Adriamycin cardiotoxicity: Possible pathogenic mechanisms

Abstract

The antitumor agent, adriamycin, causes in humans a cardiomyopathy associated with elevated tissue Ca 2+. Hence, adriamycin was tested for an ability to affect the Ca 2+ influx mediated by the slow channels in ventricular cells of isolated perfused chick hearts. The fast Na + channels were blocked by tetrodotoxin or voltage inactivated by elevated (25 m m) K +, thus rendering the hearts inexcitable. Low concentrations of adriamycin (0.01 to 0.05 mg/ml) restored excitability in the form of slow action potentials (APs), and enhanced the maximum upstroke velocity ( + V ̇ max ) of slow APs induced by isoproterenol (10 −6 m). Higher concentrations (0.1 to 0.5 mg/ml) did not induce slow APs, and actually depressed or blocked the isoproterenol-induced slow APs. On the contractions recorded from hearts perfused with normal Tyrode solution, adriamycin also had a dual effect: at low concentrations, it had a positive inotropic action, whereas at higher concentrations, it had a negative inotropic action. Adriamycin (0.05 mg/ml) caused the cyclic AMP level to increase by about 50% over the control within 15 min, thus suggesting that this might be responsible for its positive inotropism. Higher concentrations (0.3 mg/ml) also raised the cyclic AMP, but the ATP level was depressed. In isolated mitochondria, adriamycin (0.5 mg/ml) depressed ADP-stimulated respiration, suggesting that impaired mitochondrial function could cause the depressed ATP levels. The results indicate that low concentrations of adriamycin augment the slow current, possibly by an increase in cyclic AMP level, whereas high concentration (0.5 mg/ml) depresses the slow current, perhaps due to lowered ATP levels. The enhanced Ca 2+ influx (via stimulation of the slow channels) could be a factor in the Ca 2+ overload associated with the adriamycin-induced cardiomyopathy.