A Calcium Antagonist Protects against Doxorubicin-Induced Impairment of Calcium Handling in Neonatal Rat Cardiac Myocytes

Abstract

The effects of doxorubicin (DOX) on intracellular calcium transients and the cardioprotective effects of a calcium antagonist on DOX-induced impairment of calcium handling were examined in neonatal rat cultured cardiac myocytes. Cultured cardiac myocytes isolated from neonatal Wistar-Kyoto rats were treated with DOX for 24 h. Field-stimulated calcium transients in single myocytes were measured in the presence or absence of isoproterenol using fura-2/AM. Calcium transients were also measured after the addition of DOX to myocytes pretreated with a calcium antagonist, benidipine. DOX reduced the amplitude, maximum velocity of increase and decrease of calcium transients and prolonged the time course of calcium transients and impaired the beta-adrenoceptor responsiveness of calcium transients in a concentration-dependent manner. The DOX-induced impairment of calcium transients and beta-adrenoceptor responsiveness was improved by 10(-8) mol/L of benidipine. However, these improvements decreased with increasing concentrations of benidipine. DOX impaired both the mobilization and removal of intracellular calcium ions in contraction-relaxation cycles and the response of calcium transients to beta-adrenoceptor stimulation. Appropriate concentration of benidipine ameliorated DOX-induced impairment of calcium dynamics, suggesting that benidipine, a long-acting calcium antagonist, has potential clinical usefulness on DOX-induced abnormal calcium handling.