EFFECTS OF MCI-154, A NEW CARDIOTONIC CA2+ SENSITIZER, ON VENTRICULARARRHYTHMIAS AND MEMBRANE IONIC CURRENTS

We examined whether a new positive inotropic agent with Ca2+-sensitizi ng activity, MCI-154, ridylamino)phenyl]-4,5-dihydro-3-(2H)-pyridazino ne hydrochloride trihydrate, had deleterious effects on ventricular ar rhythmias, since several phosphodiesterase III inhibitors have been sh own to aggravate arrhythmias in our earlier studies. Continuous infusi on of MCI-154 (1 mu g/kg/min for 15 min) did not suppress or aggravate the arrhythmias generated in the two-stage coronary ligation-, digita lis- and adrenaline-induced canine arrhythmia models studied. Also in the case of a bolus injection of 30 mu g/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 mu M) did not increase the inward Ca2 current under the condition where these currents were increased by is oprenaline. These results indicate that MCI-154 does not aggravate ven tricular arrhythmias and does not act on membrane currents associated with arrhythmogenesis. Thus, MCI-154 may become a useful positive inot ropic agent with little arrhythmogenic effect.