Role of alpha1A adrenoceptor subtype in production of the positive inotropic effect mediated via myocardial alpha,adrenoceptors in the rabbit papillary muscle: influence of selective alpha1A subtype antagonists WB 4101 and 5-methylurapidil

Summary In order to elucidate the contribution of alpha_1A subtype to the positive inotropic effect mediated by myocardial alpha, adrenoceptors, the influence of the alpha_1A selective antagonists WB 4101 and 5-methylurapidil on the alpha,-mediated positive inotropic effect (induced by phenylephrine in the presence of a beta adrenoceptor blocking agent bupranolol) was assessed in the isolated rabbit papillary muscle. WB 4101 (10^–9-10^–7mol/l) shifted the concentration-response curve of the alpha,-mediated positive inotropic effect to the right in parallel, but the slope of Schild plot did not meet the competitive antagonism: WB 4101 shifted the curve by log one unit at 10^–9 mol/1, whereas it did not cause further shift at higher concentrations of 10^–8 and 10^–7 mol/l. WB 4101 did not affect the beta adrenoceptor-mediated positive inotropic effect. 5-Methylurapidil (10^–9 to 10^–7 mol/l) shifted the curve of alpha₁-mediated positive inotropic effect to the right and downwards in a concentration-dependent manner; the slope of Schild plot calculated at the level of 20% of the maximum response to phenylephrine was close to unity. 5-Methylurapidil at 3 × 10^–7 mol/1 abolished the alpha₁-mediated positive inotropic effect. In addition, 5-methylurapidil inhibited the beta adrenoceptor-mediated positive inotropic effect in the same concentration range as it antagonized the alpha₁-mediated positive inotropic effect, indicating that 5-methylurapidil is not selective for myocardial alpha, adrenoceptors. In the membrane fraction derived from the rabbit ventricular muscle, 5-methylurapidil displaced the specific binding of [³H]CGP-12177 with high affinity, whereas WB 4101 did not affect the [³H]CGP-12177 binding in the concentration range that it antagonized the alpha,-mediated positive inotropic effect. The present results indicate that alpha_1A adrenoceptor subtype plays a role in production of the positive inotropic effect mediated by myocardial alpha, adrenoceptors, but the extent is less than that mediated by alpha_1B subtype in the rabbit ventricular myocardium.Send offprint requests to M. Endoh at the above address