Investigation of the different adrenoceptor targets of nebivolol enantiomers in rat thoracic aorta

Abstract

Background and purpose: Nebivolol is a highly selective b1-adrenoceptor antagonist with b3-adrenoceptor agonist properties and is a racemate mixture of D-and L-enantiomers. However, the cellular mechanisms of the effects of each enantiomer are not yet clear and are a matter for debate. The aim of the present experiments was to determine the adrenoceptors involved in the vascular effects of D-and L-enantiomers of nebivolol in rat thoracic aorta. Experimental approach: Responses to nebivolol enantiomers were evaluated in rings of thoracic aorta from male SpragueDawley rats.), but not L-nebivolol, significantly shifted to the right the concentration-response curve to phenylephrine, an a1-adrenoceptor agonist, in a concentration-dependent manner. For the following experiments, aortic rings were constricted with endothelin 1 and now both enantiomers produced an endothelium-dependent relaxation of the rings involving the nitric oxide pathway. This relaxation was not modified by 1 mmol·L -1 CGP 20,712A (b1-adrenoceptor antagonist), but significantly blunted by 7 mmol·L -1 L-74,8337 (b3-adrenoceptor antagonist). However, only the vasorelaxation induced by D-nebivolol was significantly reduced by 1 mmol·L -1 ICI 118,551 (b2-adrenoceptor antagonist). Conclusions and implications:Our results suggest that the nebivolol enantiomers act on different targets. D-nebivolol induced vasorelaxation by activating b2-and b3-adrenoceptors and antagonizing a1-adrenoceptors. L-nebivolol induced vasorelaxation by activating only b3-adrenoceptors in our model. Our results emphasize that nebivolol is a b1-adrenoceptor antagonist with several important pharmacological differences from other b1-adrenoceptor antagonists.

β3‐AR and the vertebrate heart: a comparative view

“…, Tran Quang et al . ). Thanks to its combined activity as β 1 ‐ARs antagonist and β 3 ‐ARs agonist, nebivolol is used in human clinical studies to evaluate the effects of β 3 ‐ARs activation.…”

Beta3-Adrenoreceptor Stimulation Ameliorates Myocardial Ischemia-Reperfusion Injury Via Endothelial Nitric Oxide Synthase and Neuronal Nitric Oxide Synthase Activation

“…Stimulation of the beta 3 -AR and activation of endothelial nitric oxide synthase (eNOS) increases NO release after nebivolol treatment to cause peripheral vasodilatation and improved endothelial function (16,17). Nebivolol might also activate the beta 2 -AR (18 –20). …”

The Beta-1-Receptor Blocker Nebivolol Elicits Dilation of Cerebral Arteries by Reducing Smooth Muscle [Ca2+]i

“…Thus we aimed to characterize the dilator properties of nebivolol in isolated basilar arteries, in such conditions, in which the intraluminal pressure and extravascular environment were controlled. Based on previous studies [ 17 , 34 , 35 , 44 ] we have used nebivolol in a range of 10 −7 to 10 −4 M which is in accordance with a range of concentrations used by others. Our data show significant dilations of BA in response to concentration-dependent administration of nebivolol ( Fig 2 ).…”

“…For example Evangelista et al reported that antioxidant properties of nebivolol can increase the “surviving” level of NO by reducing its oxidative inactivation in human umbilical vein endothelial cells, and that beta-1/2/3 adrenoceptors may play role in the development of nebivolol-induced dilation [ 43 ]. Moreover, Georgescu et al showed nebivolol induces beta-2 adrenoceptor-mediated and Ca 2+ activated potassium channel induced hyperpolarization with the consequent relaxation in mice renal arteries [ 35 ], whereas, Tran-Quang et al has demonstrated nebivolol-induced specific, either beta-2 and beta-3 agonist or alpha-1 and beta-1 antagonist adrenoceptor-mediated relaxations in rat aortic rings [ 44 ]. It was also observed that nebivolol elicits the release of hyperpolarizing factor via activation of calcium activated potassium channels [ 34 ] that—in part—maintains vessel relaxation when eNOS (endothelial NO synthase) is inhibited [ 17 ].…”

“…Our data show significant dilations of BA in response to concentration-dependent administration of nebivolol ( Fig 2 ). Since the EC 50 is 7.8 ± 0.19 x 10 −6 M, we performed measurements with specific inhibitors near this EC 50 range in the presence of nebivolol arbitrarily at 10 −5 M. Despite the calculated pharmacologically relevant plasma concentrations in humans after taking 5 mg nebivolol orally, it is in the nM range, but it still elicits a significant decrease in systemic vascular resistance [ 44 ], and it may result in dilation in human cerebral arteries. It is also possible that smaller cerebral vessels are even more sensitivity to nebivolol, as it is a general characteristics of microvessels that their sensitivity to various drugs and stimuli increases as the size (diameter) of vessels decreases [ 51 ].…”