Comparison of cardiac actions of doxorubicin, pirarubicin and aclarubicin in isolated guinea-pig heart.

The cardiac actions of doxorubicin were compared with those of pirarubicin and aclarubicin to understand the mechanisms responsible for differences in cardiotoxic effects of anthracycline agents. In left atrial muscle preparations obtained from guinea-pig heart and stimulated at 2 Hz, anthracyclines produced positive inotropic effects. The magnitude of the effect was pirarubicin > doxorubicin > aclarubicin. The order for depression of potentiated postrest contraction and prolongation of the time to peak twitch tension was doxorubicin > pirarubicin > aclarubicin. Drug washout following a 2-h incubation with 100 microM doxorubicin prevented a further increase in the time to peak twitch tension, caused a marked recovery of depressed potentiated postrest contractions, and augmented the positive inotropic effect. Pirarubicin and doxorubicin, but not aclarubicin, caused a parallel rightward shift of the dose-response curve for the negative inotropic effect of acetylcholine. The potency of inhibition of [3H]quinuclidinyl benzilate binding was pirarubicin > doxorubicin > aclarubicin. These results indicate that three anthracycline anticancer agents share similar effects on cardiac muscle contractility and on muscarinic acetylcholine receptors. The actions of aclarubicin were weak compared to those of doxorubicin or pirarubicin. Increases in the time to peak twitch tension and the depression of potentiated postrest contraction are apparently mediated by mechanisms different from those responsible for the positive inotropic effects or antagonism at muscarinic acetylcholine receptors.