Adriamycin causes dual inotropic effects through complex modulation of myocardial Ca2+ handling

Effects of adriamycin (ADR) on the twitch contraction of isolated guinea pi g cardiac muscles were examined to elucidate its actions on intracellular C a2+ mobilization. In right ventricular papillary muscles, ADR (100-300 mu m ol/L) caused positive inotropy when the muscles were constantly stimulated at low frequencies (0.1-0.5 Hz), whereas it caused negative inotropy when t he muscles were stimulated at higher frequencies (2.0-3.0 Hz). Action poten tial duration was prolonged significantly by ADR, especially at the lower f requencies. The potentiation of twitch contraction of the first beat (B1) f ollowing a short rest period (2-10s) in ventricular muscles was inhibited b y ADR. In untreated papillary muscles, B1 contraction showed time-dependent decay in response to a prolongation of the preceding rest period up to 120 s. ADR (300 mu mol/L) caused ryanodin-like acceleration for the early B1 d ecay with rest period less than 20s, but a substantial deceleration for the later B1 decay (greater than or equal to 30s). In left atrial muscles stim ulated constantly, ADR had significant negative inotropy throughout the ent ire range of stimulation frequencies tested (0.1-4.0 Hz). The post-rest pot entiation of B1 contraction of atrial muscle in the presence of nifedipine was also inhibited by ADR. These findings suggest that ADR has dual inotrop ic 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 p robably through the Na+/Ca2+ exchange.