra; Nishiyama, Akira; Kompanowska-Jezierska, Elzbieta; Sadowski, Janusz; Kramer, Herbert J; Červenka, Luděk

    2016-04-01

    The role of the intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. ANG II-dependent malignant hypertension was induced by 13 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. It was hypothesized that pharmacologically-induced inhibition of the ACE2/ANG 1-7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II-dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1-7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1-7 complex did not significantly modify the course of malignant hypertension in I3C-induced Cyp1a1-Ren-2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis. PMID:26833491

  15. Angiotensin receptors in an Australian marsupial, the brushtail possum Trichosurus vulpecula

    Energy Technology Data Exchange (ETDEWEB)

    Sernia, C.; Lello, P.; Thomas, W.G. (Univ. of Queensland, St Lucia (Australia))

    1990-01-01

    In this study, the binding properties of angiotensin receptors were examined in the liver, adrenal, brain, and vascular tissue of the brushtail possum, Trichosurus vulpecula. With 125I-Ile5-angiotensin II as the radioligand, the binding affinity (Ka) and receptor number (R0) were estimated for the liver (Ka = 3.60 +/- 0.31 liters/nmol; R0 = 23.8 +/- 1.30 pmol/g tissue; n = 8) and adrenal (Ka = 1.68 +/- 0.29 liters/nmol; R0 = 1.67 +/- 0.23 pmol/g tissue; n = 8). Specific binding was not found in any of seven areas of the possum brain (n = 6), whereas the expected binding was present in similar areas of the rat brain. Using angiotensin III or the antagonist Sar1-Ala8-angiotensin II as radioligands or changing the composition of the incubation buffer did not alter the outcome. Moreover, the intracerebroventricular injection of 1 and 5 nmol of angiotensin II did not elicit an increase in blood pressure which could be attributed to brain angiotensin II (AII) receptors. Ligand affinities of the adrenal and liver receptors were found to be in the following decreasing order: Val5-AII greater than Ile5-AII = Ile5-AIII greater than Sar1-Ala8-AII greater than Sar1-Gly8-AII greater than Sar1-Leu8-AII greater than Ile5-AI greater than hexapeptide greater than Phe3-Tyr8-AII. The cardiovascular AII receptor was investigated by generating dose-response curves of the pressor activity of Ile5-AII and six AII analogs infused intravenously. It was concluded that liver, adrenal, and vascular AII receptors in the marsupial possum have characteristics similar to those in eutherian mammals. However, the failure to find brain AII receptors raises the possibility that those functions mediated by such receptors in the eutherian brain are absent in the possum and perhaps other marsupials.

  16. Angiotensin receptors in an Australian marsupial, the brushtail possum Trichosurus vulpecula

    International Nuclear Information System (INIS)

    In this study, the binding properties of angiotensin receptors were examined in the liver, adrenal, brain, and vascular tissue of the brushtail possum, Trichosurus vulpecula. With 125I-Ile5-angiotensin II as the radioligand, the binding affinity (Ka) and receptor number (R0) were estimated for the liver (Ka = 3.60 +/- 0.31 liters/nmol; R0 = 23.8 +/- 1.30 pmol/g tissue; n = 8) and adrenal (Ka = 1.68 +/- 0.29 liters/nmol; R0 = 1.67 +/- 0.23 pmol/g tissue; n = 8). Specific binding was not found in any of seven areas of the possum brain (n = 6), whereas the expected binding was present in similar areas of the rat brain. Using angiotensin III or the antagonist Sar1-Ala8-angiotensin II as radioligands or changing the composition of the incubation buffer did not alter the outcome. Moreover, the intracerebroventricular injection of 1 and 5 nmol of angiotensin II did not elicit an increase in blood pressure which could be attributed to brain angiotensin II (AII) receptors. Ligand affinities of the adrenal and liver receptors were found to be in the following decreasing order: Val5-AII greater than Ile5-AII = Ile5-AIII greater than Sar1-Ala8-AII greater than Sar1-Gly8-AII greater than Sar1-Leu8-AII greater than Ile5-AI greater than hexapeptide greater than Phe3-Tyr8-AII. The cardiovascular AII receptor was investigated by generating dose-response curves of the pressor activity of Ile5-AII and six AII analogs infused intravenously. It was concluded that liver, adrenal, and vascular AII receptors in the marsupial possum have characteristics similar to those in eutherian mammals. However, the failure to find brain AII receptors raises the possibility that those functions mediated by such receptors in the eutherian brain are absent in the possum and perhaps other marsupials

  17. Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

    Institute of Scientific and Technical Information of China (English)

    Yan-Huan Feng; Ping Fu

    2016-01-01

    Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS) among patients with type 2 diabetic kidney disease.Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use ofmonotherapy, without applying any language restrictions.Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy,""dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc.Study Selection: The selected articles were carefully reviewed.We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus.Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin Ⅱ receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension.However, existing literature has presented mixed results, in particular, related to patient safety.In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons.Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility.Further trials are warranted to study the combination therapy as an evidence-based practice.

  18. Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Yan-Huan Feng

    2016-01-01

    Full Text Available Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS among patients with type 2 diabetic kidney disease. Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use of monotherapy, without applying any language restrictions. Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy," "dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc. Study Selection: The selected articles were carefully reviewed. We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus. Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin II receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension. However, existing literature has presented mixed results, in particular, related to patient safety. In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons. Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility. Further trials are warranted to study the combination therapy as an

  19. Uptake and metabolism of the novel peptide angiotensin-(1-12 by neonatal cardiac myocytes.

    Directory of Open Access Journals (Sweden)

    Sarfaraz Ahmad

    Full Text Available BACKGROUND: Angiotensin-(1-12 [Ang-(1-12] functions as an endogenous substrate for the productions of Ang II and Ang-(1-7 by a non-renin dependent mechanism. This study evaluated whether Ang-(1-12 is incorporated by neonatal cardiac myocytes and the enzymatic pathways of ¹²⁵I-Ang-(1-12 metabolism in the cardiac myocyte medium from WKY and SHR rats. METHODOLOGY/PRINCIPAL FINDINGS: The degradation of ¹²⁵I-Ang-(1-12 (1 nmol/L in the cultured medium of these cardiac myocytes was evaluated in the presence and absence of inhibitors for angiotensin converting enzymes 1 and 2, neprilysin and chymase. In both strains uptake of ¹²⁵I-Ang-(1-12 by myocytes occurred in a time-dependent fashion. Uptake of intact Ang-(1-12 was significantly greater in cardiac myocytes of SHR as compared to WKY. In the absence of renin angiotensin system (RAS enzymes inhibitors the hydrolysis of labeled Ang-(1-12 and the subsequent generation of smaller Ang peptides from Ang-(1-12 was significantly greater in SHR compared to WKY controls. ¹²⁵I-Ang-(1-12 degradation into smaller Ang peptides fragments was significantly inhibited (90% in WKY and 71% in SHR in the presence of all RAS enzymes inhibitors. Further analysis of peptide fractions generated through the incubation of Ang-(1-12 in the myocyte medium demonstrated a predominant hydrolytic effect of angiotensin converting enzyme and neprilysin in WKY and an additional role for chymase in SHR. CONCLUSIONS/SIGNIFICANCE: These studies demonstrate that neonatal myocytes sequester angiotensin-(1-12 and revealed the enzymes involved in the conversion of the dodecapeptide substrate to biologically active angiotensin peptides.

  20. Angiotensin II Inhibits Insulin Binding to Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Su-Jin Oh

    2011-06-01

    Full Text Available BackgroundInsulin-mediated glucose uptake in insulin target tissues is correlated with interstitial insulin concentration, rather than plasma insulin concentration. Therefore, insulin delivery to the interstitium of target tissues is very important, and the endothelium may also play an important role in the development of insulin resistance.MethodsAfter treating bovine aortic endothelial cells with angiotensin II (ATII, we observed the changes in insulin binding capacity and the amounts of insulin receptor (IR on the cell membranes and in the cytosol.ResultsAfter treatment of 10-7M ATII, insulin binding was decreased progressively, up to 60% at 60 minutes (P<0.05. ATII receptor blocker (eprosartan dose dependently improved the insulin binding capacity which was reduced by ATII (P<0.05. At 200 µM, eprosartan fully restored insulin binding capacity, althogh it resulted in only a 20% to 30% restoration at the therapeutic concentration. ATII did not affect the total amount of IR, but it did reduce the amount of IR on the plasma membrane and increased that in the cytosol.ConclusionATII decreased the insulin binding capacity of the tested cells. ATII did not affect the total amount of IR but did decrease the amount of IR on the plasma membrane. Our data indicate that ATII decreases insulin binding by translocating IR from the plasma membrane to the cytosol. The binding of insulin to IR is important for insulin-induced vasodilation and transendothelial insulin transport. Therefore, ATII may cause insulin resistance through this endothelium-based mechanism.

  1. Angiotensin II Removes Kidney Resistance Conferred by Ischemic Preconditioning

    Directory of Open Access Journals (Sweden)

    Hee-Seong Jang

    2014-01-01

    Full Text Available Ischemic preconditioning (IPC by ischemia/reperfusion (I/R renders resistance to the kidney. Strong IPC triggers kidney fibrosis, which is involved in angiotensin II (AngII and its type 1 receptor (AT1R signaling. Here, we investigated the role of AngII/AT1R signal pathway in the resistance of IPC kidneys to subsequent I/R injury. IPC of kidneys was generated by 30 minutes of bilateral renal ischemia and 8 days of reperfusion. Sham-operation was performed to generate control (non-IPC mice. To examine the roles of AngII and AT1R in IPC kidneys to subsequent I/R, IPC kidneys were subjected to either 30 minutes of bilateral kidney ischemia or sham-operation following treatment with AngII, losartan (AT1R blocker, or AngII plus losartan. IPC kidneys showed fibrotic changes, decreased AngII, and increased AT1R expression. I/R dramatically increased plasma creatinine concentrations in non-IPC mice, but not in IPC mice. AngII treatment in IPC mice resulted in enhanced morphological damage, oxidative stress, and inflammatory responses, with functional impairment, whereas losartan treatment reversed these effects. However, AngII treatment in non-IPC mice did not change I/R-induced injury. AngII abolished the resistance of IPC kidneys to subsequent I/R via the enhancement of oxidative stress and inflammatory responses, suggesting that the AngII/AT1R signaling pathway is associated with outcome in injury-experienced kidney.

  2. Angiotensin-Converting Enzyme Inhibitors and Active Tuberculosis

    Science.gov (United States)

    Wu, Jiunn-Yih; Lee, Meng-Tse Gabriel; Lee, Si-Huei; Lee, Shih-Hao; Tsai, Yi-Wen; Hsu, Shou-Chien; Chang, Shy-Shin; Lee, Chien-Chang

    2016-01-01

    Abstract Numerous epidemiological data suggest that the use of angiotensin-converting enzyme inhibitors (ACEis) can improve the clinical outcomes of pneumonia. Tuberculosis (TB) is an airborne bacteria like pneumonia, and we aimed to find out whether the use of ACEis can decrease the risk of active TB. We conducted a nested case–control analysis by using a 1 million longitudinally followed cohort, from Taiwan national health insurance research database. The rate ratios (RRs) for TB were estimated by conditional logistic regression, and adjusted using a TB-specific disease risk score (DRS) with 71 TB-related covariates. From January, 1997 to December, 2011, a total of 75,536 users of ACEis, and 7720 cases of new active TB were identified. Current use (DRS adjusted RR, 0.87 [95% CI, 0.78–0.97]), but not recent and past use of ACEis, was associated with a decrease in risk of active TB. Interestingly, it was found that chronic use (>90 days) of ACEis was associated with a further decrease in the risk of TB (aRR, 0.74, [95% CI, 0.66–0.83]). There was also a duration response effect, correlating decrease in TB risk with longer duration of ACEis use. The decrease in TB risk was also consistent across all patient subgroups (age, sex, heart failure, cerebrovascular diseases, myocardial infraction, renal diseases, and diabetes) and patients receiving other cardiovascular medicine. In this large population-based study, we found that subjects with recent and chronic use of ACEis were associated with decrease in TB risk. PMID:27175655

  3. Angiotensin II facilitates fibrogenic effect of TGF-β1 through enhancing the down-regulation of BAMBI caused by LPS: a new pro-fibrotic mechanism of angiotensin II.

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    Yu-Sheng Li

    Full Text Available Angiotensin II has progressively been considered to play an important role in the development of liver fibrosis, although the mechanism isn't fully understood. The aim of this study was to investigate a possible pro-fibrotic mechanism, by which angiotensin II would enhance the pro-fibrotic effect of transforming growth factor beta 1 (TGF-β1 through up-regulation of toll-like receptor 4 (TLR4 and enhancing down-regulation of TGF-β1 inhibitory pseudo-receptor-BAMBI caused by LPS in hepatic stellate cells (HSCs. Firstly, the synergistic effects of angiotensin II, TGF-β1 and LPS on collagen 1α production were confirmed in vitro by ELISA, in which angiotensin II, LPS and TGF-β1 were treated sequentially, and in vivo by immunofluorescence, in the experiments single or multiple intra-peritoneally implanted osmotic mini-pumps administrating angiotensin II or LPS combined with intra-peritoneal injections of TGF-β1 were used. We also found that only LPS and TGF-β1 weren't enough to induce obvious fibrogenesis without angiotensin II. Secondly, to identify the reason of why angiotensin II is so important, the minute level of TLR4 in activated HSCs - T6 and primary quiescent HSCs of rat, up-regulation of TLR4 by angiotensin II and blockage by different angiotensin II receptor type 1 (AT1 blockers in HSCs were assayed by western blotting in vitro and immunofluorescence in vivo. Finally, BAMBI expression level, which is regulated by LPS-TLR4 pathway, was detected by qRT-PCR and results showed angiotensin II enhanced the down-regulation of BAMBI mRNA caused by LPS in vitro and in vivo, and TLR4 neutralization antibody blocked this interactive effect. These data demonstrated that angiotensin II enhances LPS-TLR4 pathway signaling and further down-regulates expression of BAMBI through up-regulation of TLR4, which results in facilitation of pro-fibrotic activity of TGF-β1. Angiotensin II, LPS and TGF-β1 act synergistically during hepatic fibrogenesis

  4. 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

  5. Different in vivo functions of the two catalytic domains of angiotensin converting enzyme (ACE)

    OpenAIRE

    Bernstein, Kenneth E.; Shen, Xiao Z.; Gonzalez-Villalobos, Romer A.; Billet, Sandrine; Okwan-Duodu, Derick; Ong, Frank S.; Fuchs, Sebastien

    2010-01-01

    Angiotensin converting enzyme (ACE) can cleave angiotensin I, bradykinin, neurotensin and many other peptide substrates in vitro. In part, this is due to the structure of ACE, a protein composed of two independent catalytic domains. Until very recently, little was known regarding the specific in vivo role of each ACE domain, and they were commonly regarded as equivalent. This is not true, as shown by mouse models with a genetic inactivation of either the ACE N- or C-domains. In vivo, most ang...

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    patients in a double-blind randomized placebo-controlled 1-year intervention trial using a predefined systolic blood pressure target of 140 mm Hg (SAFIR study). Each group of 41 patients did not differ in terms of age, blood pressure, comorbidity, antihypertensive treatment, dialysis parameters, and......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...

  7. Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN

    OpenAIRE

    Rai, Partab; Lederman, Rivka; Haque, Shabirul; Rehman, Shabina; Kumar, Viki; Sataranatrajan, Kavithalakshmi; Malhotra, Ashwani; Kasinath, Balakuntalam S.; Singhal, Pravin C.

    2014-01-01

    Mammalian target of rapamycin (mTOR) has been reported to contribute to the development of HIV-associated nephropathy (HIVAN). We hypothesized that HIV may be activating renal tissue mTOR pathway through renin angiotensin system (RAS) via Angiotensin Receptor Type II receptor (AT2R). Renal tissues of Vpr transgenic and Tg26 (HIVAN) mice displayed enhanced phosphorylation of mTOR and p70S6K. Aliskiren, a renin inhibitor attenuated phosphorylation of both mTOR and p70S6K in renal tissues of HIV...

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

    DEFF Research Database (Denmark)

    Stenman, Emelie; Edvinsson, Lars

    2004-01-01

    MCA occlusion (P<0.05). The angiotensin II type 1 (AT1) receptor antagonists candesartan and losartan abolished the enhanced responses to angiotensin II (P<0.05), whereas the AT2 receptor antagonist PD123319 had no effect. The amount of AT1 receptor mRNA was lower in the occluded MCAs compared with....... 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. 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. Reduced plasma levels of angiotensin-(1-7 and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

    Directory of Open Access Journals (Sweden)

    E.P. Velloso

    2007-04-01

    Full Text Available The relationship between preeclampsia and the renin-angiotensin system (RAS is poorly understood. Angiotensin I-converting enzyme (ACE is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II and inactivating the vasodilator angiotensin-(1-7 (Ang-(1-7. ACE (I/D polymorphism is characterized by the insertion (I or deletion (D of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D polymorphism was correlated with plasma Ang-(1-7 levels and several RAS components in both preeclamptic (N = 20 and normotensive pregnant women (N = 20. The percentage of the ACE DD genotype (60% in the preeclamptic group was higher than that for the control group (35%; however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260. The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 ± 5.06 vs 27.6 ± 3.25 nmol Hip-His Leu-1 min-1 mL-1 in DD control patients; P = 0.0005. Plasma renin activity was markedly reduced in preeclampsia (0.81 ± 0.2 vs 3.43 ± 0.8 ng Ang I mL plasma-1 h-1 in DD normotensive patients; P = 0.0012. A reduced plasma level of Ang-(1-7 was also observed in preeclamptic women (15.6 ± 1.3 vs 22.7 ± 2.5 pg/mL in the DD control group; P = 0.0146. In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

  11. Serum levels of renin, angiotensin-converting enzyme and angiotensin II in patients treated by surgical excision, propranolol and captopril for problematic proliferating infantile haemangioma.

    Science.gov (United States)

    Sulzberger, L; Baillie, R; Itinteang, T; de Jong, S; Marsh, R; Leadbitter, P; Tan, S T

    2016-03-01

    The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by β-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH. PMID:26612192

  12. Determination of the exact molecular requirements for type 1 angiotensin receptor epidermal growth factor receptor transactivation and cardiomyocyte hypertrophy.

    Science.gov (United States)

    Smith, Nicola J; Chan, Hsiu-Wen; Qian, Hongwei; Bourne, Allison M; Hannan, Katherine M; Warner, Fiona J; Ritchie, Rebecca H; Pearson, Richard B; Hannan, Ross D; Thomas, Walter G

    2011-05-01

    Major interest surrounds how angiotensin II triggers cardiac hypertrophy via epidermal growth factor receptor transactivation. G protein-mediated transduction, angiotensin type 1 receptor phosphorylation at tyrosine 319, and β-arrestin-dependent scaffolding have been suggested, yet the mechanism remains controversial. We examined these pathways in the most reductionist model of cardiomyocyte growth, neonatal ventricular cardiomyocytes. Analysis with [(32)P]-labeled cardiomyocytes, wild-type and [Y319A] angiotensin type 1 receptor immunoprecipitation and phosphorimaging, phosphopeptide analysis, and antiphosphotyrosine blotting provided no evidence for tyrosine phosphorylation at Y319 or indeed of the receptor, and mutation of Y319 (to A/F) did not prevent either epidermal growth factor receptor transactivation in COS-7 cells or cardiomyocyte hypertrophy. Instead, we demonstrate that transactivation and cardiomyocyte hypertrophy are completely abrogated by loss of G-protein coupling, whereas a constitutively active angiotensin type 1 receptor mutant was sufficient to trigger transactivation and growth in the absence of ligand. These results were supported by the failure of the β-arrestin-biased ligand SII angiotensin II to transactivate epidermal growth factor receptor or promote hypertrophy, whereas a β-arrestin-uncoupled receptor retained these properties. We also found angiotensin II-mediated cardiomyocyte hypertrophy to be attenuated by a disintegrin and metalloprotease inhibition. Thus, G-protein coupling, and not Y319 phosphorylation or β-arrestin scaffolding, is required for epidermal growth factor receptor transactivation and cardiomyocyte hypertrophy via the angiotensin type 1 receptor. PMID:21383310

  13. Association between the intrarenal renin-angiotensin system and renal injury in chronic kidney disease of dogs and cats.

    Science.gov (United States)

    Mitani, Sawane; Yabuki, Akira; Taniguchi, Kazuyuki; Yamato, Osamu

    2013-02-01

    The association of renin and angiotensin II, which are potent components of the renin-angiotensin system, with the severity of chronic renal disease was investigated immunohistochemically in dogs and cats. Immunoreactivities of renin and angiotensin II were evaluated quantitatively, and their correlations with the degrees of glomerulosclerosis, glomerular hypertrophy, interstitial cell infiltration and interstitial fibrosis were statistically analyzed. Immunoreactivities for renin were detected in afferent arteries in both dogs and cats. The score of renin-positive signals showed no correlation with plasma creatinine concentration or any of the histopathological parameters, except for the diameter of glomeruli in dogs. Immunoreactivities for angiotensin II were detected in tubules (primarily proximal tubules) and interstitial mononuclear cells in both dogs and cats. The score of tubular angiotensin II correlated with glomerulosclerosis and cell infiltration in cats but not in dogs. The score of interstitial angiotensin II correlated with plasma creatinine concentration, glomerulosclerosis, cell infiltration and fibrosis in dogs and with glomerulosclerosis and cell infiltration in cats. In conclusion, the results of the study suggest that intrarenal renin-angiotensin system is correlated with the severity of kidney disease, with the underlying mechanism differing between dogs and cats. PMID:22986274

  14. Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span.

    Science.gov (United States)

    Kumar, Sandeep; Dietrich, Nicholas; Kornfeld, Kerry

    2016-02-01

    Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new

  15. Angiotensin converting enzyme and memory: preclinical and clinical data.

    Science.gov (United States)

    Sudilovsky, A; Turnbull, B; Croog, S H; Crook, T

    effects, and these are prevented if captopril is administered previously (Koller et al, 1979). Also, chronic oral treatment with captopril produces changes of brain renin angiotensin system parameters which suggest inhibition of AII biosyntheses in the brain (Scholkens et al, 1983). It is conceivable therefore, that our findings with prolonged administration of captopril are exerted through reduced formation of AII. Other possible mechanisms through which captopril may affect cognition include peptide-protein systems (Ganten et al, 1982, Sudilovsky et al, 1988) or the modulation of cerebral blood flow autoregulation mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2856549

  16. Angiotensin Converting Enzyme (ACE Inhibitor Extends Caenorhabditis elegans Life Span.

    Directory of Open Access Journals (Sweden)

    Sandeep Kumar

    2016-02-01

    Full Text Available Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms

  17. Mechanisms of fetal and neonatal renal impairment by pharmacologic inhibition of angiotensin.

    Science.gov (United States)

    Chevalier, Robert L

    2012-01-01

    The renin-angiotensin system is highly conserved through evolutionary history, and has multiple functions in addition to maintaining cardiovascular homeostasis: these include the regulation of renal cell survival and cell death, and development of the kidney. The importance of angiotensin (ANG) in normal kidney development was first recognized in infants with renal maldevelopment born to mothers treated with angiotensin converting enzyme (ACE) inhibitors or with ANG AT1 receptor blockers. The molecular role of ANG in renal development has been elucidated using gene targeting in mice, revealing major effects in branching morphogenesis, vasculogenesis, development of the papilla and renal concentrating mechanism. Although exposure of the fetus to ANG inhibitors is potentially harmful throughout pregnancy, effects are greater in late compared to early gestation. Significant differences between humans and rodents in placental transfer of ANG and timing of renal development contributed to initial delays in recognizing the teratogenic effects of ANG inhibitors. Although administration of ACE or AT1 receptor inhibitors can slow progression of renal disease in older children, ANG inhibition in the neonatal period can aggravate renal injury due to congenital urinary tract obstruction. Neonates are also far more sensitive than older children to the hypotensive actions these agents and doses must be markedly reduced to avoid precipitating oliguria. Understanding the complex interactions of the maturing renin-angiotensin system in the perinatal period is essential in the use of ANG or renin inhibitors in women during childbearing years or in neonates with cardiovascular or renal disease. PMID:22876894

  18. Het bepalen van de plasma renine activiteit door middel van de radioimmunochemische bepaling van angiotensine I

    NARCIS (Netherlands)

    Elvers LH; Somers HHJ; Loeber JG

    1986-01-01

    De plasma renine activiteit (PRA) wordt gemeten door de radioimmunochemische bepaling (RIA) van het angiotensine I (AI) dat gevormd wordt tijdens incubatie van het renine met zijn substraat (angiotensinogeen). Om degradatie van het gevormde AI door peptidases te voorkomen worden als angiotensinases

  19. 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

  20. Cricothyroidotomy in a angiotensin-converting enzyme (ACE Inhibitor tongue´s angioedema.

    Directory of Open Access Journals (Sweden)

    Acle-Cervera L, Morales-Angulo C, García-Zornoza R, Rubio Suárez A

    2013-01-01

    Full Text Available Hereditary angioedema by inhibitors of Angiotensin Converting Enzyme(ACE is a very rare disorder. It usually affects the upper airway mucosa andproduce rapidly evolving acute exacerbations requiring urgent treatment.We repost the case of a patient being treated with ACE inhibitors and anreview of prevalence, pathophysiology and management of angioedemawith ACE inhibitors for treatment and the latest treatments.

  1. Postanesthetic Severe Oral Angioedema in Patient’s Taking Angiotensin-Converting Enzyme Inhibitor

    Directory of Open Access Journals (Sweden)

    Acílio Marques

    2014-01-01

    Full Text Available Angiotensin-converting enzyme (ACE inhibitors are the leading cause of a drug-induced angioedema. This occurrence is frequently underdiagnosed, but its relapse can be life-threatening. The authors’ intention in reporting this clinical case is to sound a warning about reviewing attitudes and surveillance to try to improve patient perioperative safety.

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

    Directory of Open Access Journals (Sweden)

    V. V. Fomin

    2016-01-01

    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.

  3. 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

  4. Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia.

    Science.gov (United States)

    Burke, Suzanne D; Zsengellér, Zsuzsanna K; Khankin, Eliyahu V; Lo, Agnes S; Rajakumar, Augustine; DuPont, Jennifer J; McCurley, Amy; Moss, Mary E; Zhang, Dongsheng; Clark, Christopher D; Wang, Alice; Seely, Ellen W; Kang, Peter M; Stillman, Isaac E; Jaffe, Iris Z; Karumanchi, S Ananth

    2016-07-01

    Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes. PMID:27270170

  5. 21 CFR 862.1085 - Angiotensin I and renin test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Angiotensin I and renin test system. 862.1085 Section 862.1085 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry...

  6. Cardiac repolarization during hypoglycaemia in type 1 diabetes: impact of basal renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Due-Andersen, Rikke; Høi-Hansen, Thomas; Larroude, Charlotte Ellen; Olsen, Niels Vidiendal; Kanters, Jørgen Kim; Boomsma, Frans; Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2008-01-01

    AIMS: Hypoglycaemia-induced cardiac arrhythmias may be involved in the pathogenesis of the 'dead-in-bed syndrome' in patients with type 1 diabetes. Evidence suggests that the renin-angiotensin system (RAS) influences the occurrence of arrhythmias. The aim of this study was to explore if basal RAS...

  7. Cardiac repolarization during hypoglycaemia and hypoxaemia in healthy males: impact of renin-angiotensin system activity

    DEFF Research Database (Denmark)

    Due-Andersen, Rikke; Høi-Hansen, Thomas; Olsen, Niels Vidiendal; Larroude, Charlotte Ellen; Kanters, Jørgen Kim; Boomsma, Frans; Pedersen-Bjergaard, Ulrik; Thorsteinsson, Birger

    2008-01-01

    AIMS: Activity in the renin-angiotensin system (RAS) may influence the susceptibility to cardiac arrhythmia. To study the effect of basal RAS activity on cardiac repolarization during myocardial stress induced by hypoglycaemia or hypoxaemia in healthy humans. METHODS AND RESULTS: Ten subjects with...

  8. POLLUTANT PARTICLES PRODUCE VASOCONSTRICTION AND ENHANCE MAPK SIGNALING VIA ANGIOTENSIN TYPE 1 RECEPTOR

    Science.gov (United States)

    Exposure to particulate matter (PM) is associated with acute cardiovascular mortality and morbidity, but the mechanisms are not entirely clear. In this study, we hypothesized that PM may activate the angiotensin type 1 receptor (AT1R), a G protein-coupled receptor that regulates ...

  9. Angiotensin-converting enzyme activity and cognitive impairment during hypoglycaemia in healthy humans

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Thomsen, Carsten E; Høgenhaven, Hans;

    2008-01-01

    INTRODUCTION: In type 1 diabetes increased risk of severe hypoglycaemia is associated with high angiotensin-converting enzyme (ACE) activity. We tested in healthy humans the hypothesis that this association is explained by the reduced ability of subjects with high ACE activity to maintain normal...

  10. THE ANGIOTENSIN CONVERTING-ENZYME-INHIBITOR PERINDOPRIL IMPROVES SURVIVAL AFTER EXPERIMENTAL MYOCARDIAL-INFARCTION IN PIGS

    NARCIS (Netherlands)

    TOBE, TJM; DELANGEN, CDJ; WEERSINK, EGL; VANWIJNGAARDEN, J; BEL, KJ; DEGRAEFF, PA; VANGILST, WH; WESSELING, H

    1992-01-01

    In this randomized, blinded study the effect of the angiotensin converting enzyme inhibitor perindopril on electrical stability after myocardial infarction in pigs was compared to placebo. The left anterior descending artery was occluded for 45 min. Perindoprilat (0.06 mg/kg, n = 12) or saline (n =

  11. Effect of angiotensin receptor blockade on endothelial function: focus on olmesartan medoxomil

    Directory of Open Access Journals (Sweden)

    Carlos Ferrario

    2009-03-01

    Full Text Available Carlos FerrarioHypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC, USAAbstract: Endothelial dysfunction is the common link between cardiovascular disease risk factors and the earliest event in the cascade of incidents that results in target organ damage. Angiotensin II, the terminal pressor effector arm of the renin-angiotensin-aldosterone system, increases blood pressure (BP by vasoconstriction and sodium and fluid retention, and has a pro-oxidative action that induces endothelial dysfunction and contributes to vascular remodeling. Angiotensin receptor blockers (ARBs reduce BP and morbidity and mortality in patients with hypertension, ventricular hypertrophy, diabetes mellitus, and renal disease. Olmesartan medoxomil is a long-acting, well-tolerated, effective ARB that prevents or reverses endothelial dysfunction in animal models of atherosclerosis, hypertension, diabetes, nephropathy, and retinopathy. Olmesartan medoxomil, a prodrug of olmesartan approved for the treatment of hypertension, has been shown to ameliorate endothelial dysfunction in patients with hypertension or diabetes. In randomized studies, the drug reduces vascular inflammation and the volume of large atherosclerotic plaques, increases the number of regenerative endothelial progenitor cells in the peripheral circulation, improves endothelium-dependent relaxation, and restores the normal resistance vessel morphology. Importantly, the impact of olmesartan medoxomil on endothelial dysfunction is thought to be independent of BP lowering.Keywords: endothelial dysfunction, angiotensin receptor blocker, olmesartan medoxomil, hypertension, atherosclerosis 

  12. Clinical Implication of the Renin-angiotensin-aldosterone Blockers in Chronic Kidney Disease Undergoing Hemodialysis

    OpenAIRE

    Morishita, Yoshiyuki; Kusano, Eiji; Nagata, Daisuke

    2014-01-01

    The renin-angiotensin-aldosterone system (RAAS) blockers have been widely used in chronic kidney disease patients undergoing hemodialysis; however, whether RAAS blockers have beneficial effects for cardiovascular disease in those patients has not been fully defined. This review focuses on the effects of RAAS blockers in chronic kidney disease undergoing hemodialysis for cardiovascular disease.

  13. Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action.

    Directory of Open Access Journals (Sweden)

    Hong Wang

    Full Text Available ACE inhibitors and ARBs (angiotensin receptor blockers have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I, an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p. that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia, and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA

  14. Angiotensin II Type 1 Receptor Signaling Regulates Feeding Behavior through Anorexigenic Corticotropin-releasing Hormone in Hypothalamus*

    OpenAIRE

    Yamamoto, Rie; Akazawa, Hiroshi; Fujihara, Hiroaki; Ozasa, Yukako; Yasuda, Noritaka; Ito, Kaoru; Kudo, Yoko; Qin, Yingjie; Ueta, Yoichi; Komuro, Issei

    2011-01-01

    The activation of renin-angiotensin system contributes to the development of metabolic syndrome and diabetes as well as hypertension. However, it remains undetermined how renin-angiotensin system is implicated in feeding behavior. Here, we show that angiotensin II type 1 (AT1) receptor signaling regulates the hypothalamic neurocircuit that is involved in the control of food intake. Compared with wild-type Agtr1a+/+ mice, AT1 receptor knock-out (Agtr1a−/−) mice were hyperphagic and obese with ...

  15. Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

    Science.gov (United States)

    Wang, Hong; Sethi, Gautam; Loke, Weng-Keong; Sim, Meng-Kwoon

    2015-01-01

    ACE inhibitors and ARBs (angiotensin receptor blockers) have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I), an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy) attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p.) that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia), and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA-I. DAA-I completely

  16. 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...

  17. Overexpression of angiotensin-converting enzyme in myelomonocytic cells enhances the immune response [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Kenneth E. Bernstein

    2016-03-01

    Full Text Available Angiotensin-converting enzyme (ACE converts angiotensin I to the vasoconstrictor angiotensin II and thereby plays an important role in blood pressure control. However, ACE is relatively non-specific in its substrate specificity and cleaves many other peptides. Recent analysis of mice overexpressing ACE in monocytes, macrophages, and other myelomonocytic cells shows that these animals have a marked increase in resistance to experimental melanoma and to infection by Listeria monocytogenes or methicillin-resistant Staphylococcus aureus (MRSA. Several other measures of immune responsiveness, including antibody production, are enhanced in these animals. These studies complement a variety of studies indicating an important role of ACE in the immune response.

  18. Effect of angiotensin Ⅱ receptor 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 angiotensin Ⅱ receptor 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.

  19. Probiotics (VSL#3 prevent endothelial dysfunction in rats with portal hypertension: role of the angiotensin system.

    Directory of Open Access Journals (Sweden)

    Sherzad K Rashid

    Full Text Available AIMS: Portal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO and endothelium-dependent hyperpolarization (EDH has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL was evaluated. METHODS: Rats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt⁻¹.day⁻¹ for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry. RESULTS: Both NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IKCa and SKCa and an increased expression of endothelial NO synthase (eNOS. In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IKCa, SKCa and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-α, IL-1α and MCP-1 levels. CONCLUSIONS: These findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system.

  20. 25-Hydroxyvitamin D status, arterial stiffness and the renin-angiotensin system in healthy humans.

    Science.gov (United States)

    Abdi-Ali, Ahmed; Nicholl, David D M; Hemmelgarn, Brenda R; MacRae, Jennifer M; Sola, Darlene Y; Ahmed, Sofia B

    2014-01-01

    Vitamin D deficiency is associated with increased arterial stiffness. We sought to clarify the influence of vitamin D in modulating angiotensin II-dependent arterial stiffness. Thirty-six healthy subjects (33 ± 2 years, 67% female, mean 25-hydroxyvitamin D 69 ± 4 nmol/L) were studied in high salt balance. Arterial stiffness, expressed as brachial pulse wave velocity (bPWV) and aortic augmentation index (AIx), was measured by tonometry at baseline and in response to angiotensin II infusion (3 ng/kg/min × 30 min then 6 ng/kg/min × 30 min). The primary outcome was change in bPWV after an angiotensin II challenge. Results were analyzed according to plasma 25-hydroxyvitamin D status: deficient (nmol/L) and sufficient (≥ 50 nmol/L). There were no differences in baseline arterial stiffness between vitamin D deficient (25-hydroxyvitamin D 40 ± 2 nmol/L) and sufficient (25-hydroxyvitamin D 80 ± 4 nmol/L) groups. Compared with sufficient vitamin D status, vitamin D deficiency was associated with a decreased arterial response to angiotensin II challenge (Δbrachial pulse wave velocity: 0.48 ± 0.44 m/s versus 1.95 ± 0.22 m/s, p=0.004; Δaortic augmentation index: 9.4 ± 3.4% versus 14.2 ± 2.7%, p=0.3), which persisted for brachial pulse wave velocity response after adjustment for covariates (p=0.03). Vitamin D deficiency is associated with increased arterial stiffness in healthy humans, possibly through an angiotensin II-dependent mechanism. PMID:24164282

  1. Severe hypoglycaemia in type 1 diabetes: impact of the renin-angiotensin system and other risk factors

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik

    2009-01-01

    renin-angiotensin system activity as a novel predictor of risk of severe hypoglycaemia in type 1 diabetes with potential clinical significance. Thus, three sequential renin-angiotensin system-related risk factors were associated with severe hypoglycaemia, and by including these factors in a common model...... which, however, must await additional independent confirmation, include prediction and possibly some prevention of severe hypoglycaemia. An evaluation of renin-angiotensin system activity may - together with assessment of other risk factors - contribute to rational individualized setting of glycaemic...... both subjects at low and at high risk within a one-year period were identified. Preliminary data suggest that this is explained by impaired capability of subjects with high renin-angiotensin system activity to maintain cognitive function during hypoglycaemia. The clinical implications of this finding...

  2. Combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide activate postnatal vasculogenesis in spontaneously hypertensive rats

    NARCIS (Netherlands)

    D. You (Dong); C. Cochain (Clément); C. Loinard (Céline); J. Vilar (Jose Manuel); B.M.E. Mees (Barend); M. Duriez (Micheline); B.I. Levy (Bernard); J.S. Silvestre (Jean Sebastien)

    2008-01-01

    textabstractCardiovascular risk factors are associated with reduction in both the number and function of vascular progenitor cells. We hypothesized that 1) hypertension abrogates postnatal vasculogenesis, and 2) antihypertensive treatment based on the combination of perindopril (angiotensin-converti

  3. Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction

    OpenAIRE

    Tomasz J. Guzik; Hoch, Nyssa E.; Brown, Kathryn A.; McCann, Louise A.; Rahman, Ayaz; Dikalov, Sergey; Goronzy, Jorg; Weyand, Cornelia; Harrison, David G

    2007-01-01

    Hypertension promotes atherosclerosis and is a major source of morbidity and mortality. We show that mice lacking T and B cells (RAG-1−/− mice) have blunted hypertension and do not develop abnormalities of vascular function during angiotensin II infusion or desoxycorticosterone acetate (DOCA)–salt. Adoptive transfer of T, but not B, cells restored these abnormalities. Angiotensin II is known to stimulate reactive oxygen species production via the nicotinamide adenosine dinucleotide phosphate ...

  4. Pengaruh Pemberian Ekstrak Etanol Buah Mengkudu terhadap Aktivitas Angiotensin Converting Enzyme (ACE) pada Tikus Wistar yang Mendapat Diet Natrium

    OpenAIRE

    Syahreza, Adri

    2012-01-01

    Hypertension is now a global problem because of the prevalence continues to increase in line with lifestyle changes. One of hypertension cause is excess intake of sodium thus will increase the fluid volume in the body. One of regulates the fluid balance in the body is mechanism of renin angiotensin aldosterone system (RAAS). Increasing activity of angiotensin converting enzyme (ACE) in the body will lead to hypertension through RAAS. ACE activation can be inhibited by ACE In...

  5. The absence of protective effect of candesartan and angiotensin IV in the moderate brain injury in rats

    International Nuclear Information System (INIS)

    Background: angiotensin receptor blockers (ARB) are protective in various models of experimental ischemic stroke. This protective effect is mediated by the stimulation of non-AT1 receptors by angiotensin II and angiotensin IV. Since traumatic brain injury shares with ischemic cerebral injury several common mechanisms, we examined if a pretreatment with the ARB candesartan, or a post-treatment with angiotensin IV are also protective in a rat model of blunt traumatic brain injury (TBI). Methods :adults Sprague Dawley rats were treated for five days with candesartan (0.5 mg/kg/day) or saline by gavage prior to the induction of diffuse moderate TBI using the impact-acceleration model. Two others groups of rats were treated by a daily intraperitoneal injection of angiotensin IV (1.5 mg/kg/day) or saline for five days following TBI. Overall neurological insult were assessed daily by measuring the neurological score. Sensitive deficits (scotch test) and sensorimotor deficits (beam-walking test) were evaluated daily from day 1 to 7 and at day 15; cognitive impairment (object recognition test) was evaluated at day 15. Results : TBI induced significant sensitive and sensorimotor deficits that were maximal at day 1 and spontaneously improved with time. At day 15, traumatised animals had a marked alteration of the working memory. Neither treatment with candesartan, angiotensin IV or with erythropoietin decreased the severity of the initial sensorimotor deficits, nor accelerate the recovery rate. Candesartan, angiotensin IV had likewise no protective effect on the cognitive deficit evaluated to day 15. Conclusion: pretreatment with candesartan and post-treatment with angiotensin IV are both ineffective to protect against sensorimotor and c ognitive impairment in a rat model of impact-acceleration TBI. (author)

  6. Angiotensin-converting enzyme insertion/deletion polymorphism does not influence the restenosis rate after coronary stent implantation

    OpenAIRE

    Ferrari, Markus; Mudra, Harald; Grip, Lars; Voudris, Vassilis; Schächinger, Volker; de Jaegere, Peter; Rieber, Johannes; Hausmann, Dirk; Rothman, Martin; Koschyk, Dietmar H.; Figulla, Hans R

    2002-01-01

    Background. Experimental studies have shown an activation of the angiotensin-converting enzyme (ACE) system as a response to endothelial injury. Recent publications have elucidated the hypothesis that the ACE gene polymorphism may influence the level of late luminal loss after coronary stent implantation. It is still unclear whether the polymorphism of the angiotensin gene is a major predictor of the extent of neointimal hyperplasia. In this multicenter study, we therefore tested the relation...

  7. Renin-angiotensin system expression and secretory function in cultured human ciliary body non-pigmented epithelium

    OpenAIRE

    Cullinane, A B; Leung, P S; Ortego, J.; Coca-Prados, M; Harvey, B J

    2002-01-01

    Background: Renin-angiotensin system (RAS) components have been identified in human ciliary body and aqueous humour, pointing to a role for the RAS in the regulation of aqueous humour dynamics. Here, the authors examine the functional expression of a RAS and the effects of angiotensin II (AII) on a signal transduction pathway and ion secretion mechanism in cultured human ciliary body non-pigmented epithelium (HNPE).

  8. 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...

  9. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis

    OpenAIRE

    Li, Nien-Chen; Lee, Austin; Whitmer, Rachel A.; Kivipelto, Miia; Lawler, Elizabeth; Kazis, Lewis E; Wolozin, Benjamin

    2010-01-01

    Objective To investigate whether angiotensin receptor blockers protect against Alzheimer’s disease and dementia or reduce the progression of both diseases. Design Prospective cohort analysis. Setting Administrative database of the US Veteran Affairs, 2002-6. Population 819 491 predominantly male participants (98%) aged 65 or more with cardiovascular disease. Main outcome measures Time to incident Alzheimer’s disease or dementia in three cohorts (angiotensin receptor blockers, lisinopril, and ...

  10. 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 ...

  11. Regulatory Networks and Complex Interactions between the Insulin and Angiotensin II Signalling Systems: Models and Implications for Hypertension and Diabetes

    OpenAIRE

    Çizmeci, Deniz; Arkun, Yaman

    2013-01-01

    Regulatory Networks and Complex Interactions between the Insulin and Angiotensin II Signalling Systems: Models and Implications for Hypertension and Diabetes Deniz Cizmeci, Yaman Arkun* Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey Abstract The cross-talk between insulin and angiotensin II signalling pathways plays a significant role in the co-occurrence of diabetes and hypertension. We developed a mathematical model of the system of ...

  12. Association of angiotensin-converting enzyme inhibitor therapy and comorbidity in diabetes: results from the Vermont diabetes information system

    OpenAIRE

    MacLean Charles D; Ramos-Nino Maria E; Littenberg Benjamin

    2008-01-01

    Abstract Background Angiotensin converting enzyme inhibitors (ACE inhibitors) reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE). ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetes Methods We surveyed 1003 adults with diabetes randomly sele...

  13. Inhibition of oxytocin-induced but not angiotensin-induced rat uterine contractions following exposure to sodium sulfide

    Energy Technology Data Exchange (ETDEWEB)

    Hayden, L.J.; Franklin, K.J.; Roth, S.H.; Moore, G.J. (Univ. of Calgary, Alberta (Canada))

    1989-01-01

    Low concentrations of sodium sulfide reversibly attenuate the contractile response of the isolate rat uterus to oxytocin without affecting angiotensin II responsiveness. These findings suggest that functionally important disulfide bonds in the rat uterine oxytocin receptor, but not the angiotensin receptor, are sensitive to hydrosulfide ion. Reduction of oxytocin receptors by hydrosulfide ion may be a mechanism by which low level of H{sub 2}S delay parturition in rats.

  14. 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...

  15. Ultrastructural immunocytochemical localization of renin and angiotensin II in the juxtaglomerular cells of the ischemic kidney in experimental renal hypertension.

    OpenAIRE

    Cantin, M; J. Gutkowska; Lacasse, J.; Ballak, M.; Ledoux, S.; Inagami, T; Beuzeron, J.; Genest, J.

    1984-01-01

    Partial ligation of the rat aorta between the renal arteries induces acute hypertension with atrophy of the left (ischemic) kidney, intense stimulation of juxtaglomerular cell (JGC) secretory activity, and significant increases in renal cortical renin activity, in plasma renin activity, and in the plasma levels of angiotensin I (AI) and angiotensin II (AII). With the unlabeled antibody technique at the light-microscopic level and various dilutions of renin antiserum, immunoreactive renin can ...

  16. 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

  17. New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: Considerations for trial design and regulatory approval.

    Science.gov (United States)

    Zannad, Faiez; Rossignol, Patrick; Stough, Wendy Gattis; Epstein, Murray; Alonso Garcia, Maria de Los Angeles; Bakris, George L; Butler, Javed; Kosiborod, Mikhail; Berman, Lance; Mebazaa, Alexandre; Rasmussen, Henrik S; Ruilope, Luis M; Stockbridge, Norman; Thompson, Aliza; Wittes, Janet; Pitt, Bertram

    2016-08-01

    Hyperkalemia is a common clinical problem, especially in patients with chronic kidney disease, diabetes mellitus, or heart failure. Treatment with renin angiotensin aldosterone system inhibitors exacerbates the risk of hyperkalemia in these patients. Concern about hyperkalemia can result in the failure to initiate, suboptimal dosing, or discontinuation of renin angiotensin aldosterone system inhibitor therapy in patients; effective treatments for hyperkalemia might mitigate such undertreatment. New treatments for hyperkalemia in development may offer better efficacy, tolerability and safety profiles than do existing approved treatments. These compounds might enable more eligible patients to receive renin angiotensin aldosterone system inhibitor therapy or to receive renin angiotensin aldosterone system inhibitors at target doses. The evidence needed to support a treatment claim (reduction in serum potassium) differs from that needed to support a prevention claim (preventing hyperkalemia to allow renin angiotensin aldosterone system inhibitor treatment). Thus, several issues related to clinical trial design and drug development need to be considered. This paper summarizes and expands upon a discussion at the Global Cardiovascular Clinical Trialists 2014 Forum and examines methodologic considerations for trials of new potassium binders for the prevention and management of hyperkalemia in patients with renin angiotensin aldosterone system inhibitor indications. PMID:27140336

  18. 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.

  19. 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

  20. 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; Christensen, Gitte Lund; Bonde, Marie Mi; Schneider, Mikael; Haunsø, Stig; Schiffer, Hans H; Burstein, Ethan S; Weiner, David M; Sheikh, Søren P

    AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms in......(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 by the...

  1. Angiotensin II and angiotensin-(1-7 decrease sFlt1 release in normal but not preeclamptic chorionic villi: an in vitro study

    Directory of Open Access Journals (Sweden)

    Moorefield Cheryl

    2010-11-01

    Full Text Available Abstract Background During preeclampsia, placental angiogenesis is impaired. Factors released from the placenta including vascular endothelial growth factor (VEGF, placental growth factor (PLGF, soluble VEGF receptor 1 (sFlt1, and soluble endoglin (sEng are regulatory molecules of placental development and function. While the renin angiotensin system has been shown to regulate angiogenic factors in other research fields, these mechanisms have not been extensively studied during pregnancy. Methods We evaluated the effects of angiotensin II (Ang II and angiotensin-(1-7 [Ang-(1-7] on the release of VEGF, PLGF, sFlt1, and sEng from placental chorionic villi (CV. CV were collected from nulliparous third-trimester normotensive and preeclamptic subjects. CV were incubated for 0, 2, 4, and 16 hours with or without Ang II (1 nM and 1 microM or Ang-(1-7 (1 nM and 1 microM. The release of VEGF, PLGF, sFlt1, sEng, lactate dehydrogenase (LDH, and human placenta lactogen (HPL was measured by ELISA. Results The release of sFlt1, PLGF, sEng from normal and preeclamptic CV increased over time. Release of sFlt1 and sEng was significantly higher from preeclamptic CV. VEGF was below the detectable level of the assay in normal and preeclamptic CV. After 2 hours, sFlt1 release from normal CV was significantly inhibited with Ang II (1 nM and 1 microM and Ang-(1-7 (1 nM and 1 microM. There was a time-dependent increase in HPL indicating that the CV were functioning normally. Conclusions Our study demonstrates a critical inhibitory role of angiotensin peptides on sFlt1 in normal pregnancy. Loss of this regulation in preeclampsia may allow sFlt1 to increase resulting in anti-angiogenesis and end organ damage in the mother.

  2. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling

    OpenAIRE

    Kim, Dongsoo; Aizawa, Toru; Wei, Heng; Pi, Xinchun; Rybalkin, Sergei D.; Berk, Bradford C.; Yan, Chen

    2004-01-01

    Angiotensin II (Ang II) and nitric oxide (NO)/natriuretic peptide (NP) signaling pathways mutually regulate each other. Imbalance of Ang II and NO/NP has been implicated in the pathophysiology of many vascular diseases. cGMP functions as a key mediator in the interaction between Ang II and NO/NP. Cyclic nucleotide phosphodiesterase 5A (PDE5A) is important in modulating cGMP signaling by hydrolyzing cGMP in vascular smooth muscle cells (VSMC). Therefore, we examined whether Ang II negatively m...

  3. Angiotensin II Reduces Lipoprotein Lipase Expression in Visceral Adipose Tissue via Phospholipase C β4 Depending on Feeding but Increases Lipoprotein Lipase Expression in Subcutaneous Adipose Tissue via c-Src.

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Uchiyama

    Full Text Available Metabolic syndrome is characterized by visceral adiposity, insulin resistance, high triglyceride (TG- and low high-density lipoprotein cholesterol-levels, hypertension, and diabetes-all of which often cause cardiovascular and cerebrovascular diseases. It remains unclear, however, why visceral adiposity but not subcutaneous adiposity causes insulin resistance and other pathological situations. Lipoprotein lipase (LPL catalyzes hydrolysis of TG in plasma lipoproteins. In the present study, we investigated whether the effects of angiotensin II (AngII on TG metabolism are mediated through an effect on LPL expression. Adipose tissues were divided into visceral adipose tissue (VAT and subcutaneous adipose tissue (SAT for comparison. AngII accelerated LPL expression in SAT but, on the contrary, suppressed its expression in VAT. In both SAT and VAT, AngII signaled through the same type 1 receptor. In SAT, AngII increased LPL expression via c-Src and p38 MAPK signaling. In VAT, however, AngII reduced LPL expression via the Gq class of G proteins and the subsequent phospholipase C β4 (PLCβ4, protein kinase C β1, nuclear factor κB, and inducible nitric oxide synthase signaling pathways. PLCβ4 small interfering RNA experiments showed that PLCβ4 expression is important for the AngII-induced LPL reduction in VAT, in which PLCβ4 expression increases in the evening and falls at night. Interestingly, PLCβ4 expression in VAT decreased with fasting, while AngII did not decrease LPL expression in VAT in a fasting state. In conclusion, AngII reduces LPL expression through PLCβ4, the expression of which is regulated by feeding in VAT, whereas AngII increases LPL expression in SAT. The different effects of AngII on LPL expression and, hence, TG metabolism in VAT and SAT may partly explain their different contributions to the development of metabolic syndrome.

  4. Different regulation of miR-29a-3p in glomeruli and tubules in an experimental model of angiotensin II-dependent hypertension: potential role in renal fibrosis.

    Science.gov (United States)

    Castoldi, Giovanna; di Gioia, Cira; Giollo, Fabrizio; Carletti, Raffaella; Bombardi, Camila; Antoniotti, Marco; Roma, Francesca; Zerbini, Gianpaolo; Stella, Andrea

    2016-03-01

    The aim of this study was to evaluate the role of the angiotensin II (Ang II) induced-differential miRNA expression in renal glomerular and tubulo-interstitial fibrosis in an experimental model of Ang II-dependent hypertension. To clarify this issue, Sprague Dawley rats were treated with Ang II (200 ng/kg per minute, n = 15) or physiological saline (n = 14) for 4 weeks. Systolic blood pressure and albuminuria were measured every 2 weeks. At the end of the experimental period, renal glomerular and tubulo-interstitial fibrosis was evaluated by histomorphometric analysis, after Sirius-Red and Masson's trichrome staining. Ang II increased systolic blood pressure (P < 0.0001), albuminuria (P < 0.01) and both glomerular and tubulo-interstitial fibrosis (P < 0.01). Using laser capture microdissection and miRNA microarray analysis this study showed that miR-29a-3p was down-regulated in renal tubules and up-regulated in glomeruli. Real-time polymerase chain reaction (PCR) experiments confirmed in Ang II-treated rats a down-regulation of miR-29a-3p in tubules (P < 0.01), while no significant changes were observed in glomeruli. Matrix metalloproteinase-2 (MMP-2) was identified as putative miR-29a-3p target (by TargetScan, miRanda, Tarbase software) and functionally confirmed by luciferase activity assay. These data demonstrate that the effects of Ang II on miR-29a-3p expression in renal tubules is different from the one exerted in the glomeruli and that miR-29a-3p targets MMP-2. These results suggest that the development of renal fibrosis at glomerular and tubulo-interstitial level depends on different molecular mechanisms. PMID:26700017

  5. Alterations in the subcellular distribution of NADPH oxidase p47(phox) in hypothalamic paraventricular neurons following slow-pressor angiotensin II hypertension in female mice with accelerated ovarian failure.

    Science.gov (United States)

    Van Kempen, Tracey A; Narayan, Ankita; Waters, Elizabeth M; Marques-Lopes, Jose; Iadecola, Costantino; Glass, Michael J; Pickel, Virginia M; Milner, Teresa A

    2016-08-01

    At younger ages, women have a lower risk for hypertension than men, but this sexual dimorphism declines with the onset of menopause. These differences are paralleled in rodents following "slow-pressor" angiotensin II (AngII) administration: young male and aged female mice, but not young females, develop hypertension. There is also an established sexual dimorphism both in the cardiovascular response to the neurohypophyseal hormone arginine vasopressin (AVP) and in the expression of oxidative stress. We examined the relationship between AngII-mediated hypertension and the cellular distribution of the superoxide generating NADPH oxidase (NOX) in AVP-expressing hypothalamic paraventricular nucleus (PVN) neurons in "menopausal" female mice. Dual-labeling immunoelectron microscopy was used to determine whether the subcellular distribution of the organizer/adapter NOX p47(phox) subunit is altered in PVN dendrites following AngII administered (14 days) during the "postmenopausal" stage of accelerated ovarian failure (AOF) in young female mice treated with 4-vinylcyclohexene diepoxide. Slow-pressor AngII elevated blood pressure in AOF females and induced a significant increase in near plasmalemmal p47(phox) and a decrease in cytoplasmic p47(phox) in PVN AVP dendrites. These changes are the opposite of those observed in AngII-induced hypertensive male mice (Coleman et al. [2013] J. Neurosci. 33:4308-4316) and may be ascribed in part to baseline differences between young females and males in the near plasmalemmal p47(phox) on AVP dendrites seen in the present study. These findings highlight fundamental differences in the neural substrates of oxidative stress in the PVN associated with AngII hypertension in postmenopausal females compared with males. J. Comp. Neurol. 524:2251-2265, 2016. © 2015 Wiley Periodicals, Inc. PMID:26659944

  6. The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis

    OpenAIRE

    Harel, Ziv; Gilbert, Cameron; Wald, Ron; Bell, Chaim; Perl, Jeff; Juurlink, David; Beyene, Joseph; Shah, Prakesh S.

    2012-01-01

    Objective To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, the Cochrane Library, and two trial registries, published up to 7 May 2011. Study selection Published and unpublished randomised controlled trials that compared combined treatment using aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers w...

  7. Radiosynthesis of (tetrazoyl-11C)irbesartan, a non-peptidic angiotensin II antagonist

    International Nuclear Information System (INIS)

    With the aim of visualizing myocardial angiotensin II receptors (ATI subtypes), [tetrazoyl-11C]2-n-butyl-1-[(2'-(1H-tetrazole-5-yl)-1,1'-biphenyl-4-yl)methyl]-4-spirocyclo-pentane-2-imidazoline-5-one ([tetrazoyl-11C]irbesartam (SR47436/BMS-186295)) 11 was synthesized in one pot in four steps from [11C]hydrogen cyanide. The labelling process which yielded [tetrazoyl-11C]irbesartan is described in detail and could be applied to the labelling of other ligands which possess the (1H-tetrazole-5-yl) moiety. Positron emission tomography (PET) studies were performed in dogs. Heart, lung and blood time-activity curves did not change. Therefore this new radioligand is not suitable for studying myocardial angiotensin II receptors with PET. (authors)

  8. Drying Technology of Angiotensin Converting Enzyme Inhibitory Peptide Derived from Bovine Casein

    Institute of Scientific and Technical Information of China (English)

    JIANG Zhanmei; Hue Guicheng; TIAN Be

    2009-01-01

    Drying technology of angiotensin converting enzyme (ACE) inhibitory peptides derived from bovine casein was investigated. No significance was observed on ACE inhibitory activity of products prepared by spay drying and freeze drying (P>0.05). Spay drying was the best drying process for practical industry production. The inlet temperature ranged from 140℃ to 160℃ and the exit temperature ranged from 70℃ to 90℃ during the spay drying process. Under the optimal eonditious, scale-up of angiotensin converted enzyme inhibitory peptide from 1 L to 10 L and the experiment was successively conducted. Peptide yield was 29% and half inhibitory concentration(IC50) was 0.53g·L-1.

  9. 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......) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even....... Therefore, a concept of dual AT1R/AT2R modulation emerges as a putative means for risk reduction in cardio-metabolic diseases. The approach employing simultaneous RAS blockade (AT1R) and RAS stimulation (AT2R) is distinct from previous attempts of double intervention in the RAS by dual blockade. Dual...

  10. Effect of angiotensin II receptor blockade on proximal tubular fluid reabsorption

    DEFF Research Database (Denmark)

    Leyssac, P P; Karlsen, F M; Holstein-Rathlou, N H

    1997-01-01

    The effect of physiological concentrations of angiotensin II on proximal tubular fluid reabsorption remains controversial. To investigate the effect of blockade of intratubular AT1 receptors on tubular reabsorption, losartan (10(-5) M) was administered by microperfusion into an early proximal...... flow rate decreased by 2.0 +/- 0.8 nl/min, and early distal NaCl concentration decreased by 4.3 +/- 0.8 mM (mean +/- SE). No changes were observed after microperfusion with saline. Because the tubuloglomerular feedback mechanism was operating in the closed-loop mode, the decreased NaCl load to the...... early and late proximal convolutions was estimated to be 7.8 nl/min (approximately 36%). It is concluded that a decrease in local luminal angiotensin II levels and/or AT1 receptor activity under free flow conditions increases the rate of proximal tubular fluid reabsorption....

  11. Angiotensin-converting enzyme: an indicator of bleomycin-induced pulmonary toxicity in humans?

    DEFF Research Database (Denmark)

    Sørensen, Peter G; Rømer, F K; Cortes, Dina

    1984-01-01

    In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or radiolog......In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or...... radiological evidence of pulmonary damage. While the static and dynamic lung function parameters were unchanged, carbon monoxide diffusion capacity (DLCO) decreased significantly (P less than 0.01) during a total of 126 days of pulsed regimen, indicating damage to the alveolar-endothelial membrane. S-ACE was...

  12. Influence of the renin-angiotensin system on human forearm blood flow

    DEFF Research Database (Denmark)

    Stadeager, C; Hesse, B; Henriksen, O; Bonde-Petersen, F; Mehlsen, J; Rasmussen, S

    1990-01-01

    Although angiotensin II is a potent vasoconstrictor agent in all tissues, including the human forearm, equivocal effects on forearm blood flow (FBF) have been found after angiotensin blockade. In 13 healthy Na(+)-depleted subjects FBF was measured by the 133Xe washout technique; subcutaneous and...... muscle blood flows were determined separately. FBF was measured during supine rest, after the arm was lowered, and during lower body negative pressure (LBNP). The measurements were repeated during intra-arterial saralasin infusion in six subjects and after intravenous administration of enalapril in seven...... subjects. FBF decreased and forearm vascular resistance (FVR) increased during arm lowering and LBNP, as the result of local and central adrenergic reflexes, respectively. We observed similar FBF and FVR values after both saralasin and enalapril, except for a decrease in FVR at rest after enalapril. It is...

  13. 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...

  14. 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.

  15. 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

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

    International Nuclear Information System (INIS)

    PET imaging has been recently introduced for investigating the type 1 angiotensin II receptor (AT1R) 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 AT1R 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 AT1R binding expressed by Ki was increased in the renal cortex by chronic ACEI treatment (p 1R density (Bmax) also revealed significant increases in AT1R in isolated glomeruli (p 1R binding in vivo in the dog renal cortex. (orig.)

  17. Does renin-angiotensin system blockade have a role in preventing diabetic retinopathy? A clinical review

    DEFF Research Database (Denmark)

    Sjølie, A K; Dodson, P; Hobbs, F R R

    2011-01-01

    Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates to...... been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although the...... primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril. The...

  18. Targeted Catalytic Inactivation of Angiotensin Converting Enzyme by Lisinopril-Coupled Transition Metal Chelates

    OpenAIRE

    Joyner, Jeff C.; Hocharoen, Lalintip; Cowan, J. A.

    2012-01-01

    A series of compounds that target reactive transition metal chelates to somatic Angiotensin Converting Enzyme (sACE-1) have been synthesized. Half maximal inhibitory concentrations (IC50) and rate constants for both inactivation and cleavage of full length sACE-1 have been determined and evaluated in terms of metal-chelate size, charge, reduction potential, coordination unsaturation, and coreactant selectivity. Ethylenediamine-tetraacetic acid (EDTA), nitrilotriacetic acid (NTA), 1,4,7,10-tet...

  19. Biased Signaling of the Angiotensin II Type 1 Receptor Can Be Mediated through Distinct Mechanisms

    OpenAIRE

    Bonde, Marie Mi; Hansen, Jonas Tind; Sanni, Samra Joke; Haunsø, Stig; Gammeltoft, Steen; Lyngsø, Christina; Hansen, Jakob Lerche

    2010-01-01

    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 facilit...

  20. 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...

  1. New drug therapies interfering with the renin-angiotensin-aldosterone system for resistant hypertension.

    Science.gov (United States)

    Monge, Matthieu; Lorthioir, Aurélien; Bobrie, Guillaume; Azizi, Michel

    2013-12-01

    There is a persistent need for the development of new antihypertensive drugs, because the control of blood pressure is still not achievable in a significant proportion of hypertensive patients. Since the approval in 2007 of aliskiren, no other new antihypertensive based on new mechanism(s) of action have been approved. In fact, the development of promising novel drugs has been stopped for safety, efficacy or marketing reasons. Despite these difficulties, the pipeline is not dry and different new antihypertensive strategies targeting the renin-angiotensin-aldosterone pathway, are in clinical development stage. The dual angiotensin II receptor-neprilysin inhibitor LCZ696, a single molecule synthetized by cocrystallisation of valsartan and the neprilysin inhibitor prodrug AHU377 is in development for resistant hypertension and for heart failure. Daglutril is a dual neprylisin-endothelin converting enzyme inhibitor which was shown to decrease BP in patients with type 2 diabetic nephropathy. Aldosterone synthase inhibitors and the third and fourth generation non-steroidal dihydropyridine based mineralocorticoid receptors blockers are new ways to target the multiple noxious effects of aldosterone in the kidney, vessels and heart. Centrally acting aminopeptidase A inhibitors block brain angiotensin III formation, one of the main effector peptides of the brain renin angiotensin system. However, a long time will be still necessary to evaluate extensively the efficacy and safety of these new approaches. In the mean time, using appropriate and personalized daily doses of available drugs, decreasing physician inertia, improving treatment adherence, improving access to healthcare and reducing treatment costs remain major objectives to reduce the incidence of resistant hypertension. PMID:24222656

  2. ANGIOTENSIN I CONVERTING ENZYME GENE POLYMORPHISM AND EXERCISE TRAINABILITY IN ELDERLY WOMEN: AN ELECTROCARDIOLOGICAL APPROACH

    OpenAIRE

    Takuro Tobina; Akira Kiyonaga; Yuko Akagi; Yukari Mori; Kojiro Ishii; Hitoshi Chiba; Munehiro Shindo; Hiroaki Tanaka

    2007-01-01

    Angiotensin I converting enzyme (ACE) gene Insertion / Deletion (I/D) polymorphism is associated with exercise trainability and exercise induced left ventricular hypertrophy. However, it is unclear whether this polymorphism influences exercise trainability in the elderly, and the electrocardiological alterations by exercise training is unknown among the genotypes. We herein investigated the association between ACE gene insertion/deletion (I/D) polymorphism, exercise trainability and the elect...

  3. Autoantibody-mediated angiotensin receptor activation contributes to preeclampsia through TNF-alpha signaling

    OpenAIRE

    Irani, Roxanna A.; Zhang, Yujin; Zhou, Cissy Chenyi; Blackwell, Sean C.; Hicks, M. John; Ramin, Susan M.; Kellems, Rodney E.; Xia, Yang

    2010-01-01

    Preeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy whose pathophysiology remains largely undefined. Recently, a circulating maternal autoantibody, the angiotensin II type I receptor agonistic autoantibody (AT1-AA), has emerged as a contributor to disease features. Increased circulating maternal tumor necrosis factor alpha (TNF-α) is also associated with the disease, however it is unknown if this factor directly contributes to preeclamptic symptoms. Here we report ...

  4. Intravital imaging reveals angiotensin II–induced transcytosis of albumin by podocytes

    OpenAIRE

    Schießl, Ina Maria; Hammer, Anna; Kattler, Veronika; Gess, Bernhard; Theilig, Franziska; Witzgall, Ralph; Castrop, Hayo

    2016-01-01

    Albuminuria is a hallmark of kidney disease of various etiologies and usually caused by deterioration of glomerular filtration barrier integrity. We recently showed that angiotensin II (Ang II) acutely increases albumin filtration in the healthy kidney. Here, we used intravital microscopy to assess the effects of Ang II on podocyte function in rats. Acute infusion of 30, 60, or 80 ng/kg per minute Ang II enhanced the endocytosis of albumin by activation of the type 1 Ang II receptor and ...

  5. Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules

    OpenAIRE

    Annayya Aroor; Marcin Zuberek; Cornel Duta; Alex Meuth; James R Sowers; Adam Whaley-Connell; Ravi Nistala

    2016-01-01

    Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT1R) and Ang II suppresses megalin expression in proximal tubule cells in vi...

  6. Renal dopamine and angiotensin II receptor signaling in age-related hypertension

    OpenAIRE

    Chugh, Gaurav; Pokkunuri, Indira; Asghar, Mohammad

    2012-01-01

    Kidneys play a vital role in long-term regulation of blood pressure. This is achieved by actions of many renal and nonrenal factors acting on the kidney that help maintain the body's water and electrolyte balance and thus control blood pressure. Several endogenously formed or circulating hormones/peptides, by acting within the kidney, regulate fluid and water homeostasis and blood pressure. Dopamine and angiotensin II are the two key renal factors that, via acting on their receptors and count...

  7. RGS4 inhibits angiotensin II signaling and macrophage localization during renal reperfusion injury independent of vasospasm.

    Science.gov (United States)

    Pang, Paul; Jin, Xiaohua; Proctor, Brandon M; Farley, Michelle; Roy, Nilay; Chin, Matthew S; von Andrian, Ulrich H; Vollmann, Elisabeth; Perro, Mario; Hoffman, Ryan J; Chung, Joseph; Chauhan, Nikita; Mistri, Murti; Muslin, Anthony J; Bonventre, Joseph V; Siedlecki, Andrew M

    2015-04-01

    Vascular inflammation is a major contributor to the severity of acute kidney injury. In the context of vasospasm-independent reperfusion injury we studied the potential anti-inflammatory role of the Gα-related RGS protein, RGS4. Transgenic RGS4 mice were resistant to 25 min injury, although post-ischemic renal arteriolar diameter was equal to the wild type early after injury. A 10 min unilateral injury was performed to study reperfusion without vasospasm. Eighteen hours after injury, blood flow was decreased in the inner cortex of wild-type mice with preservation of tubular architecture. Angiotensin II levels in the kidneys of wild-type and transgenic mice were elevated in a sub-vasoconstrictive range 12 and 18 h after injury. Angiotensin II stimulated pre-glomerular vascular smooth muscle cells (VSMCs) to secrete the macrophage chemoattractant RANTES, a process decreased by angiotensin II R2 (AT2) inhibition. However, RANTES increased when RGS4 expression was suppressed implicating Gα protein activation in an AT2-RGS4-dependent pathway. RGS4 function, specific to VSMC, was tested in a conditional VSMC-specific RGS4 knockout showing high macrophage density by T2 MRI compared with transgenic and non-transgenic mice after the 10 min injury. Arteriolar diameter of this knockout was unchanged at successive time points after injury. Thus, RGS4 expression, specific to renal VSMC, inhibits angiotensin II-mediated cytokine signaling and macrophage recruitment during reperfusion, distinct from vasomotor regulation. PMID:25469849

  8. Luteolin Inhibits Angiotensin II-Stimulated VSMC Proliferation and Migration through Downregulation of Akt Phosphorylation

    OpenAIRE

    Tongda Xu; Hong Zhu; Dongye Li; Yasong Lang; Lijuan Cao; Yang Liu; Wanling Wu; Dan Chen

    2015-01-01

    Luteolin is a naturally occurring flavonoid found in many plants that possesses cardioprotective properties. The purpose of this study was to elucidate the effect of luteolin on vascular smooth muscle cells (VSMCs) proliferation and migration induced by Angiotensin II (Ang II) and to investigate the mechanism(s) of action of this compound. Rat VSMCs were cultured in vitro, and the proliferation and migration of these cells following Ang II stimulation were monitored. Different doses of luteol...

  9. 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...

  10. Milk protein-derived peptide inhibitors of angiotensin-I-converting enzyme

    OpenAIRE

    FitzGerald, Richard J.; Meisel, Hans

    2000-01-01

    peer-reviewed Numerous casein and whey protein-derived angiotensin-I-converting enzyme (ACE) inhibitory peptides/hydrolysates have been identified. Clinical trials in hypertensive animals and humans show that these peptides/hydrolysates can bring about a significant reduction in hypertension. These peptides/hydrolysates may be classified as functional food ingredients and nutraceuticals due to their ability to provide health benefits i.e. as functional food ingredients in reduc...

  11. 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...

  12. A Crucial Role in Fertility for the Oyster Angiotensin-Converting Enzyme Orthologue CgACE

    OpenAIRE

    Riviere, Guillaume; Fellous, Alexandre; Franco, Alban; Bernay, Benoit; Favrel, Pascal

    2011-01-01

    Angiotensin-converting enzyme (ACE) is a highly conserved metallopeptidase. In mammals, the somatic isoform governs blood pressure whereas the germinal isoform (tACE) is required for fertility. In Ecdysozoans, ACE-like enzymes are implicated in reproduction. Despite ACE orthologues being present from bacteria to humans, their function(s) remain(s) unknown in distant organisms such as Lophotrochozoans. In silico analysis of an oyster (Crassostrea gigas) EST library suggested the presence of an...

  13. Hemodynamic, morphometric and autonomic patterns in hypertensive rats - renin-angiotensin system modulation

    Directory of Open Access Journals (Sweden)

    Fernanda S. Zamo

    2010-01-01

    Full Text Available BACKGROUND: Spontaneously hypertensive rats develop left ventricular hypertrophy, increased blood pressure and blood pressure variability, which are important determinants of heart damage, like the activation of renin-angiotensin system. AIMS: To investigate the effects of the time-course of hypertension over 1 hemodynamic and autonomic patterns (blood pressure; blood pressure variability; heart rate; 2 left ventricular hypertrophy; and 3 local and systemic Renin-angiotensin system of the spontaneously hypertensive rats. METHODS: Male spontaneously hypertensive rats were randomized into two groups: young (n=13 and adult (n=12. Hemodynamic signals (blood pressure, heart rate, blood pressure variability (BPV and spectral analysis of the autonomic components of blood pressure were analyzed. LEFT ventricular hypertrophy was measured by the ratio of LV mass to body weight (mg/g, by myocyte diameter (μm and by relative fibrosis area (RFA, %. ACE and ACE2 activities were measured by fluorometry (UF/min, and plasma renin activity (PRA was assessed by a radioimmunoassay (ng/mL/h. Cardiac gene expressions of Agt, Ace and Ace2 were quantified by RT-PCR (AU. RESULTS: The time-course of hypertension in spontaneously hypertensive rats increased BPV and reduced the alpha index in adult spontaneously hypertensive rats. Adult rats showed increases in left ventricular hypertrophy and in RFA. Compared to young spontaneously hypertensive rats, adult spontaneously hypertensive rats had lower cardiac ACE and ACE2 activities, and high levels of PRA. No change was observed in gene expression of Renin-angiotensin system components. CONCLUSIONS: The observed autonomic dysfunction and modulation of Renin-angiotensin system activity are contributing factors to end-organ damage in hypertension and could be interacting. Our findings suggest that the management of hypertensive disease must start before blood pressure reaches the highest stable levels and the consequent

  14. 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...

  15. Effect of Jatropha curcas Peptide Fractions on the Angiotensin I-Converting Enzyme Inhibitory Activity

    OpenAIRE

    Segura-Campos, Maira R.; Fanny Peralta-González; Arturo Castellanos-Ruelas; Chel-Guerrero, Luis A.; David A. Betancur-Ancona

    2013-01-01

    Hypertension is one of the most common worldwide diseases in humans. Angiotensin I-converting enzyme (ACE) plays an important role in regulating blood pressure and hypertension. An evaluation was done on the effect of Alcalase hydrolysis of defatted Jatropha curcas kernel meal on ACE inhibitory activity in the resulting hydrolysate and its purified fractions. Alcalase exhibited broad specificity and produced a protein hydrolysate with a 21.35% degree of hydrolysis and 34.87% ACE inhibition. U...

  16. Peptides Derived from Rhopilema esculentum Hydrolysate Exhibit Angiotensin Converting Enzyme (ACE) Inhibitory and Antioxidant Abilities

    OpenAIRE

    Jun Li; Qian Li; Jingyun Li; Bei Zhou

    2014-01-01

    Jellyfish (Rhopilema esculentum) was hydrolyzed using alcalase, and two peptides with angiotensin-I-converting enzyme (ACE) inhibitory and antioxidant activities were purified by ultrafiltration and consecutive chromatographic methods. The amino acid sequences of the two peptides were identified as VKP (342 Da) and VKCFR (651 Da) by electrospray ionization tandem mass spectrometry. The IC50 values of ACE inhibitory activities of the two peptides were 1.3 μM and 34.5 μM, respectively. Molecula...

  17. Why is plasma angiotensin-converting enzyme activity elevated in hyperthyroidism?

    OpenAIRE

    Roulston, J. E.; Gold, A; Wright, M.; Walker, S. W.

    1987-01-01

    The elevation in plasma angiotensin-converting enzyme (ACE) levels observed in patients with hyperthyroidism is unexplained. In this study three hypotheses were investigated. Results from a study using rats treated with thyroid hormones indicated that the increased ACE was not due to increased cleavages of enzyme from lung endothelia. Data from patients with specific tissue damage argue against a nonspecific release of ACE from damaged cells. Data from cultured cell experiments, however, stro...

  18. Angiotensin I-Converting Enzyme Inhibitor Activity on Egg Albumen Fermentation

    OpenAIRE

    Nahariah, N.; A M Legowo; Abustam, E.; Hintono, A.

    2015-01-01

    Lactobacillus plantarum is used for fermentation of fish products, meat and milk. However, the utilization of these bacteria in egg processing has not been done. This study was designed to evaluate the potential of fermented egg albumen as a functional food that is rich in angiotensin I-converting enzyme inhibitors activity (ACE-inhibitor activity) and is antihypertensive. A completely randomized design was used in this study with six durations of fermentation (6, 12, 18, 24, 30, and 36 h) as...

  19. Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies

    OpenAIRE

    Ligia Guerrero; Julián Castillo; Mar Quiñones; Santiago Garcia-Vallvé; Lluis Arola; Gerard Pujadas; Begoña Muguerza

    2012-01-01

    Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric metho...

  20. Post-exercise reduction in blood pressure in hypertensive subjects: effects of angiotensin converting enzyme inhibition.

    OpenAIRE

    Beaulieu, M.; Nadeau, A.; Lacourcière, Y; Cléroux, J

    1993-01-01

    1. Much attention has been given to the effects of various classes of antihypertensive drugs on blood pressure and haemodynamics. The effects of a single bout of exercise on post-exercise blood pressure have also been studied by several investigators. However, the combined effects of prior exercise and antihypertensive medication has drawn less attention. 2. We examined the separate and combined effects of a single bout of exercise and of angiotensin converting enzyme (ACE) inhibition with a ...

  1. Prejunctional angiotensin II receptors. Facilitation of norepinephrine release in the human forearm.

    OpenAIRE

    Clemson, B; L. Gaul; Gubin, S S; Campsey, D M; MCCONVILLE, J; Nussberger, J.; Zelis, R

    1994-01-01

    To determine if peripheral angiotensin II (Ang II) prejunctional receptors facilitating NE release exist in humans, we used [3H]NE kinetic methodology to measure forearm NE spillover during intrabrachial arterial Ang II infusions in eight normal male subjects. We used the following protocol to optimize conditions for demonstrating these receptors: (a) lower body negative pressure (-15 mmHg) to increase sympathetic nerve activity to skeletal muscle; and (b) intraarterial nitroprusside to maint...

  2. 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...

  3. Cholinergic signal activated renin angiotensin system associated with cardiovascular changes in the ovine fetus

    OpenAIRE

    Geng, Chunsong; Mao, Caiping; Wu, Lei; Cheng, Yu; Liu, Rulu; Chen, Bingxin; Chen, Ling; Zhang, Lubo; Xu, Zhice

    2010-01-01

    Aim: Cholinergic regulation is important in the control of cardiovascular and endocrine responses. The mechanisms behind cardiovascular responses induced by cholinergic activation are explored by studying hormonal systems, including renin-angiotensin and vasopressin (VP). Results: In chronically prepared fetal sheep, intravenous infusion of the cholinergic agonist carbachol increased fetal systolic, diastolic, and mean arterial pressure accompanied with bradycardia at near-term. Although int...

  4. Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

    Science.gov (United States)

    Vilas-Boas, Walkíria Wingester; Jr, Antônio Ribeiro-Oliveira; da Cunha Ribeiro, Renata; Vieira, Renata Lúcia Pereira; Almeida, Jerusa; Nadu, Ana Paula; Silva, Ana Cristina Simões e; Santos, Robson Augusto Souza

    2008-01-01

    AIM: To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS: Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) I, Ang II, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components. RESULTS: PRA, Ang I, Ang II and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang I levels and between Ang II and Ang I were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang II remained unchanged in splanchnic and peripheral circulation in patients under β-blockade, whereas the relationship between Ang II and Ang I was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. CONCLUSION: In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang II in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio. PMID:19058308

  5. Expression and clinical significance of angiotensin II type 1 receptor in human hepatocellular carcinoma

    OpenAIRE

    Duan, Yun-fei; Li, Xiao-dong; Zhu, Feng; Zhang, Feng

    2013-01-01

    This study aimed to investigate the expression of angiotensin II type 1 receptor (AT-1R) mRNA and the AT-1R protein in human primary hepatocellular carcinoma (PHC), and to attempt to elucidate their association with pathological and clinical characteristics. Fresh tumor and normal liver tissues were obtained from 44 patients with PHC following hepatectomies. AT-1R mRNA levels were quantitatively analyzed by quantitative polymerase chain reaction (qPCR) while the protein levels were assessed b...

  6. Association between Angiotensin-Converting Enzyme Inhibitors and Troponin in Acute Coronary Syndrome

    Directory of Open Access Journals (Sweden)

    Luiz Minuzzo

    2014-12-01

    Full Text Available Background: Cardiovascular disease is the leading cause of mortality in the western world and its treatment should be optimized to decrease severe adverse events. Objective: To determine the effect of previous use of angiotensin-converting enzyme inhibitors on cardiac troponin I measurement in patients with acute coronary syndrome without ST-segment elevation and evaluate clinical outcomes at 180 days. Methods: Prospective, observational study, carried out in a tertiary center, in patients with acute coronary syndrome without ST-segment elevation. Clinical, electrocardiographic and laboratory variables were analyzed, with emphasis on previous use of angiotensin-converting enzyme inhibitors and cardiac troponin I. The Pearson chi-square tests (Pereira or Fisher's exact test (Armitage were used, as well as the non-parametric Mann-Whitney's test. Variables with significance levels of 0.5 ng / mL were high blood glucose at admission (p = 0.0034 and ST-segment depression ≥ 0.5 mm in one or more leads (p = 0.0016. The use of angiotensin-converting inhibitors prior to hospitalization was associated with troponin ≤ 0.5 ng / mL (p = 0.0482. The C-statistics for this model was 0.77. Conclusion: This study showed a correlation between prior use of angiotensin-converting enzyme inhibitors and reduction in the myocardial necrosis marker troponin I in patients admitted for acute coronary syndrome without ST-segment elevation. However, there are no data available yet to state that this reduction could lead to fewer severe clinical events such as death and re-infarction at 180 days.

  7. 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...

  8. Enzyme Hydrolysates from Stichopus horrens as a New Source for Angiotensin-Converting Enzyme Inhibitory Peptides

    OpenAIRE

    Bita Forghani; Afshin Ebrahimpour; Jamilah Bakar; Azizah Abdul Hamid; Zaiton Hassan; Nazamid Saari

    2012-01-01

    Stichopus horrens flesh was explored as a potential source for generating peptides with angiotensin-converting enzyme (ACE) inhibitory capacity using 6 proteases, namely alcalase, flavourzyme, trypsin, papain, bromelain, and protamex. Degree of hydrolysis (DH) and peptide profiling (SDS-PAGE) of Stichopus horrens hydrolysates (SHHs) was also assessed. Alcalase hydrolysate showed the highest DH value (39.8%) followed by flavourzyme hydrolysate (32.7%). Overall, alcalase hydrolysate exhibited t...

  9. 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. PMID:27000216

  10. Increased methylglyoxal formation with upregulation of renin angiotensin system in fructose fed Sprague Dawley rats.

    Science.gov (United States)

    Dhar, Indu; Dhar, Arti; Wu, Lingyun; Desai, Kaushik M

    2013-01-01

    The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs). Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories) for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs). HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH), proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats. PMID:24040205

  11. 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 ...

  12. Transdermal contraception and the renin-angiotensin-aldosterone system in premenopausal women.

    Science.gov (United States)

    Odutayo, Ayodele; Cherney, David; Miller, Judith; Ahmed, Sofia B; Lai, Vesta; Dunn, Sheila; Pun, Nicole; Moineddin, Rahim; Hladunewich, Michelle A

    2015-03-15

    The oral contraceptive pill (OCP) activates the renin-angiotensin-aldosterone system (RAAS) through first-pass hepatic metabolism. Although usually benign, RAAS activation may have detrimental effects on renal and hemodynamic function in some women. Since combined hormonal contraception with the transdermal patch (EVRA) does not undergo first-pass hepatic metabolism, we hypothesized that the RAAS response would be different from that of OCP subjects. Thirty-five nonsmoking, premenopausal women (15 control subjects, 10 OCP subjects, and 10 contraceptive patch subjects) without evidence of cardiovascular disease, renal disease, or diabetes were studied. Baseline angiotensinogen, renin, angiotensin II, aldosterone, and plasma renin activity were assessed along with hormonal and hemodynamic responses to simulated orthostatic stress using incremental lower body negative pressure (LBNP; -15, -25, and -40 mmHg). Baseline levels of angiotensinogen, angiotensin II, and plasma renin activity were significantly higher in OCP subjects compared with normotensive control and contraceptive patch subjects (P versus control subjects only (P < 0.05). Plasma renin levels were significantly lower at baseline in contraceptive patch subjects compared with normotensive control and OCP subjects (P < 0.05). In response to LBNP, increases in renin, angiotensin II, and aldosterone were attenuated in contraceptive patch subjects in conjunction with an exaggerated decline in mean arterial pressure (P < 0.05 vs. control and OCP subjects). The contraceptive patch in healthy premenopausal women is associated with an impaired ability to maintain blood pressure in response to LBNP, possibly due to insensitivity of the endogenous RAAS. Further evaluation may be beneficial in women with kidney disease. PMID:25587124

  13. 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...

  14. Different angiotensin receptor blockers and incidence of diabetes: a nationwide population-based cohort study

    OpenAIRE

    Chang, Chia-Hsuin; Chang, Yi-Cheng; Wu, Li-Chiu; Lin, Jou-Wei; Chuang, Lee-Ming; Lai, Mei-Shu

    2014-01-01

    Background Angiotensin receptor blockers (ARBs) have been shown to exert various peroxisome proliferator-activated receptor gamma (PPARγ) binding activities and insulin-sensitizing effects. The objective of this study was to investigate the association of different ARBs with new-onset diabetes mellitus. Methods In the respective cohort, a total of 492,530 subjects who initiated ARB treatment between January 2004 and December 2009 were identified from Taiwan National Health Insurance Database....

  15. The role of renin angiotensin system intervention in stage B heart failure.

    LENUS (Irish Health Repository)

    Collier, Patrick

    2012-04-01

    This article outlines the link between the renin angiotensin aldosterone system (RAAS) and various forms of cardiomyopathy, and also reviews the understanding of the effectiveness of RAAS intervention in this phase of ventricular dysfunction. The authors focus their discussion predominantly on patients who have had previous myocardial infarction or those who have left ventricular hypertrophy and also briefly discuss the role of RAAS activation and intervention in patients with alcoholic cardiomyopathy.

  16. Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

    Institute of Scientific and Technical Information of China (English)

    Walkiria Wingester Vilas-Boas; Ant(o)nio Ribeiro-Oliveira Jr; Renata da Cunha Ribeiro; Renata Lúcia Pereira Vieira; Jerusa Almeida; Ana Paula Nadu; Ana Cristina Sim(o)es e Silva; Robson Augusto Souza Santos

    2008-01-01

    AIM: To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS: Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) Ⅰ, Ang Ⅱ, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components.RESULTS: PRA, Ang Ⅰ, Ang Ⅱ and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang Ⅰ levels and between Ang Ⅱ and Ang Ⅰ were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang Ⅱ remained unchanged in splanchnic and peripheral circulation in patients under 13-blockade, whereas the relationship between Ang Ⅱ and Ang Ⅰ was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup.CONCLUSION: In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang Ⅱ in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio.

  17. 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...

  18. A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors

    OpenAIRE

    Cressman, Alex M; Macdonald, Erin M.; Fernandes, Kimberly A.; Gomes, Tara; Paterson, J. Michael; Muhammad M Mamdani; Juurlink, David N.; ,

    2015-01-01

    Aims Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined. Methods We conducted a nes...

  19. Angiotensin II stimulates cardiac fibroblast migration via the differential regulation of matrixins and RECK

    OpenAIRE

    Siddesha, Jalahalli M.; Valente, Anthony J.; SAKAMURI, SIVA S.V.P.; Yoshida, Tadashi; Gardner, Jason D.; Somanna, Naveen; Takahashi, Chiaki; Noda, Makoto; Chandrasekar, Bysani

    2013-01-01

    Sustained induction and activation of matrixins (matrix metalloproteinases or MMPs), and the destruction and deposition of extracellular matrix (ECM), are the hallmarks of cardiac fibrosis. The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) is a unique membrane-anchored endogenous MMP inhibitor. We hypothesized that elevated angiotensin II (Ang II), which is associated with fibrosis in the heart, differentially regulates MMPs and RECK both in vivo and in vitro. Continuous i...

  20. Increased methylglyoxal formation with upregulation of renin angiotensin system in fructose fed Sprague Dawley rats.

    Directory of Open Access Journals (Sweden)

    Indu Dhar

    Full Text Available The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs. Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs. HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH, proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.

  1. Effects of angiotensin-converting enzyme inhibition and bradykinin peptides in rats with myocardial infarction

    OpenAIRE

    Qu, Zhe; Xu, Hongxin; Tian, Yihao

    2015-01-01

    Background and objective: Angiotensin-converting enzyme (ACE) inhibitors have been reported to decrease myocardial remodeling and faciliate cardiac function improvement in the setting myocardial infarction by affecting bradykinin. The purpose of this study was to evaluate the combination effects of perindopril and bradykinin (BK) in rats with myocardial infarction. Methods: Wistar Rats underwent to left anterior descending (LAD) coronary artery ligation were allocated into MI group (n = 6); P...

  2. Therapeutic potential of targeting the renin angiotensin system in portal hypertension

    OpenAIRE

    2013-01-01

    Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis. Drug therapy to reduce portal pressure involves targeting two vascular beds. The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin II, endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells. The second approach is to reduce mesen...

  3. Search for potential angiotensin converting enzyme (ACE)-inhibitors from plants.

    Science.gov (United States)

    Lacaille-Dubois; Franck, U; Wagner, H

    2001-01-01

    MeOH extracts, fractions and pure substances from Musanga cecropioides, Cecropia species and Crataegus oxyacantha /C. monogyna were screened by using an in vitro bio-assay based on the inhibition of Angiotensin Converting Enzyme (ACE), as measured from the enzymatic cleavage of the chromophore-fluorophore-labelled substrate dansyltriglycine into dansylglycine and diglycine. Phenolic acids showed no significant ACE-inhibition whereas flavonoids and proanthocyanidins demonstrated inhibitory activity at 0.33 mg/ml using this test system. PMID:11292239

  4. 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...

  5. 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 ...

  6. Effect of deafferentation of the rat tongue on plasma corticosterone, aldosterone, angiotensin and ACTH levels

    International Nuclear Information System (INIS)

    The effect of deafferentation of the tongue on the plasma level of hormones involved in regulation of the sodium ion level -- aldosterone, corticosterone, ACTH, and angiotensin -- was studied. Plasma hormone levels were determined by radioimmunoassay. The results indicate the important role of orosensory and taste perception in the processes of regulation of the sodium balance in the body. The experiments in this study were conducted on rats

  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. Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection

    Directory of Open Access Journals (Sweden)

    Lindsey J. Reese

    2012-01-01

    Full Text Available Background. Liver fibrosis is accelerated in HIV and hepatitis C coinfection, mediated by profibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is attenuate liver fibrosis in coinfection. Methods. A retrospective review of 156 coinfected subjects was conducted to analyze the association between exposure to ACE-Is and liver fibrosis. Noninvasive indices of liver fibrosis (APRI, FIB-4, Forns indices were compared between subjects who had taken ACE-Is and controls who had not taken them. Linear regression was used to evaluate ACE-I use as an independent predictor of fibrosis. Results. Subjects taking ACE-Is for three years were no different than controls on the APRI and the FIB-4 but had significantly higher scores than controls on the Forns index, indicating more advanced fibrosis. The use of ACE-Is for three years remained independently associated with an elevated Forns score when adjusted for age, race, and HIV viral load (P<0.001. There were significant associations between all of the indices and significant fibrosis, as determined clinically and radiologically. Conclusions. There was not a protective association between angiotensin inhibition and liver fibrosis in coinfection. These noninvasive indices may be useful for ruling out significant fibrosis in coinfection.

  9. 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.)

  10. Renin-angiotensin-aldosterone system blockade in chronic kidney disease: current strategies and a look ahead.

    Science.gov (United States)

    Viazzi, Francesca; Bonino, Barbara; Cappadona, Francesca; Pontremoli, Roberto

    2016-08-01

    The Renin-Angiotensin-Aldosterone System (RAAS) is profoundly involved in the pathogenesis of renal and cardiovascular organ damage, and has been the preferred therapeutic target for renal protection for over 30 years. Monotherapy with either an Angiotensin Converting Enzime Inhibitor (ACE-I) or an Angiotensin Receptor Blocker (ARB), together with optimal blood pressure control, remains the mainstay treatment for retarding the progression toward end-stage renal disease. Combining ACE-Is and ARBs, or either one with an Aldosterone Receptor Antagonist (ARA), has been shown to provide greater albuminuria reduction, and to possibly improve renal outcome, but at an increased risk of potentially severe side effects. Moreover, combination therapy has failed to provide additional cardiovascular protection, and large prospective trials on hard renal endpoints are lacking. Therefore this treatment should, at present, be limited to selected patients with residual proteinuria and high renal risk. Future studies with novel agents, which directly act on the RAAS at multiple levels or have a more favourable side effect profile, are greatly needed to further explore and define the potential for and the limitations of profound pharmacologic RAAS inhibition. PMID:26984204

  11. Gene polymorphisms of renin-angiotensin-aldosterone system components and the progression of chronic kidney diseases

    Directory of Open Access Journals (Sweden)

    Agata Kujawa-Szewieczek

    2010-08-01

    Full Text Available The renin-angiotensin-aldosterone system (RAAS plays an important role in the pathogenesis of hypertension as well as cardiovascular diseases and chronic kidney diseases. Among the most frequently studied RAAS gene polymorphisms are the angiotensin-converting enzyme insertion/deletion (I/D, angiotensinogen M235T and angiotensin II receptor type 1 A1166C polymorphisms.A significant correlation was found between the I/D polymorphism and cardiovascular morbidity and mortality rates. However, there was no significant correlation between I/D, M235T, A1166C polymorphism and arterial hypertension. The role of I/D polymorphism in the development and progression of chronic kidney disease is also non-conclusive. However, DD genotype has been identified as relevant for loss of renal function both in patients with IgA nephropathy and in patients of Asian origin with diabetic nephropathy.The relationship between RAAS gene polymorphism and transplanted kidney function has not been confirmed in large prospective and retrospective studies. Conclusion: there is no clear opinion concerning the influence of RAAS genotypes on the prevalence of post-transplant hypertension or erythrocytosis.Although a role of RAAS gene polymorphism in kidney function deterioration could not be ruled out, it is more likely that a variety of genetic and environmental factors influence the progression of chronic kidney diseases.

  12. Angiotensins processing activities in the venom and epidermic mucus of Scorpaena plumieri.

    Science.gov (United States)

    Tenório, Humberto de Araújo; Costa, Ricardo Bezerra; Costa Marques, Maria Elizabeth; Victor Dos Santos, Claudio Wilian; Gomes, Francis Soares; Vieira Pereira, Hugo Juarez

    2016-09-01

    The venom of marine animals is a rich source of compounds with remarkable selectivity and functional diversity. Scorpaena plumieri is the most venomous fish in the Brazilian fauna and is responsible for relatively frequent accidents involving anglers and bathers. In humans, its venom causes edema, erythema, ecchymoses, anxiety, nausea, vomiting, and syncope. The venom is chemically characterized by Sp-CTx, a enzyme able to generate an initial endothelium-dependent relaxation response, followed by a contraction response. This study sought to investigate the proteolytic activities regarding vasopeptides angiotensin I and II. Both the venom and the epidermal mucus presented angiotensin conversion activity for angiotensin I, as well as a capacity to form Ang 1-7 directly via Ang I and II. Captopril (10 μM) and EDTA (1 mM) were able to abolish the converting activity of the venom and the epidermal mucus, representing the first description of a converting activity in S. plumieri venom and epidermal mucus. PMID:27215174

  13. Outcome of Venom Bradykinin Potentiating Factor on Renin Angiotensin System in Irradiated Rats

    International Nuclear Information System (INIS)

    Scorpion Venom contains a strong bradykinin potentiating factor (BPF) exhibiting angiotensin converting enzyme inhibition (ACEI). Irradiation and stimulation of renin-angiotensin system (RAS) induce oxidative stress. Interruption of the RAS by an ACEI or angiotensin II receptor blocker (ARB) losartan (LOS) and/or gamma-rays (4 Gy) were evaluated. Rats received 6 doses of BPF (1μg/g body wt) or of LOS (5 μg/g body wt). Treatment with BPF induced significant elevation in the level of potassium (K) and significant drop in the level of sodium (Na) and uric acid. Treatment with LOS significantly depressed the level of Na and uric acid compared to control. Irradiation discerned a significant elevation in malondialdehyde (MDA), advanced oxidative protein product (AOPP), aldosterone, Na, urea and creatinine, and a significant drop in the haematological values, glutathione (GSH), calcium (Ca) and uric acid. A significant decrease in MDA, aldosterone, urea, creatinine and uric acid compared to irradiated group was observed in irradiated treated groups. Irradiated animals treated with LOS showed a significant decrease in Na and chloride (Cl) compared to the irradiated group. Considerable amelioration of radiation-induced depression in haematopoiesis, improvement of oxidative stress and kidney function by BPF as ACEI or LOS as ARB are detected. Results add further identification to the properties of BPF

  14. Gene expression profiling following maternal deprivation: Involvement of the brain renin-angiotensin system

    Directory of Open Access Journals (Sweden)

    Wolfgang Wurst

    2009-05-01

    Full Text Available The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP, where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differentially regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently up-regulated genes, angiotensinogen, was validated using in-situ hybridization. Angiotensinogen is the precursor of angiotensin II, the main effector of the brain renin-angiotensin system (RAS, which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1 antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain a nd ACTH release following maternal separation. AT(1 receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and contribute to identifying signaling cascades that control stress system activity in the neonate.

  15. Effects of angiotensin II and ionomycin on fluid and bicarbonate absorption in the rat proximal tubule

    Energy Technology Data Exchange (ETDEWEB)

    Chatsudthipong, V.; Chan, Y.L.

    1986-03-01

    Microperfusion of proximal convoluted tubule(PCT) and peritubular capillaries was performed to examine the effects of angiotensin II(Ang II) and ionomycin on fluid and bicarbonate absorption. Bicarbonate was determined by microcalorimetry and C-14 inulin was used as a volume marker. The rates of bicarbonate absorption (JHCO/sub 3/) was 143 peq/min x mm and fluid absorption(Jv) was 2.70 nl/min x mm, when PCT and capillary perfusate contained normal Ringer solution. Addition of Ang II (10/sup -6/M) to the capillary perfusate caused reductions of JHCO/sub 3/ and Jv by 35%. A similar effect was observed when ionomycin was added to the capillary perfusate. Ang II antagonist, (Sar/sup 1/, Ile/sup 8/)-Angiotensin II(10/sup -6/M), completely blocked the inhibitory effect of Ang II on Jv and JHCO/sub 3/. Removal of calcium from both luminal and capillary perfusate did not change the effect of Ang II on Jv and JHCO/sub 3/. Our results indicate that Ang II inhibits the sodium-hydrogen exchanger in the proximal tubule via interacting with angiotensin receptor. The mechanism of Ang II action may involve mobilization of intracellular calcium.

  16. 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.

  17. 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

  18. Evidence for extracellular, but not intracellular, generation of angiotensin II in the rat adrenal zona glomerulosa

    International Nuclear Information System (INIS)

    Based on the observation that high levels of renin and angiotensin II (Ang II) are found in the adrenal zona glomerulosa (ZG), it has been postulated that Ang II is formed intracellularly by the renin-converting enzyme cascade in this tissue. To test this hypothesis, the authors examined renin-angiotensin system components in subcellular fractions of the rat adrenal ZG. Renin activity and immunoreactive-Ang II (IR-Ang II) were observed in vesicular fractions but were not colocalized. In addition, angiotensinogen, angiotensin I, and converting enzyme were not observed in the renin or IR-Ang II-containing vesicular fractions. These data do not support the hypothesis that Ang II is formed intracellularly within the renin-containing vesicles of the ZG. Rather, since modulatable renin release from adrenal ZG slices was observed and renin activity was found in dense vesicular fractions (33-39% sucrose), it is likely that Ang II formation in the ZG is extracellular and initiated by the release of vesicular renin. In ZG lysomal fractions 125I-labeled Ang II was degraded to 125I-labeled des-[Phe8]Ang II. Since Ang II antibodies do not recognize des-[Phe8]Ang II, these finding explain why IR-Ang II in the ZG is due predominantly to Ang II and not to its C-terminal immunoreactive fragments

  19. Tissue Renin-Angiotensin Systems: A Unifying Hypothesis of Metabolic Disease

    Directory of Open Access Journals (Sweden)

    Jeppe eSkov

    2014-02-01

    Full Text Available The actions of angiotensin peptides are diverse and locally acting tissue renin-angiotensin systems (RAS are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g. diabetes and its complications and blockers of RAS have been demonstrated to prevent diabetes in humans.Hyperglycemia, obesity, hypertension, and cortisol are well-known risk factors of metabolic disease and all stimulate tissue RAS whereas glucagon-like peptide-1, vitamin D, and aerobic exercise are inhibitors of tissue RAS and to some extent can prevent metabolic disease. Furthermore, an activated tissue RAS deteriorates the same risk factors creating a system with several positive feedback pathways. The primary effector hormone of the RAS, angiotensin II, stimulates reactive oxygen species, induces tissue damage, and can be associated to most diabetic complications. Based on these observations we hypothesize that an activated tissue RAS is the principle cause of metabolic syndrome and type 2 diabetes, and additionally is mediating the majority of the metabolic complications. The involvement of positive feedback pathways may create a self-reinforcing state and explain why metabolic disease initiate and progress. The hypothesis plausibly unify the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control.

  20. Association between Angiotensin II Type 1 Receptor Polymorphism and Sudden Cardiac Death in Myocardial Infarction

    Science.gov (United States)

    Kruzliak, Peter; Kovacova, Gabriela; Pechanova, Olga; Balogh, Stefan

    2013-01-01

    Objective. The renin-angiotensin system is involved in the pathogenesis of coronary artery disease and myocardial infarction (MI). Angiotensin II (Ang II) has many adverse effects such as vasoconstriction and vascular remodeling, and these actions are mediated by the angiotensin II type 1 receptor (AT1R). Patients and Methods. A total of 1376 patients were recruited from January 2010 to April 2012. The study group consisted of 749 patients with ACS (317 females and 432 males) and of 627 healthy controls. Results. The ACS patients demonstrated a lower proportion of AA genotypes and AC genotypes but higher proportions of CC genotypes than the control population. The AT1R CC genotype conferred a 2.76-fold higher risk of MI compared with the genotype AC and AA. In addition, the CC genotype was also associated with a 4.08 times higher risk of left anterior descending artery infarction and a 3.07 times higher risk of anterior wall infarction. We also found that the CC genotype was independently associated with sudden cardiac death. In Summary. This study demonstrated that the AT1R CC genotype is an independent risk factor for ACS incidence, and this genotype is associated with a greater ACS severity and greater risk of sudden cardiac death. PMID:24167376

  1. Effect of angiotensin II, ATP, and ionophore A23187 on potassium efflux in adrenal glomerulosa cells

    International Nuclear Information System (INIS)

    Angiotensin II stimulus on perifused bovine adrenal glomerulosa cells elicited an increase in 86Rb efflux from cells previously equilibrated with the radioisotope. When 45Ca fluxes were measured under similar conditions, it was observed that Ca and Rb effluxes occurred within the first 30 s of the addition of the hormone and were independent of the presence of external Ca. The 86Rb efflux due to angiotensin II was inhibited by quinine and apamin. The hypothesis that the angiotensin II response is a consequence of an increase in the K permeability of the glomerulosa cell membrane triggered by an increase in cytosolic Ca is supported by the finding that the divalent cation ionophore A23187 also initiated 86Rb or K loss (as measured by an external K electrode). This increased K conductance was also seen with 10(-4) M ATP. Quinine and apamin greatly reduced the effect of ATP or A23187 on 86Rb or K release in adrenal glomerulosa cells. The results suggest that Ca-dependent K channels or carriers are present in the membranes of bovine adrenal glomerulosa cells and are sensitive to hormonal stimulus

  2. Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

    Science.gov (United States)

    Xu, Bing-Can; Long, Hui-Bao; Luo, Ke-Qin

    2016-01-01

    Tert-butylhydroquinone (tBHQ), as an antioxidant, has been widely used for many years to prevent oxidization of food products. The aim of this study was to investigate whether tBHQ activates endothelial nitric oxide synthase (eNOS) to prevent endothelial dysfunction and lower blood pressure. The role of Akt in tBHQ-induced eNOS phosphorylation was examined in human umbilical vein endothelial cells (HUVEC) or in mice. tBHQ treatment of HUVEC increased both Akt-Ser473 phosphorylation, accompanied with increased eNOS-Ser1177 phosphorylation and NO release. Mechanically, pharmacologic or genetic inhibition of Akt abolished tBHQ-enhanced NO release and eNOS phosphorylation in HUVEC. Gain-function of PTEN or inhibition of 26S proteasome abolished tBHQ-enhanced Akt phosphorylation in HUVEC. Ex vivo analysis indicated that tBHQ improved Ach-induced endothelium-dependent relaxation in LPC-treated mice aortic arteries, which were abolished by inhibition of Akt or eNOS. In animal study, administration of tBHQ significantly increased eNOS-Ser1177 phosphorylation and acetylcholine-induced vasorelaxation, and lowered AngII-induced hypertension in wildtype mice, but not in mice deficient of Akt or eNOS. In conclusion, tBHQ via proteasome-dependent degradation of PTEN increases Akt phosphorylation, resulting in upregulation of eNOS-derived NO production and consequent improvement of endothelial function in vivo. In this way, tBHQ lowers blood pressure in hypertensive mice. PMID:27435826

  3. Use of beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and breast cancer survival: Systematic review and meta-analysis.

    Science.gov (United States)

    Raimondi, Sara; Botteri, Edoardo; Munzone, Elisabetta; Cipolla, Carlo; Rotmensz, Nicole; DeCensi, Andrea; Gandini, Sara

    2016-07-01

    Breast cancer (BC) is the second leading cause of cancer death among women in Western Countries. Beta-blocker (BB) drugs, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) were suggested to have a favorable role in the development and progression of BC. We have performed a meta-analysis to clarify the potential benefits of these drugs on BC survival. A total number of 46 265 BC patients from eleven papers were included, ten independent studies on BB use and seven on ACEi/ARB use. The summary hazard ratio (SHR) was estimated by pooling the study-specific estimates with random effects models and maximum likelihood estimation. We assessed the homogeneity of the effects across studies and evaluated between-study heterogeneity by meta-regression and sensitivity analyses. We found a significant improvement in BC specific survival for patients treated with BB drugs at the time of BC diagnosis (SHR: 0.44; 95%CI: 0.26-0.73 with I(2)  = 78%). We also observed a borderline significant improvement in disease free survival for subjects treated with BB (SHR: 0.71, 95%CI: 0.19-1.03). No association of ACEi/ARB use with disease free and overall survival was found. In conclusion, we report epidemiological evidence that BB improve BC-specific survival. Clinical trials addressing this hypothesis are warranted. PMID:26916107

  4. Intrarenal distributions and changes of Angiotensin-converting enzyme and Angiotensin-converting enzyme 2 in feline and canine chronic kidney disease.

    Science.gov (United States)

    Mitani, Sawane; Yabuki, Akira; Sawa, Mariko; Chang, Hye-Sook; Yamato, Osamu

    2014-01-01

    Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system (RAS). ACE2 is a newly identified member of the RAS. The present immunohistochemical study focused on changes in intrarenal ACE and ACE2 immunoreactivity in feline and canine chronic kidney disease (CKD). ACE immunoreactivity was predominantly observed in the brush border of the proximal tubules in dogs and cats. ACE immunoreactivity was lower in CKD kidneys than in normal kidneys, and quantitative analysis demonstrated negative correlations between ACE and renal tissue damage in dogs. ACE2 immunoreactivity was also detected in the proximal tubules; it increased or decreased with CKD in dogs, depending on the renal region assessed. The changes in ACE and ACE2 in CKD were associated with the plasma creatinine concentration in dogs. Findings from dogs with glomerulonephritis were similar to those from dogs with non-glomerulonephritis. The present study suggests that changes in the intrarenal expression of ACE and ACE2 contribute to the pathological mechanisms of canine CKD, but not to the mechanisms of feline CKD. PMID:24004970

  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. Hyponatremia in a patient with scleroderma renal crisis: a potential role of activated renin-angiotensin system

    Directory of Open Access Journals (Sweden)

    Fukasawa Hirotaka

    2012-06-01

    Full Text Available Abstract Background Scleroderma renal crisis is an important complication of scleroderma (systemic sclerosis that is associated with significant morbidity and mortality. On the other hand, hyponatremia has never been reported in patients with scleroderma renal crisis. Case presentation A 66-year-old man with scleroderma was admitted to our hospital for an evaluation of renal dysfunction and extreme hypertension. The laboratory evaluation revealed remarkably high plasma renin activity in association with microangiopathic hemolytic anemia, and the anti-RNA polymerase III antibody assessment was positive. The patient was diagnosed with scleroderma renal crisis and was started treatment with enalapril maleate, an angiotensin-converting enzyme inhibitor. During hospitalization, the patient developed symptomatic hyponatremia three times and each laboratory analysis revealed improperly high levels of antidiuretic hormone without signs of extracellular fluid volume depletion as well as remarkably high plasma renin activities and angiotensin levels. However, hyponatremia has not been demonstrated to occur as a result of combined therapy with candesartan cilexetil, an angiotensin II receptor blocker, and aliskiren fumarate, a direct renin inhibitor. The plasma renin activities and angiotensin levels were normalized and the renal function was maintained after treatment. Conclusions To our best knowledge, this is the first documented case of scleroderma renal crisis complicated with hyponatremia. This report also suggests that the activated renin-angiotensin system may play a role in the development of hyponatremia and that hyponatremia should be taken into consideration as a rare but possible complication associated with screloderma renal crisis.

  7. 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

  8. 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

    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 candes...

  9. Expression and transport of Angiotensin II AT1 receptors in spinal cord, dorsal root ganglia and sciatic nerve of the rat

    OpenAIRE

    Pavel, Jaroslav; Tang, Hui; Brimijoin, Stephen; Moughamian, Armen; Nishioku, Tsuyoshi; Benicky, Julius; Saavedra, Juan M.

    2008-01-01

    To clarify the role of Angiotensin II in the regulation of peripheral sensory and motor systems, we initiated a study of the expression, localization and transport of Angiotensin II receptor types in the rat sciatic nerve pathway, including L4–L5 spinal cord segments, the corresponding dorsal root ganglia (DRGs) and the sciatic nerve.

  10. Differential regulation of renal angiotensin-converting enzyme (ACE) and ACE2 during ACE inhibition and dietary sodium restriction in healthy rats

    NARCIS (Netherlands)

    Hamming, I.; van Goor, H.; Turner, A. J.; Rushworth, C. A.; Michaud, A. A.; Corvol, P.; Navis, G.

    2008-01-01

    Angiotensin-converting enzyme (ACE) 2 is thought to counterbalance ACE by breakdown of angiotensin (Ang) II and formation of Ang(1-7). Both enzymes are highly expressed in the kidney, but reports on their regulation differ. To enhance our understanding of the regulation of renal ACE and ACE2, we inv

  11. Different modulatory effects of ammonium ions on angiotensin vascular actions in isolated rat aortic and renal arteries

    Directory of Open Access Journals (Sweden)

    Popescu Raducu I.

    2012-01-01

    Full Text Available In the present study, we were interested in the vascular effects of angiotensin II on perfused rings of the rat thoracic aorta and renal artery. Our results demonstrated different modulator alterations of these preparations induced by ammonium ions. Unlike the aortic rings, which exhibited only a reduction of angiotensin-induced contractility by NH4Cl, the renal artery preparations showed both activation of vasoconstriction and inhibition of vasorelaxation in the ring precontracted with phenylephrine or noradrenalin. These results are interpreted as a modulation by the ammonium ions of vascular reactions induced by the stimulation of the vasoconstrictor AT1 receptor on the one side and AT2 vasodilator receptors on the other. The potentiation of renal vasoconstriction accompanied by the reduction of angiotensin vasodilation by NH4Cl suggests the possibility of involvement from the blood flow and renal vascular tonus disturbances induced by ammonium ions during hyperammonemia of various causes.

  12. Effect of angiotensin II, catecholamines and glucocorticoid on corticotropin releasing factor (CRF-induced ACTH release in pituitary cell cultures.

    Directory of Open Access Journals (Sweden)

    Murakami,Kazuharu

    1984-08-01

    Full Text Available The effects of angiotensin II, catecholamines and glucocorticoid on CRF-induced ACTH release were examined using rat anterior pituitary cells in monolayer culture. Synthetic ovine CRF induced a significant ACTH release in this system. Angiotensin II produced an additive effect on CRF-induced ACTH release. The ACTH releasing activity of CRF was potentiated by epinephrine and norepinephrine. Dopamine itself at 0.03-30 ng/ml did not show any significant effect on ACTH release, but it inhibited CRF-induced ACTH release. Corticosterone at 10(-7 and 10(-6M inhibited CRF-induced ACTH release. These results indicate that angiotensin II, catecholamines and glucocorticoid modulate ACTH release at the pituitary level.

  13. The pressor effect of angiotensin-(1-7 in the rat rostral ventrolateral medulla involves multiple peripheral mechanisms

    Directory of Open Access Journals (Sweden)

    Rita C. Oliveira

    2013-01-01

    Full Text Available OBJECTIVE: In the present study, the peripheral mechanism that mediates the pressor effect of angiotensin-(1-7 in the rostral ventrolateral medulla was investigated. METHOD: Angiotensin-(1-7 (25 pmol was bilaterally microinjected in the rostral ventrolateral medulla near the ventral surface in urethane-anesthetized male Wistar rats that were untreated or treated (intravenously with effective doses of selective autonomic receptor antagonists (atenolol, prazosin, methyl-atropine, and hexamethonium or a vasopressin V1 receptor antagonist [d(CH25 -Tyr(Me-AVP] given alone or in combination. RESULTS: Unexpectedly, the pressor response produced by angiotensin-(1-7 (16 ± 2 mmHg, n = 12, which was not associated with significant changes in heart rate, was not significantly altered by peripheral treatment with prazosin, the vasopressin V1 receptor antagonist, hexamethonium or methyl-atropine. Similar results were obtained in experiments that tested the association of prazosin and atenolol; methyl-atropine and the vasopressin V1 antagonist or methyl-atropine and prazosin. Peripheral treatment with the combination of prazosin, atenolol and the vasopressin V1 antagonist abolished the pressor effect of glutamate; however, this treatment produced only a small decrease in the pressor effect of angiotensin-(1-7 at the rostral ventrolateral medulla. The combination of hexamethonium with the vasopressin V1 receptor antagonist or the combination of prazosin, atenolol, the vasopressin V1 receptor antagonist and methyl-atropine was effective in blocking the effect of angiotensin-(1-7 at the rostral ventrolateral medulla. CONCLUSION: These results indicate that angiotensin-(1-7 triggers a complex pressor response at the rostral ventrolateral medulla that involves an increase in sympathetic tonus, release of vasopressin and possibly the inhibition of a vasodilatory mechanism.

  14. Chronic Renin-Angiotensin System (RAS) Blockade May Not Induce Hypotension During Anaesthesia for Bariatric Surgery.

    Science.gov (United States)

    Salvetti, Guido; Di Salvo, Claudio; Ceccarini, Giovanni; Abramo, Antonio; Fierabracci, Paola; Magno, Silvia; Piaggi, Paolo; Vitti, Paolo; Santini, Ferruccio

    2016-06-01

    The use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) for the treatment of hypertensive obese patients is steadily increasing. Some studies have reported that the use of these drugs was associated with an increased risk of hypotensive episodes, during general anaesthesia. The number of bariatric procedures is also increasing worldwide, but there is a lack of studies investigating the hypotensive effect of renin-angiotensin system (RAS) blockers in severely obese patients during general anaesthesia for bariatric surgery. The aim of this pilot study was to evaluate hemodynamic changes induced by general anaesthesia in obese patients chronically treated with ACE-I or ARB compared to a control group not treated with antihypertensive therapy. Fourteen obese subjects (mean body mass index (BMI) 47.5 kg/m(2)) treated with ACE-I or ARB and twelve obese (mean BMI 45.7 kg/m2) controls not treated with antihypertensive therapy underwent general anaesthesia to perform laparoscopic bariatric surgery. Systolic blood pressure, diastolic blood pressure, and heart rate were monitored continuously and registered at different time points: T0 before induction, then at 2, 5, 7, 10, 15, 20, 30, 60, 90, 120, and 150 min after induction, and the last time point taken following recovery from anaesthesia. A progressive reduction of both systolic and diastolic blood pressure values was observed without significant differences between the two groups. A similar trend of heart rate values was observed. In conclusion, our pilot study suggests that RAS blockers may be continued during the perioperative period in patients undergoing bariatric surgery, without increasing the risk of hypotensive episodes. PMID:26328531

  15. QM/MM investigation of the catalytic mechanism of angiotensin-converting enzyme.

    Science.gov (United States)

    Mu, Xia; Zhang, Chunchun; Xu, Dingguo

    2016-06-01

    Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II and degrades bradykinin and other vasoactive peptides. ACE inhibitors are used to treat diseases such as hypertension and heart failure. It is thus highly desirable to understand the catalytic mechanism of ACE, as this should facilitate the design of more powerful and selective ACE inhibitors. ACE exhibits two different active domains, the C-domain and the N-domain. In this work, we systematically investigated the inhibitor- and substrate-binding patterns in the N-domain of human ACE using a combined quantum mechanical and molecular mechanical approach. The hydrolysis of hippuryl-histidyl-leucine (HHL) as catalyzed by the N-domain of human somatic ACE was explored, and the effects of chloride ion on the overall reaction were also investigated. Two models, one with and one without a chloride ion at the first binding position, were then designed to examine the chloride dependence of inhibitor-substrate binding and the catalytic mechanism. Our calculations indicate that the hydrolysis reaction follows a stepwise general base/general acid catalysis path. The estimated mean free energy barrier height in the two models is about 15.6 kcal/mol, which agrees very well with the experimentally estimated value of 15.8 kcal/mol. Our simulations thus suggest that the N-domain is in a mixed form during ACE-catalyzed hydrolysis, with the single-chloride-ion and the double-chloride-ion forms existing simultaneously. Graphical Abstract Superposition of ACE C- and N- domains. PMID:27184002

  16. Development of a Spectrophotometric Method for Monitoring Angiotensin-Converting Enzyme in Dairy Products

    Directory of Open Access Journals (Sweden)

    Julijana Tomovska*, S. Presilski, N. Gjorgievski, N. Tomovska1, M. S. Qureshi2 and N. P. Bozinovska3

    2013-01-01

    Full Text Available The angiotensin-converting enzyme (ACE regulates the levels of blood pressure through generation of angiotensin-II from angiotensin-I. It is of great importance to have a reliable and yet simple method for a quantitative determination ACE inhibitory peptides in whey of milk products. A rapid, simple, sensitive and accurate spectrophotometric kinetic method has been developed for determination of ACE inhibitory peptides, using competitive inhibition. Samples of dairy product from the market were used for the determination of ACE inhibitory peptides in whey. Holmquist’s kinetic method was used for determining ACE inhibitory activity in blood serum and Ronca-Testoni method was used for the determination of ACE inhibitory activity in whey. Enzymatic inhibition activity was determined using 0.8 mmol/L FAPGG (N-[3-(Furyl –Acryloyl]-L-Phenylalanyl Glycyl Glycyne as the substrate in 50 mmol/L Tris buffer at pH 8.2 at 37°C and a standard serum containing ACE. First, a solution of whey was mixed in a 1 to 10 ratio with serum (elevation containing high ACE activity. The enzymatic activity was determined by monitoring the decrease in absorbance at 340 nm as result of hydrolysis of the substrate. The concentration of ACE inhibitory peptides was determined from a standard curve of inhibitor concentration versus percent of ACE inhibition. The study suggests that the method possesses good reproducibility and accuracy. The linear range enabled determination of high enzymatic activity of ACE and all ACE inhibitory peptides from dairy products act as competitive inhibitors.

  17. 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

  18. Nandrolone increases angiotensin-I converting enzyme activity in rats tendons

    Directory of Open Access Journals (Sweden)

    Rita de Cassia Marqueti

    2015-06-01

    Full Text Available INTRODUCTION: The renin-angiotensin system (RAS has been associated with several biological processes of the human body, regulating, among others blood pressure and water and electrolytes balance. Moreover, RAS also regulates connective tissue growth. Recently, studies have shown that the use of nandrolone modifies the angiotensin-I converting enzyme (ACE activity and increases collagen deposition in the heart. OBJECTIVE: The aim of study was to evaluate the Angiotensin-I converting enzyme (ACE activity in the superficial flexor tendon (SFT and in serum after load exercise in combination with anabolic androgenic steroid (AAS administration after training session and six weeks of detraining. METHODS: Forty-eight Wistar rats were used into two groups (G1 and G2 subdivided into four subgroups: Sedentary (S; trained (T; AAS-treated (Deca-Durabolin(r, 5mg/kg, twice a week sedentary rats (AAS and AAS-treated and trained animals (AAST. Trained groups performed jumps in water: four series of 10 jumps each, followed by a 30 sec interval between the series, for seven weeks. RESULTS: Training increased ACE activity in the SFT compared to the control group (p <0.05. Both AAS and AAST groups presented higher ACE activity levels (p < 0.05. The AAST increased the ACE activity only compared to the trained animals. Only the AAST group presented significant higher levels of ACE in the serum. In the G2 group, all experimental groups presented decreased ACE activity in the serum and in the tendon, as compared to the control group. CONCLUSION: This study indicates that AAS administration and its combination with exercise increased ACE activity of tendons. AAS abuse could compromise tendon adaptation causing maladaptive remodeling.

  19. Direct proof for local generation and release of angiotensin II in peripheral human vascular tissue.

    Science.gov (United States)

    Mizuno, K; Niimura, S; Tani, M; Haga, H; Inagami, T; Fukuchii, S

    1991-01-01

    Previously we reported that immunoreactive angiotensin II (Ang II) release from isolated perfused human umbilical veins was inhibited by the angiotensin-converting enzyme inhibitor captopril. To further investigate the mechanism by which Ang II is generated in the blood vessels of humans, we examined the effects of various inhibitors of the renin-angiotensin system (captopril, delapril, N-acetyl-pepstatin, and human renin inhibitor KRI-1314) on Ang II release from perfused human umbilical cord veins in vitro. Isolated human umbilical veins were perfused with Krebs-Ringer solution, and immunoreactive Ang II released into the perfusate was measured directly by using a Sep-Pak C18 cartridge connected to the perfusion system. Both captopril and delapril diacid (10(-9) to 5 x 10(-6) mol/L), an active metabolite of delapril hydrochloride, suppressed the Ang II release in a dose-dependent fashion; the maximal percent suppression of Ang II release evoked by these inhibitors (5 x 10(-6) mol/L) was 56% and 64%, respectively, for captopril and delapril. Both N-acetyl-pepstatin (10(-9) to 10(-5) mol/L) and KRI-1314 (10(-9) to 10(-6) mol/L) suppressed Ang II release in a dose-related manner. At a 10(-6) mol/L concentration, KRI-1314 produced a 74% reduction in the basal rate of Ang II release, and a reduction threefold greater than the maximal reduction in basal Ang II release produced by N-acetyl-pepstatin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2009152

  20. Changes in the renin angiotensin system during the development of colorectal cancer liver metastases

    International Nuclear Information System (INIS)

    Blockade of the renin angiotensin system (RAS) via angiotensin I converting enzyme (ACE) inhibition reduces growth of colorectal cancer (CRC) liver metastases in a mouse model. In this work we defined the expression of the various components of the RAS in both tumor and liver during the progression of this disease. Immunohistochemistry and quantitative RT-PCR was used to examine RAS expression in a mouse CRC liver metastases model. CRC metastases and liver tissue was assessed separately at key stages of CRC liver metastases development in untreated (control) mice and in mice treated with the ACE inhibitor captopril (750 mg/kg/day). Non-tumor induced (sham) mice indicated the effect of tumors on normal liver RAS. The statistical significance of multiple comparisons was determined using one-way analysis of variance followed by Bonferroni adjustment with SAS/STAT software. Reduced volume of CRC liver metastases with captopril treatment was evident. Local RAS of CRC metastases differed from the surrounding liver, with lower angiotensin II type 1 receptor (AT1R) expression but increased ANG-(1-7) receptor (MasR) compared to the liver. The AT1R localised to cancer and stromal infiltrating cells, while other RAS receptors were detected in cancer cells only. Tumor induction led to an initial increase in AT1R and ACE expression while captopril treatment significantly increased ACE expression in the final stages of tumor growth. Conversely, captopril treatment decreased expression of AT1R and angiotensinogen. These results demonstrate significant changes in RAS expression in the tumor-bearing captopril treated liver and in CRC metastases. The data suggests the existence of a tumor-specific RAS that can be independently targeted by RAS blockade

  1. Angiotensin II clamp prevents the second step in renal apical NHE3 internalization during acute hypertension

    DEFF Research Database (Denmark)

    Leong, Patrick K K; Yang, Li E; McDonough, Alicia A;

    2002-01-01

    Acute hypertension inhibits proximal tubule (PT) sodium reabsorption. The resultant increase in NaCl delivery to the macula densa suppresses renin release. We tested whether the sustained pressure-induced inhibition of PT sodium reabsorption requires a renin-mediated decrease in ANG II levels...... hypertension, including diuresis and redistribution of PT NHE3 into intracellular membranes, require a responsive renin-angiotensin system and that the responses may be induced by the sustained increase in NaCl delivery to the macula densa during acute hypertension....

  2. Autonomic dysregulation in ob/ob mice is improved by inhibition of angiotensin-converting enzyme

    OpenAIRE

    Hilzendeger, A.M.; da Costa Goncalves, A.C.; Plehm, R.; Diedrich, A.; Gross, V; J.B. Pesquero; Bader, M

    2010-01-01

    The leptin-deficient ob/ob mice are insulin resistant and obese. However, the control of blood pressure in this model is not well defined. The goal of this study was to evaluate the role of leptin and of the renin-angiotensin system in the cardiovascular abnormalities observed in obesity using a model lacking leptin. To this purpose, we measured blood pressure in ob/ob and control animals by radiotelemetry combined with fast Fourier transformation before and after both leptin and enalapril tr...

  3. Anti-Plasmodium Activity of Angiotensin II and Related Synthetic Peptides

    OpenAIRE

    Ceres Maciel; Vani Xavier de Oliveira Junior; Marcos Antonio Fázio; Rafael Nacif-Pimenta; Antonio Miranda; Pimenta, Paulo F. P.; Margareth Lara Capurro

    2008-01-01

    Plasmodium species are the causative agents of malaria, the most devastating insect-borne parasite of human populations. Finding and developing new drugs for malaria treatment and prevention is the goal of much research. Angiotensins I and II (ang I and ang II) and six synthetic related peptides designated Vaniceres 1-6 (VC1-VC6) were assayed in vivo and in vitro for their effects on the development of the avian parasite, Plasmodium gallinaceum. Ang II and VC5 injected into the thoraces of th...

  4. Pharmacophore-based structure optimization of angiotensin converting enzyme inhibitory peptide

    Institute of Scientific and Technical Information of China (English)

    WANG Wei; SHEN ShengRong; FENG FengQin; HE GuoQing; WANG ZhanLi

    2008-01-01

    Chemical feature based pharmacophore models were generated for an angiotensin converting enzyme (ACE) inhibitory peptide using the Discovery Studio 2.0 pharmacophore modeling approach. The pharmacophore hypothesis selected has five features (one negative lonizable region, one hydrogen bond donor, one hydrogen bond acceptor and two hydrophobic functional groups). Additionally, ACE inhibitory hexapeptide previously obtained from silkworm pupae protein was optimized to target the ACE based on the selected pharmacophore. The results suggest that tri-peptide (thr-val-phe) may be structural determinant of ACE activity. Docking studies further provided confidence for the validity of the selected pharmacophore model to perform structure optimization of the ACE inhibitory peptide.

  5. Angiotensin-converting enzyme (ACE-I/D) polymorphism frequency in Brazilian soccer players.

    Science.gov (United States)

    Coelho, Daniel Barbosa; Pimenta, Eduardo; Rosse, Izinara Cruz; Veneroso, Christiano; Pussieldi, Guilherme; Becker, Lenice Kapes; Carvalho, Maria-Raquel; Silami-Garcia, Emerson

    2016-06-01

    This study aimed to analyze the angiotensin-converting enzyme (ACE-I/D) allelic and genotypic frequencies in Brazilian soccer players of different ages. The study group comprised 353 players from first-division clubs in the under (U)-14, U-15, U-17, U-20, and professional categories. The allelic and genotypic frequencies did not differ significantly in any of the categories between the group of players and the control group. This was the first study of ACE-I/D polymorphism in Brazilian soccer players. PMID:27232187

  6. Angiotensin I-Converting Enzyme Inhibitory Peptides of Chia (Salvia hispanica) Produced by Enzymatic Hydrolysis

    OpenAIRE

    Maira Rubi Segura Campos; Fanny Peralta González; Luis Chel Guerrero; David Betancur Ancona

    2013-01-01

    Synthetic angiotensin I-converting enzyme (ACE-I) inhibitors can have undesirable side effects, while natural inhibitors have no side effects and are potential nutraceuticals. A protein-rich fraction from chia (Salvia hispanica L.) seed was hydrolyzed with an Alcalase-Flavourzyme sequential system and the hydrolysate ultrafiltered through four molecular weight cut-off membranes (1 kDa, 3 kDa, 5 kDa, and 10 kDa). ACE-I inhibitory activity was quantified in the hydrolysate and ultrafiltered fra...

  7. Hypoxia-Induced Collagen Synthesis of Human Lung Fibroblasts by Activating the Angiotensin System

    Directory of Open Access Journals (Sweden)

    Shan-Shan Liu

    2013-12-01

    Full Text Available The exact molecular mechanism that mediates hypoxia-induced pulmonary fibrosis needs to be further clarified. The aim of this study was to explore the effect and underlying mechanism of angiotensin II (Ang II on collagen synthesis in hypoxic human lung fibroblast (HLF cells. The HLF-1 cell line was used for in vitro studies. Angiotensinogen (AGT, angiotensin converting enzyme (ACE, angiotensin II type 1 receptor (AT1R and angiotensin II type 2 receptor (AT2R expression levels in human lung fibroblasts were analysed using real-time polymerase chain reaction (RT-PCR after hypoxic treatment. Additionally, the collagen type I (Col-I, AT1R and nuclear factor κappaB (NF-κB protein expression levels were detected using Western blot analysis, and NF-κB nuclear translocation was measured using immunofluorescence localization analysis. Ang II levels in HLF-1 cells were measured with an enzyme-linked immunosorbent assay (ELISA. We found that hypoxia increased Col-I mRNA and protein expression in HLF-1 cells, and this effect could be inhibited by an AT1R or AT2R inhibitor. The levels of NF-κB, RAS components and Ang II production in HLF-1 cells were significantly increased after the hypoxia exposure. Hypoxia or Ang II increased NF-κB-p50 protein expression in HLF-1 cells, and the special effect could be inhibited by telmisartan (TST, an AT1R inhibitor, and partially inhibited by PD123319, an AT2R inhibitor. Importantly, hypoxia-induced NF-κB nuclear translocation could be nearly completely inhibited by an AT1R or AT2R inhibitor. Furthermore pyrrolidine dithiocarbamate (PDTC, a NF-κB blocker, abolished the expression of hypoxia-induced AT1R and Col-I in HLF-1 cells. Our results indicate that Ang II-mediated NF-κB signalling via ATR is involved in hypoxia-induced collagen synthesis in human lung fibroblasts.

  8. Purification and characterization of angiotensin II AT2 receptors from neonatal rat kidney.

    OpenAIRE

    Ciuffo, G M; Heemskerk, F M; Saavedra, J M

    1993-01-01

    Angiotensin II (Ang II) AT2 receptors were purified 40,000-fold to a nearly homogeneous state after solubilization from neonatal rat kidney membranes with 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propane-sulfonic acid. Comparable IC50 values for the soluble extract (0.32 nM) and membranes (0.31 nM) were obtained by competition curves with 125I-labeled CGP42112, a selective AT2 ligand. Binding to AT2 receptors in the soluble extract was not sensitive to dithiothreitol. AT2 receptors ...

  9. Effects of angiotensin blockade on the splanchnic circulation in normotensive humans

    DEFF Research Database (Denmark)

    Stadeager, C; Hesse, B; Henriksen, O; Christensen, N J; Bonde-Petersen, F; Mehlsen, J; Giese, Jacob

    1989-01-01

    The effects of angiotensin-converting enzyme inhibition (ACE-I) by enalapril on splanchnic (n = 10) and central hemodynamics (n = 9) were examined in moderately salt-depleted healthy volunteers, at rest and during 15-20 min of lower body negative pressure (LBNP), reducing mean arterial pressure by...... levels during ACE-I. We conclude that, in normal sodium-depleted humans, acute ACE-I decreases splanchnic vascular resistance at rest and abolishes splanchnic vasoconstriction during LBNP. Furthermore, it may interfere with autonomic nervous system control of the circulation....

  10. THE CAPABILITIES OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN CLINICAL PRACTICE: FOCUS ON VASOPROTECTION

    Directory of Open Access Journals (Sweden)

    D. B. Nebieridze

    2015-12-01

    Full Text Available Data of large-scale research that shows comprehensive abilities of an angiotensin converting enzyme (ACE inhibitors in clinical practice were represented. The traditional usage of ACE inhibitors in patients with arterial hypertension and chronic heart failure has extended recently. The study results demonstrate the efficacy of ACE inhibitors in slowing down of disease progression related to atherosclerosis and prove the possibility of a new clinical approach. Evidences support new strategic abilities of a number of ACE inhibitors (ramipril, perindopril, which are associated with vasoprotection.

  11. THE CAPABILITIES OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN CLINICAL PRACTICE: FOCUS ON VASOPROTECTION

    Directory of Open Access Journals (Sweden)

    D. B. Nebieridze

    2007-01-01

    Full Text Available Data of large-scale research that shows comprehensive abilities of an angiotensin converting enzyme (ACE inhibitors in clinical practice were represented. The traditional usage of ACE inhibitors in patients with arterial hypertension and chronic heart failure has extended recently. The study results demonstrate the efficacy of ACE inhibitors in slowing down of disease progression related to atherosclerosis and prove the possibility of a new clinical approach. Evidences support new strategic abilities of a number of ACE inhibitors (ramipril, perindopril, which are associated with vasoprotection.

  12. Angiotensin II blockade, YKL-40 and maintenance of sinus rhythm after electrical cardioversion for atrial fibrillation

    DEFF Research Database (Denmark)

    Tveit, Arnljot; Seljeflot, Ingebjørg; Smith, Pal;

    2013-01-01

    cardioversion (ECV) for persistent AF and serum levels of YKL-40. A secondary point of interest was a potential effect of the angiotensin receptor blocker candesartan on YKL-40 levels. In the Candesartan in the Prevention of Relapsing Atrial Fibrillation (CAPRAF) study, 171 patients with persistent AF were......High levels of the novel inflammatory marker YKL-40 have been demonstrated in inflammatory environments and in remodeling of the extracellular matrix. Both are key components in atrial wall remodeling in atrial fibrillation (AF). We studied the relation between rhythm outcome after electrical...

  13. Relative Atrial Natriuretic Peptide Deficiency and Inadequate Renin and Angiotensin II Suppression in Obese Hypertensive Men

    DEFF Research Database (Denmark)

    Asferg, Camilla L; Nielsen, Søren J; Andersen, Ulrik B;

    2013-01-01

    Obesity is a strong risk factor for hypertension, but the mechanisms by which obesity leads to hypertension are incompletely understood. On this background, we assessed dietary sodium intake, serum levels of natriuretic peptides (NPs), and the activity of the renin-angiotensin system in 63 obese...... hypertensive men (obeseHT: body mass index, ≥30.0 kg/m(2); 24-hour ambulatory blood pressure, ≥130/80 mm Hg), in 40 obese normotensive men (obeseNT: body mass index, ≥30.0 kg/m(2); 24-hour ambulatory blood pressure,...

  14. 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...

  15. 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

    The blood-brain barrier (BBB), a complex of endothelial and glial barriers, controls passage of cells and solutes between the blood and central nervous system (CNS). Blood-brain barrier breakdown refers to entry of cells and/or solutes. We were interested whether the renin-angiotensin system 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...

  16. Palmitoylethanolamide treatment reduces blood pressure in spontaneously hypertensive rats: involvement of cytochrome p450-derived eicosanoids and renin angiotensin system.

    Directory of Open Access Journals (Sweden)

    Giuseppina Mattace Raso

    Full Text Available Palmitoylethanolamide (PEA, a peroxisome proliferator-activated receptor-α agonist, has been demonstrated to reduce blood pressure and kidney damage secondary to hypertension in spontaneously hypertensive rat (SHR. Currently, no information is available concerning the putative effect of PEA on modulating vascular tone. Here, we investigate the mechanisms underpinning PEA blood pressure lowering effect, exploring the contribution of epoxyeicosatrienoic acids, CYP-dependent arachidonic acid metabolites, as endothelium-derived hyperpolarizing factors (EDHF, and renin angiotensin system (RAS modulation. To achieve this aim SHR and Wistar-Kyoto rats were treated with PEA (30 mg/kg/day for five weeks. Functional evaluations on mesenteric bed were performed to analyze EDHF-mediated vasodilation. Moreover, mesenteric bed and carotid were harvested to measure CYP2C23 and CYP2J2, the key isoenzymes in the formation of epoxyeicosatrienoic acids, and the soluble epoxide hydrolase, which is responsible for their degradation in the corresponding diols. Effect of PEA on RAS modulation was investigated by analyzing angiotensin converting enzyme and angiotensin receptor 1 expression. Here, we showed that EDHF-mediated dilation in response to acetylcholine was increased in mesenteric beds of PEA-treated SHR. Western blot analysis revealed that the increase in CYP2C23 and CYP2J2 observed in SHR was significantly attenuated in mesenteric beds of PEA-treated SHR, but unchanged in the carotids. Interestingly, in both vascular tissues, PEA significantly decreased the soluble epoxide hydrolase protein level, accompanied by a reduced serum concentration of its metabolite 14-15 dihydroxyeicosatrienoic acid, implying a reduction in epoxyeicosatrienoic acid hydrolisis. Moreover, PEA treatment down-regulated angiotensin receptor 1 and angiotensin converting enzyme expression, indicating a reduction in angiotensin II-mediated effects. Consistently, a damping of the

  17. Sandwich immunoassay for the hapten angiotensin II. A novel assay principle based on antibodies against immune complexes.

    Science.gov (United States)

    Towbin, H; Motz, J; Oroszlan, P; Zingel, O

    1995-04-26

    Immunoassays for haptens such as short peptides or drugs are usually based on the principle of competition for a limited number of binding sites on antibody molecules. Owing to the small size of these antigens it has been thought that two specific antibodies cannot simultaneously bind a hapten. However, antisera containing so called anti-metatypic antibodies have been reported (Voss et al. (1988) Mol. Immunol. 25, 751-759) that bind to hapten-mAb complexes in a reaction where conformational changes on the primary antibody are important. Here, we report on monoclonal antibody pairs able to form ternary complexes with the octapeptide angiotensin II. The first mAb (mAb1) is conventional and binds angiotensin II with high affinity (Kd 10(-11) M). The secondary (anti-metatypic) mAbs (mAbs2s) recognize the immune complex consisting of angiotensin II bound to mAb1, but only poorly recognize mAb1 alone. An immunization technique involving tolerization with uncomplexed mAb1 was used to generate mAb2s. None of the mAbs2s were able to bind angiotensin II by themselves but all efficiently bound the complex of angiotensin II and mAb1. All mAb2s stabilized the angiotensin II-mAb1 complex and one mAb2 distinctly improved the specificity of the assay for angiotensin II. By either labelling mAb1 and immobilizing mAb2 (or vice versa) two-site immunometric assays with detection limits of 1 pg/ml angiotensin II have been established. The kinetics of the complex formation was investigated by fiber optic biospecific interaction analysis (FOBIA), a system allowing real time observation of binding events on the surface of a glass fiber. The association rate towards the liganded conformation of mAb1 was higher than towards the free mAb1. By contrast, the mAb2s dissociated at similar rates from complexed and uncomplexed mAb1. PMID:7745246

  18. Angiotensin II rapidly increases phosphatidate-phosphoinositide synthesis and phosphoinositide hydrolysis and mobilizes intracellular calcium in cultured arterial muscle cells.

    OpenAIRE

    Smith, J B; Smith, L; Brown, E R; Barnes, D; Sabir, M A; Davis, J S; Farese, R V

    1984-01-01

    Smooth muscle cells were cultured from rat thoracic aorta and labeled to a stable specific activity with 45Ca2+, myo-[2-3H]inositol, or 32Pi. The efflux of 45Ca2+ was monitored over 10-sec intervals. Angiotensin II (AII) increased the amount of 45Ca2+ lost by 5-fold in the first 10-sec interval after the addition of AII and by 10-fold in the second 10-sec interval. AII-stimulated 45Ca2+ release was blocked by the angiotensin antagonist [1-sarcosine, 8-leucine]AII and by La3+. The removal of e...

  19. The link between angiotensin II-mediated anxiety and mood disorders with NADPH oxidase-induced oxidative stress

    OpenAIRE

    Liu, Feng; Havens, Jennifer; Yu, Qi; Wang, Gang; Davisson, Robin L.; Pickel, Virginia M.; Iadecola, Costantino

    2012-01-01

    The renin-angiotensin system (RAS) and its active peptide angiotensin II (AngII) have major involvements not only in hypertension but also in mood and anxiety disorders. Substantial evidence supports the notion that AngII acts as a neuromodulator in the brain. In this review, we provide an overview of the link between the RAS and anxiety or mood disorders, and focus on recent advances in the understanding of AngII-linked, NADPH oxidase-derived oxidative stress in the central nervous system, w...

  20. Early pharmacological inhibition of angiotensin-I converting enzyme activity induces obesity in adulthood

    Directory of Open Access Journals (Sweden)

    Kely ede Picoli Souza

    2015-04-01

    Full Text Available We have investigated early programming of body mass in order to understand the multifactorial etiology of obesity. Considering that the renin-angiotensin system is expressed and functional in the white adipose tissue (WAT and modulates its development, we reasoned whether early transitory inhibition of angiotensin-I converting enzyme activity after birth could modify late body mass development. Therefore, newborn Wistar rats were treated with enalapril (10 mg/kg of body mass or saline, starting at the first day of life until the age of 16 days. Between days 90th and 180th, a group of these animals received high fat diet (HFD. Molecular, biochemical, histological and physiological data were collected. Enalapril treated animals presented hyperphagia, overweight and increased serum level of triglycerides, total cholesterol and leptin, in adult life. Body composition analyses revealed higher fat mass with increased adipocyte size in these animals. Molecular analyses revealed that enalapril treatment increases neuropeptide Y (NPY and cocaine- and amphetamine-regulated transcript (CART gene expression in hypothalamus, fatty acid synthase (FAS and hormone-sensitive lipase (HSL gene expression in retroperitoneal WAT and decreases peroxixome proliferators-activated receptor (PPAR γ, PPARα, uncoupling protein (UCP 2 and UCP3 gene expression in WAT. The results of the current study indicate that enalapril administration during early postnatal development increases body mass, adiposity and serum lipids in adulthood associated with enhanced food intake and decreased metabolic activity in WAT, predisposing to obesity in adulthood.