Angiotensin AT<sub>2</sub> receptors: cardiovascular hope or hype?

Widdop, Robert E; Jones, Emma S; Hannan, Ruth Elizabeth; Gaspari, Tracey

doi:10.1038/sj.bjp.0705448

Cited by 214 publications

(257 citation statements)

References 190 publications

(361 reference statements)

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“…The AT 1 receptor is involved in the regulation of arterial blood pressure (vasoconstriction), electrolyte balance (antinatriuresis), thirst, hormone secretion (aldosterone), and renal function (De Gasparo et al 2000). In contrast, AT 2 receptors can produce opposite effects to those by the AT 1 receptor, i.e., natriuresis and vasodilatation (Widdop et al 2003).…”

Section: Angiotensin Receptorsmentioning

confidence: 99%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT 1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT 2 receptor antagonists, Ca 2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT 1-7 ), adrenergic (α 1 , α 2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP 2 ), adenosine (A 1 , A 2 , and A 3 ), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

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Section: Angiotensin Receptorsmentioning

confidence: 99%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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“…In addition, under certain conditions, AT2 receptors form heterodimers with AT1 receptors, which results in the attenuation of AT1-mediated effects on ANG II (1). Several studies confirmed that ANG II binding to AT2 results in an increase in the formation of vasodilator agents, such as NO, prostanoids, and bradykinin [68].…”

Section: Nhe3mentioning

confidence: 76%

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

Mello-Aires¹,

Dellova²,

Castelo‐Branco³

et al. 2017

Nephrol Renal Dis

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This article reviews the main body of knowledge regarding NHE1 and NHE3 exchangers and their interaction with Angiotensin II, Angiotensin-(1-7), Aldosterone and Arginine Vasopressin, particularly their renal actions. This work addresses the biphasic effects of different hormonal doses on NHE1 or NHE3 in proximal tubule in Wistar, SHR (hypertensives) and their control WKY (normotensives) rats or MDCK cells (which share similarities with the collecting duct). The hormones were applied alone, with their inhibitors or plus agents that change the [Ca 2+ ]i. The data are compatible with hormonal stimulation of these exchangers by increases of [Ca 2+ ]i in lower range, and inhibition at high [Ca 2+ ]i. In MDCK cells and Wistar rats, low doses of ANG II, ALDO or AVP stimulated the exchangers, while high doses inhibited them. ANG-(1-7), in Wistar or WKY rats has inverse, dose-dependent effects. In SHR rats, the biphasic effects of ANG-(1-7) were similar to the effects of ANG II, ALDO or AVP in Wistar rats. The interactions between these effects may represent a mechanism that regulates extracellular volume. In hypertensives animals, a high plasma level of ANG-(1-7) inhibited NHE3 in the proximal tubule, which mitigated hypertension. Figure 6 shows a schematic model to describe these biphasic hormonal effects.

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“…In the presence of an angiotensin AT 1 receptor antagonist, angiotensin II caused a 30% increase in the diameter of preconstricted, microperfused rabbit afferent and efferent arterioles in a PD-123,319-sensitive manner Endo et al, 1997). This acute angiotensin AT 2 receptor-mediated vasodilator response may be endothelium-dependent or independent and appears to involve a range of signaling pathways, including nitric oxide and bradykinin production, activation of cytochrome P-450 epoxygenase pathways and modulation of K + channel activity (Widdop et al, 2003). Moreover, in the human heart, it has been recently shown that angiotensin AT 2 receptor stimulation in coronary microarteries induces endothelium-dependent vasodilation which is mediated by bradykinin B 2 receptors and nitric oxide (Batenburg et al, 2004a).…”

Section: Discussionmentioning

confidence: 99%

“…In the vasculature, it has been demonstrated that acute angiotensin AT 2 receptor stimulation leads to relaxation of isolated arteries, including rabbit renal arterioles Endo et al, 1997), rabbit cerebral arteries (Haberl, 1994) and rat mesenteric arteries (Widdop et al, 2002(Widdop et al, , 2003. In the human heart, angiotensin II exerts an acute vasodilating effect in the coronary microcirculation through angiotensin AT 2 receptor stimulation (Batenburg et al, 2004a,b).…”

Section: Introductionmentioning

confidence: 99%

Negative inotropic effect of selective AT2 receptor stimulation and its modulation by the endocardial endothelium

Castro-Chaves¹,

Soares²,

Fontes‐Carvalho³

et al. 2008

European Journal of Pharmacology

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Angiotensin II is an octapeptide whose effects are mediated by two types of receptors. AT 1 receptors are responsible for the vasoconstrictor, positive inotropic and growth promoting properties, while AT 2 receptors have been linked to vasodilator and anti-mitogenic properties. In this study we investigated the effects of selective AT 2 receptor stimulation on myocardial contractility and lusitropy. Effects of selective AT 2 receptor activation were evaluated in rabbit right papillary muscles (n = 96) by adding increasing concentrations of H-9395, an AT 2 receptor agonist, alone or in presence of a selective AT 1 receptor antagonist (ZD-7155), or alternatively, by adding increasing concentrations of angiotensin II in presence of ZD-7155. In the latter conditions, selective AT 2 receptor activation was also performed in presence of NG-nitro-L-Arginine, indomethacin, proadifen, hydroxocobalamin, apamin plus charybdotoxin, Hoe-140 or PD-123,319, as well as, after endocardial endothelium removal. Selective AT 2 stimulation induced a negative inotropic and lusitropic effect in the first three protocols. This effect was completely abolished after selective removal of the endocardial endothelium and blunted in presence of Hoe-140, hydroxocobalamin, apamin plus charybdotoxin and PD-123,319, but maintained in presence of NG-nitro-L-Arginine, indomethacin or proadifen. Selective AT 2 receptor stimulation induces a negative inotropic and lusitropic effect, which is modulated by endocardial endothelium and mediated by bradykinin B 2 receptors through NO release and calcium dependent potassium channels activation. Such findings may help to better understand the therapeutic effects of selective AT 1 antagonists, which are increasingly used for treating cardiovascular diseases.

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Angiotensin AT₂ receptors: cardiovascular hope or hype?

Abstract: British Journal of Pharmacology (2003) 140, 809–824. doi:

Cited by 214 publications

References 190 publications

Current and prospective pharmacological targets in relation to antimigraine action

Current and prospective pharmacological targets in relation to antimigraine action

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

Negative inotropic effect of selective AT2 receptor stimulation and its modulation by the endocardial endothelium

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Angiotensin AT2 receptors: cardiovascular hope or hype?

Abstract: British Journal of Pharmacology (2003) 140, 809–824. doi:

Cited by 214 publications

References 190 publications

Current and prospective pharmacological targets in relation to antimigraine action

Current and prospective pharmacological targets in relation to antimigraine action

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

Negative inotropic effect of selective AT2 receptor stimulation and its modulation by the endocardial endothelium

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Angiotensin AT₂ receptors: cardiovascular hope or hype?