Biphasic antagonisms by beta-blockers against positive inotropic response through beta1-adrenoceptors in isolated canine right ventricular muscles: possible involvement of two beta 1-adrenoceptor subtypes.
In isolated canine right ventricular muscles, we investigated the differences in antagonisms by beta-blockers against the positive inotropic effects (PIEs) of isoproterenol, a nonselective agonist, and T-0509, a beta1-selective agonist. The selective beta1-blockers atenolol and bisoprolol antagonized the PIE of T-0509 monophasically in Schild analysis, showing pA2 values of 7.05 and 7.63, respectively. On the other hand, both blockers produced biphasic antagonism against the PIE of isoproterenol (ISO); therefore, two pKB values were obtained (7.75 and 4.25 and 7.82 and 5.76, respectively). Nadolol, a nonselective beta-blocker, also antagonized the PIE of T-0509 monophasically (pA2 value 7.58), but antagonized the PIE of ISO biphasically (pKB values 7.42 and 4.39). Because the different mode of antagonism by three beta-blockers between T-0509 and ISO could not be explained by the selectivities of beta-agonists and blockers for beta1- and beta2-adrenoceptors in the heart, two subtypes of beta1-adrenoceptors may exist together in canine ventricular muscles, and atenolol, bisoprolol, and nadolol may act as antagonists for the two subtypes with two different affinities.
Kurosawa
H
H
Department of Pharmacology, Tohoku University School of Medicine, Tanabe Seiyaku, Saitama, Japan.
Yanagisawa
T
T
Taira
N
N
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D017298:Bisoprolol / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005260:Female; D007545:Isoproterenol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000737:chemistry; D009248:Nadolol / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000145:classification; D013268:Stimulation, Chemical
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D018342:Receptors, Adrenergic, beta-1; D009248:Nadolol; D001262:Atenolol; C025342:RP333; D007545:Isoproterenol; D017298:Bisoprolol