Inhibition of cardiac phosphodiesterase III by the novel cardiotonic agent 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride.

The novel cardiotonic agent 6[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (MCI-154) was investigated for its cardiovascular effects and its mechanism of action. In the anaesthetized rat MCI-154 (0.01-0.3 mumol/kg i.v., bolus injection) produced a dose-dependent increase in left ventricular dP/dt, and a decrease in mean arterial pressure. A relatively small increase in heart rate was observed. The drug inhibited selectively canine cardiac phosphodiesterase III (IC50 2.5 +/- 0.6 mumol/l). In skinned porcine trabeculae, MCI-154 produced only a small increase in the Ca2+-sensitivity of the contractile proteins. The results suggest that MCI-154 is a potent cardiotonic agent, and that inhibition of phosphodiesterase III may be a important component of this effect.