Effects of MCI-154, a new cardiotonic Ca2+ sensitizer, on ventricular arrhythmias and membrane ionic currents

We examined whether a new positive inotropic agent with Ca(2+)-sensitizing activity, MCI-154, 6-[4-(4-pyridylamino)phenyl]-4, 5-dihydro-3-(2H)-pyridazinone hydrochloride trihydrate, had deleterious effects on ventricular arrhythmias, since several phosphodiesterase III inhibitors have been shown to aggravate arrhythmias in our earlier studies. Continuous infusion of MCI-154 (1 microgram/kg/min for 15 min) did not suppress or aggravate the arrhythmias generated in the two-stage coronary ligation-, digitalis- and adrenaline-induced canine arrhythmia models studied. Also in the case of a bolus injection of 30 micrograms/kg, MCI-154 did not aggravate the adrenaline-induced arrhythmias. To explain these results in vivo, a whole-cell voltage-clamp experiment on guinea-pig ventricular cells was performed. MCI-154 (10-100 microM) did not increase the inward Ca2+ current under the condition where these currents were increased by isoprenaline. These results indicate that MCI-154 does not aggravate ventricular arrhythmias and does not act on membrane currents associated with arrhythmogenesis. Thus, MCI-154 may become a useful positive inotropic agent with little arrhythmogenic effect.