Potent stimulation of myofilament force and adenosine triphosphatase activity of canine cardiac muscle through a direct enhancement of troponin C Ca++ binding by MCI-154, a novel cardiotonic agent.
In the present study we have analyzed a likely biochemical mechanism underlying the Ca++-sensitizing action of MCI-154 (6-[4-(4'-pyridyl)aminophenyl)-4,5-dihydro-3(2H)-pyridazinone hydrochloride), a novel cardiotonic agent, on the contractile protein system. MCI-154 (10(-7) to 10(-4) M) enhanced the tension development induced by -log molar-free Ca++ concentration (pCa) 5.8 in chemically skinned fiber from the canine right ventricular muscle in a concentration-dependent manner. At pCa 7.0, MCI-154 (10(-7) to 10(-4) M) markedly increased adenosine triphosphatase (ATPase) activities of canine myofibrils and reconstituted actomyosin. In myofibrils and reconstituted actomyosin, MCI-154 (10(-7) to 10(-4) M) caused a parallel shift of the pCa-ATPase activity relation curve to the left without affecting the maximum activity, suggesting an increase in Ca++ sensitivity. MCI-154 (10(-8) to 10(-4) M) had little effect on actin-activated, Mg++, Ca++ and (K+, EDTA)-ATPase activities of myosin. Ca++ binding to cardiac myofibrils or purified cardiac troponin was increased by 10(-4) M MCI-154. These results suggest that MCI-154 enhances Ca++ binding to cardiac troponin C to elevate the Ca++ sensitivity of myofilaments and thus may cause a positive inotropic action in cardiac muscle. MCI-154 may provide a valuable tool for studying the molecular mechanism by which Ca++ regulates the contractile system.
Kitada
Y
Y
Research Center, Mitsubishi Kasei Corporation, Yokohama, Japan.
Kobayashi
M
M
Narimatsu
A
A
Ohizumi
Y
Y
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000494:pharmacology; D004285:Dogs; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects*; D009210:Myofibrils / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding; D011724:Pyridazines / Q000494:pharmacology*; D014336:Troponin / Q000378:metabolism*; D019209:Troponin C; D016276:Ventricular Function
D002316:Cardiotonic Agents; D011724:Pyridazines; D014336:Troponin; D019209:Troponin C; C052228:MCI 154; D000242:Cyclic AMP; D000251:Adenosine Triphosphatases; D002118:Calcium