title: An angiotensin-converting enzyme inhibitor protects against doxorubicin-induced impairment of calcium handling in neonatal rat cardiac myocytes.
abstract: 1. The effects of doxorubicin (DOX) on intracellular calcium transients were examined in neonatal rat cultured cardiac myocytes, as were the cardioprotective effects of an angiotensin-converting enzyme (ACE) inhibitor on DOX-induced impairment of calcium handling. 2. 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 in the absence of isoproterenol using fura-2/AM. Calcium transients were also measured after the addition of DOX to myocytes pretreated with M-I (an active metabolite of delapril HCL, an ACE inhibitor. 3. Doxorubicin reduced the amplitude and maximum velocity of increase and decrease of calcium transients, prolonged the time-course of calcium transients and impaired the beta-adrenoceptor responsiveness of calcium transients in a dose-dependent manner. The DOX-induced impairment of calcium transients and beta-adrenoceptor responsiveness was improved by M-I. 4. Doxorubicin impaired both the mobilization and sequestration of intracellular calcium ions in contraction-relaxation cycles and the response of calcium transients to beta-adrenoceptor stimulation. The ACE inhibitor ameliorated DOX-induced impairment of calcium dynamics, suggesting ihat M-I, an active metabolite of delapril, protects against DOX-induced abnormal calcium handling leading to cardiac dysfunction.
authors.affiliation: Fourth Department of Internal Medicine, Shimane Medical University, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Maeda
authors.forename: M
authors.initials: M
authors.lastname: Honda
authors.forename: T
authors.initials: T
authors.lastname: Kuramochi
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Takabatake
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004558:Electric Stimulation; D006706:Homeostasis / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D011943:Receptors, Adrenergic, beta; D004317:Doxorubicin; D007545:Isoproterenol; D002118:Calcium