Abstract
Cationic amphiphilic drugs such as imipramine, chlorimipramine, chlorpromazine, chlorphentermine, and chloroquine have been shown to cause myocardial toxicity including arrhythmia, cardiomyopathy, and myocarditis. Since calcium transport by sarcoplasmic reticulum (SR) plays a critical role in contraction-relaxation coupling of myocardium, the toxicity exhibited by these drugs could be due to their effects on this phenomenon. Hence, we have studied the effects in vitro and in vivo of imipramine, chlorimipramine, chlorpromazine, chloroquine, and chlorphentermine on cardiac SR 45Ca-uptake and Ca2+-ATPase in male Fisher-344 rats. For in vitro studies, cardiac SR was prepared from normal rat hearts. For in vivo studies, rats were treated with drugs by oral gavage (p.o) at a dose of 20 pair-fed. All these drugs in vitro inhibited the cardiac SR 45Ca-uptake to a varying extent. The order of potency is chlorimipramine > chlorpromazine > imipramine > chlorphentermine > chloroquine. The inhibitory pattern of these drugs on cardiac SR Ca2+-ATPase also followed the same trend. The chlorinated analogs of these drugs are more potent in inhibiting 45Ca-uptake as well as Ca2+-ATPase as compared to their nonchlorinated con-geners. In vivo, all the drugs except chloroquine inhibited the 45Ca-uptake and Ca2+-ATPase activity to a different extent. The inhibition of cardiac SR calcium pump activity was seen as early as 7 days of treatment with chlorimipramine whereas all the other drugs (imipramine, chlorpromazine, and chlorphentermine) inhibited this calcium pump only at 21 days of treatment. Although in vivo chloroquine-induced inhibition of calcium pump activity did not reach significant level, it seems that there may be an effect at higher concentrations. In summary, the present results indicate that these cationic amphiphilic drugs might be exerting myocardial toxicity due to changes in cellular Ca2+ homeostasis because of their effects on cardiac SR calcium transport phenomenon. © 1992 Wiley-Liss, Inc.
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