Coronary vasoconstrictor influence of angiotensin II is reduced in remodeled myocardium after myocardial infarction

2006 ◽  
Vol 291 (5) ◽  
pp. H2082-H2089 ◽  
Author(s):  
Daphne Merkus ◽  
David B. Haitsma ◽  
Oana Sorop ◽  
Frans Boomsma ◽  
Vincent J. de Beer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Plasma Levels ◽  
Vascular Tone ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Volume Blood ◽  
Coronary Vasoconstrictor

The renin-angiotensin system plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume, blood pressure, and vascular tone. Because AT1 receptors have been described in the coronary microcirculation, we investigated whether ANG II contributes to the regulation of coronary vascular tone and whether its contribution is altered during exercise. Since the renin-angiotensin system is activated after myocardial infarction, resulting in an increase in circulating ANG II, we also investigated whether the contribution of ANG II to the regulation of vasomotor tone is altered after infarction. Twenty-six chronically instrumented swine were studied at rest and while running on a treadmill at 1–4 km/h. In 13 swine, myocardial infarction was induced by ligation of the left circumflex coronary artery. Blockade of AT1 receptors (irbesartan, 1 mg/kg iv) had no effect on myocardial O2 consumption but resulted in an increase in coronary venous O2 tension and saturation both at rest and during exercise, reflecting coronary vasodilation. Despite increased plasma levels of ANG II after infarction and maintained coronary arteriolar AT1 receptor levels, the vasodilation evoked by irbesartan was significantly reduced both at rest and during exercise. In conclusion, despite elevated plasma levels, the vasoconstrictor influence of ANG II on the coronary circulation in vivo is reduced after myocardial infarction. This reduction in ANG II-induced coronary vasoconstriction may serve to maintain perfusion of the remodeled myocardium.

scholarly journals Controlled Hemorrhage Sensitizes Angiotensin II-Elicited Hypertension through Activation of the Brain Renin-Angiotensin System Independently of Endoplasmic Reticulum Stress

2022 ◽  
Vol 2022 ◽  
pp. 1-13
Author(s):  
Guo-Biao Wu ◽  
Hui-Bo Du ◽  
Jia-Yi Zhai ◽  
Si Sun ◽  
Jun-Ling Cui ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protein Expression ◽  
Plasma Levels ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Phenylbutyric Acid ◽  
The Brain

Hemorrhagic shock is associated with activation of renin-angiotensin system (RAS) and endoplasmic reticulum stress (ERS). Previous studies demonstrated that central RAS activation produced by various challenges sensitizes angiotensin (Ang) II-elicited hypertension and that ERS contributes to the development of neurogenic hypertension. The present study investigated whether controlled hemorrhage could sensitize Ang II-elicited hypertension and whether the brain RAS and ERS mediate this sensitization. Results showed that hemorrhaged (HEM) rats had a significantly enhanced hypertensive response to a slow-pressor infusion of Ang II when compared to sham HEM rats. Treatment with either angiotensin-converting enzyme (ACE) 1 inhibitor, captopril, or ACE2 activator, diminazene, abolished the HEM-induced sensitization of hypertension. Treatment with the ERS agonist, tunicamycin, in sham HEM rats also sensitized Ang II-elicited hypertension. However, blockade of ERS with 4-phenylbutyric acid in HEM rats did not alter HEM-elicited sensitization of hypertension. Either HEM or ERS activation produced a greater reduction in BP after ganglionic blockade, upregulated mRNA and protein expression of ACE1 in the hypothalamic paraventricular nucleus (PVN), and elevated plasma levels of Ang II but reduced mRNA expression of the Ang-(1-7) receptor, Mas-R, and did not alter plasma levels of Ang-(1-7). Treatment with captopril or diminazene, but not phenylbutyric acid, reversed these changes. No treatments had effects on PVN protein expression of the ERS marker glucose-regulated protein 78. The results indicate that controlled hemorrhage sensitizes Ang II-elicited hypertension by augmenting RAS prohypertensive actions and reducing RAS antihypertensive effects in the brain, which is independent of ERS mechanism.

scholarly journals The renin-angiotensin system: going beyond the classical paradigms

2019 ◽  
Vol 316 (5) ◽  
pp. H958-H970 ◽  
Author(s):  
Robson Augusto Souza Santos ◽  
Gavin Y. Oudit ◽  
Thiago Verano-Braga ◽  
Giovanni Canta ◽  
Ulrike Muscha Steckelings ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Protective Effects ◽  
Ang Ii ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Amino Terminal ◽  
Angiotensin Peptides ◽  
Protective Actions

Thirty years ago, a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin-(1−7) [ANG-(1−7)] generation in vivo. Later, angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction, and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS that followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of ANG II, the ANG II type 2 receptor (AT2R), in contrast to the other, the ANG II type 1 receptor (AT1R), which mediates deleterious actions of this peptide, e.g., in the setting of cardiovascular disease. Very recently, another branch of the RAS was discovered, based on angiotensin peptides in which the amino-terminal aspartate was replaced by alanine, the alatensins. Ala-ANG-(1−7) or alamandine was shown to interact with Mas-related G protein-coupled receptor D, and the first functional data indicated that this peptide also exerts protective effects in the cardiovascular system. This review summarizes the presentations given at the International Union of Physiological Sciences Congress in Rio de Janeiro, Brazil, in 2017, during the symposium entitled “The Renin-Angiotensin System: Going Beyond the Classical Paradigms,” in which the signaling and physiological actions of ANG-(1−7), ACE2, AT2R, and alatensins were reported (with a focus on noncentral nervous system-related tissues) and the therapeutic opportunities based on these findings were discussed.

Identification and activation of autocrine renin-angiotensin system in adult ventricular myocytes

1995 ◽  
Vol 269 (5) ◽  
pp. H1791-H1802 ◽  
Author(s):  
X. Zhang ◽  
D. E. Dostal ◽  
K. Reiss ◽  
W. Cheng ◽  
J. Kajstura ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Contractile Function ◽  
Renin Angiotensin System ◽  
In Vivo Model ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Cellular Hypertrophy ◽  
Molecular Components

To date, the demonstration that the molecular components of the renin-angiotensin system (RAS) are present in adult ventricular myocytes is lacking. In addition, whether the RAS is upregulated under conditions of overload and myocyte hypertrophy in vivo remains to be determined. By employing an in vivo model of ischemic cardiomyopathy in rats, we document that adult myocytes express genes for renin, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II (ANG II) receptors. Moreover, renin, ACE, and ANG II receptor mRNAs increased in stressed myocytes undergoing cellular hypertrophy. At the protein level, the percentage of myocytes containing renin, ANG I, and ANG II was significantly increased in the overloaded heart. The number of binding sites for ANG II per myocyte also markedly increased under this setting. These results provide direct evidence of the existence of a myocyte RAS, which may be activated in pathological states of the heart to support myocyte growth and contractile function.

scholarly journals Activation of a local renin angiotensin system in podocytes by glucose

2008 ◽  
Vol 294 (4) ◽  
pp. F830-F839 ◽  
Author(s):  
Raghu V. Durvasula ◽  
Stuart J. Shankland
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Renin Angiotensin System ◽  
Receptor Expression ◽  
Ang Ii ◽  
Podocyte Injury ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Prorenin Receptor

ANG II is a critical mediator of diabetic nephropathy. Pharmacologic inhibition of ANG II slows disease progression beyond what could be predicted by the blood pressure lowering effects alone, suggesting the importance of nonhemodynamic pathways of ANG II in mediating disease. Podocyte injury and loss are cardinal features of diabetic nephropathy. Mounting evidence suggests that the podocyte is a direct target of ANG II-mediated signaling in diabetic renal disease. We have tested the hypothesis that high glucose leads to the activation of a local angiotensin system in podocytes and delineated the underlying pathways involved. Cultured podocytes were exposed to standard glucose (5 mM), high glucose (40 mM), or mannitol as an osmotic control. ANG II levels in cell lysates were measured in the presence or absence of inhibitors of angiotensin-converting enzyme (captopril), chymase (chymostatin), and renin (aliskiren) activity. The effects of glucose on renin and angiotensin subtype 1 receptor expression and protein levels were determined. Exposure to high glucose resulted in a 2.1-fold increase ANG II levels mediated through increased renin activity, as exposure to high glucose increased renin levels and preincubation with Aliskiren abrogated glucose-induced ANG II production. Relevance to the in vivo setting was demonstrated by showing glomerular upregulation of the prorenin receptor in a podocyte distribution early in the course of experimental diabetic nephropathy. Furthermore, high glucose increased angiotensin subtype 1 receptor levels by immunofluorescence and Western blot. Taken together, the resultant activation of a local renin angiotensin system by high glucose may promote progressive podocyte injury and loss in diabetic nephropathy.

scholarly journals Local renin-angiotensin system mediates endothelial dilator dysfunction in aging arteries

2016 ◽  
Vol 311 (3) ◽  
pp. H849-H854 ◽  
Author(s):  
Sheila Flavahan ◽  
Fumin Chang ◽  
Nicholas A. Flavahan
Keyword(s):  
Arterial Wall ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
No Donor ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Isolated Arteries ◽  
F344 Rats ◽  
Local Generation

Aging impairs endothelium-dependent NO-mediated dilatation, which results from increased production of reactive oxygen species (ROS). The local generation of angiotensin II (ANG II) is increased in aging arteries and contributes to inflammatory and fibrotic activity of smooth muscle cells and arterial wall remodeling. Although prolonged in vivo ANG II inhibition improves the impaired endothelial dilatation of aging arteries, it is unclear whether this reflects inhibition of intravascular or systemic ANG II systems. Experiments were therefore performed on isolated tail arteries from young (3–4 mo) and old (22–24 mo) F344 rats to determine if a local renin-angiotensin system contributes to the endothelial dilator dysfunction of aging. Aging impaired dilatation to the endothelial agonist acetylcholine but did not influence responses to a nitric oxide (NO) donor (DEA NONOate). Dilatation to acetylcholine was greatly reduced by NO synthase inhibition [nitro-l-arginine methyl ester (l-NAME)] in young and old arteries. In isolated arteries, acute inhibition of angiotensin-converting enzyme (ACE) (perindoprilat), renin (aliskiren), or AT1 receptors (valsartan, losartan) did not influence dilatation to acetylcholine in young arteries but increased responses in old arteries. After ANG II inhibition, the dilator response to acetylcholine was similar in young and old arteries. ROS activity, which was increased in endothelium of aging arteries, was also reduced by inhibiting ANG II (perindoprilat, losartan). Renin expression was increased by 5.6 fold and immunofluorescent levels of ANG II were confirmed to be increased in aging compared with young arteries. Exogenous ANG II inhibited acetylcholine-induced dilatation. Therefore, aging-induced impairment of endothelium-dependent dilatation in aging is caused by a local intravascular renin-angiotensin system. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/angii-and-aging-induced-endothelial-dysfunction/ .

ANG II reduces net acid secretion in rat outer medullary collecting duct

2003 ◽  
Vol 285 (5) ◽  
pp. F930-F937 ◽  
Author(s):  
Susan M. Wall ◽  
Michael P. Fischer ◽  
Dawn M. Glapion ◽  
Mae De La Calzada
Keyword(s):  
Acid Secretion ◽  
Collecting Duct ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Acid Base Balance ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Medullary Collecting Duct

In rat outer medullary collecting duct (OMCD), the mechanism(s) and regulation of H+ secretion are not understood fully. The effect of changes in acid-base balance and the renin-angiotensin system on net H+ secretion was explored. Rats received NaCl, NaHCO3, NH4Cl, or nothing in their drinking water for 7 days. Total ammonia and total CO2 ( JtCO2) fluxes were measured in OMCD tubules perfused in vitro from rats in each treatment group. JtCO2 was reduced in tubules from rats drinking NH4Cl relative to those drinking NaHCO3. Because NH4Cl intake increases plasma renin and aldosterone, we asked if upregulation of the renin-angiotensin system reduces net H+ secretion. Deoxycorticosterone pivalate administered in vivo did not affect JtCO2. However, ANG II given in vivo at 0.1 ng/min reduced JtCO2 by 35%. To determine if ANG II has a direct effect on acid secretion, JtCO2 was measured with ANG II applied in vitro. ANG II (10-8 M) present in the bath solution reduced JtCO2 by 35%. This ANG II effect was not observed in the presence of the AT1 receptor blocker candesartan. In conclusion, in rat OMCD, JtCO2 is paradoxically reduced with NH4Cl ingestion. Increased circulating ANG II, as occurs during metabolic acidosis, reduces JtCO2.

Counter-regulatory effects played by the ACE – Ang II – AT1 and ACE2 – Ang-(1–7) – Mas axes on the reactive oxygen species-mediated control of vascular function: perspectives to pharmacological approaches in controlling vascular complications

VASA ◽  
2014 ◽  
Vol 43 (6) ◽  
pp. 404-414 ◽  
Author(s):  
Laena Pernomian ◽  
Larissa Pernomian ◽  
Carolina Baraldi Araújo Restini
Keyword(s):  
Reactive Oxygen Species ◽  
Vascular Tone ◽  
Vascular Dysfunction ◽  
Reactive Oxygen ◽  
Renin Angiotensin System ◽  
Electrolyte Balance ◽  
Oxygen Species ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

The Renin-Angiotensin system plays an important role in the regulation of systemic blood pressure as well as in fluid and electrolyte balance. It is divided into two described axes, the ACE – Ang II – AT1 receptor, with Ang II as the main mediator, and the ACE2 – Ang-(1–7) – Mas receptor, with Ang-(1–7) responsible for the main effects. The main vascular effect induced by Ang II is contraction, while Ang-(1–7) includes relaxation in several vascular beds. Ang II also activates several cytokines that are important in the genesis of vascular inflammation and hypertrophy. In this context, Ang-(1–7) seems to have a protective role. Both AT1 and Mas receptors modulate, in different ways, the generation of, which are involved in the control of vascular tone and the genesis of vascular dysfunction triggered by several diseases, including diabetes mellitus, arterial hypertension and atherosclerosis. Thereby, this review presents an overview of the modulation played by the whole Renin-Angiotensin system on the reactive oxygen species-mediated control of vascular tone and the oxidative stress-elicited vascular dysfunction.

scholarly journals A novel role for miR-133a in centrally mediated activation of the renin-angiotensin system in congestive heart failure

2017 ◽  
Vol 312 (5) ◽  
pp. H968-H979 ◽  
Author(s):  
Neeru M. Sharma ◽  
Shyam S. Nandi ◽  
Hong Zheng ◽  
Paras K. Mishra ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Paraventricular Nucleus ◽  
Renin Angiotensin System ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

An activated renin-angiotensin system (RAS) within the central nervous system has been implicated in sympathoexcitation during various disease conditions including congestive heart failure (CHF). In particular, activation of the RAS in the paraventricular nucleus (PVN) of the hypothalamus has been recognized to augment sympathoexcitation in CHF. We observed a 2.6-fold increase in angiotensinogen (AGT) in the PVN of CHF. To elucidate the molecular mechanism for increased expression of AGT, we performed in silico analysis of the 3′-untranslated region (3′-UTR) of AGT and found a potential binding site for microRNA (miR)-133a. We hypothesized that decreased miR-133a might contribute to increased AGT in the PVN of CHF rats. Overexpression of miR-133a in NG108 cells resulted in 1.4- and 1.5-fold decreases in AGT and angiotensin type II (ANG II) type 1 receptor (AT1R) mRNA levels, respectively. A luciferase reporter assay performed on NG108 cells confirmed miR-133a binding to the 3′-UTR of AGT. Consistent with these in vitro data, we observed a 1.9-fold decrease in miR-133a expression with a concomitant increase in AGT and AT1R expression within the PVN of CHF rats. Furthermore, restoring the levels of miR-133a within the PVN of CHF rats with viral transduction resulted in a significant reduction of AGT (1.4-fold) and AT1R (1.5-fold) levels with a concomitant decrease in basal renal sympathetic nerve activity (RSNA). Restoration of miR-133a also abrogated the enhanced RSNA responses to microinjected ANG II within the PVN of CHF rats. These results reveal a novel and potentially unique role for miR-133a in the regulation of ANG II within the PVN of CHF rats, which may potentially contribute to the commonly observed sympathoexcitation in CHF. NEW & NOTEWORTHY Angiotensinogen (AGT) expression is upregulated in the paraventricular nucleus of the hypothalamus through posttranscriptional mechanism interceded by microRNA-133a in heart failure. Understanding the mechanism of increased expression of AGT in pathological conditions leading to increased sympathoexcitation may provide the basis for the possible development of new therapeutic agents with enhanced specificity.

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