NEBIVOLOL INDUCES ENDOTHELIUM-DEPENDENT RELAXATIONS OF CANINE CORONARY-ARTERIES

Nebivolol is a new beta-1-antagonist that acutely reduces arterial blood pressure without depressing cardiac function. The present study was designed to determine the effect of nebivolol on coronary arteries. Rings of canine left anterior descending coronary (LAD) artery with or without endothelium were suspended in organ chambers and the isometric tension was recorded. In some experiments, the transmembrane potential of the smooth muscle cells was recorded by electrophysiological methods. During contractions to prostaglandin F2-alpha, nebivolol induced concentration-dependent relaxations of the coronary arteries. The enantiomer, l-nebivolol, also induced comparable relaxations; however, d-nebivolol induced smaller relaxations. The relaxations induced by nebivolol and its enantiomer were significantly larger in tissues with than in those without endothelium. The differences between tissues with and without endothelium were abolished by nitro-L-arginine (3 x 10(-5) M) or methylene blue (10(-5) M). The nebivolol-induced relaxations were not affected by indomethacin (10(-5) M), phentolamine (5 x 10(-6) M), propranolol (5 x 10(-6) M), or methysergide (3 x 10(-6) M). Nebivolol at a subthreshold concentration for inducing relaxation (3 x 10(-7) M) did not significantly affect endothelium-dependent relaxations to acetylcholine but potentiated ADP-induced endothelium-dependent relaxations. The potentiation is stereoselective for l-nebivolol. Nebivolol induced a small hyperpolarization of the coronary smooth muscle with endothelium (1 mV). These observations demonstrate that (a) nebivolol induces relaxations of canine coronary arteries that are mainly mediated by endothelium-derived relaxing factor(s); these effects are not related to the alpha- and beta-adrenergic- or serotonergic 5-HT1- and 5-HT2-blocking properties of the compound; (b) nebivolol potentiates ADP-induced endothelium-dependent relaxations; and (c) l-nebivolol is more potent than d-nebivolol in inducing and potentiating endothelium-dependent relaxations.