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  1. Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats

    OpenAIRE

    Lee, Eunjo; Song, Min-ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Kim, Inkyeom

    2016-01-01

    CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats...

  2. Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

    Science.gov (United States)

    Lee, Eunjo; Song, Min-Ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Kim, Inkyeom

    2016-09-01

    CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

  3. Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

    DEFF Research Database (Denmark)

    Lemkens, Pieter; Nelissen, Jelly; Meens, Merlijn J P M T

    2012-01-01

    Arteries from young healthy animals respond to chronic changes in blood flow and blood pressure by structural remodeling. We tested whether the ability to respond to decreased (-90%) or increased (+100%) blood flow is impaired during the development of deoxycorticosterone acetate (DOCA)-salt hype...

  4. ALLOPURINOL DOES NOT DECREASE BLOOD PRESSURE OR PREVENT THE DEVELOPMENT OF HYPERTENSION IN THE DOCA-SALT RAT MODEL

    Science.gov (United States)

    Szasz, Theodora; Linder, A. Elizabeth; Davis, Robert P.; Burnett, Robert; Fink, Gregory D.; Watts, Stephanie W.

    2010-01-01

    Reactive oxygen species (ROS) play an important role in the pathogenesis of hypertension, disease in which ROS levels and markers of oxidative stress are increased. Xanthine oxidase (XO) is a ROS-producing enzyme the activity of which may increase during hypertension. Studies on XO inhibition effects on BP have yielded controversial results. We hypothesized that XO inhibition would decrease BP or attenuate the development of DOCA-salt hypertension. We administered the XO inhibitor, allopurinol (50 mg/kg/day, orally) or its vehicle to rats during the established or development stages of DOCA-salt hypertension. We validated XO inhibition by HPLC measurements of XO metabolites in urine, serum and tissues demonstrating decrease in products, increase in substrates and detection of the active metabolite of allopurinol, oxypurinol. We monitored BP continuously via radiotelemetry and performed gross evaluations of target organs of hypertension. Allopurinol treatment did not impact the course of DOCA-salt hypertension, regardless of the timing of administration. Aside from a significant decrease in pulse pressure in allopurinol-treated rats, no positive differences were observed between the allopurinol and the vehicle-treated rats. We conclude that XO does not play an important role in the development or maintenance of hypertension in the rat DOCA-salt hypertension model. PMID:20881613

  5. The Endocannabinoid System Affects Myocardial Glucose Metabolism in the DOCA-Salt Model of Hypertension

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    Agnieszka Polak

    2018-03-01

    Full Text Available Background/Aims: Recent interest in the use of cannabinoids as therapeutic agents has revealed the involvement of the endogenous cannabinoid system (ECS in the regulation of the cardiovascular system in hypertension. Abnormalities in glucose metabolism and insulin action are commonly detected in hypertensive animals. Thus, potential antihypertensive drugs should be investigated with respect to modulation of glucose homeostasis. Therefore, the aim of the present study was to evaluate the effects of the ECS activation after chronic fatty acid amide hydrolase inhibitor (URB597 administration on plasma glucose and insulin concentrations as well as parameters of myocardial glucose metabolism in the deoxycorticosterone acetate (DOCA-salt hypertensive rats, an animal model of secondary hypertension. Methods: Hypertension was induced by DOCA (25mg/kg injections and addition of 1% NaCl in the drinking water for six weeks. Chronic activation of the ECS was performed by URB597 (1mg/kg injections for two weeks. We examined fasting plasma levels of insulin (ELISA, glucose and intramyocardial glycogen (colorimetric method. Expressions of glucose transporters (GLUT1, 4 and selected proteins engaged in GLUT translocation as well as glucose metabolism were determined using Western blotting. Results: Hypertension induced hypoinsulinemia with concomitant lack of significant changes in glycemia, reduced intramyocardial glycogen content and increased pyruvate dehydrogenase (PDH expression in the cardiac muscle. Importantly, chronic URB597 administration in the hypertensive rats increased insulin concentration, elevated plasmalemmal GLUT1 and GLUT4 expression and concomitantly improved myocardial glycogen storage. Conclusion: Chronic administration of fatty acid amide hydrolase (FAAH inhibitor has potential protective properties on myocardial glucose metabolism in hypertension.

  6. Central Infusion of Angiotensin II Type 2 Receptor Agonist Compound 21 Attenuates DOCA/NaCl-Induced Hypertension in Female Rats

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    Shu-Yan Dai

    2016-01-01

    Full Text Available The present study investigated whether central activation of angiotensin II type 2 receptor (AT2-R attenuates deoxycorticosterone acetate (DOCA/NaCl-induced hypertension in intact and ovariectomized (OVX female rats and whether female sex hormone status has influence on the effects of AT2-R activation. DOCA/NaCl elicited a greater increase in blood pressure in OVX females than that in intact females. Central infusion of compound 21, a specific AT2-R agonist, abolished DOCA/NaCl pressor effect in intact females, whereas same treatment in OVX females produced an inhibitory effect. Real-time RT-PCR analysis revealed that DOCA/NaCl enhanced the mRNA expression of hypertensive components including AT1-R, ACE-1, and TNF-α in the paraventricular nucleus of hypothalamus in both intact and OVX females. However, the mRNA expressions of antihypertensive components such as AT2-R, ACE-2, and IL-10 were increased only in intact females. Central AT2-R agonist reversed the changes in the hypertensive components in all females, while this agonist further upregulated the expression of ACE2 and IL-10 in intact females, but only IL-10 in OVX females. These results indicate that brain AT2-R activation plays an inhibitory role in the development of DOCA/NaCl-induced hypertension in females. This beneficial effect of AT2-R activation involves regulation of renin-angiotensin system and proinflammatory cytokines.

  7. O impacto de um sistema de agendamento antecipado de docas para carga e descarga na gestão da cadeia de suprimentos

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    Fabrício Mello Mulato

    2006-03-01

    Full Text Available O agendamento antecipado de docas para recebimento e expedição de veículos pode gerar grandes benefícios para todos os envolvidos na cadeia de suprimentos, por meio de melhorias na eficiência, na utilização dos recursos, no fluxo de cargas e na visibilidade. Tempos de espera ao redor das docas têm como conseqüência a perda de receitas, custos extras, insatisfação de motoristas e alta rotatividade de funcionários para as transportadoras. Este artigo procura mostrar porque alguns aspectos relacionados ao agendamento e programação de docas não podem ser subestimados e como esse conceito pode trazer efeitos positivos que se transformam em vantagem competitiva. Para ilustrar os benefícios dessa prática, foram realizados estudos de casos em empresas que implantaram um sistema informatizado para este tipo de problema. Nos estudos de casos, observou-se que a ferramenta implementada trouxe melhorias nas variáveis analisadas: a distribuição mais uniforme dos carregamentos ao longo do mês e a redução do tempo médio de permanência dos veículos.     Palavras-chaves: Agendamento de docas, Cadeia de Suprimentos, Logística.

  8. Long-term inhibition of xanthine oxidase by febuxostat does not decrease blood pressure in deoxycorticosterone acetate (DOCA-salt hypertensive rats.

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    Theodora Szasz

    Full Text Available Xanthine oxidase and its products, uric acid and ROS, have been implicated in the pathogenesis of cardiovascular disease, such as hypertension. We have previously reported that allopurinol inhibition of XO does not alter the progression of deoxycorticosterone acetate (DOCA-salt hypertension in rats. However other researchers have observed a reduction in blood pressure after allopurinol treatment in the same model. To resolve this controversy, in this study we used the newer and more effective XO inhibitor febuxostat, and hypothesized that a more complete XO blockade might impair hypertension development and its end-organ consequences. We used DOCA-salt hypertensive rats and administered vehicle (salt water or febuxostat (orally, 5 mg/kg/day in salt water in a short-term "reversal" experiment (2 weeks of treatment 3 weeks after DOCA-salt beginning and a long-term "prevention" experiment (treatment throughout 4 weeks of DOCA-salt. We confirmed XO inhibition by febuxostat by measuring circulating and tissue levels of XO metabolites. We found an overall increase in hypoxanthine (XO substrate and decrease in uric acid (XO product levels following febuxostat treatment. However, despite a trend for reduced blood pressure in the last week of long-term febuxostat treatment, no statistically significant difference in hemodynamic parameters was observed in either study. Additionally, no change was observed in relative heart and kidney weight. Aortic media/lumen ratio was minimally improved by long-term febuxostat treatment. Additionally, febuxostat incubation in vitro did not modify contraction of aorta or vena cava to norepinephrine, angiotensin II or endothelin-1. We conclude that XO inhibition is insufficient to attenuate hypertension in the rat DOCA-salt model, although beneficial vascular effects are possible.

  9. Long-term inhibition of xanthine oxidase by febuxostat does not decrease blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats.

    Science.gov (United States)

    Szasz, Theodora; Davis, Robert Patrick; Garver, Hannah S; Burnett, Robert J; Fink, Gregory D; Watts, Stephanie W

    2013-01-01

    Xanthine oxidase and its products, uric acid and ROS, have been implicated in the pathogenesis of cardiovascular disease, such as hypertension. We have previously reported that allopurinol inhibition of XO does not alter the progression of deoxycorticosterone acetate (DOCA)-salt hypertension in rats. However other researchers have observed a reduction in blood pressure after allopurinol treatment in the same model. To resolve this controversy, in this study we used the newer and more effective XO inhibitor febuxostat, and hypothesized that a more complete XO blockade might impair hypertension development and its end-organ consequences. We used DOCA-salt hypertensive rats and administered vehicle (salt water) or febuxostat (orally, 5 mg/kg/day in salt water) in a short-term "reversal" experiment (2 weeks of treatment 3 weeks after DOCA-salt beginning) and a long-term "prevention" experiment (treatment throughout 4 weeks of DOCA-salt). We confirmed XO inhibition by febuxostat by measuring circulating and tissue levels of XO metabolites. We found an overall increase in hypoxanthine (XO substrate) and decrease in uric acid (XO product) levels following febuxostat treatment. However, despite a trend for reduced blood pressure in the last week of long-term febuxostat treatment, no statistically significant difference in hemodynamic parameters was observed in either study. Additionally, no change was observed in relative heart and kidney weight. Aortic media/lumen ratio was minimally improved by long-term febuxostat treatment. Additionally, febuxostat incubation in vitro did not modify contraction of aorta or vena cava to norepinephrine, angiotensin II or endothelin-1. We conclude that XO inhibition is insufficient to attenuate hypertension in the rat DOCA-salt model, although beneficial vascular effects are possible.

  10. Chronic Blockade of Brain Endothelin Receptor Type-A (ETA Reduces Blood Pressure and Prevents Catecholaminergic Overactivity in the Right Olfactory Bulb of DOCA-Salt Hypertensive Rats

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    Luis R. Cassinotti

    2018-02-01

    Full Text Available Overactivity of the sympathetic nervous system and central endothelins (ETs are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA-salt hypertensive rats. Following brain ET receptor type A (ETA blockade by BQ610 (selective antagonist, transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ETA blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein in the right OB of hypertensive animals. However, ETA blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ETA are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension.

  11. Chronic Blockade of Brain Endothelin Receptor Type-A (ETA) Reduces Blood Pressure and Prevents Catecholaminergic Overactivity in the Right Olfactory Bulb of DOCA-Salt Hypertensive Rats.

    Science.gov (United States)

    Cassinotti, Luis R; Guil, María J; Schöller, Mercedes I; Navarro, Mónica P; Bianciotti, Liliana G; Vatta, Marcelo S

    2018-02-27

    Overactivity of the sympathetic nervous system and central endothelins (ETs) are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB) also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Following brain ET receptor type A (ET A ) blockade by BQ610 (selective antagonist), transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH) were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ET A blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein) in the right OB of hypertensive animals. However, ET A blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ET A are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension.

  12. Role of Acetyl Salicylic Acid in Controlling the DOCA-Salt Induced Hypertension in Rats by Stimulating the Synthesis of r-Cortexin in the Kidney.

    Science.gov (United States)

    Maji, Uttam Kumar; Jana, Pradipta; Chatterjee, Mitali; Karmakar, Sanmay; Saha, Arup; Ghosh, Tamal Kanti

    2018-03-01

    Hypertension is a metabolic disease which is caused by vasoconstriction and that results into elevated blood pressure. A chronic hypertensive condition affects and even damages to various systems in the body. Presence of renal cortexin (r-cortexin), an antihypertensive protein, which is released from the kidney cortex controls the blood pressure. The effect of r-cortexin was mediated through nitric oxide (NO), a universal vasodilating agent. In our study, acetyl salicylic acid (aspirin), a well-known activator of the endothelial nitric oxide synthase (eNOS) induced r-cortexin synthesis. The hypertensive rat model was prepared by injecting deoxy corticosterone acetate (DOCA). Synthesis of r-cortexin was measured by the anti-r-cortexin antibody which was raised in adult white Wister albino rat model. NO level was determined by using methemoglobin method and later confirmed by chemiluminescence method. Change in blood pressure was determined indirectly by using NIBP monitoring system. Aspirin increased the r-cortexin expression from 64.36 ± 12.6 nM to 216.7 ± 21.31 nM in DOCA induced hypertensive rats. The mechanism was proved with the findings of increased level of NO from 0.4 to 1.9 µM. The DOCA induced blood pressure was also decreased from 139.39 ± 7.36 mm of Hg to 116.57 ± 6.89 mm of Hg in case of systolic blood pressure and in case of diastolic pressure from 110.41 ± 7 mm of Hg to 86.4 ± 2.76 mm of Hg that are quite approximate. So, from this study it has been found that aspirin induces the r-cortexin synthesis in kidney cortex through the activation of eNOS in DOCA induced hypertensive rats.

  13. Peroxisome Proliferator-Activated Receptor-α Activation Decreases Mean Arterial Pressure, Plasma Interleukin-6, and COX-2 While Increasing Renal CYP4A Expression in an Acute Model of DOCA-Salt Hypertension

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    Dexter L. Lee

    2011-01-01

    Full Text Available Peroxisome proliferator-activated receptor-alpha (PPAR-α activation by fenofibrate reduces blood pressure and sodium retention during DOCA-salt hypertension. PPAR-α activation reduces the expression of inflammatory cytokines, such as interleukin-6 (IL-6. Fenofibrate also induces cytochrome P450 4A (CYP4A and increases 20-hydroxyeicosatetraenoic acid (20-HETE production. This study tested whether the administration of fenofibrate would reduce blood pressure by attenuating plasma IL-6 and renal expression of cyclooxygenase-2 (COX-2, while increasing expression of renal CYP4A during 7 days of DOCA-salt hypertension. We performed uni-nephrectomy on 12–14 week old male Swiss Webster mice and implanted biotelemetry devices in control, DOCA-salt (1.5 mg/g treated mice with or without fenofibrate (500 mg/kg/day in corn oil, intragastrically. Fenofibrate significantly decreased mean arterial pressure and plasma IL-6. In kidney homogenates, fenofibrate increased CYP4A and decreased COX-2 expression. There were no differences in renal cytochrome P450, family 2, subfamily c, polypeptide 23 (CYP2C23 and soluble expoxide hydrolase (sEH expression between the groups. Our results suggest that the blood pressure lowering effect of PPAR-α activation by fenofibrate involves the reduction of plasma IL-6 and COX-2, while increasing CYP4A expression during DOCA-salt hypertension. Our results may also suggest that PPAR-α activation protects the kidney against renal injury via decreased COX-2 expression.

  14. The influence of DOCA-salt hypertension and chronic administration of the FAAH inhibitor URB597 on KCa2.3/KCa3.1-EDH-type relaxation in rat small mesenteric arteries.

    Science.gov (United States)

    Kloza, Monika; Baranowska-Kuczko, Marta; Malinowska, Barbara; Karpińska, Olga; Harasim-Symbor, Ewa; Kasacka, Irena; Kozłowska, Hanna

    2017-12-01

    The aim of this study was to examine the influence of deoxycorticosterone acetate-salt (DOCA-salt) hypertension and chronic treatment with the fatty acid amide hydrolase inhibitor, URB597, on small and intermediate conductance calcium-activated potassium channels and endothelium-dependent hyperpolarization (K Ca 2.3/K Ca 3.1-EDH) in rat small mesenteric arteries (sMAs). The EDH-type response was investigated, in endothelium-intact sMAs using a wire myograph, by examining acetylcholine-evoked vasorelaxation in the presence of N ω -nitro-L-arginine methyl ester and indomethacin (inhibitors of nitric oxide synthase and cyclooxygenase, respectively). In normo- and hypertension the efficacy of EDH-type relaxation was similar and inhibition of K Ca 2.3 and K Ca 3.1 by UCL1684 and TRAM-34, respectively, given alone or in combination, attenuated EDH-mediated vasorelaxation. K Ca 3.1 expression and NS309 (K Ca 2.3/K Ca 3.1 activator)-induced relaxation was reduced in sMAs of DOCA-salt rats. Endothelium denudation and incubation with UCL1684 and TRAM-34 attenuated the maximal NS309-evoked vasorelaxation in both groups. URB597 had no effect in functional studies, but increased the expression of K Ca 3.1 in the sMAs. K Ca 2.3/K Ca 3.1-EDH-mediated relaxation was maintained in the sMAs of DOCA-salt rats despite endothelial dysfunction and down-regulation of K Ca 3.1. Furthermore, K Ca 3.1 played a key role in the EDH-type dilator response of sMAs in normo- and hypertension. The hypotensive effect of URB597 is independent of K Ca 2.3/K Ca 3.1-EDH-type relaxation. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Interactions of PPAR α and GLUT4 in DOCA/salt-induced renal ...

    African Journals Online (AJOL)

    olayemitoyin

    1Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Benin, Nigeria. ... MATERIALS AND METHODS ... used as 25mg slow release pellets prepared in our ... volume (UV) was determined by gravimetrically.

  16. Papel da ouabaína endógena sobre o sistema cardiovascular do modelo de hipertensão arterial DOCA-SAL.

    OpenAIRE

    Camilla Ferreira Wenceslau

    2012-01-01

    Tem sido demonstrado que na hipertensão arterial ocorre aumento de ouabaína plasmática, um inibidor da Na+K+-ATPase. Em 1998, Ferrari et al. desenvolveram uma molécula denominada de rostafuroxina, a qual é capaz de antagonizar os efeitos da ouabaína por deslocar a ligação desse glicosídeo com a Na+K+-ATPase. Dentro desse contexto, parece razoável sugerir que um anti-hipertensivo capaz de antagonizar os efeitos da ouabaína possa representar uma nova ferramenta farmacológica para o tratamento d...

  17. Curative effect of sesame oil in a rat model of chronic kidney disease.

    Science.gov (United States)

    Liu, Chuan-Teng; Chien, Se-Ping; Hsu, Dur-Zong; Periasamy, Srinivasan; Liu, Ming-Yie

    2015-12-01

    Chronic kidney disease causes a progressive and irreversible loss of renal function. We investigated the curative effect of sesame oil, a natural, nutrient-rich, potent antioxidant, in a rat model of chronic kidney disease. Chronic kidney disease was induced by subcutaneously injecting uni-nephrectomized rats with deoxycorticosterone acetate (DOCA) and 1% NaCl [DOCA/salt] in drinking water. Four weeks later, the rats were gavaged with sesame oil (0.5 or 1 mL/kg per day) for 7 days. Renal injury, histopathological changes, hydroxyl radical, peroxynitrite, lipid peroxidation, Nrf2, osteopontin expression, and collagen were assessed 24 h after the last dose of sesame oil. Blood urea nitrogen, creatinine, urine volume, and albuminuria were significantly higher in the DOCA/salt treated rats than in control rats. Sesame oil significantly decreased these four tested parameters in DOCA/salt treated rats. In addition, creatinine clearance rate and nuclear Nrf2 expression were significantly decreased in the DOCA/salt treated rats compared to control rats. Sesame oil significantly decreased hydroxyl radical, peroxynitrite level, lipid peroxidation, osteopontin, and renal collagen deposition, but increased creatinine clearance rate and nuclear Nrf2 expression in DOCA/salt treated rats. We conclude that supplementation of sesame oil mitigates DOCA/salt induced chronic kidney disease in rats by activating Nrf2 and attenuating osteopontin expression and inhibiting renal fibrosis in rats. © 2015 Asian Pacific Society of Nephrology.

  18. Reduction-sensitive micelles self-assembled from amphiphilic chondroitin sulfate A-deoxycholic acid conjugate for triggered release of doxorubicin.

    Science.gov (United States)

    Liu, Hongxia; Wu, Shuqin; Yu, Jingmou; Fan, Dun; Ren, Jin; Zhang, Lei; Zhao, Jianguo

    2017-06-01

    Reduction-sensitive chondroitin sulfate A (CSA)-based micelles were developed. CSA was conjugated with deoxycholic acid (DOCA) via a disulfide linkage. The bioreducible conjugate (CSA-ss-DOCA) can form self-assembled micelles in aqueous medium. The critical micelle concentration (CMC) of CSA-ss-DOCA conjugate is 0.047mg/mL, and its mean diameter is 387nm. The anticancer drug doxorubicin (DOX) was chosen as a model drug, and was effectively encapsulated into the micelles with high loading efficiency. Reduction-sensitive micelles and reduction-insensitive control micelles displayed similar DOX release behavior in phosphate buffered saline (PBS, pH7.4). Notably, DOX release from the reduction-sensitive micelles in vitro was accelerated in the presence of 20mM glutathione-containing PBS environment. Moreover, DOX-loaded CSA-ss-DOCA (CSA-ss-DOCA/DOX) micelles exhibited intracellular reduction-responsive characteristics in human gastric cancer HGC-27 cells determined by confocal laser scanning microscopy (CLSM). Furthermore, CSA-ss-DOCA/DOX micelles demonstrated higher antitumor efficacy than reduction-insensitive control micelles in HGC-27 cells. These results suggested that reduction-sensitive CSA-ss-DOCA micelles had the potential as intracellular targeted carriers of anticancer drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Sodium pump activity and calcium relaxation in vascular smooth muscle of deoxycorticosterone acetate-salt rats

    International Nuclear Information System (INIS)

    Soltis, E.E.; Field, F.P.

    1986-01-01

    The Na + -K + pump activity was determined in femoral arterial smooth muscle from deoxycorticosterone acetate (DOCA)-salt hypertensive rats using potassium relaxation and ouabain-sensitive 86 Rb uptake as indices. The membrane-stabilizing effect of calcium and its relation to Na + -K + pump activity also were examined. Femoral arteries from DOCA-salt rats exhibited a greater relaxation in response to potassium addition after contraction with norepinephrine in a low potassium (0.6 mM) Krebs solution. The concentration of potassium required to produce a 50% relaxation was significantly less in DOCA-salt rats. Ouabain-sensitive 86 Rb uptake was significantly greater at 3, 10, and 20 minutes of 86 Rb incubation in femoral arteries from DOCA-salt rats. Linear regression analysis revealed a significant correlation between the uptake of 86 Rb and time of incubation in both control and DOCA-salt rats. A significant difference in the slopes of the regression lines showed that the rate of uptake was greater in DOCA-salt rats. No difference was observed in ouabain-insensitive 86 Rb uptake. A dose-dependent relaxation in response to increasing concentrations of calcium following contraction to norepinephrine was observed in femoral arteries from control and DOCA-salt rats. The relaxation was directly dependent on the level of extracellular potassium and was blocked by ouabain. Femoral arteries from DOCA-salt rats relaxed to a significantly greater extent in response to calcium at each level of potassium when compared with controls. These results provide further evidence for an increase in Na + -K + pump activity in vascular smooth muscle from DOCA-salt hypertensive rats

  20. (−-Epicatechin Reduces Blood Pressure and Improves Left Ventricular Function and Compliance in Deoxycorticosterone Acetate-Salt Hypertensive Rats

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    Douglas Jackson

    2018-06-01

    Full Text Available (−-Epicatechin (E is a flavanol found in green tea and cocoa and has been shown to attenuate tumour necrosis factor alpha (TNF-α-mediated inflammation, improve nitric oxide levels, promote endothelial nitric oxide synthase (eNOS activation and inhibit NADPH oxidase. This study investigated the effect of 28 days of low epicatechin dosing (1 mg/kg/day on the cardiovascular function of deoxycorticosterone acetate (DOCA-salt hypertensive rats. Wistar rats (n = 120, 8 weeks of age underwent uninephrectomy and were randomised into four groups (uninephrectomy (UNX, UNX + E, DOCA, DOCA + E. DOCA and DOCA + E rats received 1% NaCl drinking water along with subcutaneous injections of 25 mg deoxycorticosterone-acetate (in 0.4 mL of dimethylformamide every fourth day. UNX + E and DOCA + E rats received 1 mg/kg/day of epicatechin by oral gavage. Single-cell micro-electrode electrophysiology, Langendorff isolated-heart assessment and isolated aorta and mesenteric organ baths were used to assess cardiovascular parameters. Serum malondialdehyde concentration was used as a marker of oxidative stress. Myocardial stiffness was increased and left ventricular compliance significantly diminished in the DOCA control group, and these changes were attenuated by epicatechin treatment (p < 0.05. Additionally, the DOCA + E rats showed significantly reduced blood pressure and malondialdehyde concentrations; however, there was no improvement in left ventricular hypertrophy, electrophysiology or vascular function. This study demonstrates the ability of epicatechin to reduce blood pressure, prevent myocardial stiffening and preserve cardiac compliance in hypertrophied DOCA-salt rat hearts.

  1. Physalis minima Leaves Extract Induces Re-Endothelialization in Deoxycorticosterone Acetate-Salt-Induced Endothelial Dysfunction in Rats

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    Dian Nugrahenny

    2018-02-01

    Full Text Available The administration of deoxy-corticosterone acetate (DOCA-salt can induce oxidative stress leading to decrease the bioavailability of nitric oxide (NO, increase senescence of circulating endothelial progenitor cells (EPCs, thus contributing to endothelial dysfunction. This study was aimed to investigate the effects of Physalis minima L. leaves extract on serum NO levels, circulating EPCs number, and histopathology of tail artery endothelial cells in DOCA-salt-induced endothelial dysfunction in rats. Twenty-five male Wistar rats were randomly divided into five groups: rats without any treatment (normal, rats treated with DOCA (10 mg/kgBW s.c. twice weekly and given 0.9% NaCl to drink ad libitum for 6 weeks, and DOCA-salt-induced rats orally supplemented with P. minima leaves extract at doses of 500, 1500, or 2500 mg/kgBW for 4 weeks. Serum NO levels were measured by colorimetry. The number of circulating EPCs (CD34+/CD133+ cells was determined by flow cytometry. The tail artery sections were histologically processed with hematoxylin-eosin staining. DOCA-salt-induced rats showed significantly (p<0.05 decrease in serum NO levels and circulating EPCs number compared to the normal. There was also more detached tail artery endothelial cells in DOCA-salt-induced rats. P. minima leaves extract at a dose of 500 mg/kgBW significantly (p<0.05 increased serum NO level and circulating EPCs number, and also induced an optimal re-endothelialization in DOCA-salt-induced rats. P. minima leave extract dose-dependently increases NO bioavailability contributing to enhanced EPCs mobilization, thereby promoting re-endothelialization in DOCA-salt-induced endothelial dysfunction in rats.

  2. Uric acid does not affect the acetylcholine-induced relaxation of aorta from normotensive and deoxycorticosterone acetate-salt hypertensive rats.

    Science.gov (United States)

    Szasz, Theodora; Watts, Stephanie W

    2010-06-01

    Uric acid (UA) results from xanthine oxidase (XO) catabolism of xanthine and is the final product of purine catabolism in humans. In this species, hyperuricemia is associated with gout, nephropathy, and increased cardiovascular disease risk. Although the effects of hyperuricemia in vascular biology are overall controversial, UA has been described as an antioxidant and as potentially improving endothelial function. Hypertension is associated with endothelial dysfunction. We hypothesized that UA improves the endothelial function of aorta from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. UA (100 microM) in the presence of the uricase inhibitor oxonic acid (10 microM) did not modify relaxation to acetylcholine (ACh) (1 nM-10 microM) in the aorta from nontreated, sham normotensive, and DOCA-salt hypertensive rats [response to 10 microM ACh for UA versus vehicle, respectively: nontreated = 37 +/- 7 versus 48 +/- 7%, sham = 53 +/- 15 versus 57 +/- 20%, DOCA = 81 +/- 4 versus 85 +/- 2% from 20 microM prostaglandin 2alpha (PGF(2alpha))-induced contraction]. Allopurinol (100 microM), a XO inhibitor, did not significantly alter the ACh-induced relaxation of sham and DOCA aortic rings (response to 10 microM ACh for allopurinol versus vehicle, respectively: sham = 61 +/- 5 versus 68 +/- 9%, DOCA = 87 +/- 6 versus 88 +/- 3% from 20 microM PGF(2alpha)-induced contraction). Uricemia, ranging from unmeasurable to 547 microM in sham and to 506 microM in DOCA rats, was not significantly different between these two groups. The expression and activity of XO, as well as the expression of uricase, were not different between sham and DOCA rat aorta. We conclude that, at least in vitro, UA does not affect the ACh-induced relaxation of normotensive and DOCA-salt hypertensive rats.

  3. In vitro photodynamic effects of scavenger receptor targeted-photoactivatable nanoagents on activated macrophages.

    Science.gov (United States)

    Yi, Bong Gu; Park, Ok Kyu; Jeong, Myeong Seon; Kwon, Seung Hae; Jung, Jae In; Lee, Seongsoo; Ryoo, Sungwoo; Kim, Sung Eun; Kim, Jin Won; Moon, Won-Jin; Park, Kyeongsoon

    2017-04-01

    Scavenger receptors (SRs) expressed on the activated macrophages in inflammation sites have been considered as the most interesting and important target biomarker for targeted drug delivery, imaging and therapy. In the present study, we fabricated the scavenger receptor-A (SR-A) targeted-photoactivatable nanoagents (termed as Ce6/DS-DOCA) by entrapping chlorin e6 (Ce6) into the amphiphilic dextran sulfate-deoxycholic acid (DS-DOCA) conjugates via physically hydrophobic interactions. Insoluble Ce6 was easily encapsulated into DS-DOCA nanoparticles by a dialysis method and the loading efficiency was approximately 51.7%. The Ce6/DS-DOCA formed nano-sized self-assembled aggregates (28.8±5.6nm in diameter), confirmed by transmission electron microscope, UV/Vis and fluorescence spectrophotometer. The Ce6/DS-DOCA nanoagents could generate highly reactive singlet oxygen under laser irradiation. Also, in vitro studies showed that they were more specifically taken up by lipopolysaccharide (LPS)-induced activated macrophages (RAW 264.7) via a SR-A-mediated endocytosis, relative to by non-activated macrophages, and notably induced cell death of activated macrophages under laser irradiation. Therefore, SR-A targetable and photoactivatable Ce6/DS-DOCA nanoagents with more selective targeting to the activated macrophages will have great potential for treatment of inflammatory diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice.

    Science.gov (United States)

    Bowen, T Scott; Eisenkolb, Sophia; Drobner, Juliane; Fischer, Tina; Werner, Sarah; Linke, Axel; Mangner, Norman; Schuler, Gerhard; Adams, Volker

    2017-01-01

    Hypertension is a key risk factor for heart failure, with the latter characterized by diaphragm muscle weakness that is mediated in part by increased oxidative stress. In the present study, we used a deoxycorticosterone acetate (DOCA)-salt mouse model to determine whether hypertension could independently induce diaphragm dysfunction and further investigated the effects of high-intensity interval training (HIIT). Sham-treated (n = 11), DOCA-salt-treated (n = 11), and DOCA-salt+HIIT-treated (n = 15) mice were studied over 4 wk. Diaphragm contractile function, protein expression, enzyme activity, and fiber cross-sectional area and type were subsequently determined. Elevated blood pressure confirmed hypertension in DOCA-salt mice independent of HIIT (P HIIT. Myosin heavy chain (MyHC) protein expression tended to decrease (∼30%; P = 0.06) in DOCA-salt vs. sham- and DOCA-salt+HIIT mice, whereas oxidative stress increased (P HIIT further prevented direct oxidant-mediated diaphragm contractile dysfunction (P hypertension induces diaphragm contractile dysfunction via an oxidant-mediated mechanism that is prevented by HIIT.-Bowen, T. S., Eisenkolb, S., Drobner, J., Fischer, T., Werner, S., Linke, A., Mangner, N., Schuler, G., Adams, V. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice. © FASEB.

  5. Preparation and Characterization of Self-Assembled Nanoparticles of Hyaluronic Acid-Deoxycholic Acid Conjugates

    Directory of Open Access Journals (Sweden)

    Xuemeng Dong

    2010-01-01

    Full Text Available Novel amphiphilic biopolymers were synthesized using hyaluronic acid (HA as a hydrophilic segment and deoxycholic acid (DOCA as a hydrophobic segment by a 1-ethyl-3-(3-dimethylaminopropyl carbodiimide mediated coupling reaction. The structural characteristics of the HA-DOCA conjugates were investigated using H1 NMR. Self-assembled nanoparticles were prepared based on HA-DOCA conjugates, and its characteristics were investigated using dynamic laser light scattering, transmission electron microscopy (TEM, and fluorescence spectroscopy. The mean diameter was about 293.5 nm with unimodal size distribution in distilled water. The TEM images revealed that the shape of HA-DOCA self-aggregates was spherical. The critical aggregation concentration (CAC was in the range of 0.025–0.056 mg/mL. The partition equilibrium constant (Kv of pyrene in self-aggregates solution was from 1.45×104 to 3.64×104. The aggregation number of DOCA groups per hydrophobic microdomain, estimated by the fluorescence quenching method using cetylpyridinium chloride, increased with increasing degree of substitution.

  6. Anti-fibrotic effect of Aliskiren in rats with deoxycorticosterone induced myocardial fibrosis and its potential mechanism

    Directory of Open Access Journals (Sweden)

    Likun Ma

    2012-05-01

    Full Text Available The objective of our study was to investigate the effect of Aliskiren, a renin inhibitor, on the deoxycorticosterone (DOCA induced myocardial fibrosis in a rat model and its underlying mechanism. A total of 45 Sprague-Dawley (SD rats underwent right nephrectomy and were randomly assigned into 3 groups: control group (CON group: silicone tube was embedded subcutaneously; DOCA treated group (DOC group: 200 mg of DOCA was subcutaneously administered; DOCA and Aliskiren (ALI treated group (ALI group: 200 mg of DOCA and 50 mg/kg/d ALI were subcutaneously and intragastrically given, respectively. Treatment was done for 4 weeks. Sirius red staining was employed to detect the expression of myocardial collagen, and the myocardial collagen volume fraction (CVF and perivascular collagen volume area (PVCA were calculated. Radioimmunoassay was carried out to measure the renin activity (RA and content of angiotensin II (Ang II in the plasma and ventricle. Western blot assay was done to detect the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2, phosphorylated ERK1/2 (PERK1/2 and matrix metalloproteinase 9 (MMP-9. In the DOC group and ALI group, the CVF and PVCA were significantly increased; the RA and Ang II levels in the plasma and ventricle were remarkably lowered when compared with the CON group. The RA and Ang II levels in the ventricle of the ALI group were significantly lower than those in the DOC group. Moreover, the expressions of ERK1/2, PERK1/2 and MMP9 were the lowest in the CON group, but those in the ALI group were significantly reduced as compared to the DOC group. ALI can inhibit the DOCA induced myocardial fibrosis independent of its pressure-lowing effect, which may be related to the suppression of RA and Ang II production, inhibition of ERK1/2 phosphorylation and MMP9 expression in the heart.

  7. Vascular reactivity of mesenteric arteries and veins to endothelin-1 in a murine model of high blood pressure.

    Science.gov (United States)

    Pérez-Rivera, Alex A; Fink, Gregory D; Galligan, James J

    2005-06-01

    We characterized vascular reactivity to endothelin-1 (ET-1) in mesenteric vessels from DOCA-salt hypertensive and SHAM control mice and assessed the effect that endothelial-derived vasodilators have on ET-1-induced vasoconstriction. Changes in the diameter of unpressurized small mesenteric arteries and veins (100- to 300-microm outside diameter) were measured in vitro using computer-assisted video microscopy. Veins were more sensitive than arteries to the contractile effects of ET-1. There was a decrease in arterial maximal responses (E(max)) compared to veins, this effect was larger in DOCA-salt arteries. The selective ET(B) receptor agonist, sarafotoxin 6c (S6c), contracted DOCA-salt and SHAM veins but did not contract arteries. The ET(B) receptor antagonist, BQ-788 (100 nM), but not the ET(A) receptor antagonist, BQ-610 (100 nM), blocked S6c responses. BQ-610 partially inhibited responses to ET-1 in mesenteric veins from DOCA-salt and SHAM mice while BQ-788 did not affect responses to ET-1. Co-administration of both antagonists inhibited responses to ET-1 to a greater extent than BQ-610 alone suggesting a possible functional interaction between ET(A) and ET(B) receptors. Responses to ET-1 in mesenteric arteries were completely inhibited by BQ-610 while BQ-788 did not affect arterial responses. Nitric oxide synthase inhibition potentiated ET-1 responses in veins from SHAM but not DOCA-salt mice. There was a prominent role for ET-mediated nitric oxide release in DOCA-salt but not SHAM arteries. In summary, these studies showed a differential regulation of ET-1 contractile mechanisms between murine mesenteric arteries and veins.

  8. Beta-adrenoceptor changes in hypertension: cause or consequence of the elevation in blood pressure?

    NARCIS (Netherlands)

    Kanczik, R.; Khamssi, M.; Michel, M. C.; Brodde, O. E.

    1988-01-01

    Cardiac, pulmonary and renal beta-adrenoceptor density and subtype distribution were measured by radioligand binding in three rat models of acquired hypertension. Dahl salt-sensitive (DS) rats on a high-sodium diet, renal hypertensive rats and DOCA-salt rats. The results were compared with

  9. Download this PDF file

    African Journals Online (AJOL)

    Uwaifoh

    2012-04-30

    Apr 30, 2012 ... ... by their reduced palatability, diet-induced anorexia, or systemic toxicity as reported by .... papaya (L.) in renal and DOCA-induced hypertension in the rat. ... International Journal of Crude Drug Research, 28(4): 257-266.

  10. Allopurinol does not decrease blood pressure or prevent the development of hypertension in the deoxycorticosterone acetate-salt rat model.

    Science.gov (United States)

    Szasz, Theodora; Linder, A Elizabeth; Davis, Robert P; Burnett, Robert; Fink, Gregory D; Watts, Stephanie W

    2010-12-01

    Reactive oxygen species play an important role in the pathogenesis of hypertension, disease in which reactive oxygen species levels and markers of oxidative stress are increased. Xanthine oxidase (XO) is a reactive oxygen species-producing enzyme the activity of which may increase during hypertension. Studies on XO inhibition effects on blood pressure have yielded controversial results. We hypothesized that XO inhibition would decrease blood pressure or attenuate the development of deoxycorticosterone acetate (DOCA)-salt hypertension. We administered the XO inhibitor, allopurinol (50 mg/kg per day, orally) or its vehicle to rats during the established or development stages of DOCA-salt hypertension. We validated XO inhibition by high-performance liquid chromatography measurements of XO metabolites in urine, serum, and tissues demonstrating a decrease in products, increase in substrates, and detection of the active metabolite of allopurinol, oxypurinol. We monitored blood pressure continuously through radiotelemetry and performed gross evaluations of target organs of hypertension. Allopurinol treatment did not impact the course of DOCA-salt hypertension regardless of the timing of administration. Aside from a significant decrease in pulse pressure in allopurinol-treated rats, no positive differences were observed between the allopurinol and the vehicle-treated rats. We conclude that XO does not play an important role in the development or maintenance of hypertension in the rat DOCA-salt hypertension model.

  11. The effectiveness of arbuscular-mycorrhizal fungi and Aspergillus niger or Phanerochaete chrysosporium treated organic amendments from olive residues upon plant growth in a semi-arid degraded soil.

    Science.gov (United States)

    Medina, A; Roldán, A; Azcón, R

    2010-12-01

    Arbuscular mycorrhizal (AM) fungi and a residue from dry olive cake (DOC) supplemented with rock phosphate (RP) and treated with either Aspergillus niger (DOC-A) or Phanerochaete chrysosporium (DOC-P), were assayed in a natural, semi-arid soil using Trifolium repens or Dorycnium pentaphyllum plants. The effects of the AM fungi and/or DOC-A were compared with P-fertilisation (P) over eleven successive harvests to evaluate the persistence of the effectiveness of the treatments. The biomass of dually-treated plants after four successive harvests was greater than that obtained for non-treated plants or those receiving the AM inoculum or DOC-A treatments after eleven yields. The AM inoculation was critical for obtaining plant growth benefit from the application of fermented DOC-A residue. The abilities of the treatments to prevent plant drought stress were also assayed. Drought-alleviating effects were evaluated in terms of plant growth, proline and total sugars concentration under alternative drought and re-watering conditions (8th and 9th harvests). The concentrations of both compounds in plant biomass increased under drought when DOC-A amendment and AM inoculation were employed together: they reinforced the plant drought-avoidance capabilities and anti-oxidative defence. Water stress was less compensated in P-fertilised than in DOC-A-treated plants. DOC-P increased D. pentaphyllum biomass, shoot P content, nodule number and AM colonisation, indicating the greater DOC-transforming ability of P. chrysosporium compared to A. niger. The lack of AM colonisation and nodulation in this soil was compensated by the application of DOC-P, particularly with AM inoculum. The management of natural resources (organic amendments and soil microorganisms) represents an important strategy that assured the growth, nutrition and plant establishment in arid, degraded soils, preventing the damage that arises from limited water and nutrient supply. Copyright © 2010 Elsevier Ltd. All rights

  12. Intracerebroventricular Infusion of the (Pro)renin Receptor Antagonist PRO20 Attenuates Deoxycorticosterone Acetate-Salt–Induced Hypertension

    Science.gov (United States)

    Li, Wencheng; Sullivan, Michelle N.; Zhang, Sheng; Worker, Caleb J.; Xiong, Zhenggang; Speth, Robert C.; Feng, Yumei

    2016-01-01

    We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT1 receptor–dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension. PMID:25421983

  13. Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

    Science.gov (United States)

    Li, Wencheng; Sullivan, Michelle N; Zhang, Sheng; Worker, Caleb J; Xiong, Zhenggang; Speth, Robert C; Feng, Yumei

    2015-02-01

    We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension. © 2014 American Heart Association, Inc.

  14. Influência de vasoconstritores associados a anestésicos locais sobre a pressão arterial de ratos hipertensos e normotensos Influence of vasoconstrictors associated with local anesthetics on the arterial pressure of hypertensive and normotensive rats

    Directory of Open Access Journals (Sweden)

    Apparecido Neri Daniel

    1999-07-01

    Full Text Available A utilização de anestésicos locais associados a vasoconstritores em pacientes hipertensos é controversa. Neste estudo, verificamos a influência desta associação sobre a pressão arterial caudal (PA em ratos hipertensos DOCA-sal. Após ligeira anestesia com éter, os anestésicos GRUPO I - lidocaína 2% sem vasoconstritor, GRUPO II - lidocaína com fenilefrina, GRUPO III - lidocaína a 2% com noradrenalina, GRUPO IV - prilocaína 3% com felipressina, GRUPO V - mepivacaína 2% com adrenalina e GRUPO VI - mepivacaína com noradrenalina foram injetados na submucosa da boca (anestesia infiltrativa, em ratos DOCA-sal e controles. A PA foi determinada 5 e 15 minutos após a primeira dose do anestésico e também 5 e 15 minutos após a segunda dose. Os dados obtidos indicaram que: a a PA dos ratos DOCA-sal (193,05 ± 4,25 mmHg; n = 43 foi significativamente superior àquela observada nos animais controles (115,64 ± 2,47 mmHg; n = 43 e, b não houve variação significativa nas PA observadas em animais DOCA-sal e controles pela administração dos anestésicos locais testados. Assim, nossos dados experimentais sugerem que a presença de agentes vasoconstritores associados à lidocaína 2%, à prilocaína 3% e à mepivacaína 2% não interferem na PA desses animais, neste modelo experimental de hipertensão.The utilization of local anesthetics associated with vasoconstrictors in hypertensive patients is controversial. The purpose of this investigation was to verify the influence of this association on the arterial pressure (AP in DOCA-salt hypertensive rats. After light ether anesthesia, the anesthetics (Group I - lidocaine 2% without vasoconstrictor; Group II - lidocaine 2% with phenylephrine, Group III - lidocaine 2% with noradrenaline- Group IV - prylocaine 3% with felypressin; Group V - mepivacaine 2% with epinephrine, and Group VI - mepivacaine 2% with norepinephrine were injected into mucobuccal fold (infiltration anesthesia, in DOCA

  15. Model based population PK-PD analysis of furosemide for BP lowering effect: A comparative study in primary and secondary hypertension.

    Science.gov (United States)

    Shukla, Mahendra; Ibrahim, Moustafa M A; Jain, Moon; Jaiswal, Swati; Sharma, Abhisheak; Hanif, Kashif; Lal, Jawahar

    2017-11-15

    Though numerous reports have demonstrated multiple mechanisms by which furosemide can exert its anti-hypertensive response. However, lack of studies describing PK-PD relationship for furosemide featuring its anti-hypertensive property has limited its usage as a blood pressure (BP) lowering agent. Serum concentrations and mean arterial BP were monitored following 40 and 80mgkg -1 multiple oral dose of furosemide in spontaneously hypertensive rats (SHR) and DOCA-salt induced hypertensive (DOCA-salt) rats. A simultaneous population PK-PD relationship using E max model with effect compartment was developed to compare the anti-hypertensive efficacy of furosemide in these rat models. A two-compartment PK model with Weibull-type absorption and first-order elimination best described the serum concentration-time profile of furosemide. In the present study, post dose serum concentrations of furosemide were found to be lower than the EC 50 . The EC 50 predicted in DOCA-salt rats was found to be lower (4.5-fold), whereas the tolerance development was higher than that in SHR model. The PK-PD parameter estimates, particularly lower values of EC 50 , K e and Q in DOCA-salt rats as compared to SHR, pinpointed the higher BP lowering efficacy of furosemide in volume overload induced hypertensive conditions. Insignificantly altered serum creatinine and electrolyte levels indicated a favorable side effect profile of furosemide. In conclusion, the final PK-PD model described the data well and provides detailed insights into the use of furosemide as an anti-hypertensive agent. Copyright © 2017. Published by Elsevier B.V.

  16. The role of chloride in deoxycorticosterone hypertension: selective sodium loading by diet or drinking fluid

    Czech Academy of Sciences Publication Activity Database

    Kuneš, Jaroslav; Zicha, Josef; Jelínek, Jiří

    2004-01-01

    Roč. 53, č. 2 (2004), s. 149-154 ISSN 0862-8408 R&D Projects: GA ČR GA305/03/0769; GA MŠk LN00A069 Institutional research plan: CEZ:AV0Z5011922 Keywords : sodium * chloride * DOCA-salt hypertension Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.140, year: 2004

  17. Metronomic chemotherapy using orally active carboplatin/deoxycholate complex to maintain drug concentration within a tolerable range for effective cancer management.

    Science.gov (United States)

    Mahmud, Foyez; Chung, Seung Woo; Alam, Farzana; Choi, Jeong Uk; Kim, Seong Who; Kim, In-San; Kim, Sang Yoon; Lee, Dong Soo; Byun, Youngro

    2017-03-10

    Metronomic chemotherapy has translated into favorable toxicity profile and capable of delaying tumor progression. Despite its promise, conventional injectable chemotherapeutics are not meaningful to use as metronomic due to the necessity of frequent administration for personalized therapy in long-term cancer treatments. This study aims to exploit the benefits of the oral application of carboplatin as metronomic therapy for non-small cell lung cancer (NSCLC). We developed an orally active carboplatin by physical complexation with a deoxycholic acid (DOCA). The X-ray diffraction (XRD) patterns showed the disappearance of crystalline peaks from carboplatin by forming the complex with DOCA. In vivo pharmacokinetic (PK) study confirmed the oral absorption of carboplatin/DOCA complex. The oral bioavailability of carboplatin/DOCA complex and native carboplatin were calculated as 24.33% and 1.16%, respectively, when a single 50mg/kg oral dose was administered. Further findings of oral bioavailability during a low-dose daily administration of the complex (10mg/kg) for 3weeks were showed 19.17% at day-0, 30.27% at day-7, 26.77% at day-14, and 22.48% at day-21, demonstrating its potential for metronomic chemotherapy. The dose dependent antitumor effects of oral carboplatin were evaluated in SCC7 and A549 tumor xenograft mice. It was found that the oral carboplatin complex exhibited potent anti-tumor activity at 10mg/kg (74.09% vs. control, Peffective and safe oral formulation of carboplatin as a metronomic chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Conditions for Mission Completion in Low Intensity Conflict: Operation Enduring Freedom-Philippines

    Science.gov (United States)

    2017-06-01

    hard stance on drug enforcement policy. He has been criticized by the international community for his rhetoric of a war on drugs with the use of...security forces to eliminate the drug problem, and also his public announcements to end bilateral exercises between the United States and the Philippines ...Army War College, 2013. http://www.dtic.mil/cgi-bin/GetTR Doc?A D=A DA588594. Boot, Max, and Richard Bennet. “Treading Softly in the Philippines

  19. Tx2-6 toxin of the Phoneutria nigriventer spider potentiates rat erectile function☆

    Science.gov (United States)

    Nunes, K.P.; Costa-Gonçalves, A.; Lanza, L.F.; Cortes, S.F.; Cordeiro, M.N.; Richardson, M.; Pimenta, A.M.C.; Webb, R.C.; Leite, R.; De Lima, M.E.

    2011-01-01

    The venom of the spider Phoneutria nigriventer contains several toxins that have bioactivity in mammals and insects. Accidents involving humans are characterized by various symptoms including penile erection. Here we investigated the action of Tx2-6, a toxin purified from the P. nigriventer spider venom that causes priapism in rats and mice. Erectile function was evaluated through changes in intracavernosal pressure/mean arterial pressure ratio (ICP/MAP) during electrical stimulation of the major pelvic ganglion (MPG) of normotensive and deoxycorticosterone-acetate (DOCA)-salt hypertensive rats. Nitric oxide (NO) release was detected in cavernosum slices with fluorescent dye (DAF-FM) and confocal microscopy. The effect of Tx2-6 was also characterized after intracavernosal injection of a non-selective nitric oxide synthase (NOS) inhibitor, L-NAME. Subcutaneous or intravenous injection of Tx2-6 potentiated the elevation of ICP/MAP induced by ganglionic stimulation. L-NAME inhibited penile erection and treatment with Tx2-6 was unable to reverse this inhibition. Tx2-6 treatment induced a significant increase of NO release in cavernosum tissue. Attenuated erectile function of DOCA-salt hypertensive rats was fully restored after toxin injection. Tx2-6 enhanced erectile function in normotensive and DOCA-salt hypertensive rats, via the NO pathway. Our studies suggest that Tx2-6 could be important for development of new pharmacological agents for treatment of erectile dysfunction. PMID:18397797

  20. Synthesis of polyphenylacetylene by radiation-induced polymerization in deoxycholic acid clathrate

    International Nuclear Information System (INIS)

    Cataldo, Franco; Strazzulla, Giovanni; Iglesias-Groth, Susana

    2009-01-01

    Phenylacetylene was polymerized as inclusion compound (clathrate) inside deoxycholic acid (DOCA) crystals. The polymerization was initiated by γ radiation and a total dose of 320 kGy was employed. The resulting polyphenylacetylene (PPA) was isolated by dissolution of deoxycholic acid in boiling ethanol. PPA high polymer was accompanied by a series of phenylacetylene oligomers, which were detected by liquid chromatographic analysis (HPLC). PPA was characterized by electronic absorption spectroscopy and by FT-IR spectroscopy in comparison to a reference PPA prepared by a stereospecific catalyst. The microstructure of PPA from inclusion polymerization was highly trans type, similar to that observed on PPA prepared by bulk radiolysis. No optical activity was detected by polarimetry on PPA prepared by inclusion polymerization. The host-guest complex PPA/DOCA was studied by differential thermal analysis (DTA) and by thermogravimetry (TGA). DTA provided evidences of the host-guest complex formation from the shift of the melting point of DOCA while the TGA confirmed the identity - in terms of thermal behaviour - of the PPA from inclusion polymerization with that from stereospecific polymerization

  1. Effect of vitamin D3, other drugs altering serum calcium or phosphorus concentrations, and desoxycorticosterone on the distribution of Tc-99m pyrophosphate between target and nontarget tissues

    International Nuclear Information System (INIS)

    Carr, E.A. Jr.; Carroll, M.; Montes, M.

    1981-01-01

    Radioactive imaging agents are chemically designed for selective distribution. Another approach to selectivity is to find stable compounds that favorably influence this distribution. Using a rat model of myocardial necrosis, we studied effects of various stable compounds (as a single, large dose or fractionated into short series) on the ratio, uptake of Tc-99m pyrophosphate (PPi) by the target lesion/uptake by the principal nontarget, bone (L/B). Vitamin D3s ability to increase L/B was mediated by the hypercalcemia and hyperphosphatemia that it caused. The hypercalcemia was accompanied by increased [Ca] in the lesion. In contrast, pulse doses of desoxycorticosterone acetate (DOCA) at 7 and 6 hr before killing increased uptake by lesion, increasing L/B from 0.19 +/- 0.03 to 0.45 +/- 0.08 (p less than 0.01), with no change in serum [Ca] and minimal changes in serum [P], [Na], and [K]. DOCA also increased the lesion-to-blood ratio from 6.5 +/- 0.07 to 15.4 +/- 3.9 (p less than 0.05). These results encourage further study of DOCA's effect and investigation of other stable drugs that may influence distribution of other imaging agents

  2. Effects of Lactobacillus plantarum TWK10-Fermented Soymilk on Deoxycorticosterone Acetate-Salt-Induced Hypertension and Associated Dementia in Rats

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    Te-Hua Liu

    2016-05-01

    Full Text Available Oxidative stress resulting from excessive production of reactive oxygen species is the major mediator of neuronal cell degeneration observed in neurodegenerative diseases, such as Alzheimer’s disease (AD and vascular dementia (VaD. Additionally, hypertension has been shown to be a positive risk factor for VaD. Therefore, the objective of this study was to investigate the effects of Lactobacillus plantarum strain TWK10 (TWK10-fermented soymilk on the protection of PC-12 cells in H2O2-, oxygen-glucose deprivation (OGD- and deoxycorticosterone acetate (DOCA-salt-induced rat models of VaD. Notably, the viabilities of H2O2-treated PC-12 cells and OGD model were significantly increased by treatment with TWK10-fermented soymilk ethanol extract (p < 0.05. In addition, oral administration of TWK10-fermented soymilk extract in DOCA-salt hypertension-induced VaD rats resulted in a significant decrease in blood pressure (p < 0.05, which was regulated by inhibiting ACE activity and promoting NO production, in addition to decreased escape latency and increased target crossing (p < 0.05. In conclusion, these results demonstrated that TWK10-fermented soymilk extract could improve learning and memory in DOCA-salt hypertension-induced VaD rats by acting as a blood pressure-lowering and neuroprotective agent.

  3. The importance of Rioja Denomination of Origin in the context of Spanish wine market La importancia de la Denominación de Origen Rioja en el contexto del mercado vitivinícola español

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    Jaime Pablo de Valenciano

    2011-01-01

    Full Text Available This article reviews the current state of the wine industry, which, it based on information from the last 20 years, has experienced a very negative balance since it has been a significant reduction in the area of vineyards with 2009 data. However, rigorous analysis of the Rioja has allowed us to show the prosperous evolution of the production and marketing of the D.O.Ca Rioja, which has facilitated its consolidation as a first in the ranking. Also, the balance in terms of exports and sales in the domestic market has been very favorable in this period, since the D.O.Ca Rioja takes first place in both markets, so much so that the D.O. has a high recognition major importing countries of the World which are Germany and the UK. For this, the main factor of differentiation of these wineries is the time remaining wine in oak barrels, giving it a unique taste that the consumer knows how to reward.En este artículo se analiza la situación actual del sector vitivinícola, el cual, basándonos en datos de los últimos 20 años, ha experimentado un balance bastante negativo ya que se ha producido una reducción significativa de la superficie de viñedo con datos de 2009. Sin embargo, el análisis riguroso de la D.O.CA Rioja nos ha permitido recoger la evolución favorable de la producción y comercialización de la D.O.CA Rioja, lo cual ha facilitado su consolidación como primera del ranking. Asimismo, el balance en cuanto a las exportaciones y las ventas en el mercado interior ha sido muy favorable en dicho periodo, ya que, la D.O.CA Rioja ocupa un lugar privilegiado en ambos mercados, tanto es así que esta DO cuenta con un alto reconocimiento en los principales países importadores del Mundo, que son Alemania y Reino Unido. Para todo ello, el principal factor de diferenciación de estas bodegas es el tiempo que permanecen los vinos en barrica de roble, lo que le da un sabor inigualable que el consumidor sabe premia.

  4. Proteinuria in mice expressing PKB/SGK-resistant GSK3.

    Science.gov (United States)

    Boini, Krishna M; Amann, Kerstin; Kempe, Daniela; Alessi, Dario R; Lang, Florian

    2009-01-01

    SGK1 is critically important for mineralocorticoid/salt-induced glomerular injury. SGK1 inactivates GSK3, which downregulates Snail, a DNA-binding molecule repressing the transcription of nephrin, a protein critically important for the integrity of the glomerular slit membrane. PKB/SGK-dependent GSK regulation is disrupted in mice carrying a mutation, in which the serine in the SGK/PKB-phosphorylation consensus sequence is replaced by alanine. The present study explored whether PKB/SGK-dependent GSK3 regulation influences glomerular proteinuria. Gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK3alpha,beta (gsk3(KI)) were compared with their wild-type littermates (gsk3(WT)). gsk3(KI) and gsk3(WT) mice were implanted with DOCA release pellets and offered 1% saline as drinking water for 21 days. Under standard diet, tap water intake and absence of DOCA, urinary flow rate, glomerular filtration rate, and urinary albumin excretion were significantly larger and blood pressure was significantly higher in gsk3(KI) than in gsk3(WT) mice. Within 18 days, DOCA/salt treatment significantly increased fluid intake and urinary flow rate, urinary protein and albumin excretion, and blood pressure in both genotypes but the respective values were significantly higher in gsk3(KI) than in gsk3(WT) mice. Plasma albumin concentration was significantly lower in gsk3(KI) than in gsk3(WT) mice. Proteinuria was abrogated by lowering of blood pressure with alpha(1)-blocker prazosin (1 microg/g body wt) in 8-mo-old mice. According to immunofluorescence, nephrin at 3 and 8 mo and podocin expression at 3 mo were significantly lower in gsk3(KI) than in gsk3(WT) mice. After 18 days, DOCA/salt treatment renal glomerular sclerosis and tubulointerstitial damage were significantly more pronounced in gsk3(KI) than in gsk3(WT) mice. The observations reveal that disruption of PKB/SGK-dependent regulation of GSK3 leads to glomerular injury with proteinuria, which may at least

  5. Norepinephrine accumulation by the rat caudal artery in the presence of hypertensive plasma

    International Nuclear Information System (INIS)

    Freas, W.; Thompson, D.A.; Hart, J.L.; Muldoon, S.M.

    1986-01-01

    We have partially isolated endogenous factors from canine plasma which inhibit 3 H-norepinephrine (NE) accumulation by the canine saphenous vein. The purpose of this study is to determine if these circulating factors may account for the observed differences in 3 H-NE uptake by hypertensive and normotensive blood vessels. Three models of hypertension were examined in this study. Blood vessels were compared from SHR and WKY rats, deoxycorticosterone acetate (DOCA) and control rats, and reduced renal mass (RRM) and control rats. There was no significant difference in 3 H-NE accumulation between blood vessels obtained from RRM and paired control rats. However, both the SHR and DOCA hypertensive caudal arteries and aorta accumulated significantly more 3 H-NE than their corresponding control tissues. There was not a significant change in 3 H-NE accumulation between hypertensive and control vena cava and mesenteric arteries. Normotensive and hypertensive plasma inhibited 3 H-NE accumulation by the rat caudal artery. However, there was not a correlation between blood pressure of plasma donor rats and accumulation of 3 H-NE. Therefore, although there are differences in 3 H-NE accumulation between hypertensive and normotensive blood vessels, plasma does not contain a factor responsible for this observed difference

  6. 25-Hydroxyvitamin D3 1-Alpha-Hydroxylase-Dependent Stimulation of Renal Klotho Expression by Spironolactone

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    Ioana Alesutan

    2013-11-01

    Full Text Available Background: Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney, is required for the suppression of 1,25(OH2D3-generating 25-hydroxyvitamin D3 1-alpha-hydroxylase (Cyp27b1 by FGF23. Conversely, 1,25(OH2D3 stimulates, by activating the vitamin D3 receptor (Vdr, the expression of klotho, thus establishing a negative feedback loop. Klotho protects against renal and vascular injury. Klotho deficiency accelerates aging and early death, effects at least partially due to excessive formation of 1,25(OH2D3 and subsequent hyperphosphatemia. Klotho expression is inhibited by aldosterone. The present study explored the interaction of aldosterone and DOCA as well as the moderately selective mineralocorticoid receptor antagonist spironolactone on klotho expression. Methods: mRNA levels were determined utilizing quantitative RT-PCR in human embryonic kidney cells (HEK293 or in renal tissues from mice without or with prior mineralocorticoid (aldosterone or DOCA and/or spironolactone treatment. In HEK293 cells, protein levels were determined by western blotting. The experiments in HEK293 cells were performed without or with silencing of CYP27B1, of vitamin D3 receptor (VDR or of mineralocorticoid receptor (NR3C2. Results: In HEK293 cells aldosterone and in mice DOCA significantly decreased KLOTHO gene expression, effects opposed by spironolactone treatment. Spironolactone treatment alone significantly increased KLOTHO and CYP27B1 transcript levels in HEK293 cells (24 hours and mice (8 hours or 5 days. Moreover, spironolactone significantly increased klotho and CYP27B1 protein levels in HEK293 cells (48 hours. Reduced NR3C2 expression following silencing did not significantly affect KLOTHO and CYP27B1 transcript levels in presence or absence of spironolactone. Silencing of CYP27B1 and VDR significantly blunted the stimulating effect of spironolactone on KLOTHO mRNA levels in HEK293 cells. Conclusion: Besides blocking the effects of

  7. NAD(P)H oxidase/nitric oxide interactions in peroxisome proliferator activated receptor (PPAR)α-mediated cardiovascular effects

    International Nuclear Information System (INIS)

    Newaz, Mohammad; Blanton, Ahmad; Fidelis, Paul; Oyekan, Adebayo

    2005-01-01

    Activation of peroxisome proliferator activated receptor (PPAR)α and its protective role in cardiovascular function has been reported but the exact mechanism(s) involved is not clear. As we have shown that PPARα ligands increased nitric oxide (NO) production and cardiovascular function is controlled by a balance between NO and free radicals, we hypothesize that PPARα activation tilts the balance between NO and free radicals and that this mechanism defines the protective effects of PPARα ligands on cardiovascular system. Systolic blood pressure (SBP) was greater in PPARα knockout (KO) mice compared with its wild type (WT) litter mates (130 ± 10 mmHg versus 107 ± 4 mmHg). L-NAME (100 mg/L p.o.), the inhibitor of NO production abolished the difference between PPARα KO and WT mice. In kidney homogenates, tissue lipid hydroperoxide generation was greater in KO mice (11.8 ± 1.4 pM/mg versus 8.3 ± 0.6 pM/mg protein). This was accompanied by a higher total NOS activity (46 ± 6%, p 2+ -dependent NOS activity in kidney homogenates of untreated PPARα WT compared with the KO mice. Clofibrate, a PPARα ligand, increased NOS activity in WT but not KO mice. Bezafibrate (30 mg/kg) reduced SBP in conscious rats (19 ± 4%, p < 0.05), increased urinary NO excretion (4.06 ± 0.53-7.07 ± 1.59 μM/24 h; p < 0.05) and reduced plasma 8-isoprostane level (45.8 ± 15 μM versus 31.4 ± 8 μM), and NADP(H) oxidase activity (16 ± 5%). Implantation of DOCA pellet (20 mg s.c.) in uninephrectomized mice placed on 1% NaCl drinking water increased SBP by a margin that was markedly greater in KO mice (193 ± 13 mmHg versus 130 ± 12 mmHg). In the rat, DOCA increased SBP and NAD(P)H oxidase activity and both effects were diminished by clofibrate. In addition, clofibrate reduced ET-1 production in DOCA/salt hypertensive rats. Thus, apart from inhibition of ET-1 production, PPARα activation exerts protective actions in hypertension via a mechanism that involves NO production and

  8. Development of a Common Format of Questionnaire Tests for a Web-based Platform of Population and Experimental Psychological Research

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    Nikulchev Evgeny

    2018-01-01

    Full Text Available A web platform for psychological research needs a single format of questionnaire tests to ensure interaction between its components. The study proposes a general test structure, variant questions, variations in response types, and an embedded domain-specific language for computations. The use of JSON is proposed and justified to store the hierarchical structure of the questionnaire test, and JSON Schema is defined as a technology suitable for the formation of the standard. From the considered validation instruments for compliance with the standard described in JSON Schema, ajv was defined as the most applicable to the task. To build the documentation, Doca is relevant, but this tool needs to be modified to meet the requirements of the task.

  9. Parietal Epithelial Cells Participate in the Formation of Sclerotic Lesions in Focal Segmental Glomerulosclerosis

    Science.gov (United States)

    Smeets, Bart; Kuppe, Christoph; Sicking, Eva-Maria; Fuss, Astrid; Jirak, Peggy; van Kuppevelt, Toin H.; Endlich, Karlhans; Wetzels, Jack F.M.; Gröne, Hermann-Josef; Floege, Jürgen

    2011-01-01

    The pathogenesis of the development of sclerotic lesions in focal segmental glomerulosclerosis (FSGS) remains unknown. Here, we selectively tagged podocytes or parietal epithelial cells (PECs) to determine whether PECs contribute to sclerosis. In three distinct models of FSGS (5/6-nephrectomy + DOCA-salt; the murine transgenic chronic Thy1.1 model; or the MWF rat) and in human biopsies, the primary injury to induce FSGS associated with focal activation of PECs and the formation of cellular adhesions to the capillary tuft. From this entry site, activated PECs invaded the affected segment of the glomerular tuft and deposited extracellular matrix. Within the affected segment, podocytes were lost and mesangial sclerosis developed within the endocapillary compartment. In conclusion, these results demonstrate that PECs contribute to the development and progression of the sclerotic lesions that define FSGS, but this pathogenesis may be relevant to all etiologies of glomerulosclerosis. PMID:21719782

  10. Mineralocorticoid hypertension: clinical and laboratory studies with special reference to selective percutaneous venography combined with aldosterone assay in the adrenal venous blood

    International Nuclear Information System (INIS)

    Wajchenberg, B.L.; Liberman, B.; Novaes, M.

    1977-01-01

    With the purpose of demonstrating the presence of hypertension, hypokalemia and alkalosis were studied. The presence of daily aldosteronism was verified in five patients; the sixth one presented no daily aldosteronism but an increase of 18-OH-DOCA production, an ACTH dependente mineralocorticoid. The presence of tumor (less than 0.9cm) could not be shown in two patients by bilateral selective adrenal venography. The aldosterone assay during catherization of adrenal vein of those patients permitted to determine the tumoral side. Attention must be given to the fact that the blood collection of adrenal vein must always be made during adrenal venography to demonstrate the presence of short unilateral tumor or bilateral disease [pt

  11. Recent advances in the physiology of whole body immersion.

    Science.gov (United States)

    Gauer, O H

    1975-01-01

    Recent investigations have furnished a complete analysis of the hemodynamic events accompanying whole-body immersion. About 700 ml of blood are translocated into the intrathoracic circulation, and heart volume increases by 180 +/- 62 ml. These changes are followed by an increase in stroke volume and cardiac output of over 30%. At the same time a reflex reduction of total peripheral resistance and venous tone occurs. Renin and aldosterone activity are reduced while the 17-hydroxycorticosteroid is not affected. Treatment of the subject with DOCA attenuates but does not extinguish the excess sodium excretion of immersion. This finding strengthens the arguments in favor of an unknown factor enhancing sodium excretion. Finally, the relative activation of the three factors that serve volume control, the excretory function of the kidney, capillary filtration pressure, and the thirst mechanism, is discussed.

  12. Chronic hypertension alters the expression of Cx43 in cardiovascular muscle cells

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    Haefliger J.-A.

    2000-01-01

    Full Text Available Connexin43 (Cx43, the predominant gap junction protein of muscle cells in vessels and heart, is involved in the control of cell-to-cell communication and is thought to modulate the contractility of the vascular wall and the electrical coupling of cardiac myocytes. We have investigated the effects of arterial hypertension on the expression of Cx43 in aorta and heart in three different models of experimental hypertension. Rats were made hypertensive either by clipping one renal artery (two kidney, one-clip renal (2K,1C model by administration of deoxycorticosterone and salt (DOCA-salt model or by inhibiting nitric oxide synthase with NG-nitro-L-arginine methyl ester (L-NAME model. After 4 weeks, rats of the three models showed a similar increase in intra-arterial mean blood pressure and in the thickness of the walls of both aorta and heart. Analysis of heart mRNA demonstrated no change in Cx43 expression in the three models compared to their respective controls. The same 2K,1C and DOCA-salt hypertensive animals expressed twice more Cx43 in aorta, and the 2K,1C rats showed an increase in arterial distensibility. In contrast, the aortae of L-NAME hypertensive rats were characterized by a 50% decrease in Cx43 and the carotid arteries did not show increased distensibility. Western blot analysis indicated that Cx43 was more phosphorylated in the aortae of 2K,1C rats than in those of L-NAME or control rats, indicating a differential regulation of aortic Cx43 in different models of hypertension. The data suggest that localized mechanical forces induced by hypertension affect Cx43 expression and that the cell-to-cell communication mediated by Cx43 channels may contribute to regulating the elasticity of the vascular wall.

  13. Tension cost correlates with mechanical and biochemical parameters in different myocardial contractility conditions

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    Cleci M. Moreira

    2012-01-01

    Full Text Available OBJECTIVES: Tension cost, the ratio of myosin ATPase activity to tension, reflects the economy of tension development in the myocardium. To evaluate the mechanical advantage represented by the tension cost, we studied papillary muscle contractility and the activity of myosin ATPase in the left ventricles in normal and pathophysiological conditions. METHODS: Experimental protocols were performed using rat left ventricles from: (1 streptozotocin-induced diabetic and control Wistar rats; (2 N-nitro-L-arginine methyl ester (L-NAME hypertensive and untreated Wistar rats; (3 deoxycorticosterone acetate (DOCA salt-treated, nephrectomized and salt- and DOCA-treated rats; (4 spontaneous hypertensive rats (SHR and Wistar Kyoto (WKY rats; (5 rats with myocardial infarction and shamoperated rats. The isometric force, tetanic tension, and the activity of myosin ATPase were measured. RESULTS: The results obtained from infarcted, diabetic, and deoxycorticosterone acetate-salt-treated rats showed reductions in twitch and tetanic tension compared to the control and sham-operated groups. Twitch and tetanic tension increased in the N-nitro-L-arginine methyl ester-treated rats compared with the Wistar rats. Myosin ATPase activity was depressed in the infarcted, diabetic, and deoxycorticosterone acetate salt-treated rats compared with control and sham-operated rats and was increased in N-nitro-L-arginine methyl ester-treated rats. These parameters did not differ between SHR and WKY rats. In the studied conditions (e.g., post-myocardial infarction, deoxycorticosterone acetate salt-induced hypertension, chronic N-nitro-L-arginine methyl ester treatment, and streptozotocin-induced diabetes, a positive correlation between force or plateau tetanic tension and myosin ATPase activity was observed. CONCLUSION: Our results suggest that the myocardium adapts to force generation by increasing or reducing the tension cost to maintain myocardial contractility with a better

  14. Diuretics prevent Rho-kinase activation and expression of profibrotic/oxidative genes in the hypertensive aortic wall.

    Science.gov (United States)

    Araos, Patricio; Mondaca, David; Jalil, Jorge E; Yañez, Cristián; Novoa, Ulises; Mora, Italo; Ocaranza, María Paz

    2016-12-01

    Diuretics are current antihypertensive drugs since they reduce blood pressure and cardiovascular risk. Increased vascular tone is modulated in a relevant way by the RhoA/Rho-kinase (ROCK) pathway, by acting on vascular smooth muscle cell contraction. This pathway has also proremodeling vascular effects. There are few data on the role of diuretics on both vascular ROCK activation and on proremodeling effects. We assessed the effects of hydrochlorothiazide (HCTZ) and spironolactone (spiro) alone and in combination with the ROCK inhibitor fasudil (FAS) on ROCK activation, gene expression of proremodeling markers and on hypertrophy in the aortic wall of hypertensive rats. Deoxycorticosterone acetate (DOCA)-salt hypertensive rats (male, Sprague-Dawley) were randomized to the specific ROCK inhibitor FAS, HCTZ, spiro or the combinations of FAS/HCTZ or FAS/spiro for 3 weeks. At the end of the study, ROCK activation (by western blot), gene expression of proremodeling markers (by reverse transcription polymerase chain reaction, RT-PCR) and vascular hypertrophy (by morphometry) were determined in the aortic wall. All treatments significantly reduced blood pressure. In the DOCA rats the p-myosin phosphatase target protein-1 (MYPT1)/t-MYPT1 ratio, index of ROCK activation was higher by 2.8 fold (p diuretics alone or in combination with FAS. In the aortic wall, both HCTZ and spiro in antihypertensive doses reduce ROCK activation, subsequent expression of genes that promote vascular remodeling and hypertrophy in this experimental model of hypertension. These effects could explain some of their clinical benefits in hypertensive patients. © The Author(s), 2016.

  15. Luz, leis e livre-concorrência: conflitos em torno das concessões de energia elétrica na cidade de São Paulo no início do século XX Light, laws and liberalism: conflicts in the São Paulo's electric light sector during the beninning of the 20th century

    Directory of Open Access Journals (Sweden)

    Alexandre Macchione Saes

    2009-01-01

    Full Text Available O artigo discute o processo de introdução da energia elétrica na cidade de São Paulo no início do século XX. A Proclamação da República marcou o início da modernização das empresas de serviços urbanos, com a introdução da eletricidade. Foi neste contexto que dois grupos iniciaram uma intensa batalha no setor elétrico paulista: o grupo nacional da Companhia Brasileira de Energia Elétrica (CBEE - conhecido também como Docas de Santos - e o canadense Light. A falta de uma legislação federal para o setor de energia elétrica legou às Câmaras Municipais o poder concedente para os serviços de eletricidade, garantindo que as relações políticas entre vereadores e empresários tivessem decisivo papel na instalação de tais serviços. Assim, o artigo descreve o processo de introdução da eletricidade em São Paulo mediante os debates sobre a regulamentação dos serviços públicos, desvendando os critérios políticos ou ideológicos que levaram a conformação de tais leis.This paper discusses the introduction of electric power in the city of São Paulo during the beginning of the 20th century. The Brazilian Republic Proclamation (1889 established the beginning of the public services companies' modernization, which through the enterprises fusion and the arrival of foreign capital allowed the electric power introduction in the main Brazilian cities. Two rival groups started a competition in the São Paulo's electric sector: the national enterprise Companhia Brasileira de Energia Elétrica (CBEE - so called as Docas de Santos - and the Canadian company Light. The inexistence of a federal legislation to electric power services had transformed municipal decisions in deterministic guidelines for utility bids, making municipal lobbying a key instrument in utility concessions. Hence, this paper issues describe the electric power introduction in the city through the debates about the utilities' rules, analyzing the political or

  16. Crustal structure of the Central Precordillera of San Juan, Argentina (31°S) using teleseismic receiver functions

    Science.gov (United States)

    Ammirati, Jean-Baptiste; Alvarado, Patricia; Perarnau, Marcelo; Saez, Mauro; Monsalvo, Guillermo

    2013-10-01

    The subduction of the Nazca plate under the South American plate around 31°S is characterized by flat slab geometry. The (Chilean) Pampean flat slab of Argentina associated with the subduction of the Juan Fernandez ridge lies in a region of a series of foreland uplifts corresponding to the thin-skinned Precordillera and basement cored Sierras Pampeanas ranges. The SIEMBRA project deployed 40 broadband stations in 2008-2009 in both the Precordillera and the Sierras Pampeanas with the aim to foster the understanding of the entire central Andean flat slab region. One of the SIEMBRA station (DOCA) located on the western flank of Sierra de la Invernada in the Central Precordillera appears particularly appropriate to study the crustal structure and eventually detect discontinuities related to terranes establishment. We thus performed a receiver function analysis using teleseismic data recorded at the DOCA station during the SIEMBRA project and from October 2011 to June 2012 using a broadband UNSJ (National University of San Juan) seismic station with the purpose to obtain crustal images with details of the intracrustal structure consistent with a mechanism that could explains both the observed earthquake depths and the uplift pattern in the Central Precordillera. Our results show that the Moho beneath the Precordillera lies at a depth of about 66 km. The Moho signal appears diminished and behaves irregularly as a function of azimuthal orientations. Although this observation could be the result of an irregular geometry it also correlates with the hypothesis of partial eclogitisation in the lower crust. Two mid-crustal discontinuities have also been revealed. The shallower one could correspond to a décollement level between the Precordilleran strata and the Cuyania basement at 21 km depth. The deeper one which the presence has been matched with a sharp decrease of the crustal seismic activity drove us to the hypothesis of a major change in crustal composition at 36 km

  17. Increased albumin permeation in eyes, aorta, and kidney of hypertensive rats fed galactose

    International Nuclear Information System (INIS)

    Tilton, R.G.; LaRose, L.; Chang, K.; Weigel, C.J.; Williamson, J.R.

    1986-01-01

    These experiments were undertaken to determine whether ingestion of galactose increases albumin permeation in the vasculature of hypertensive rats. 50% dextrin (control) or 50% galactose diets were fed to unilaterally nephrectomized, male Sprague-Dawley rats weighing 200 g. Hypertension (systolic pressure >175 mmHg) was induced by weekly IM injections of 25 mg/kg DOCA and 1% saline drinking water; 3 months later 125 I-albumin permeation was assessed in whole eyes, aorta and kidneys. 125 I-albumin permeation was significantly increased in all 3 tissues of hypertensive rats (n = 9) vs controls (n = 9): aorta (3.30 +/- 0.19 (SD) vs 2.87 +/- 0.14), eye (3.15 +/- 0.14 vs 2.59 +/- 0.11), and kidney (6.58 +/- 0.63 vs 3.85 +/- 0.50). Albumin permeation was increased still further in hypertensive rats fed the galactose diet (n = 8): aorta (3.75 +/- 0.38), eye (3.82 +/- 0.17), and kidney (10.74 +/- 3.13). Hypertension +/- galactose feeding had no effect on albumin permeation in lung, skin, or brain. These findings indicate that: (1) hypertension increases albumin permeation in vessels affected by diabetic vascular diseases, and 2) hypertension-induced increases in albumin permeation are increased still further by galactose ingestion, presumably mediated by imbalances in polyol/insitol metabolism (analogous to those induced by diabetes) independent of hyperglycemia and/or insulinopenia

  18. Atrial natriuretic peptide in the locus coeruleus and its possible role in the regulation of arterial blood pressure, fluid and electrolyte homeostasis

    International Nuclear Information System (INIS)

    Geiger, H.; Sterzel, R.B.; Bahner, U.; Heidland, A.; Palkovits, M.

    1991-01-01

    Atrial natriuretic factor (ANP) is present in neuronal cells of the locus coeruleus and its vicinity in the pontine tegmentum and moderate amount of ANP is detectable in this area by radioimmunoassay. The ANP is known as a neuropeptide which may influence the body salt and water homeostasis and blood pressure by targeting both central and peripheral regulatory mechanisms. Whether this pontine ANP cell group is involved in any of these regulatory mechanisms, the effect of various types of hypertension and experimental alterations in the salt and water balance on ANP levels was measured by radioimmunoassay in the locus coeruleus of rats. Adrenalectomy, as well as aldosterone and dexamethasone treatments failed to alter ANP levels in the locus coeruleus. Reduced ANP levels were measured in spontaneously hypertensive rats, and in diabetes insipidus rats with vasopressin replacement. In contrast to these situations, elevated ANP levels were found in rats with DOCA-salt or 1-Kidney-1-clip hypertension. These data suggest a link between ANP levels in the locus coeruleus and fluid volume homeostasis. Whether this link is causal and connected with the major activity of locus coeruleus neurons needs further information

  19. Drug-Drug Multicomponent Solid Forms: Cocrystal, Coamorphous and Eutectic of Three Poorly Soluble Antihypertensive Drugs Using Mechanochemical Approach.

    Science.gov (United States)

    Haneef, Jamshed; Chadha, Renu

    2017-08-01

    The present study deals with the application of mechanochemical approach for the preparation of drug-drug multicomponent solid forms of three poorly soluble antihypertensive drugs (telmisartan, irbesartan and hydrochlorothiazide) using atenolol as a coformer. The resultant solid forms comprise of cocrystal (telmisartan-atenolol), coamorphous (irbesartan-atenolol) and eutectic (hydrochlorothiazide-atenolol). The study emphasizes that solid-state transformation of drug molecules into new forms is a result of the change in structural patterns, diminishing of dimers and creating new facile hydrogen bonding network based on structural resemblance. The propensity for heteromeric or homomeric interaction between two different drugs resulted into diverse solid forms (cocrystal/coamorphous/eutectics) and become one of the interesting aspects of this research work. Evaluation of these solid forms revealed an increase in solubility and dissolution leading to better antihypertensive activity in deoxycorticosterone acetate (DOCA) salt-induced animal model. Thus, development of these drug-drug multicomponent solid forms is a promising and viable approach to addressing the issue of poor solubility and could be of considerable interest in dual drug therapy for the treatment of hypertension.

  20. The occurrence of fungi, yeasts and bacteria in the air of a Spanish winery during vintage.

    Science.gov (United States)

    Garijo, Patrocinio; Santamaría, Pilar; López, Rosa; Sanz, Susana; Olarte, Carmen; Gutiérrez, Ana Rosa

    2008-07-15

    This research studies the presence of microorganisms of enological interest (yeasts, bacteria and molds) and their evolution in the air of a wine cellar. The samples were taken throughout the winemaking campaign (September-December) in a winery of the D.O.Ca. Rioja, Spain. They were collected using an airIDEAL atmosphere sampler from Biomerieux. For the isolation, specific selective media were used for each group of microorganisms. The results obtained indicate that the presence in the winery air of the various different microorganisms studied is directly related to the winemaking processes that are taking place in the winery. Thus, the number of molds present decreases once grapes have ceased to be brought into the winery. The maximum number of yeasts in the air is found when all the vats in the cellar are fermenting, while the lactic bacteria are not detected until the first malolactic fermentation begins. The species of yeasts and molds identified are also related to the winemaking processes. The coincidence of strains of Saccharomyces cerevisiae among those present in the vats during alcoholic fermentation and those isolated from the air, confirms the role of the latter as a transmitter of microorganisms.

  1. In Vitro Investigation of Self-Assembled Nanoparticles Based on Hyaluronic Acid-Deoxycholic Acid Conjugates for Controlled Release Doxorubicin: Effect of Degree of Substitution of Deoxycholic Acid

    Directory of Open Access Journals (Sweden)

    Wen-Hao Wei

    2015-03-01

    Full Text Available Self-assembled nanoparticles based on a hyaluronic acid-deoxycholic acid (HD chemical conjugate with different degree of substitution (DS of deoxycholic acid (DOCA were prepared. The degree of substitution (DS was determined by titration method. The nanoparticles were loaded with doxorubicin (DOX as the model drug. The human cervical cancer (HeLa cell line was utilized for in vitro studies and cell cytotoxicity of DOX incorporated in the HD nanoparticles was accessed by the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. In addition, cellular uptake of fluorescently labeled nanoparticles was also investigated. An increase in the degree of deoxycholic acid substitution reduced the size of the nanoparticles and also enhanced their drug encapsulation efficiency (EE, which increased with the increase of DS. A higher degree of deoxycholic acid substitution also lead to a lower release rate and an initial burst release of doxorubicin from the nanoparticles. In summary, the degree of substitution allows the modulation of the particle size, drug encapsulation efficiency, drug release rate, and cell uptake efficiency of the nanoparticles. The herein developed hyaluronic acid-deoxycholic acid conjugates are a good candidate for drug delivery and could potentiate therapeutic formulations for doxorubicin–mediated cancer therapy.

  2. Dinâmica de populações e fitossociologia de plantas daninhas no cultivo do feijão-caupi e mandioca no sistema corte e queima com o uso de arado Phytosociology of weeds in cowpea and cassava crops under the slash-and-burn with plow

    Directory of Open Access Journals (Sweden)

    L.J.P Marques

    2011-01-01

    Full Text Available Este estudo investigou a composição florística das plantas daninhas em área queimada durante três anos agrícolas. A pesquisa foi conduzida no município de Zé Doca, Maranhão. O preparo da área no primeiro ano agrícola (2006/2007 foi realizado com corte e queima da vegetação para o cultivo de milho seguido do feijão-caupi. No segundo e no terceiro ano agrícola, o preparo da área consistiu de aração para o cultivo do milho seguido de mandioca (2007/2008 e depois para o feijão-caupi em sucessão à cultura de mandioca (2008/2009. A coleta das plantas daninhas ocorreu nas culturas de feijão-caupi e mandioca aos 30 e 60 dias após a semeadura (DAS, no primeiro e no segundo ano agrícola, respectivamente, e no feijão-caupi aos 30 DAS do terceiro ano agrícola, com retângulo (0,5 x 0,3 m lançado 10 vezes ao acaso na área cultivada. A cada lançamento, as plantas daninhas foram colhidas, para contagem, identificação, secagem e, assim, obter os índices fitossociológicos. O fogo reduziu a diversidade e o número das plantas daninhas. As espécies com maior valor de IVI foram Imperata brasiliensis, Sida glomerata e Corchorus argutus, após o fogo na cultura do feijãocaupi; e Juncus sp., Spermacoce verticillata, Aeschynomene americana e Cyperus sp., após preparo da área com aração nas culturas de mandioca e feijão-caupi. As plantas de capoeira ocorreram depois da queima, porém sua importância foi reduzida com o passar do tempo.This study investigated the floristic composition of weeds in a burnt area in Zé Doca, Maranhão, during three agricultural years. The preparation of the area at the first crop year (2006/ 2007 was by slash-and-burn for maize cultivation, followed by cowpea. In the second and third crop years, the preparation of the area consisted of plowing for maize cultivation, followed by cassava (2007/2008 and later, by cowpea in rotation with cassava (2008/2009. Weed collection in the cowpea and cassava crops

  3. Effect of saline loading on uranium-induced acute renal failure in rats

    International Nuclear Information System (INIS)

    Hishida, A.; Yonemura, K.; Ohishi, K.; Yamada, M.; Honda, N.

    1988-01-01

    Studies were performed to examine the effect of saline loading on uranium-induced acute renal failure (ARF) in rats. Forty-eight hours after the i.v. injection of uranyl acetate (UA, 5 mg/kg), inulin clearance rate (Cin) decreased to approximately 43% of the control value in water drinking rats (P less than 0.005). Animals receiving continuous isotonic saline infusion following UA showed higher urine flow and Cin (60% of control, P less than 0.01), and lessened intratubular cast formation when compared with water-drinking ARF rats. A short-term saline infusion following UA did not attenuate the decline in Cin (43% of control). An inverse relationship was found between Cin and the number of casts (r = -0.75, P less than 0.01). Multiple regression analysis showed that standardized partial regression coefficient is statistically significant between Cin and cast formation (-0.69, P less than 0.05), but not between Cin and tubular necrosis (-0.07, P greater than 0.05). Renin depletion caused by DOCA plus saline drinking did not attenuate the decline in Cin in ARF (47% of control). No significant difference was found in urinary uranium excretion between water-drinking and saline-infused ARF rats. The findings suggest that continuous saline infusion following UA attenuates the decline in Cin in ARF rats; and that this beneficial effect of saline loading is associated with lessened cast formation rather than with suppressed renin-angiotensin activity or enhanced urinary-uranium excretion

  4. Occurrence of pesticides and some of their degradation products in waters in a Spanish wine region

    Science.gov (United States)

    Herrero-Hernández, E.; Andrades, M. S.; Álvarez-Martín, A.; Pose-Juan, E.; Rodríguez-Cruz, M. S.; Sánchez-Martín, M. J.

    2013-04-01

    SummaryA multi-residual analytical method based on solid phase extraction (SPE) followed by liquid chromatography-electrospray ionisation-mass spectrometry (LC-MS) was developed to monitor pesticides in natural waters. Fifty-eight compounds, including herbicides, fungicides, insecticides and some of their degradation products, were surveyed to evaluate the quality of natural waters throughout the wine-growing region of La Rioja (Rioja DOCa). Ninety-two sampling points were selected, including surface and ground waters that could be affected by agricultural activities covering the region's three sub-areas. Different parameters that may affect the efficiency of the SPE procedure were optimised (sorbent type, elution solvent and sample volume), and matrix-matched standards were used to eliminate the variable matrix effect and ensure good quantification. The developed method allows the determination of target compounds below the level established by the European Union for waters for human use with suitable precision (relative standard deviations lower than 18%) and accuracy (with recoveries over 61%). Forty compounds included in this study (six insecticides, 12 herbicides, 16 fungicides and six degradation products) were detected in one or more samples. The herbicides terbuthylazine, its metabolite desethyl terbuthylazine, fluometuron and ethofumesate and the fungicides pyrimethanil and tebuconazole were the compounds most frequently detected in water samples (present in more than 60% of the samples). Concentrations above 0.1 μg L-1 were detected for 37 of the compounds studied, and in several cases recorded values of over 18 μg L-1. The results reveal the presence of pesticides in most of the samples investigated. In 64% of groundwaters and 62% of surface waters, the sum of compounds detected was higher than 0.5 μg L-1 (the limit established by EU legislation for the sum of all pesticides detected in waters for human use).

  5. Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.

    Science.gov (United States)

    Arai, Kiyoshi; Homma, Tsuyoshi; Morikawa, Yuka; Ubukata, Naoko; Tsuruoka, Hiyoyuki; Aoki, Kazumasa; Ishikawa, Hirokazu; Mizuno, Makoto; Sada, Toshio

    2015-08-15

    The present study was designed to characterize the pharmacological profile of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist. In the radioligand-binding assay, CS-3150 inhibited (3)H-aldosterone binding to mineralocorticoid receptor with an IC50 value of 9.4nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 36 and 713nM, respectively. CS-3150 also showed at least 1000-fold higher selectivity for mineralocorticoid receptor over other steroid hormone receptors, glucocorticoid receptor, androgen receptor and progesterone receptor. In the reporter gene assay, CS-3150 inhibited aldosterone-induced transcriptional activation of human mineralocorticoid receptor with an IC50 value of 3.7nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 66 and 970nM, respectively. CS-3150 had no agonistic effect on mineralocorticoid receptor and did not show any antagonistic or agonistic effect on glucocorticoid receptor, androgen receptor and progesterone receptor even at the high concentration of 5μM. In adrenalectomized rats, single oral administration of CS-3150 suppressed aldosterone-induced decrease in urinary Na(+)/K(+) ratio, an index of in vivo mineralocorticoid receptor activation, and this suppressive effect was more potent and longer-lasting than that of spironolactone and eplerenone. Chronic treatment with CS-3150 inhibited blood pressure elevation induced by deoxycorticosterone acetate (DOCA)/salt-loading to rats, and this antihypertensive effect was more potent than that of spironolactone and eplerenone. These findings indicate that CS-3150 is a selective and highly potent mineralocorticoid receptor antagonist with long-lasting oral activity. This agent could be useful for the treatment of hypertension, cardiovascular and renal disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agnieszka [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland); Toczek, Marek [Department of Experimental Physiology and Pathophysiology Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok (Poland); Bielawska, Katarzyna [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland); Skrzydlewska, Elżbieta, E-mail: elzbieta.skrzydlewska@umb.edu.pl [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland)

    2016-06-15

    Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB{sub 1} receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB{sub 1} receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance in the

  7. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

    International Nuclear Information System (INIS)

    Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agnieszka; Toczek, Marek; Bielawska, Katarzyna; Skrzydlewska, Elżbieta

    2016-01-01

    Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB 1 receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB 1 receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance in the liver of

  8. Seville and the double guadalquivir: a brief analysis of the recent city-river integration phenomenon

    Directory of Open Access Journals (Sweden)

    Peter Ribon Monteiro

    2009-12-01

    Full Text Available Após um complexo conjunto de obras hidráulicas realizado durante o século 20, o rio Guadalquivir, principal curso d'água da Andaluzia (Espanha, sofre uma série de intervenções físicas que altera radicalmente seu desenho desde sua foz até Sevilha. Dentro dos limites dessa cidade, a reconfiguração - iniciada pela corta de Tablada (anos 20 e seguida pelas cortas de Triana (anos 50 e da Cartuja (anos 70, com o objetivo de melhorar as atividades portuárias e evitar constantes inundações - provoca uma curiosa duplicação do rio, que se desdobra em um trecho" histórico" (então estancado e transformado em doca e um trecho" vivo" (por onde segue até o mar. Ao mesmo tempo, a capital andaluza se expande às zonas sul (incentivada pela Exposição Iberoamericana de 1929, leste e norte, tornando-se sede da nova região metropolitana. Com os investimentos para a Exposição Internacional de 1992 (Expo'92, são, finalmente, ocupados, os terrenos da Cartuja, a oeste do centro histórico, e o rearranjo dos sistemas ferroviário e rodoviário devolve à cidade um grande trecho do rio então isolado (avenida Torneo. Enquanto o porto se direciona ao sul, junto da zona de Tablada, o velho cais do Arenal ganha o primeiro projeto de reintegração do rio à cidade. Novos passeios e pontes interligando o antigo núcleo urbano à Cartuja complementam essa nova paisagem, com o respaldo dos atuais planos urbanísticos. Com a descrição histórica desse processo e de uma breve análise visual do duplo Guadalquivir, buscamos identificar valores refletidos na atual conformação urbana do rio, detendo-nos, especialmente, à abertura realizada (e que segue em andamento em seu" histórico" curso.

  9. Estudo sobre os riscos da profissão de estivador do Porto do Mucuripe em Fortaleza Occupational risks among dock workers in the Port of Mucuripe, Fortaleza, Brazil

    Directory of Open Access Journals (Sweden)

    Francisco Fábio Gadelha Cavalcante

    2005-12-01

    Full Text Available Os estivadores do Porto do Mucuripe são trabalhadores sem vínculo empregatício com a Companhia Docas do Ceará. Atuam no convés e no porão dos navios, fazendo o embarque, o desembarque e a organização dos contêineres. Neste ambiente de constante exposição a riscos, o médico do trabalho é fundamental na organização de planos de prevenção de acidentes, de educação dos trabalhadores e de monitorização dos riscos. O objetivo do artigo é caracterizar e conhecer o estivador, correlacionar o ambiente portuário e o seu processo produtivo com os fatores de risco e os agravos associados, bem como ressaltar a importância da medicina do trabalho para o controle de tais riscos. O trabalho de campo foi desenvolvido nos meses de janeiro e de fevereiro de 2003, com a aplicação de 60 questionários aos estivadores. A análise dos dados evidencia que os principais problemas de saúde inerentes à profissão de estivador são, entre outros, os distúrbios osteoarticulares (hérnia de disco e desgastes na articulação do joelho e metabólicos (diabetes e hipertensão arterial. Estes se devem não só ao trabalho, mas também e, com grande influência, ao contexto de vida destes profissionais.The stevedores of the Port of Mucuripe are workers without employment bond with the Company Dock of Ceará. They act in the deck and the stowage of the ships, making the embarkment, the landing and the organization of containers. In this environment of constant exposition to risks, occupational physician is basic in the organization of plans of prevention of accidents, education of the workers and monitorization of the risks. The objective of this article is to characterize and to know the stevedore’s job, to correlate the port environment and its productive process with the factors of risk and the damages associates, as well as standing out the importance of the Occupational Medicine for the control of such risks. The fieldwork was developed in the