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.
Eto
K
K
Department of Pharmacology, Yamanashi Medical University, Japan.
Xue
Y X
YX
Hashimoto
K
K
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control*; D002118:Calcium / Q000502:physiology*; D002316:Cardiotonic Agents / Q000097:blood / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003331:Coronary Vessels / Q000502:physiology; D004285:Dogs; D004594:Electrophysiology; D004837:Epinephrine; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010042:Ouabain; D018408:Patch-Clamp Techniques; D011724:Pyridazines / Q000097:blood / Q000494:pharmacology*
D002316:Cardiotonic Agents; D007473:Ion Channels; D011724:Pyridazines; D010042:Ouabain; C052228:MCI 154; D002118:Calcium; D004837:Epinephrine