Lack of evidence that nebivolol is a β3-adrenoceptor agonist

• Published in: European journal of pharmacology Vol. 654; no. 1; pp. 86 - 91
• Main Authors: Frazier, Elfaridah P., Michel-Reher, Martina B., van Loenen, Pieter, Sand, Carsten, Schneider, Tim, Peters, Stephan L.M., Michel, Martin C.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01-03-2011; Elsevier
• Subjects: Adrenergic beta-1 Receptor Antagonists - administration & dosage; Adrenergic beta-1 Receptor Antagonists - pharmacology; agonists; animal ovaries; Animals; antagonists; Benzopyrans - administration & dosage; Benzopyrans - pharmacology; Biological and medical sciences; bladder; blood vessels; Chinese hamster ovary cell; Chinese hamsters; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP - metabolism; Dose-Response Relationship, Drug; Ethanolamines - administration & dosage; Ethanolamines - pharmacology; Humans; Male; Medical sciences; myocytes; Nebivolol; pharmacology; Pharmacology. Drug treatments; Propanolamines - pharmacology; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3 - drug effects; Receptors, Adrenergic, beta-3 - metabolism; smooth muscle; Urinary bladder; Urinary Bladder - drug effects; Urinary Bladder - metabolism; vasodilation; β3-Adrenoceptor; Nebivolol; Chinese hamster ovary cell; Urinary bladder; β3-Adrenoceptor; Agonist; Rodentia; β3-Adrenergic receptor; In vitro; Adrenoceptor; β-Adrenergic receptor; Ovary; Vertebrata; β; Mammalia; β1-Adrenergic receptor; Urinary system; Female genital system; Antihypertensive agent; Antagonist; Hamster; Beta blocking agent
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2010.11.036

Nebivolol is a selective β1-adrenoceptor antagonist which, in addition, displays endothelium-dependent vasodilating properties in humans and other species. β3-Adrenoceptors have been proposed to be a molecular target of nebivolol-induced vasodilatation. Therefore, we have investigated possible β3-adrenoceptor agonism by nebivolol for relaxation of the human and rat urinary bladder (prototypical β3-adrenoceptor-mediated responses) as well as for cAMP accumulation in Chinese hamster ovary cells stably transfected with the human β-adrenoceptor subtypes. Nebivolol concentration-dependently relaxed both human and rat isolated urinary bladder strips but with low potency, similar to that reported for vasodilatation. However, nebivolol-induced bladder relaxation in either species was not inhibited by the β3-adrenoceptor antagonist SR 59,230A (10μM), although this compound inhibited the isoprenaline-induced relaxation with the expected potency. In radioligand binding studies nebivolol had lower affinity for human β3-adrenoceptors than the other two β-adrenoceptor subtypes, but this low affinity was in line with its potency to relax the bladder or isolated blood vessels. In functional studies nebivolol even in high concentrations did not stimulate cAMP formation via any of the three cloned human β-adrenoceptors or in rat bladder smooth muscle cells. Taken together these data demonstrate that nebivolol can relax not only vascular but also urinary bladder smooth muscle. However, they do not support the hypothesis that nebivolol is an agonist at cloned human β3-adrenoceptors or in rat or human urinary bladder.