Selective inhibition by E4080, a novel bradycardic agent, of positive chronotropic responses to norepinephrine in isolated dog hearts

Abstract

E4080, a novel bradycardic agent acts on various ionic currents including the hyperpolarization-activated inward current ( I f), L-type Ca 2+ current ( I Ca) and ATP-sensitive K + (K ATP +) current in mammalian heart and vascular tissues. We thus investigated the chronotropic and inotropic effects of E4080 and its interaction with the positive cardiac responses to norepinephrine, 3-isobutyl-1-methyl-xanthine (IBMX) and Bay k 8644 in the isolated, blood-perfused dog right atria and left ventricles. E4080 (0.01–1 μmol) decreased the sinus rate and atrial and ventricular contractile forces in a dose-related manner. Glibenclamide (3 μmol) partly blocked the decrease in atrial force but not the decreases in sinus rate and ventricular force induced by E4080. Atropine (10 nmol) did not affect the negative cardiac responses to E4080. E4080 )0.01−1 μmol) inhibited the positive chronotropic responses to norepinephrine and IBMX dose dependently, but did not inhibit the positive inotropic ones in isolated atria. E4080 affected neither positive chronotropic nor inotropic responses to Bay k 8644. These results suggest that (1) the activation of K ATP + channels by E4080 is partly related to the decrease in atrial force but not the decreases in sinus rate and ventricular force, and (2) the selective inhibition of E4080 of the cyclic AMP-dependent positive chronotropic responses but not inotropic ones is probably due to the inhibition of I f rather than other properties, e.g., activation of K ATP + channels and inhibition of I Ca in the dog heart.