Adriamycin Causes Dual Inotropic Effects Through Complex Modulation of Myocardial Ca2+ Handling

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Abstract
Effects of adriamycin (ADR) on the twitch contraction of isolated guinea pig cardiac muscles were examined to elucidate its actions on intracellular Ca2+ mobilization. In right ventricular papillary muscles, ADR (100-300μmol/L) caused positive inotropy when the muscles were constantly stimulated at low frequencies (0.1-0.5 Hz), whereas it caused negative inotropy when the muscles were stimulated at higher frequencies (2.0-3.0 Hz). Action potential duration was prolonged significantly by ADR, especially at the lower frequencies. The potentiation of twitch contraction of the first beat (B1) following a short rest period (2-10s) in ventricular muscles was inhibited by ADR. In untreated papillary muscles, B1 contraction showed time-dependent decay in response to a prolongation of the preceding rest period up to 120s. ADR (300μmol/L) caused ryanodin-like acceleration for the early B1 decay with rest period less than 20s, but a substantial deceleration for the later B1 decay (≥30s). In left atrial muscles stimulated constantly, ADR had significant negative inotropy troughout the entire range of stimulation frequencies tested (0.1-4.0 Hz). The post-rest potentiation of B1 contraction of atrial muscle in the presence of nifedipine was also inhibited by ADR. These findings suggest that ADR has dual inotropic effects through a complex modulation of myocardial Ca2+ handling, which may involve (1) an increase of Ca2+ influx through a prolongation of action potential duration, (2) ryanodine-like inhibition of Ca2+ release from the sarcoplasmic reticulum, and (3) inhibition of sarcolemmal Ca2+ extrusion probably through the Na+/Ca2+ exchange.