Mixed β₃‐adrenoceptor agonist and α₁‐adrenoceptor antagonist properties of nebivolol in rat thoracic aorta

Abstract

1 Nebivolol, a selective b-adrenoceptor (b 1 -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 a 1 and b 3 -ARs in nebivolol-induced vasodilatation. 2 The responses to nebivolol were investigated in vitro in thoracic aortic rings isolated from male Sprague-Dawley rats. 3 Nebivolol (0.1-10 mM) significantly shifted the concentration-response curve to phenylephrine, an a 1 -AR agonist, to the right in a concentration-dependent manner (pA 2 ¼ 6.5). Conversely, the concentration-response curve to endothelin 1 (ET1) was unaffected by nebivolol. 4 In ET1-precontracted rings, nebivolol induced a concentration-dependent relaxation, which was unaffected by nadolol (a b 1 /b 2 -AR antagonist) but was significantly reduced by L-748,337 (a b 3 -AR antagonist), endothelium removal or pretreatment with L-NMMA (an NOS inhibitor). Similar results were obtained with a b 3 -AR agonist, SR 58611A. 5 It was concluded that, in rat aorta, nebivolol-induced relaxation results from both inhibition of a 1 -ARs and activation of b 3 -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.

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

“…This may be due to the effects of metoprolol on the β2AR (Rozec et al 2006). Nebivolol is more selective for the β1AR (Rozec et al 2006). We found no further differences in the pathologies of the mice.…”

“…However, metoprolol appeared to reduce the growth rate of liver tumors by half, since the tumors from this group were approximately half the volume of those from the control and nebivolol-treated mice. This may be due to the effects of metoprolol on the β2AR (Rozec et al 2006). Nebivolol is more selective for the β1AR (Rozec et al 2006).…”

“…In contrast, βAR blockade with metoprolol or other β-blockers decreases mortality after acute myocardial infarct by 23 to 39 %, improves the health of individuals with heart failure, and may reduce the development of atherosclerosis (reviewed in Bristow 2000; Ellison and Gandhi 2005). Nebivolol, which is more selective for the β1 versus the β2 receptor than metoprolol, produces similar effects to metoprolol on the heart (Grassi et al 2003;Rozec et al 2006). Nebivolol also improves oxidative stress, insulin sensitivity, and plasma soluble P-selectin and adiponectin levels in hypertensive patients (Celik et al 2006;Rozec et al 2006).…”

“…Nebivolol, which is more selective for the β1 versus the β2 receptor than metoprolol, produces similar effects to metoprolol on the heart (Grassi et al 2003;Rozec et al 2006). Nebivolol also improves oxidative stress, insulin sensitivity, and plasma soluble P-selectin and adiponectin levels in hypertensive patients (Celik et al 2006;Rozec et al 2006). These effects may be due to offtarget activation of the α 1 -adrenergic receptor (Celik et al 2006;Rozec et al 2006).…”

“…Nebivolol also improves oxidative stress, insulin sensitivity, and plasma soluble P-selectin and adiponectin levels in hypertensive patients (Celik et al 2006;Rozec et al 2006). These effects may be due to offtarget activation of the α 1 -adrenergic receptor (Celik et al 2006;Rozec et al 2006).…”