AT<sub>2</sub> receptors contribute to acute blood pressure-lowering and vasodilator effects of AT<sub>1</sub> receptor antagonism in conscious normotensive but not hypertensive rats

Duke, Lisa Michelle; Evans, Roger G.; Widdop, Robert E

doi:10.1152/ajpheart.01096.2004

Cited by 39 publications

(33 citation statements)

References 52 publications

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“…Despite overwhelming data supporting AT 2 receptor-mediated vasodilation, [3][4][5][6][33][34][35] for instance, in the preparations investigated in these studies, 2,11,12 we were unable to demonstrate such vasodilation in response to the AT 2 receptor agonist C21 in rat, mouse, and human vessels. Yet, our current study does support C21-induced vasorelaxation, albeit in an AT receptor-independent manner, possibly involving blockade of Ca 2ϩ transport into the cell.…”

Section: Perspectivescontrasting

confidence: 57%

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Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

et al. 2012

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Abstract-Angiotensin II type 2 (AT 2 ) receptor stimulation has been linked to vasodilation. Yet, AT 2 receptor-independent hypertension and hypotension (or no effect on blood pressure) have been observed in vivo after application of the AT 2 receptor agonist compound 21 (C21). We, therefore, studied its effects in vitro, using preparations known to display AT 2 receptor-mediated responses. Hearts of Wistar rats, spontaneously hypertensive rats (SHRs), C57Bl/6 mice, and AT 2 receptor knockout mice were perfused according to Langendorff. Mesenteric and iliac arteries of these animals, as well as coronary microarteries from human donor hearts, were mounted in Mulvany myographs. In the coronary vascular bed of Wistar rats, C57Bl/6 mice, and AT 2 receptor knockout mice, C21 induced constriction followed by dilation. SHR hearts displayed enhanced constriction and no dilation. Irbesartan (angiotensin II type 1 receptor blocker) abolished the constriction and enhanced or (in SHRs) reintroduced dilation, and PD123319 (AT 2 receptor blocker) did not block the latter. C21 relaxed preconstricted vessels of all species, and this did not depend on angiotensin II receptors, the endothelium, or the NO-guanylyl cyclase-cGMP pathway. C21 constricted SHR iliac arteries but none of the other vessels, and irbesartan prevented this. C21 shifted the concentration-response curves to U46619 (thromboxane A 2 analog) and phenylephrine (␣-adrenoceptor agonist) but not ionomycine (calcium ionophore) to the right. In conclusion, C21 did not cause AT 2 receptor-mediated vasodilation. Yet, it did induce vasodilation by blocking calcium transport into the cell and constriction via angiotensin II type 1 receptor stimulation. The latter effect is enhanced in SHRs. These data may explain the varying effects of C21 on blood pressure in vivo. (Hypertension. 2012;60:722-729.)

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Section: Perspectivescontrasting

confidence: 57%

“…S timulation of the angiotensin (Ang) II type 2 (AT 2 ) receptor mediates vasorelaxant, [1][2][3][4][5][6] natriuretic, 7 growthsuppressing, 8 and antifibrotic 9 effects. As such, it seems to counteract Ang II type 1 (AT 1 ) receptor-mediated effects.…”

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confidence: 99%

Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

et al. 2012

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“…5,6,14 -17 Evidence for a vasodepressor role of AT 2 R has usually been obtained from studies using male animals, where AT 1 R blockade is often required to uncover the vasodepressor response to an AT 2 R agonist. 5,6,14,15,17 Previous studies have investigated the response to Ang II in females using only high doses. 8,10,18 Therefore, this is the first study to show that not only does low-dose Ang II decrease MAP in female rats, but it did so without a background of AT 1 R blockade.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

et al. 2008

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Abstract-The renin-angiotensin system is a far more complex enzymatic cascade than realized previously. Mounting evidence suggests sex-specific differences in the regulation of the renin-angiotensin system and arterial pressure. We examined the hemodynamic responses, angiotensin II receptor subtypes, and angiotensin-converting enzyme 2 gene expression levels after graded doses of angiotensin II in males and females. Mean arterial pressure was measured via telemetry in male and female rats in response to a 2-week infusion of vehicle, low-dose (50 ng/kg per minute SC) or high-dose (400 ng/kg per minute SC) angiotensin II. The effect of concurrent infusion of the angiotensin II type 2 receptor (AT 2 R) blocker (PD123319) was also examined. The arterial pressure response to high-dose angiotensin II was attenuated in females compared with males (24Ϯ8 mm Hg versus 42Ϯ5 mm Hg; P for the interaction between sex and treatment Ͻ0.002). Remarkably, low-dose angiotensin II decreased arterial pressure (11Ϯ4 mm Hg; P for the interaction between sex and treatment Ͻ0.02) at a dose that did not have an effect in males. This decrease in arterial pressure in females was abolished by AT 2 R blockade. Renal AT 2 R, angiotensin-converting enzyme 2, and left ventricular AT 2 R mRNA gene expressions were markedly greater in females than in males with a renal angiotensin II type 1a receptor:AT 2 R ratio of Ϸ1 in females. Angiotensin II infusion did not affect renal AT 2 R mRNA expression but resulted in significantly less left ventricular mRNA expression. Renal angiotensin-converting enzyme 2 mRNA expression levels were greater in females than in males treated with high-dose angiotensin II (Ϸ2.5 fold; P for the interaction between sex and treatment Ͻ0.05). In females, enhancement of the vasodilatory arm of the renin-angiotensin system, in particular, AT 2 R and angiotensin-converting enzyme 2 mRNA expression, may contribute to the sex-specific differences in response to renin-angiotensin system activation. (Hypertension. 2008;52:666-671.)Key Words: basic science Ⅲ gender differences Ⅲ gene expression/regulation Ⅲ hypertension Ⅲ angiotensin receptors C ardiovascular disease is the leading cause of death in the Western world, and, contrary to popular belief, mortality rates for cardiovascular disease are greater in women than men. 1,2 Significant differences in survival after a heart attack have been revealed, with 42% of women who experience heart attacks dying within 1 year, compared with 24% of men. 2 The reasons for these differences in outcomes are unknown but require urgent explanation.Hypertension is a major risk factor for cardiovascular disease, with the renin-angiotensin system (RAS) playing a predominant role in the regulation of arterial pressure in both sexes. The potent end product, angiotensin II (Ang II), acts via 2 main subtypes of receptors responsible for vasoconstriction, sodium reabsorption and cell proliferation (in the rodents there are 2 further subtypes: type 1a [AT 1a R] and type 1b [AT 1b R]), as well as vasodil...

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“…For example, contradictory results have been obtained, even by the same group, concerning its modulatory role on the pressor effect of Ang II mediated through AT 1 receptors. 46,47 Of note is the possibility that PD123319 could interfere with nonreceptor-mediated effects or with other receptors, homodimers, or heterodimers, such as AT 1 /Mas. 36 In the presence of indomethacin and L-NAME treatment, the decrease in perfusion pressure produced by Ang- (1-7) in the presence of the AT 1 receptor blocker losartan was blunted.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Functional Interaction of the Angiotensin-(1–7) Receptor Mas With AT ₁ and AT ₂ Receptors in the Mouse Heart

et al. 2005

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Abstract-The aim of this study was to evaluate the angiotensin (Ang)-(1-7) effects in isolated mouse hearts. The hearts of male C57BL/6J and knockout mice for the Ang-(1-7) receptor Mas were perfused by the Langendorff method. After a basal period, the hearts were perfused for 20 minutes with Krebs-Ringer solution (KRS) alone (control) or KRS containing Ang-(1-7) (0.22 pmol/L), the Mas antagonist A-779 (115 nmol/L), the angiotensin type 1 receptor antagonist losartan (2.2 mol/L), or the angiotensin type 2 receptor antagonist PD123319 (130 nmol/L). To evaluate the involvement of Ang receptors, prostaglandins, and nitric oxide in the Ang-(1-7) effects, the hearts were perfused for 20 to 30 minutes with KRS containing either A-779, losartan, PD123319, indomethacin, or N G -nitro-L-arginine methyl ester (L-NAME) alone or in association with subsequent Ang-(1-7) perfusion. In addition, hearts from Mas-knockout mice were perfused for 20 minutes with KRS containing Ang-(1-7) (0.22 pmol/L) and losartan. Ang-(1-7) alone did not change the perfusion pressure. Strikingly, in the presence of losartan, 0.22 pmol/L Ang-(1-7) induced a significant decrease in perfusion pressure, which was blocked by A-779, indomethacin, and L-NAME. Furthermore, this effect was not observed in Mas-knockout mice. In contrast, in the presence of PD123319, Ang-(1-7) produced a significant increase in perfusion pressure. This change was not modified by the addition of A-779. Losartan reduced but did not abolish this effect. Our results suggest that Ang-(1-7) produces complex vascular effects in isolated, perfused mouse hearts involving interaction of its receptor with angiotensin type 1-and type 2-related mechanisms, leading to the release of prostaglandins and nitric oxide. Key Words: receptors, angiotensin Ⅲ cardiac function Ⅲ heart Ⅲ angiotensin antagonist Ⅲ prostaglandins I n the last decade, the classic renin-angiotensin system (RAS) concept has undergone important changes. 1,2 Many novel biologically active components were described, such as angiotensin (Ang)-(1-7), Ang III, and Ang IV. Ang-(1-7) is now considered an important component of the RAS, with actions similar to or even opposite those displayed by Ang II. 1,3,4 Moreover, chronic treatment with Ang-converting enzyme inhibitors and/or angiotensin type 1 (AT 1 ) receptor blockers increases plasma Ang-(1-7) levels up to 25-fold, [5][6][7] suggesting that this heptapeptide could be involved in the beneficial effects observed with these therapies. 5,8 In addition, many studies have observed that Ang-(1-7) has a bradykinin-potentiating activity in several vascular beds and species. 9 -13 Recently, using mice with targeted disruption of the Mas proto-oncogene 14 and Mas-transfected cells, Santos et al 15 identified Ang-(1-7) as an endogenous ligand for the G protein-coupled receptor encoded by Mas. 15 Furthermore, the novel Ang-(1-7)-forming enzyme ACE2 16,17 has been reported to be an important regulator of the RAS. 18 This enzyme can form Ang-(1-7) by at least 2 different pathways: dire...

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AT₂ receptors contribute to acute blood pressure-lowering and vasodilator effects of AT₁ receptor antagonism in conscious normotensive but not hypertensive rats

Cited by 39 publications

References 52 publications

Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

Evidence for a Functional Interaction of the Angiotensin-(1–7) Receptor Mas With AT ₁ and AT ₂ Receptors in the Mouse Heart

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AT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats

Cited by 39 publications

References 52 publications

Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

Enhanced Angiotensin II Type 2 Receptor Mechanisms Mediate Decreases in Arterial Pressure Attributable to Chronic Low-Dose Angiotensin II in Female Rats

Evidence for a Functional Interaction of the Angiotensin-(1–7) Receptor Mas With AT 1 and AT 2 Receptors in the Mouse Heart

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AT₂ receptors contribute to acute blood pressure-lowering and vasodilator effects of AT₁ receptor antagonism in conscious normotensive but not hypertensive rats

Evidence for a Functional Interaction of the Angiotensin-(1–7) Receptor Mas With AT ₁ and AT ₂ Receptors in the Mouse Heart