Comparison of the effects of MCI-154, a new cardiotonic agent, and some Ca2+-sensitizing agents on the response of the contractile system to Ca2+ in skinned cardiac muscle

Several cardiotonic agents (MCI-154, sulmazole, pimobendan and adibendan) were examined for their ability to influence Ca2+-activated tension development and MgATP-activated tension development in the absence of free Ca2+ (rigor tension), using the chemically skinned fiber from guinea pig papillary muscles. MCI-154, sulmazole, pimobendan and adibendan all increased the tension development induced by pCa (-log[Ca2+]M) 5.8 in a concentration-dependent manner (10(-6) to 10(-4) M). The order of the potency was as follows: MCI-154 greater than pimobendan greater than adibendan greater than sulmazole. MCI-154 enhanced the maximum tension developed at pCa 4.4 but sulmazole, pimobendan and adibendan did not enhance it. MCI-154, but not sulmazole, pimobendan and adibendan, enhanced the tension development induced by pMgATP (-log[MgATP]M) 6.0 in the absence of free Ca2+. MCI-154, sulmazole, pimobendan and adibendan concentration-dependently (10(-7) to 10(-4) M) increased the force of contraction in isolated guinea pig papillary muscles. The order of the potency was as follows: MCI-154 greater than adibendan greater than pimobendan greater than sulmazole. These results demonstrated that the Ca2+-sensitizing action on the contractile system may be involved in the positive inotropic action of MCI-154, sulmazole, pimobendan and adibendan, and that MCI-154 is the most potent among these drugs. Furthermore, sulmazole, pimobendan and adibendan did not enhance the interaction of actin and myosin, suggesting that the mechanism of actions of these drugs are qualitatively different from that of MCI-154.