SELECTIVE-INHIBITION BY E4080, A NOVEL BRADYCARDIAC AGENT, OF POSITIVE CHRONOTROPIC RESPONSES TO NOREPINEPHRINE IN ISOLATED DOG HEARTS

E4080, a novel bradycardic agent acts on various ionic currents includ ing the hyperpolarization-activated inward current (I(f)), L-type Ca2 current (I(Ca)) and ATP-sensitive K+ (K(ATP)+) current in mammalian h eart and vascular tissues. We thus investigated the chronotropic and i notropic effects of E4080 and its interaction with the positive cardia c responses to norepinephrine, 3-isobutyl-1-methyl-xanthine (IBMX) and Bay k 8644 in the isolated, blood-perfused dog right atria and left v entricles. E4080 (0.01-1 mumol) decreased the sinus rate and atrial an d ventricular contractile forces in a dose-related manner. Glibenclami de (3 mumol) partly blocked the decrease in atrial force but not the d ecreases in sinus rate and ventricular force induced by E4080. Atropin e (10 nmol) did not affect the negative cardiac responses to E4080. E4 080 (0.01-1 mumol) inhibited the positive chronotropic responses to no repinephrine and IBMX dose dependently, but did not inhibit the positi ve inotropic ones in isolated atria. E4080 affected neither positive c hronotropic nor inotropic responses to Bay k 8644. These results sugge st that (1) the activation of K(ATP)+ channels by E4080 is partly rela ted to the decrease in atrial force but not the decreases in sinus rat e and ventricular force, and (2) the selective inhibition of E4080 of the cyclic AMP-dependent positive chronotropic responses but not inotr opic ones is probably due to the inhibition of If rather than other pr operties, e.g., activation of K(ATP)+ channels and inhibition of I(Ca) in the dog heart.