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(Circulation. 2004;110:948-954.)
© 2004 American Heart Association, Inc.

Original Articles

Endothelial ß₃-Adrenoceptors Mediate Vasorelaxation of Human Coronary Microarteries Through Nitric Oxide and Endothelium-Dependent Hyperpolarization

C. Dessy, PhD; S. Moniotte, MD, PhD; P. Ghisdal, PhD; X. Havaux, MS; P. Noirhomme, MD; J.L. Balligand, MD, PhD

From the Unit of Pharmacology and Therapeutics (C.D., S.M., P.G., J.L.B.) and Divisions of Cardiology (X.H.) and Cardiovascular Surgery (P.N.), Saint-Luc University Clinic and Université Catholique de Louvain, Brussels, Belgium.

Correspondence to Dr J.L. Balligand, Unit of Pharmacology and Therapeutics, Université Catholique de Louvain, FATH5349, avenue E. Mounier 53, B-1200, Brussels, Belgium. E-mail Balligand{at}mint.ucl.ac.be

Received June 16, 2003; de novo received December 26, 2003; revision received May 6, 2004; accepted May 10, 2004.

Background— Coronary vessel tone is modulated in part by ß-adrenergic relaxation. However, the implication of specific ß-adrenoceptor subtypes and their downstream vasorelaxing mechanism(s) in human coronary resistance arteries is poorly defined. ß₃-Adrenoceptors were recently shown to vasodilate animal vessels and are expressed in human hearts.

Methods and Results— We examined the expression and functional role of ß₃-adrenoceptors in human coronary microarteries and their coupling to vasodilating nitric oxide (NO) and/or hyperpolarization mechanisms. The expression of ß₃-adrenoceptor mRNA and protein was demonstrated in extracts of human coronary microarteries. Immunohistochemical analysis revealed their exclusive localization in the endothelium, with no staining of vascular smooth muscle. In contractility experiments in which videomicroscopy was used, the nonspecific ß-agonist isoproterenol and the ß₃-preferential agonist BRL37344 evoked an 50% relaxation of endothelin-1-preconstricted human coronary microarteries. Relaxations were blocked by the ß₁/ß₂/ß₃-adrenoceptor antagonist bupranolol but were insensitive to the ß₁/ß₂-adrenoceptor antagonist nadolol, confirming a ß₃-adrenoceptor-mediated pathway. Relaxation in response to BRL37344 was absent in human coronary microarteries devoid of functional endothelium. When human coronary microarteries were precontracted with KCl (thereby preventing vessel hyperpolarization), the relaxation to BRL37344 was reduced to 15.5% and totally abrogated by the NO synthase inhibitor L--nitroarginine, confirming the participation of a NO synthase-mediated relaxation. The NO synthase-independent relaxation was completely inhibited by the Ca²⁺-activated K⁺ channel inhibitors apamin and charybdotoxin, consistent with an additional endothelium-derived hyperpolarizing factor-like response. Accordingly, membrane potential recordings demonstrated vessel hyperpolarization in response to ß₃-adrenoceptor stimulation.

Conclusions— ß₃-adrenoceptors are expressed in the endothelium of human coronary resistance arteries and mediate adrenergic vasodilatation through both NO and vessel hyperpolarization.

Key Words: receptors, adrenergic, beta • endothelium-derived factors • nitric oxide • vasodilation

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