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

J C Rüegg

    Circulation
    |March 1, 1986
    PubMed

    Insights

    New cardiotonic drugs, sulmazole and pimobendane, enhance cardiac muscle contraction by increasing myofilament sensitivity to calcium. This calcium-sensitizing effect contributes to their positive inotropic action in heart muscle.

    Area of Science:

    • Cardiology
    • Pharmacology
    • Muscle Physiology

    Background:

    • Cardiac muscle contraction is regulated by intracellular calcium, but this relationship is not fixed.
    • New positive inotropic drugs can modulate this relationship, affecting heart contractility.
    • Studying calcium sensitivity in skinned cardiac fibers allows precise control over ionic conditions.

    Purpose of the Study:

    • To investigate the mechanism of action of novel cardiotonic drugs, sulmazole and pimobendane.
    • To determine if these drugs modulate the sensitivity of cardiac myofilaments to calcium.
    • To explore the role of troponin in the drugs' effects.

    Main Methods:

    • Experiments were conducted on chemically skinned mammalian cardiac fibers, lacking a functional sarcoplasmic reticulum.
    • Fibers were exposed to varying calcium concentrations (Ca++) in a controlled ionic environment.
    • The effects of sulmazole and pimobendane on calcium-induced contraction were measured.

    Main Results:

    • Sulmazole and pimobendane increased calcium-induced contraction in skinned cardiac fibers by 30-50% at low calcium levels (1 microM).
    • This effect was attributed to increased myofilament sensitivity to calcium, potentially via enhanced troponin calcium affinity for sulmazole.
    • No effect was observed in skinned smooth muscle fibers lacking troponin.

    Conclusions:

    • The positive inotropic effects of sulmazole and pimobendane may be partly due to their calcium-sensitizing action on cardiac myofilaments.
    • These drugs enhance the contractile response of cardiac muscle to calcium.
    • Other mechanisms increasing intracellular free calcium may also contribute to their overall effect.

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