Experimental evidences of nitric oxide-dependent vasodilatory activity of nebivolol, a third-generation beta-blocker

Nebivolol is a new and selective beta1-adrenergic receptor antagonist whose haemodynamic profile is different from that of classical beta-blockers. The blood pressure lowering effects of nebivolol are, at least partially, due to the direct vasodilation as a result of nitric oxide (NO) release from endothelial cells. Several in vitro studies unequivocally show that, at least in certain vascular districts (particularly in small diameter, non-conduit vessels) and in platelets, nebivolol can stimulate an increase of endothelial NO, which becomes available at the smooth muscle layers and induces vasorelaxation. Nebivolol appears to interact with the endothelial NO pathway in two complementary ways: it increases NO synthase (NOS) activity and reduces the NO-scavenging radical superoxide anion, by re-directing deranged NOS activity, from superoxide to NO production. Nebivolol appears also to possess a complementary antioxidant activity, through which the pathological ROS-induced depression of intracellular NO levels can be prevented. Depending on the studies, evidences for a role of different receptors have been obtained. Although the interaction of nebivolol with cell receptors and the mechanisms of signal transduction into eNOS activation are not yet fully delineated, that nebivolol increases NO production and extracellular release has been proved not only by confirming its inhibition by NOS blockers, but also by measuring NO levels in mediums and cells in several different experimental settings.