Effects of new inotropic agents on Ca++ sensitivity of contractile proteins.

In cardiac muscle the relationship between contraction and the intracellular free calcium concentration is not unique but may vary over a wide range, as when influenced by new positive inotropic drugs. Modulation of the sensitivity of myofilaments to calcium may be studied in chemically skinned fibers devoid of a functional sarcoplasmic reticulum and in which the ionic composition of the interfilament space can be controlled and influenced at will. At low levels of activation with Ca++ (1 microM), the new nonglycosidic, nonadrenergic cardiotonic drugs sulmazole (AR-L 115 BS) and pimobendane (UD-CG 115 BS) increase calcium-induced contraction of skinned mammalian cardiac fibers by 30% to 50% in concentrations at which they exert a positive inotropic effect in vivo. The effect on skinned fibers is due to an increase in the sensitivity of the myofilaments to calcium and, at least in the case of sulmazole, may be attributed to an increase in calcium affinity of troponin. Calcium-induced contraction of skinned fibers from vertebrate smooth muscle that lacks troponin is not activated by sulmazole and pimobendane. Thus the positive inotropic action of these new cardiotonic drugs might be accounted for in part by their calcium-sensitizing action of myofilaments, although other mechanisms that increase intracellular free calcium may be involved as well.