ALPHA(1)-ADRENOCEPTOR SUBTYPES MEDIATING INOTROPIC AND ELECTROPHYSIOLOGICAL EFFECTS IN MAMMALIAN MYOCARDIUM

Stimulation of alpha(1)-adrenoceptors produces a positive inotropic ef fect in rat and rabbit ventricular myocardium via different mechanisms , the prolongation of action potential duration (APD) exclusively in t he former and an increase in myofibrillar Ca2+ sensitivity in large pa rt in the latter. This study was designed to determine whether the two inotropic mechanisms are mediated by different alpha(1)-adrenoceptor subtypes. In rat papillary muscles, the positive inotropic effect and APD prolongation induced by phenylephrine (in the presence of proprano lol) were inhibited by WB-4101, but not affected by chlorethylclonidin e (CEC). WB-4101, but not CEC, blocked the phenylephrine-induced inhib ition of the transient outward current (I-to) in rat ventricular cells . On the other hand, WB-4101 and CEC each antagonized the positive ino tropic effect of phenylephrine in rabbit papillary muscles. However, t he phenylephrine-induced APD prolongation observed in rabbit papillary muscles was blocked only by WB-4101. These results indicate that the WB-4101-sensitive alpha(1)-adrenoceptor subtype mediates the positive inotropism that is correlated with the APD prolongation resulting from I-to reduction, whereas the CEC-sensitive subtype mediates the positi ve inotropism that is probably associated with increased myofibrillar Ca2+ sensitivity. Radioligand binding studies with [H-3]prazosin showe d a similar ratio of alpha(1A)- to alpha(1B)-adrenoceptor subtypes in rat and rabbit ventricular myocardium, implying that the different deg ree of contribution of each action mechanism to the overall inotropic effect in the two species cannot be explained by distribution of the a lpha(1)-adrenoceptor subtypes.