On the Mechanism by Which Doxorubicin Abolishes the Oscillatory Events Induced by Ca Overload in Single Cardiac Myocytes

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Abstract
The mechanism by which doxorubicin (DOXO) modifies the voltage and current changes induced by Ca overload was investigated in isolated guinea pig ventricular myocytes. In the presence of norepinephrine (NE 0.1 microM), drive induces an oscillatory potential (Vos) superimposed on a prolonged depolarization (Vex): DOXO (10-50 microM) decreases or abolishes Vos but exaggerates Vex. In high [Ca]o (5.4-8.1 mM), drive induces Vos and Vex, and DOXO has the same effects as in NE. Trains of voltage-clamp steps induce Ios and Iex (the currents underlying Vos and Vex, respectively): DOXO decreases or abolishes Ios but increases Iex both in NE and high [Ca]o. DOXO does not decrease the slow inward current Isi. Caffeine (5 mM) abolishes Vos and Ios and increases Vex and Iex (as DOXO does), and adding DOXO slightly increased Vex and Iex. Ni (2 mM) (which blocks Na-Ca exchange) decreases or abolishes DOXO-induced Vex and Iex. In papillary muscles, reduced [Na]o or high [Ca]o increases force, but DOXO has little inotropic effect. Reduced [Na]o and high [Ca]o also increase force less in the presence of DOXO. We conclude that DOXO abolishes Vos and Ios but not by blocking the adrenergic receptor, decreasing Isi, or inhibiting Na-Ca exchange. Instead, DOXO may act by impairing uptake and release of Ca by the sarcoplasmic reticulum membrane.

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