title: Comparison of the affinity of beta-blockers for two states of the beta 1-adrenoceptor in ferret ventricular myocardium.
abstract: We compared the potency of 11 clinically available beta-blockers as antagonists of the positive inotropic effects of (-)-isoprenaline and CGP12177 on ferret ventricular myocardium. (-)-CGP12177, (-)-pindolol and (-)-alprenolol were non-conventional partial agonists with intrinsic activity of 0.7, 0.2 and 0.1 respectively. All beta-blockers antagonized in a concentration-dependent and surmountable manner the positive inotropic effects of both (-)-isoprenaline and CGP12177. The potency of each beta-blocker was consistently higher against (-)-isoprenaline than against CGP12177. Two groups of beta-blockers were identified. In one group the difference between the pK(B) values of blockade against (-)-isoprenaline and CGP12177 was 1.1 - 1.6 log units ((-)-alprenolol, (-)-pindolol, (-)-bupranolol, nadolol and carvedilol). In the other group the pK(B) difference was of 2.1 - 3.0 log units ((-)-atenolol, metoprolol, bisoprolol, sotalol, (-)-propranolol and (-)-timolol). The beta-blockers competed with (-)-[(125)I]-cyanopindolol for binding to ventricular beta(1)-adrenoceptors. The binding affinities correlated with the corresponding blocking potencies against (-)-isoprenaline. On average the pK(i) values were 0.5 log units smaller than the pK(B) values against (-)-isoprenaline but 1.6 log units greater than the pK(B) values against CGP12177. In ferret ventricle the effects of (-)-isoprenaline appear to be antagonized by beta-blockers through the state of the beta(1)-adrenoceptor for which (-)-[(125)I]-cyanopindolol and beta-blockers have high affinity. The cardiostimulant effects of CGP12177 appear to be mediated through a low-affinity state of the beta(1)-adrenoceptor for which beta-blockers have low affinity.
authors.affiliation: Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Lowe
authors.forename: James A
authors.initials: JA
authors.lastname: Lynham
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Kaumann
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D013268:Stimulation, Chemical
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D018342:Receptors, Adrenergic, beta-1