title: Lack of evidence that nebivolol is a β₃-adrenoceptor agonist.
abstract: 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.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Amsterdam, Meibergdreef 15, Amsterdam, The Netherlands.
authors.forename: Elfaridah P
authors.initials: EP
authors.lastname: Frazier
authors.forename: Martina B
authors.initials: MB
authors.lastname: Michel-Reher
authors.forename: Pieter
authors.initials: P
authors.lastname: van Loenen
authors.forename: Carsten
authors.initials: C
authors.lastname: Sand
authors.forename: Tim
authors.initials: T
authors.lastname: Schneider
authors.forename: Stephan L M
authors.initials: SL
authors.lastname: Peters
authors.forename: Martin C
authors.initials: MC
authors.lastname: Michel
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D000068577:Nebivolol; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects* / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D058671:Adrenergic beta-1 Receptor Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D011412:Propanolamines; D022702:Receptors, Adrenergic, beta-3; D000068577:Nebivolol; D000242:Cyclic AMP