ICI 147,798 causes insurmountable antagonism against T-0509, a selective β₁-adrenoceptor agonist, but surmountable antagonism against isoproterenol

In canine right ventricular muscle, the influence of ICI 147,798, a slowly dissociable β₁-adrenoceptor antagonist, on the positive inotropic effect and cyclic AMP production of T-0509, a selective β₁-agonist, and isoproterenol, a nonselective β-agonist, were examined to elucidate the properties of the high- and low-affinity states or subtypes of β¹-adrenoceptor. ICI 147,798 (1 × 10^-8-1 × 10 ^-5 M) produced biphasic concentration-response curves for the positive inotropic effect of T-0509 that were due to its insurmountable antagonism against the lower concentrations of T-0509. The maximum of the biphasic curves were almost the same as Ca_max. Analysis of hemiequilibrium antagonism by ICI 147,798 against T-0509 showed the dissociation constant (pK_B) of ICI 147,798 to be 8. On the other hand, ICI 147,798 produced a parallel rightward shift of the curves of isoproterenol. Schild analysis showed pA₂ to be 7.98 ± 0.04, suggesting competitive antagonism. The concentration-response curve for the increase in cyclic AMP elicited by T-0509 in the presence of 1 × 10^-6 M ICI 147,798 was also biphasic, but slightly depressed as compared with that of control, whereas that elicited by isoproterenol was shifted to the right. The positive inotropy and increase in cyclic AMP produced by T-0509 and isoproterenol in the presence of ICI 147,798 may be mediated by the low-affinity state of β₁-adrenoceptor, which mechanism may be different from that producing the positive inotropy through the high-affinity state of β₁-adrenoceptor.