Abstract 558: Role of Angiotensin Converting Enzyme 2/angiotensin (1-7)/mas Axis in the Hypotensive Effect of Azilsartan

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Jun Iwanami ◽  
Masaki Mogi ◽  
Kana Tsukuda ◽  
Xiao-Li Wang ◽  
Kousei Ohshima ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Drug Administration ◽  
Group Treatment ◽  
Mrna Level ◽  
Weight Ratio ◽  
Hypotensive Effect ◽  
Ang Ii ◽  
Converting Enzyme

Objective: The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE)2/Ang (1-7)/Mas axis against the ACE/Ang II/ Ang II type 1 (AT 1 ) receptor axis in blood pressure control has been highlighted. We examined the possibility that this axis might be involved in the anti-hypertensive effect of newly developed Ang II type 1 (AT 1 ) receptor blocker (ARB), azilsartan, in comparison with olmesartan. Methods: Human renin (hRN) and human angiotensinogen (hANG) double transgenic mice (hRN/hANG-Tg) were used. Ten-week-old male hRN/hANG-Tg mice were administrated control chow or three different doses (1, 5 and 10mg/kg/day) of ARBs, azilsartan or olmesartan in chow for 4 weeks. Blood pressure was analyzed by radio telemetry method before drug administration and every two weeks after medication. Four weeks after drug administration, expression of ACE2 mRNA level was assessed by real time RT-PCR method. Results: Blood pressure was significantly higher in hRN/hANG-Tg mice compared with that in wild type (WT) mice. Treatment with all doses of azilsartan decreased blood pressure to the level of WT mice. Treatment with olmesartan (1 mg/kg/day) decreased blood pressure; however, this decrease was weaker than that with azilsartan at the same dose. Olmesartan (5 and 10 mg/kg/day) decreased blood pressure to the WT mice level; however, the reduction of blood pressure in the night-time was stronger in azilsartan group. Expression of ACE2 mRNA was decreased in heart and kidney of hRN/hANG-Tg mice compared with WT mice. This decrease in ACE2 mRNA expression was attenuated by administration of azilsartan, but not by olmesartan treatment. The ratio of heart to body weight ratio was decreased in all azilsartan-treated groups, but this decrease was observed only in 10 mg/kg/day of olmesartan-treated group. Treatment with azilsartan even at lower dose increased the urinary excretion of Na. Conclusion: These results suggested that hypotensive effect of azilsartan may involve the activation of ACE2/Ang(1-7)/Mas axis with AT 1 receptor blockade. Further investigation will reveal the pathophysiological role of ACE2/Ang(1-7)/Mas axis in blood ptessure control and contribute to discuss further the possible drug effect of ARBs beyond class effect.

Abstract P059: A A Role of Aminopeptidase A in the Brain on Cardiovascular Regulation of Conscious Rat

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Takuto Nakamura ◽  
Masanobu Yamazato ◽  
Akio Ishida ◽  
Yusuke Ohya
Keyword(s):  
Blood Pressure ◽  
Protein Expression ◽  
Drinking Behavior ◽  
Cardiovascular Regulation ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Aminopeptidase A ◽  
The Brain

Objective: Aminopeptidase A (APA) have important role in conversion of Ang II to Ang III. Intravenous APA administration lowers blood pressure in hypertensive rats. In contrast, APA inhibition in the brain lowers blood pressure in hypertensive rats. Therefore APA might have different role on cardiovascular regulation. However, a role of APA and Ang III on cardiovascular regulation especially in the brain has not been fully understood. Our purpose of present study was to investigate a role of APA and Ang III in the brain on cardiovascular regulation in conscious state. Method: 12-13 weeks old Wistar Kyoto rat (WKY) and 12-16 weeks old spontaneously hypertensive rat (SHR) were used. i) APA distribution in the brain was evaluated by immunohistochemistry. Protein expression of APA was evaluated by Western blotting. Enzymatic activity of APA was evaluated using L-glutamic acid γ-(4-nitroanilide) as a substrate. ii) WKY received icv administration of Ang II 25ng/2μL and Ang III 25ng/2μL. We recorded change in mean arterial pressure (MAP) in conscious and unrestraied state and measured induced drinking time. iii) SHR received icv administeration of recombinant APA 400ng/4μL. We recorded change in MAP in conscious and unrestraied state and measured induced drinking time. Result: i) APA was diffusely immunostained in the cells of brain stem including cardiovascular regulatory area such as rostral ventrolateral medulla. Protein expression and APA activity in the brain were similar between WKY (n=3) and SHR (n=3).ii) Icv administration of Ang II increased MAP by 33.8±3.8 mmHg and induced drinking behavior for 405±90 seconds (n=4). Icv administration of Ang III also increased MAP by 24.7±2.4 mmHg and induced drinking behavior for 258±62 seconds (n=3). These vasopressor activity and induced drinking behavior was completely blocked by pretretment of angiotensin receptor type 1 blocker.iii) Icv administration of APA increased MAP by 10.0±1.7 mmHg (n=3). Conclusion: These results suggested that Ang III in the brain increase blood pressure by Angiotensin type 1 receptor dependent mechanism and APA in the brain may involved in blood pressure regulation as a vasopressor enzyme.

Role of arteria baroreceptor input on thirst and urinary responses to intracerebroventricular angiotensin II

1993 ◽  
Vol 265 (3) ◽  
pp. R591-R595 ◽  
Author(s):  
R. L. Thunhorst ◽  
S. J. Lewis ◽  
A. K. Johnson
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Arterial Blood Pressure ◽  
Water Intake ◽  
Enzyme Inhibitor ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Arterial Blood ◽  
Endogenous Formation

Intracerebroventricular (icv) infusion of angiotensin II (ANG II) in rats elicits greater water intake under hypotensive, compared with normotensive, conditions. The present experiments used sinoaortic baroreceptor-denervated (SAD) rats and sham-operated rats to examine if the modulatory effects of arterial blood pressure on water intake in response to icv ANG II are mediated by arterial baroreceptors. Mean arterial blood pressure (MAP) was raised or lowered by intravenous (i.v.) infusions of phenylephrine (1 or 10 micrograms.kg-1 x min-1) or minoxidil (25 micrograms.kg-1 x min-1), respectively. The angiotensin-converting enzyme inhibitor captopril (0.33 mg/min) was infused i.v. to prevent the endogenous formation of ANG II during testing. Urinary excretion of water and solutes was measured throughout. Water intake elicited by icv ANG II was inversely related to changes in MAP. Specifically, rats drank more water in response to icv ANG II when MAP was reduced by minoxidil but drank less water when MAP was elevated by phenylephrine. The influence of changing MAP on the icv ANG II-induced drinking responses was not affected by SAD. These results suggest that the modulatory effects of arterial blood pressure on icv ANG II-induced drinking can occur in the absence of sinoaortic baroreceptor input.

scholarly journals Angiotensin II Receptor Type 1-Mediated Vascular Oxidative Stress and Proinflammatory Gene Expression in Aldosterone-Induced Hypertension: The Possible Role of Local Renin-Angiotensin System

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1688-1696 ◽  
Author(s):  
Yuki Hirono ◽  
Takanobu Yoshimoto ◽  
Noriko Suzuki ◽  
Toru Sugiyama ◽  
Maya Sakurada ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Renin Angiotensin System ◽  
Aortic Tissue ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Renin Angiotensin

Recently, aldosterone has been shown to activate local renin-angiotensin system in vitro. To elucidate the potential role of local renin-angiotensin system in aldosterone-induced cardiovascular injury, we investigated the effects of selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL), angiotensin (Ang) II type 1 receptor antagonist candesartan (ARB), and superoxide dismutase mimetic tempol (TEM) on the development of hypertension, vascular injury, oxidative stress, and inflammatory-related gene expression in aldosterone-treated hypertensive rats. The increased systolic blood pressure and vascular inflammatory changes were attenuated by cotreatment either with EPL, ARB, or TEM. Aldosterone increased angiotensin-converting enzyme expression in the aortic tissue; its effects were blocked by EPL but not by ARB or TEM. Aldosterone also increased Ang II contents in the aortic tissue in the presence of low circulating Ang II concentrations. Aldosterone induced expression of various inflammatory-related genes, whose effects were abolished by EPL, whereas the inhibitory effects of ARB and TEM varied depending on the gene. Aldosterone caused greater accumulation of the oxidant stress marker 4-hydroxy-2-neonenal in the endothelium; its effect was abolished by EPL, ARB, or TEM. Aldosterone increased mRNA levels of reduced nicotinamide adenine dinucleotide phosphate oxidase components; their effect was abolished by EPL, whereas ARB and TEM decreased only the p47phox mRNA level but not that of p22phox or gp91phox. The present findings suggest that the Ang II-dependent pathway resulting from vascular angiotensin-converting enzyme up-regulation and Ang II-independent pathway are both involved in the underlying mechanisms resulting in the development of hypertension, vascular inflammation, and oxidative stress induced by aldosterone.

Role of the At 2 Receptor in the Cardioprotective Effect of At 1 Antagonist in Mice with Chronic Heart Failure Induced by Coronary Ligation

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 704-704
Author(s):  
Jiang Xu ◽  
Oscar A Carretero ◽  
Yun-He Liu ◽  
Edward G Shesely ◽  
Fang Yang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Function ◽  
Cardioprotective Effect ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Coronary Ligation ◽  
Regulation Of Blood Pressure

P63 Angiotensin II (Ang II) acts mainly on two receptor subtypes: type 1 (AT 1 ) and type 2 (AT 2 ). Most of the known biological actions of Ang II are mediated via AT 1 receptors; however, the role of the AT 2 receptor is less well defined. We hypothesized that blockade of AT 1 receptors increases circulating Ang II levels, which in turn activates the AT 2 receptor and induces cardioprotection. In mice which lack AT 2 receptors, the effect of an AT 1 antagonist (AT 1 -ant) would be diminished or absent. AT 2 receptor knockout mice (-/-) and their wild-type littermates (+/+) were subjected to myocardial infarction (MI) by ligating the left anterior descending coronary artery. One month after MI, each strain of mice received either vehicle or AT 1 -ant (valsartan, 50 mg/kg/day in drinking water) for 3 months. Systolic blood pressure (SBP) was measured weekly and echocardiography performed once a month. Basal SBP and cardiac function did not differ between +/+ and -/-. Three months after MI, SBP and cardiac function changed similarly in both strains receiving vehicle. Valsartan significantly increased EF and decreased LVDd and mass and these effects were diminished in -/- (table). Our results suggest that under basal conditions, the AT 2 receptor may not play an important role in regulation of blood pressure and cardiac function; however, it does appear to be an important component in the cardioprotective effect of AT 1 -ant.

Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications

2013 ◽  
Vol 126 (7) ◽  
pp. 471-482 ◽  
Author(s):  
Vaibhav B. Patel ◽  
Nirmal Parajuli ◽  
Gavin Y. Oudit
Keyword(s):  
Diabetes Mellitus ◽  
Angiotensin Converting Enzyme ◽  
Vascular Function ◽  
Systolic Dysfunction ◽  
Cardiovascular Complications ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Obesity And Diabetes

Diabetes mellitus results in severe cardiovascular complications, and heart disease and failure remain the major causes of death in patients with diabetes. Given the increasing global tide of obesity and diabetes, the clinical burden of diabetes-induced cardiovascular disease is reaching epidemic proportions. Therefore urgent actions are needed to stem the tide of diabetes which entails new prevention and treatment tools. Clinical and pharmacological studies have demonstrated that AngII (angiotensin II), the major effector peptide of the RAS (renin–angiotensin system), is a critical promoter of insulin resistance and diabetes mellitus. The role of RAS and AngII has been implicated in the progression of diabetic cardiovascular complications and AT1R (AngII type 1 receptor) blockers and ACE (angiotensin-converting enzyme) inhibitors have shown clinical benefits. ACE2, the recently discovered homologue of ACE, is a monocarboxypeptidase which converts AngII into Ang-(1–7) [angiotensin-(1–7)] which, by virtue of its actions on the MasR (Mas receptor), opposes the effects of AngII. In animal models of diabetes, an early increase in ACE2 expression and activity occurs, whereas ACE2 mRNA and protein levels have been found to decrease in older STZ (streptozotocin)-induced diabetic rats. Using the Akita mouse model of Type 1 diabetes, we have recently shown that loss of ACE2 disrupts the balance of the RAS in a diabetic state and leads to AngII/AT1R-dependent systolic dysfunction and impaired vascular function. In the present review, we will discuss the role of the RAS in the pathophysiology and treatment of diabetes and its complications with particular emphasis on potential benefits of the ACE2/Ang-(1–7)/MasR axis activation.

Reactive Oxygen Species-Mediated Homologous Downregulation of Angiotensin II Type 1 Receptor Mrna by Angiotensin II

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 688-688
Author(s):  
Toshihiro Ichiki ◽  
Kotaro Takeda ◽  
Akira Takeshita
Keyword(s):  
Reactive Oxygen Species ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Mrna Expression ◽  
Crucial Role ◽  
Oxygen Species ◽  
Ang Ii ◽  
Stimulation Of

58 Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of Angiotensin II (Ang II) through type 1 Ang II receptor (AT1-R). However, the role of ROS in the regulation of AT1-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT1-R by Ang II. Ang II (10 -6 mol/L) decreased AT1-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells (VSMC). Ang II dose-dependently (10 -8 -10 -6 ) suppressed AT1-R mRNA at 6 hours of stimulation. Preincubation of VSMC with N-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT1-R mRNA. The effect of NAC was due to stabilization of the AT1-R mRNA that was destabilized by Ang II. Ang II did not affect the promoter activity of AT1-R gene. Diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase failed to inhibit the Ang II-induced AT1-R mRNA downregulation. The Ang II-induced AT1-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as PD98059 whereas DPI did not inhibit it. To confirm the role of ROS in the regulation of AT1-R mRNA expression, VSMC were stimulated with H 2 O 2 . H 2 O 2 suppressed the AT1-R mRNA expression and activated ERK. These results suggest that production of ROS and activation of ERK are critical for downregulation of AT1-R mRNA. The differential effect of NAC and DPI on the downregulation of AT1-R mRNA may suggest the presence of other sources than NADH/NADPH oxidase pathway for ROS in Ang II signaling. Generation of ROS through stimulation of AT1-R not only mediates signaling of Ang II but may play a crucial role in the adaptation process of AT1-R to the sustained stimulation of Ang II.

MO092THE ROLE OF CALCIUM IN UROMODULIN EXPRESSION AND SECRETION FROM RENAL MEDULLARY EPITHELIAL CELLS OF HYPERTENSIVE AND NORMOTENSIVE RATS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Philipp Boder ◽  
Sheon Mary ◽  
Lesley Graham ◽  
Christian Delles
Keyword(s):  
Blood Pressure ◽  
Epithelial Cells ◽  
Mrna Level ◽  
Extracellular Calcium ◽  
Female Rats ◽  
Thick Ascending Limb ◽  
Molecular Signaling ◽  
Extracellular Secretion ◽  
Wistar Kyoto

Abstract Background and Aims Uromodulin (UMOD) is the most abundantly secreted protein found within the urine, primarily produced by medullary thick ascending limb (mTAL) epithelial cells of the kidneys. There is accruing genetic evidence implicating UMOD in blood pressure regulation and consequently hypertension. The molecular signaling induced by calcium in the kidney and its influence on blood pressure are not well understood. The aim of this study was to investigate the potential role of extracellular calcium and the calcium-sensing receptor (CaSR) in mTAL on UMOD production and secretion in TAL cells with the hope of defining novel clinical targets for the treatment of hypertension. Method Kidneys were harvested from normotensive Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive (SHRSP) female rats. To determine the effect of extracellular calcium on UMOD secretion, mTAL tubules were incubated in media with and without 1mM calcium, nifedipine (10µM), NPS2143 (1 or 5 µM) and spermine (2mM). Extracellular and intracellular UMOD protein levels were detected by Western blot. Gene expression of Umod was determined by qRT-PCR. Results Calcium increased mTAL tubule UMOD secretion in WKY and SHRSP. Nifedipine slightly decreased UMOD secretion in WKY without calcium. In both strains, NPS2143 increased calcium-induced UMOD secretion, with an enhanced effect in SHRSP. Stimulation of CaSR with spermine decreased UMOD secretion in WKY. Analysis of intracellular UMOD levels in these conditions demonstrated increased accumulation when extracellular secretion was low, and vice versa. Incubation of primary mTAL cells with calcium confirmed increased localisation of UMOD at the membrane compared to the cytosol, without any major differences in cell morphology. The Umod mRNA level changes were not statistically significant among conditions. Conclusion Trafficking of UMOD in the mTAL is influenced by the type of CaSR ligand and the biased nature of G-protein coupled CaSR signalling. Unravelling the signalling events post-calcium will be necessary for identification of key regulators of UMOD secretion and provide new sites for therapeutic intervention in hypertension.

Abstract 12: The Role Of Memory Gamma Delta T Cells In Hypertension And Vascular Damage

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Kevin D Comeau ◽  
Pierre Paradis ◽  
Ernesto L Schiffrin
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
Γδ T Cells ◽  
Effector Memory ◽  
Ang Ii ◽  
Mesenteric Lymph Nodes ◽  
Initial Exposure ◽  
Perivascular Adipose Tissue ◽  
Mild Hypertensive

Background: We recently demonstrated that γδ T cells participate in the pathogenesis of hypertension. Evidence also suggests that memory T cells may develop during an initial hypertensive episode, sensitizing mice to develop hypertension to further mild hypertensive challenges. However, whether memory γδ T cells develop and play a role in hypertension remains unknown. Our objective is to determine if memory γδ T cells sensitize mice to develop hypertension in response to a mild hypertensive challenge. Methods: Ten-12-week-old C57BL/6J mice were exposed or not to a hypertensive challenge (490 ng/kg/min angiotensin II (Ang II), SC) for two weeks, followed by a two-week washout period, and then infused with a subpressor dose of Ang II (140 ng/kg/min Ang II, SC) for two weeks. Blood pressure was measured via telemetry and central, effector, and resident memory γδ T cells were profiled by flow cytometry. Results: Mice exposed to the first hypertensive challenge had a higher systolic blood pressure than the sham group at the end of the subpressor hypertensive challenge (149±6 vs. 122±3 mmHg, P <0.001). After 14-days of Ang II infusion, effector memory γδ T cells increased 5.2-fold in the mesenteric artery perivascular adipose tissue (PVAT, 1.25±0.37% vs. 0.24±0.12%, P <0.05), and 1.8-fold in the mesenteric lymph nodes (mLN, 1.49±0.03% vs. 0.82±0.15%, P <0.05) compared to sham treated mice. After repeated Ang II infusion, central memory γδ T cells decreased by 57% in the aortic PVAT (6.79±1.46% vs. 15.69±2.87%, P <0.05), and by 22% in the mLN (0.18±0.01% vs. 0.23±0.01%, P <0.05) compared to control mice. Conclusion: An initial exposure to a hypertensive stimulus sensitizes mice to develop hypertension to a subsequent subpressor hypertensive challenge and results in the development of memory γδ T cells.

Sign in / Sign up

Export Citation Format

Share Document