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 β-blockers against the positive inotropic effects (PIEs) of isoproterenol, a nonselective agonist, and T-0509, a β 1 -selective agonist. The selective β 1 -bSockbrs atenolol and bisoprolol antagonized the PIE of T-0509 monophasically in Schild analysis, showing pA 2 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 pK B values were obtained (7.75 and 4.25 and 7.82 and 5.76, respectively). Nadolol, a nonselective β-blocker, also antagonized the PIE of T-0509 monophasically (pA 2 value 7.58), but antagonized the PIE of ISO biphasically (pK B values 7.42 and 4.39). Because the different mode of antagonism by three β-blockers between T-0509 and ISO could not be explained by the selectivities of β-agonists and blockers for β 1 - and β 2 -adrenoceptors in the heart, two subtypes of β 1 -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.