Nebivolol induces calcium-independent signaling in endothelial cells by a possible beta-adrenergic pathway

Nebivolol is a highly selective beta (1)-adrenoreceptor-blocking agent with a peculiar pharmacodynamic profile. It has peripheral acute vasodilating p roperties that are mediated by modulation of the endogenous production of n itric oxide. In this study we analyzed the different signaling pathways im plicated in the response of human umbilical vein endothelial cells to nebiv olol. Its effect on endothelial transduction pathways was determined by ass aying phospholipase C and A(2) activities and cyclic adenosine monophosphat e (AMP) production. Variations in intracellular calcium concentration were also measured. Our results showed that nebivolol activates a calcium-indepe ndent transduction pathway that implicates an increase in adenylate cyclase and phospholipase A(2) activity. beta (1)- or beta (2)-Adrenoreceptor anta gonists do not inhibit the action of nebivolol. However, its action on cycl ic AMP production is inhibited by bupranolol, a beta (1-3)-adrenoreceptor a ntagonist, and S-(-)-cyanopindolol, a selective beta (3)-adrenoreceptor ant agonist. Nebivolol also dose-dependently increased nitrite production. This effect was inhibited by bupranolol, suggesting that the possible action of nebivolol on beta (3)-adrenoreceptor is involved in its vasodilating prope rties. This study suggests that nebivolol could behave as a beta (3)-adreno receptor agonist and induce some calcium-independent pathways implicating p hospholipase A(2) and adenylate cyclase. This agonistic activity of nebivol ol seems to be responsible for its endothelium-dependent vasodilating activ ity.