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(Circulation Research. 2003;92:322.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Divergent Roles of Angiotensin II AT₁ and AT₂ Receptors in Modulating Coronary Microvascular Function

Cuihua Zhang, Travis W. Hein, Wei Wang, Lih Kuo

From the Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M University System Health Science Center, College Station, Tex.

Correspondence to Lih Kuo, PhD, Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M University System Health Science Center, College Station, TX 77843-1114. E-mail LKUO{at}tamu.edu

Angiotensin II (Ang II) is a potent vasoconstrictor in the peripheral circulation and has been implicated in many cardiovascular diseases associated with elevated oxidative stress. However, its direct vasomotor action and its linkage to oxidative stress–induced vascular dysfunction in the coronary microcirculation remain elusive. In this study, we directly assessed the vasomotor action of Ang II in isolated porcine coronary arterioles and also examined whether Ang II can modulate endothelium-dependent nitric oxide (NO)-mediated dilation via superoxide production. Ang II evoked vasoconstriction at a low concentration (1 nmol/L) and dilations at higher concentrations (>10 nmol/L). Ang II type 1 (AT₁) receptor antagonist losartan abolished vasoconstriction, whereas Ang II type 2 (AT₂) receptor antagonist PD 123319 eliminated vasodilation. Adenosine stimulated a significant arteriolar NO production and dilation. NO synthase inhibitor N^G-monomethyl-L-arginine (L-NMMA) abolished stimulated NO production and attenuated vasodilation. Pretreating vessels with a subvasomotor concentration of Ang II (0.1 nmol/L, 60 minutes) mimicked inhibitory effects of L-NMMA. Ang II–mediated inhibition was not observed in the presence of L-NMMA or after endothelial removal but was prevented by losartan, superoxide scavenger TEMPOL, or NADPH oxidase inhibitor apocynin. Dihydroethidium staining showed that Ang II elicited losartan- and TEMPOL-sensitive superoxide production in arterioles. These results demonstrate that Ang II evokes AT₁ receptor–mediated vasoconstriction and AT₂ receptor–mediated vasodilation of coronary arterioles. Ang II at a subvasomotor level impairs endothelium-dependent NO-mediated dilation attributable to elevated superoxide production via AT₁ receptor activation of NADPH oxidase. These data may partly explain the impaired coronary flow regulation in heart diseases associated with an upregulated renin-angiotensin system.

Key Words: angiotensin • free radicals • microcirculation • nitric oxide • vasodilation

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