Abstract
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.
Footnotes
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Send reprint requests to: Dr. Michael Korth, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitäts-Krankenhaus Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. E-mail: korth{at}uke.uni-hamburg.de
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↵1 This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Ko 659/5-1).
- Abbreviations:
- MTO
- mitoxantrone
- SR
- sarcoplasmic reticulum
- APD
- action potential duration
- APD90
- APD measured at 90% of repolarization
- TTX
- tetrodotoxin
- AP clamp
- action potential clamp
- [Ca2+]i
- intracellular Ca2+concentration
- R
- ratio
- Received November 18, 1999.
- Accepted February 1, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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