AN ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR PROTECTS AGAINST DOXORUBICIN-INDUCED IMPAIRMENT OF CALCIUM HANDLING IN NEONATAL RAT CARDIAC MYOCYTES

1, The effects of doxorubicin (DOX) on intracellular calcium transient s were examined in neonatal rat cultured cardiac myocytes, as were the cardioprotective effects of an angiotensin-converting enzyme (ACE) in hibitor on DOX-induced impairment of calcium handling, 2, Cultured car diac myocytes isolated from neonatal Wistar-Kyoto rats were treated wi th DOX for 24h, Field-stimulated calcium transients in single myocytes were measured in the presence or in the absence of isoproterenol usin g fura-2/AM, Calcium transients were also measured after the addition of DOX to myocytes pretreated with M-I (an active metabolite of delapr il HCI, an ACE inhibitor,3, Doxorubicin reduced the amplitude and maxi mum velocity of increase and decrease of calcium transients, prolonged the time-course of calcium transients and impaired the beta-adreuocep tor responsiveness of calcium transients in a dose-dependent manner, T he DOX-induced impairment of calcium transients and beta-adrenoceptor responsiveness was improved by M-I. 4, Doxorubicin impaired both the m obilization and sequestration of intracellular calcium ions in contrac tion-relaxation cycles and the response of calcium transients to beta- adrenoceptor stimulation, The ACE inhibitor ameliorated DOX-induced im pairment of calcium dynamics, suggesting that M-I, an active metabolit e of delapril, protects against DOX-induced abnormal calcium handling leading to cardiac dysfunction.