Angiotensin Type 2 and Mas Receptor Activation Prevents Myocardial Fibrosis and Hypertrophy through the Reduction of Inflammatory Cell Infiltration and Local Sympathetic Activity in Angiotensin II-Dependent Hypertension

Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of angiotensin II-dependent hypertension whether the activation of the potentially protective arm of the renin-angiotensin system, through AT2 or Mas receptor stimulation, counteracts the onset of myocardial fibrosis and hypertrophy, and whether these effects are mediated by inflammatory mechanism and/or sympathetic activation. Sprague Dawley rats (n = 67) were treated for 1 (n = 25) and 4 (n = 42) weeks and divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis); (b) Ang II+Compound 21 (C21, 0.3 mg/kg/day, intraperitoneal); (c) Ang II+Ang 1-7 (576 µg/kg/day, intraperitoneal); (d) Ang II+Losartan (50 mg/kg/day, per os); (e) control group (physiological saline, sub cutis). Systolic blood pressure was measured by tail cuff method and, at the end of the experimental period, the rats were euthanized and the heart was excised to evaluate myocardial fibrosis, hypertrophy, inflammatory cell infiltration and tyrosine hydroxylase expression, used as marker of sympathetic activity. Ang II caused a significant increase of blood pressure, myocardial interstitial and perivascular fibrosis and myocardial hypertrophy, as compared to control groups. C21 or Ang 1-7 administration did not modify the increase in blood pressure in Ang II treated rats, but both prevented the development of myocardial fibrosis and hypertrophy. Treatment with losartan blocked the onset of hypertension and myocardial fibrosis and hypertrophy in Ang II treated rats. Activation of AT2 receptors or Mas receptors prevents the onset of myocardial fibrosis and hypertrophy in Ang II-dependent hypertension through the reduction of myocardial inflammatory cell infiltration and tyrosine hydroxylase expression. Unlike what happens in case of treatment with losartan, the antifibrotic and antihypertrophic effects that follow the activation of the AT2 or Mas receptors are independent on the modulation of blood pressure.

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Renal Vascular Response to Angiotensin II Administration in Two Kidneys-One Clip Hypertensive Rats Treated with High Dose of Estradiol: The Role of Mas Receptor

International Journal of Vascular Medicine ◽

10.1155/2021/6643485 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Samira Choopani ◽

Mehdi Nematbakhsh

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Ovariectomized Rats ◽

Ang Ii ◽

Vascular Response ◽

Hypertensive Rats ◽

Vascular Responses ◽

Mas Receptor ◽

Renal Vascular

Backgrounds. High blood pressure is one of the most important causes of death around the world. The renin-angiotensin system (RAS) and estradiol are two important items that regulate arterial blood pressure in women. However, hypertension, RAS, and sex hormone estradiol may influence renal vascular responses. This study was designed to determine the role of Mas receptor (MasR) on renal vascular response to angiotensin II (Ang II) administration in two kidneys-one clip (2K1C) hypertensive rats treated with estradiol. Method. The ovariectomized rats were subjected to 2K1C or non-2K1C and simultaneously treated with estradiol (500 μg/kg/weekly) or placebo for a period of 4 weeks. Subsequently, under anesthesia, renal vascular responses to graded doses of Ang II administration with MasR blockade (A779) or its vehicle were determined. Results. A779 or its vehicle did not alter mean arterial pressure (MAP), renal perfusion pressure (RPP), and renal blood flow (RBF). However, in non-2K1C rats, Ang II infusion decreased RBF and increased renal vascular resistance (RVR) responses in a dose-related manner ( P treat < 0.0001 ). The greatest responses were found in ovariectomized estradiol-treated rats that received A779 ( P group < 0.05 ) in non-2K1C rats. Such findings were not detected in 2K1C hypertensive rats. For example, in estradiol-treated rats that received A779, at 1000 ng/kg/min of Ang II infusion, RBF reduced from 1.6 ± 0.2 to 0.89 ± 0.19 ml/min in non-2K1C rats, and it reduced from 1.6 ± 0.2 to 1.2 ± 0.2 ml/min in 2K1C rats. Conclusion. Hypertension induced by 2K1C may attenuate the role of A779 and estradiol in renal vascular responses to Ang II infusion. Perhaps, this response can be explained by the reduction of Ang II type 1 receptor (AT1R) expression in the 2K1C hypertensive rats.

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Blood pressure in streptozotocin-treated Brattleboro and Long-Evans rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1990.258.4.r852 ◽

1990 ◽

Vol 258 (4) ◽

pp. R852-R859 ◽

Cited By ~ 3

Author(s):

K. C. Tomlinson ◽

S. M. Gardiner ◽

T. Bennett

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Angiotensin Ii ◽

Insulin Treatment ◽

Renin Angiotensin System ◽

Brattleboro Rats ◽

Ang Ii ◽

Angiotensin System ◽

Resting Blood Pressure ◽

Long Evans

The diabetogenic agent streptozotocin (STZ) was injected intraperitoneally in Long-Evans and arginine vasopressin (AVP)-deficient Brattleboro rats. Twenty-eight days later both strains had a bradycardia and systolic hypotension; STZ-treated Brattleboro rats also had diastolic hypotension. The vasopressin (V1-receptor) antagonist, d(CH2)5[Tyr(Et)]DAVP, had no effect on resting blood pressure (BP) or heart rate (HR) in either strain of rat, indicating the relative maintenance of diastolic BP in STZ-treated Long-Evans rats was not dependent on acute vascular actions of AVP. Captopril caused a modest hypotension in all groups of rats, indicating that BP was not differentially dependent on the renin-angiotensin system in the different groups. In the presence of captopril and the ganglion blocker, pentolinium tartrate, the AVP-mediated recovery in BP was impaired in STZ-treated Long-Evans rats. During administration of d(CH2)5[Tyr(Et)]DAVP and pentolinium, the angiotensin II (ANG II)-mediated BP recovery was smaller in both groups of STZ-treated rats, indicating that this abnormality was not likely to be caused by inhibition of renin release by AVP. The abnormalities in ANG II- and AVP-mediated recovery were prevented by insulin treatment.

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Angiotensin II Blockade during Combined Thiazide—β-Adrenoreceptor-Blocker Treatment

Clinical Science ◽

10.1042/cs057123s ◽

1979 ◽

Vol 57 (s5) ◽

pp. 123s-125s ◽

Cited By ~ 2

Author(s):

H. Ibsen ◽

A. Leth ◽

A. McNair ◽

J. Giese

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Diastolic Blood Pressure ◽

Plasma Volume ◽

Renin Angiotensin System ◽

Plasma Renin ◽

Close Correlation ◽

Ang Ii ◽

Arterial Blood ◽

Change In Mean

1. Sixteen patients (11 male, five female), median age 41 years, with essential hypertension insufficiently controlled by hydrochlorothiazide (75 mg/day; diastolic blood pressure ≥ 100 mmHg), were studied. 2. Plasma renin concentration [renin], plasma angiotensin II concentration ([ANG II]), plasma volume and exchangeable sodium (NaE) were determined, and a saralasin infusion (5·4 nmol min−1 kg−1) was carried out while the patients were on thiazide alone and, in 14 cases, 3 months after addition of a β-adrenoreceptor blocker (propranolol, six, metoprolol, six, and atenolol, two patients). 3. On thiazide alone, saralasin caused a significant decrease in mean arterial blood pressure in 12 out of 16 patients. The saralasin response was closely related to pre-saralasin plasma [ANG II] (r = −0·73, P < 0·01). Plasma [renin] and [ANG II] were higher than normal in the group as a whole. 4. After addition of a β-adrenoreceptor blocker systolic and diastolic blood pressure decreased from 164/109 mmHg to 136/94 mmHg. Plasma [renin] and [ANG II] decreased by 40 and 58% respectively. At this point, saralasin caused no significant change in mean arterial pressure. No close correlation was found between plasma [renin] or [ANG II] or saralasin response on thiazide treatment and changes in blood pressure during subsequent thiazide/β-adrenoreceptor-blocker treatment. Plasma volume and NaE did not change significantly. 5. In patients with thiazide-induced stimulation of the renin—angiotensin system, addition of a β-adrenoreceptor blocker leads to suppression of the system and, at the same time, ANG II-dependence of blood pressure disappears. This contributes to the antihypertensive effect of β-adrenoreceptor blockers in this particular situation.

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NG-monomethyl-L-arginine and nitroarginine potentiate pressor responsiveness of vasoconstrictors in conscious rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1992.262.6.r1137 ◽

1992 ◽

Vol 262 (6) ◽

pp. R1137-R1144 ◽

Cited By ~ 9

Author(s):

K. P. Conrad ◽

S. L. Whittemore

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Pressor Response ◽

Renin Angiotensin System ◽

Rat Aorta ◽

Bolus Administration ◽

Ang Ii ◽

Baseline Blood Pressure ◽

Conscious Rats ◽

Pressor Responses

NG-monomethyl-L-arginine (NMA) and nitroarginine have been reported to be competitive inhibitors of the production of endothelium-derived relaxing factor (EDRF). In chronically instrumented conscious rats, we observed that the pressor response of NMA was attenuated by pretreatment with L-arginine but not by pretreatment with D-arginine, phentolamine, or meclofenamate. Inhibitors of the renin-angiotensin system, captopril and [Sar1,Ile5,Thr8]angiotensin II, did not significantly affect the pressor response of NMA, either. Ten to fifteen minutes after bolus administration of 7-15 mg/kg NMA, when baseline blood pressure was virtually restored, the pressor responses of angiotensin II (ANG II), norepinephrine, and arginine vasopressin were significantly potentiated by approximately 30-40% compared with control values. This potentiation was prevented by pretreatment with L- but not D-arginine. It was also observed in conscious rats subjected to ganglionic blockade. Likewise, the pressor responses of ANG II were significantly increased during infusions of 2 and 5 micrograms/min nitroarginine methyl ester (NAME), dosages that raised baseline blood pressure by 6 +/- 2 and 15 +/- 3 mmHg, respectively. During administration of 5 and 50 micrograms/min NAME, hypotensive responses of methacholine and histamine were only modestly attenuated compared with the responses recorded during infusions of phenylephrine, which raised resting blood pressure to comparable levels. Finally, in freshly isolated rat aorta, NMA inhibited basal and stimulated production of guanosine 3',5'-cyclic monophosphate in a manner comparable to reduced hemoglobin, a known inhibitor of EDRF.(ABSTRACT TRUNCATED AT 250 WORDS)

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Rapid elicitation of salt appetite by an intravenous infusion of angiotensin II in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.270.5.r1092 ◽

1996 ◽

Vol 270 (5) ◽

pp. R1092-R1098 ◽

Cited By ~ 16

Author(s):

D. A. Fitts ◽

R. L. Thunhorst

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Intravenous Infusion ◽

Enzyme Inhibitor ◽

Direct Action ◽

Renin Angiotensin System ◽

Salt Appetite ◽

Ang Ii ◽

Direct Stimulation ◽

Arterial Blood

A role for the renal renin-angiotensin system in the direct stimulation of salt appetite in the rat remains controversial because attempts to elicit the behavior by intravenous administration of angiotensin II (ANG II) have been unconvincing. We recently demonstrated that depletion-induced salt appetite was attenuated by selective blockade of peripheral ANG II synthesis with an intravenous dose of converting enzyme inhibitor [captopril (Cap)] that does not block the synthesis of ANG II inside the blood brain barrier. We now show that intravenous ANG II at 30 ng/min rapidly reestablishes salt appetite in Cap-blocked rats. The mean arterial blood pressure (MAP) of unblocked, sodium-depleted rats was normal, but Cap-blocked, depleted rats had low MAP. An intravenous infusion of ANG II in Cap-blocked rats brought MAP into the normal range and elicited water and salt drinking within 90 min. Phenylephrine also normalized MAP but failed to elicit fluid intake in Cap-blocked, sodium-deficient rats. Sodium and water balances tended to be more positive during ANG II than during phenylephrine infusions. Thus circulating ANG II may stimulate both thirst and salt appetite by a direct action on the brain and not by causing natriuresis or by raising the blood pressure.

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Abstract 528: Angiotensin-ii Induces Strain-dependent Renovascular Remodeling in Mice

Hypertension ◽

10.1161/hyp.60.suppl_1.a528 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Sathnur Pushpakumar ◽

Sourav Kundu ◽

Denise Coley ◽

Srikanth Givvimani ◽

Suresh C Tyagi ◽

...

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Angiotensin Ii ◽

Renin Angiotensin System ◽

Organ Damage ◽

Vascular Density ◽

Ang Ii ◽

Renal Vasculature ◽

Renal Vascular ◽

Strain Dependent

Activation of renin-angiotensin system and production of Angiotensin-II plays an important role in several pathological processes leading to end stage renal disease. Sustained hypertension induces renovascular remodeling in both intra and extra-renal vasculature by altering extracellular matrix (ECM) components. Recent studies in vascular remodeling have shown strain-dependent phenotypic variation in carotid artery and in pulmonary hypertension indicating a genetic basis for disease susceptibility. We hypothesized that sensitivity to develop hypertension to angiotensin-II infusion and subsequent renovascular remodeling will vary depending on the genetic background. C57BL/6J (WT) and TIMP2 -/- mice were used in this study. Osmotic pumps loaded with Angiotensin-II (Ang-II) were introduced into a dorsal subcutaneous pocket for delivery at 250 ng. kg -1 . min -1 . Pumps loaded with saline served as controls for both groups. Blood pressure, renal vascular blood flow, renal vascular density, collagen and elastin deposition, oxidative stress and tissue levels of MMP-2 and MMP-9 were determined. Results: TIMP2 -/- mice had higher baseline mean blood pressure (130.5±6.4 mm Hg) compared to WT mice (111.07±7.3 mm Hg). After 4 weeks of Ang-II treatment, mean arterial pressure increased to 150.33±11.9 in TIMP2 -/- mice compared to 129.9±5.7 mm Hg in WT mice. The renal cortical blood flow was reduced in TIMP2 -/- mice (1125 flux units) compared to WT (1350 flux units) and untreated controls. Barium angiography demonstrated decreased renal vascular density in TIMP2 -/- mice compared to WT group. Peri-glomerular and vascular collagen deposition was increased in TIMP2 -/- and WT, whereas elastin was reduced and disrupted in TIMP2 -/- renal vasculature. Intracellular reactive oxygen species production was predominant in TIMP2 -/- group than in WT or control animals. Conclusion: Our results suggest that in Ang-II induced hypertension, renovascular response is strain dependent and TIMP2 -/- mice appear to be more susceptible to end organ damage than WT mice.

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Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00096.2016 ◽

2016 ◽

Vol 311 (5) ◽

pp. H1287-H1296 ◽

Cited By ~ 21

Author(s):

Germán E. González ◽

N.-E. Rhaleb ◽

Martin A. D'Ambrosio ◽

Pablo Nakagawa ◽

Tang-Dong Liao ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Systolic Blood Pressure ◽

Myocardial Fibrosis ◽

Western Blotting ◽

Ang Ii ◽

Lv Dysfunction ◽

Induced Hypertension ◽

Galectin 3 ◽

Genetic Deletion

Galectin-3 (Gal-3), a member of the β-galactoside lectin family, has an important role in immune regulation. In hypertensive rats and heart failure patients, Gal-3 is considered a marker for an unfavorable prognosis. Nevertheless, the role and mechanism of Gal-3 action in hypertension-induced target organ damage are unknown. We hypothesized that, in angiotensin II (ANG II)-induced hypertension, genetic deletion of Gal-3 prevents left ventricular (LV) adverse remodeling and LV dysfunction by reducing the innate immune responses and myocardial fibrosis. To induce hypertension, male C57BL/6J and Gal-3 knockout (KO) mice were infused with ANG II (3 μg·min−1·kg−1 sc) for 8 wk. We assessed: 1) systolic blood pressure by plethysmography, 2) LV function and remodeling by echocardiography, 3) myocardial fibrosis by histology, 4) cardiac CD68+ macrophage infiltration by histology, 5) ICAM-1 and VCAM-1 expression by Western blotting, 6) plasma cytokines, including interleukin-6 (IL-6), by enzyme-linked immunosorbent assay, and 7) regulatory T (Treg) cells by flow cytometry as detected by their combined expression of CD4, CD25, and FOXP3. Systolic blood pressure and cardiac hypertrophy increased similarly in both mouse strains when infused with ANG II. However, hypertensive C57BL/6J mice suffered impaired ejection and shortening fractions. In these mice, the extent of myocardial fibrosis and macrophage infiltration was greater in histological sections, and cardiac ICAM-1, as well as plasma IL-6, expression was higher as assessed by Western blotting. However, all these parameters were blunted in Gal-3 KO mice. Hypertensive Gal-3 KO mice also had a higher number of splenic Treg lymphocytes. In conclusion, in ANG II-induced hypertension, genetic deletion of Gal-3 prevented LV dysfunction without affecting blood pressure or LV hypertrophy. This study indicates that the ANG II effects are, in part, mediated or triggered by Gal-3 together with the related intercellular signaling (ICAM-1 and IL-6), leading to cardiac inflammation and fibrosis.

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Central angiotensin II and PGE2 act independently to increase blood pressure in conscious sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1987.252.1.r73 ◽

1987 ◽

Vol 252 (1) ◽

pp. R73-R77

Author(s):

B. A. Breuhaus ◽

J. E. Chimoskey

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Arterial Pressure ◽

Pressor Response ◽

Renin Angiotensin System ◽

Cyclooxygenase Inhibitors ◽

Ang Ii ◽

Intracerebroventricular Infusion ◽

Flunixin Meglumine ◽

The Brain

Conscious adult female sheep chronically prepared with nonocclusive indwelling vascular and cerebroventricular catheters were used to determine whether centrally administered prostaglandin E2 (PGE2) increases blood pressure by activation of the brain renin angiotensin system or whether centrally administered angiotensin II (ANG II) increases blood pressure by stimulating prostaglandin synthesis in the brain. Intracerebroventricular (ivt) ANG II, 50 ng X kg-1 X min-1, increased arterial pressure 23 mmHg (P less than 0.01) 30 min after the start of infusion. Infusion of the ANG II antagonist [Sar1-Thr8]ANG II (sarthran), 1,000 ng X kg-1 X min-1 ivt, had no effect on arterial pressure when given by itself but reduced the ivt ANG II-induced pressor response to 5 mmHg (P less than 0.05) when the two peptides were infused at the same time. Intracerebroventricular infusion of sarthran did not alter the pressor responses to intracarotid (ic) PGE2 or to ivt PGE2. Blood pressure increased 21 mmHg (P less than 0.01) 30 min after the start of PGE2 infusion when PGE2 was given ic by itself, compared with 17 mmHg (P less than 0.01) when PGE2 was given ic at the same time as sarthran was given ivt. Blood pressure increased 14 mmHg (P less than 0.01) 30 min after the start of PGE2 infusion when PGE2 was given ivt by itself, compared with 16 mmHg (P less than 0.01) when PGE2 was given ivt at the same time as sarthran was given ivt. Pretreatment with the cyclooxygenase inhibitors indomethacin, 4 mg/kg sc, or flunixin meglumine, 3 mg/kg iv, did not alter the ivt ANG II-induced pressor response.(ABSTRACT TRUNCATED AT 250 WORDS)

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