Mixed beta3-adrenoceptor agonist and alpha1-adrenoceptor antagonist properties of nebivolol in rat thoracic aorta

Abstract

Nebivolol, a selective beta-adrenoceptor (beta1-AR) antagonist, induces vasodilatation by an endothelium- and NO-cGMP-dependent pathway. However, the mechanisms involved in the vascular effect of nebivolol have not been established. Thus, we evaluated the role of alpha1 and beta3-ARs in nebivolol-induced vasodilatation. The responses to nebivolol were investigated in vitro in thoracic aortic rings isolated from male Sprague-Dawley rats. Nebivolol (0.1-10 microM) significantly shifted the concentration-response curve to phenylephrine, an alpha1-AR agonist, to the right in a concentration-dependent manner (pA2 = 6.5). Conversely, the concentration-response curve to endothelin 1 (ET1) was unaffected by nebivolol. In ET1-precontracted rings, nebivolol induced a concentration-dependent relaxation, which was unaffected by nadolol (a beta1/beta2-AR antagonist) but was significantly reduced by L-748,337 (a beta3-AR antagonist), endothelium removal or pretreatment with L-NMMA (an NOS inhibitor). Similar results were obtained with a beta3-AR agonist, SR 58611A. It was concluded that, in rat aorta, nebivolol-induced relaxation results from both inhibition of alpha1-ARs and activation of beta3-ARs. In addition, we confirmed that the endothelium and the NO pathway are involved in the vascular effect of nebivolol. The identification of these vascular targets of nebivolol indicate that it has therapeutic potential for the treatment of pathological conditions associated with an elevation of sympathetic tone, such as heart failure and hypertension.

Figure 1

Concentration–response curves to phenylephrine (PE; a) and endothelin (ET1; b) in the absence and the presence of increasing concentrations of nebivolol constructed in rat thoracic aortic rings. Each point is the mean of n experiments and vertical lines show the s.e.m. When no error bar is shown, the error is smaller than the symbol. ^*P<0.05 and ^**P<0.01 indicate significant differences from PE or ET1 alone.

Figure 2

Concentration–relaxation response curves for nebivolol in rat thoracic aortic rings precontracted with ET1 in different experimental conditions. The mean curves are shown resulting from subtraction of the spontaneous relaxation of control vessels pretreated or not with nadolol or L-748,337 (a), L-NMMA (b) and after endothelium removal (b). Results are expressed as the percentage of relaxation from the maximal contraction level induced by ET1. Each point is the mean of n experiments, and vertical lines show the s.e.m. When no error bar is shown, the error is smaller than the symbol (^*P<0.05 and ^**P<0.01 indicate significant differences of arterial rings pretreated with L-NMMA from control; ⁺P<0.05 and ⁺⁺P<0.01 indicate significant differences of arterial rings without endothelium from control).

Figure 3

Concentration–relaxation curves for SR 58611A in rat thoracic aortic rings precontracted with ET1 in different experimental conditions. The mean curves are shown resulting from subtraction of the spontaneous relaxation of control vessels pretreated or not with nadolol or L-748,337 (a) and L-NMMA (b) and after endothelium removal (b). Results are expressed as the percentage of relaxation from the maximal contraction level induced by ET1. Each point is the mean of n experiments, and vertical lines show the s.e.m. When no error bar is shown, the error is smaller than the symbol (^*P<0.05 and ^**P<0.01 indicate significant differences of arterial rings pretreated with L-NMMA from control; ⁺P<0.05 and ⁺⁺P<0.01 indicate significant differences of arterial rings without endothelium from control).