Takuji Tanimoto

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.

Cyclic adenosine monophosphate modulation of contractility via slow Ca2+ channels in chick heart

Abstract The catecholamines exert a positive inotropic effect associated with elevated tissue cyclic AMP levels and possibly with increase in the number of membrane slow cationic channels available for voltage activation. In the present study, catecholamines (isoproterenol, dopamine and dobutamine) were tested for their ability to affect the maximum upstroke velocity (+ V max ) of the slow action potentials, the first derivative ( d T d t ) of developed tension accompanying the slow responses, and the tissue cyclic AMP levels in the ventricular myocardium of isolated perfused chick hearts. To study the slow channels exclusively, the fast Na + channels were voltage inactivated by elevated (25 m m ) K + . In this condition of functional removal of the fast channels, the heart could not be excited by intense electrical stimulation. It was found that these catecholamines induced slow action potentials accompanied by contractions. Elevation of the concentration of these agents produced increases in + V max , d T d t , and cyclic AMP in a dose-dependent fashion; a close correlation was obtained between the cyclic AMP level, + V max and d T d t . These results support the hypothesis that the increases in + V max of the slow action potentials and in contraction are explained by increase in the number of available slow channels mediated by intracellular cyclic AMP levels, and the resulting increase in the Ca 2+ influx.