Angiotensin II Type 2 Receptor–Mediated Vasodilation in Human Coronary Microarteries

Abstract

Background-Angiotensin (Ang) II type 2 (AT 2 ) receptor stimulation results in coronary vasodilation in the rat heart. In contrast, AT 2 receptor-mediated vasodilation could not be observed in large human coronary arteries. We studied Ang II-induced vasodilation of human coronary microarteries (HCMAs). Methods and Results-HCMAs (diameter, 160 to 500 m) were obtained from 49 heart valve donors (age, 3 to 65 years).Ang II constricted HCMAs, mounted in Mulvany myographs, in a concentration-dependent manner (pEC 50 , 8.6Ϯ0.2; maximal effect [E max ], 79Ϯ13% of the contraction to 100 mmol/L K ϩ ). The Ang II type 1 receptor antagonist irbesartan prevented this vasoconstriction, whereas the AT 2 receptor antagonist PD123319 increased E max to 97Ϯ14% (PϽ0.05). The increase in E max was larger in older donors (correlation ⌬E max versus age, rϭ0.47, PϽ0.05). The PD123319-induced potentiation was not observed in the presence of the NO synthase inhibitor L-NAME, the bradykinin type 2 (B 2 ) receptor antagonist Hoe140, or after removal of the endothelium. Ang II relaxed U46619-preconstricted HCMAs in the presence of irbesartan by maximally 49Ϯ16%, and PD123319 prevented this relaxation. Finally, radioligand binding studies and reverse transcription-polymerase chain reaction confirmed the expression of AT 2 receptors in HCMAs. Conclusions-AT 2 receptor-mediated vasodilation in the human heart appears to be limited to coronary microarteries and is mediated by B 2 receptors and NO. Most likely, AT 2 receptors are located on endothelial cells, and their contribution increases with age.

Angiotensin Type 2 Receptor in Resistance Arteries of Type 2 Diabetic Hypertensive Patients

“…It was reported recently that AT 2 R-mediated vasodilation occurs in the coronary microcirculation of nondiseased hearts in a cohort of subjects with a wide age range. 16 As well, in healthy young subjects treated for 1 week with an AT 1 R antagonist, intrabrachial arterial infusion of the AT 2 R antagonist PD123319 resulted in increased BP, with no changes in forearm vascular responses. 27 Ang II elicited dose-dependent AT 2 R-mediated vasodilation only in resistance arteries from hypertensive diabetic patients treated for 1 year with valsartan.…”

“…15 AT 2 Rs have been demonstrated in the human coronary microcirculation, where they may contribute to vasodilation. 16 Studies in cellular and animal models suggest that AT 2 R counteracts many AT 1 R actions by inducing vasodilation, antiproliferation, and apoptosis. 2 We showed recently in animal models of hypertension that AT 2 R is upregulated and mediates vasodilation only when AT 1 Rs are blocked, 6,7 suggesting that AT 2 R participates in the mechanisms whereby Ang II receptor antagonism lowers blood pressure (BP).…”

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

“…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). Nitric oxide released either from cardiac endothelial cells or generated within cardiac myocytes can directly influence cardiac contractile function (Shah et al, 2000).…”

Blood pressure and renal hemodynamic effects of angiotensin fragments

“…They are expressed in human skin 33,34 and in the coronary circulation. 35 In the adult human renal cortex, AT 2 receptor mRNA is mainly expressed in interlobular arteries. 36 Effects of Ang II on blood pressure and sodium-volume homeostasis Ang II increases arterial pressure via two principal effects.…”

“…In general, it is assumed that AT 2 receptors oppose the responses mediated by AT 1 receptors. 35,75,76 Although the AT 1 receptor is involved in pressor, vasoconstrictor and antinatriuretic effects, the AT 2 receptor appears to mediate depressor effects, vasodilation and natriuresis. 77,78 AT 2 receptor stimulation could increase the production of NO and cGMP either by increasing bradykinin production and bradykinin B2 receptor stimulation or by direct activation of NO production.…”