Background— Coronary vessel tone is modulated in part by β-adrenergic relaxation. However, the implication of specific β-adrenoceptor subtypes and their downstream vasorelaxing mechanism(s) in human coronary resistance arteries is poorly defined. β₃-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 β₃-adrenoceptors in human coronary microarteries and their coupling to vasodilating nitric oxide (NO) and/or hyperpolarization mechanisms. The expression of β₃-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 β-agonist isoproterenol and the β₃-preferential agonist BRL37344 evoked an ≈50% relaxation of endothelin-1-preconstricted human coronary microarteries. Relaxations were blocked by the β₁/β₂/β₃-adrenoceptor antagonist bupranolol but were insensitive to the β₁/β₂-adrenoceptor antagonist nadolol, confirming a β₃-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-ω-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 β₃-adrenoceptor stimulation.

Conclusions— β₃-adrenoceptors are expressed in the endothelium of human coronary resistance arteries and mediate adrenergic vasodilatation through both NO and vessel hyperpolarization.