INCREASE IN CA++ SENSITIVITY OF THE CONTRACTILE SYSTEM BY MCI-154, A NOVEL CARDIOTONIC AGENT, IN CHEMICALLY SKINNED FIBERS FROM THE GUINEA-PIG PAPILLARY-MUSCLES

  • 1 November 1987
    • journal article
    • research article
    • Vol. 243  (2) , 633-638
Abstract
The effects of MCI-154, a novel cardiotonic agent, on the contractile protein system and the sarcoplasmic reticulum (SR) were investigated by using thin bundles of chemically skinned fibers from the guinea pig papillary muscles. In the skinned muscle fibers treated with 50 .mu.g/ml of saponin, MCI-154 shifted the -log[Ca++]M-tension relation curve to the left and upward in the concentration-dependent manner (10-7 to 10-4 M). This was confirmed also in the skinned muscle fibers treated with 250 .mu.g/ml of saponin which destroyed not only the surface membrane but also the function of SR. Sulmazole (10-4 M) shifted the -log[Ca++]M-tension relation curve to the left but the effect was about 100 times less potent than that of MCI-154. Unlike MCI-154, sulmazole had little effect on the maximum tension development induced by -log[Ca++]M 4.4. Milrinone did not affect the Ca++-induced tension development in the skinned cardiac fibers. Higher concentration of MCI-154 (10-4 M) also increased amplitude of -log[Mg-ATP]M-tension-curve in the absence of free Ca++ ion (bell-shaped curve) to the upward. Initial rate and plateau phase of Ca++ uptake by the SR in the skinned fibers treated with 50 .mu.g/ml of saponin was increased slightly by MCI-154 at the concentrations of 10-6 and 10-4 M. MCI-154 had no effect on the Ca++-induced Ca++ release mechanism in the SR. These results suggest that an increase in Ca++ sensitivity of the contractile protein system is responsible for, at least in part, the mechanism of the positive inotropic action of MCI-154. The effects of high concentration of MCI-154 on the maximal Ca++-activated tension development and on the -log[MG-ATP]M-tension relation suggest that the drug facilitates the interaction between actin and myosin. No direct action of MCI-154 on the cardiac SR was found to contribute to the positive inotropic action of the drug.