Mixed beta3-adrenoceptor agonist and alpha1-adrenoceptor antagonist properties of nebivolol in rat thoracic aorta.
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.
Rozec
Bertrand
B
L'institut du thorax, Inserm U533, Faculté de Médecine, 1 rue Gaston Veil, BP 53508, Nantes F-44035, France.
Quang
Thuy Tran
TT
Noireaud
Jacques
J
Gauthier
Chantal
C
D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D004983:Ethanolamines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D000068577:Nebivolol; D009569:Nitric Oxide / Q000502:physiology; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D000068577:Nebivolol; D010656:Phenylephrine; D009569:Nitric Oxide