title: Beta-adrenoceptor-mediated cAMP accumulation in cardiac cells: effects of nebivolol.
abstract: The effects of nebivolol, the racemic mixture of the SRRR and RSSS enantiomers, on beta-adrenoceptor-mediated cAMP accumulation in living cardiac cells were compared to those of beta-adrenoceptor antagonists. Serum-free cultivation of cardiac cells from ventricles of 2 to 3-day-old Wistar rats resulted in a population of contractile cardiac cells almost free of mesenchymal non-myocardial cells. Isoproterenol stimulated beta 1- as well as beta 2-adrenoceptor sites. Selective beta 1- and beta 2-receptor site occlusion, in the presence of an appropriate concentration of the selective beta 2-adrenoceptor antagonist, ICI 118-551, or the selective beta 1-adrenoceptor antagonist, CGP 20712-A, showed that the receptor population consisted of mostly the beta 1-adrenergic subtype. The latter could be specifically stimulated by noradrenaline. Nebivolol and d-nebivolol (SRRR) inhibited noradrenaline-induced cAMP accumulation with IC50 values of 22 and 15 nM, respectively. CGP 20712-A was 10 times more active and atenolol was 7 times less active than nebivolol. Both assays, beta-adrenoceptor binding and cAMP accumulation, evidenced beta-adrenoceptor antagonistic properties only for the d-enantiomer of nebivolol (SRRR). 1-Nebivolol (RSSS) showed no beta-adrenergic activity.
authors.affiliation: Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse, Belgium.
authors.forename: P J
authors.initials: PJ
authors.lastname: Pauwels
authors.forename: J E
authors.initials: JE
authors.lastname: Leysen
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004983:Ethanolamines / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D000068577:Nebivolol; D009638:Norepinephrine / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D000068577:Nebivolol; D000242:Cyclic AMP; D007545:Isoproterenol; D009638:Norepinephrine