Adriamycin causes dual inotropic effects through complex modulation of myocardial Ca2+ handling.
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 (100-300 micromol/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 (B 1) following a short rest period (2-10 s) 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 120 s. ADR (300 micromol/L) caused ryanodin-like acceleration for the early B1 decay with rest period less than 20 s, but a substantial deceleration for the later B1 decay (> or =30 s). In left atrial muscles stimulated constantly, ADR had significant negative inotropy throughout the entire range of stimulation frequencies tested (0.1-4.0 Hz). The post-rest potentiation of B 1 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.
Matsushita
T
T
Department of Cardiology, Aichi Prefectural Owari Hospital Cardiovascular Center, Ichinomiya, Japan. toyo@qa2.so-net.ne.jp
Okamato
M
M
Toyama
J
J
Kodama
I
I
Ito
S
S
Fukutomi
T
T
Suzuki
S
S
Itoh
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D004558:Electric Stimulation / Q000379:methods; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology
D004317:Doxorubicin; D009543:Nifedipine; D002118:Calcium