Vol. 293, Issue 2, 501-508, May 2000

Effects of Mitoxantrone on Excitation-Contraction Coupling in Guinea Pig Ventricular Myocytes¹

Ge-Xin Wang, Xiao-Bo Zhou and Michael Korth

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany

The mechanisms of the inotropic effect of mitoxantrone (MTO), a synthetic dihydroxyanthracenedione derivative with antineoplastic activity, was investigated in guinea pig ventricular myocytes using whole-cell patch-clamp methods combined with fura-2 fluorescence and cell-edge tracking techniques. In right ventricular papillary muscles, 30 µM MTO increased isometric force of contraction as well as action potential duration (APD) in a time-dependent manner. The force of contraction was increased approximately 3-fold within 4 h. This positive inotropic effect was accompanied by a prolongation of time to peak force and relaxation time. In current-clamped single myocytes treated with 30 µM MTO for 30 min, an increase of cell shortening by 77% and a prolongation of APD by 19% was observed. Peak amplitude of the intracellular Ca²⁺ transients was also increased by 10%. The contribution of APD prolongation to the enhancement of cell shortening induced by MTO was assessed by clamping control myocytes with action potentials of various duration. Prolongation of APD₉₀ (ADP measured at 90% of repolarization) by 24% led to an increase of cell shortening by 13%. When the cells were clamped by an action potential with constant APD, MTO still caused an increase of cell shortening by 59% within 30 min. No increase of the peak intracellular Ca²⁺ transients, however, was observed under this condition. We conclude that both the APD prolongation and a direct interaction with the contractile proteins contributed to the positive inotropic effect of MTO.