Trimetazidine improved Ca2+ handling in isoprenaline-mediated myocardial injury of rats.
Dysregulation of intracellular Ca2+ homeostasis plays an important role in mediating myocardial injury. We tested the hypothesis that treatment with trimetazidine (TMZ) would improve intracellular Ca2+ handling in myocardial injury of rats. The control group received saline only (10 ml kg(-1) day(-1), i.p.) for 7 days. In a second group, isoprenaline (ISO; 5 mg kg(-1) day(-1), s.c.) was administered to rats for 2 days to induce an acute injury of the myocardium. In a third group, treatment with TMZ (10 mg kg(-1) day(-1), i.p.) was initiated 1 day before ISO administration and continued for 7 days (n = 7 rats in each group). Histopathological evaluation showed that TMZ prevented ISO-induced myocardial damage. TMZ preserved the ATP levels and decreased the maleic dialdehyde (MDA) content in the hearts compared with ISO-treated rats. The diastolic [Ca2+]i measured by loading with fura-2 AM in isolated cardiomyocytes was increased significantly in ISO-treated rats compared to the control animals. TMZ prevented the rise of diastolic [Ca2+]i and the depression of caffeine-induced Ca2+ transients caused by ISO administration. The reduction in sarcoplasmic reticulum (SR) Ca2+ content in the heart cells and in cardiac SR Ca2+-ATPase activity in ISO-treated rats was abolished by TMZ, although there were no differences in SR Ca2+-ATPase protein levels between the control, ISO and ISO + 7 mz-treated rats. In addition, TMZ prevented the reduction in sarcolemmal L-type Ca2+ current density in the heart cells induced by ISO treatment. These results demonstrate that the treatment of rats with TMZ inhibited the increase of diastolic [Ca2+]i and prevented the decrease of SR Ca2+ content, SR Ca2+-ATPase activity and L-type Ca2+ current density in cardiomyocytes in ISO-mediated myocardial injury of rats. These changes in Ca2+ handling could help to explain the favourable action of TMZ in myocardial injury.
Meng
Dan
D
Research Institute of Cardiovascular Disease, First Affiliated Hospital, Human Functional Genetics Laboratory of Jiangsu Province of Nanjing Medical University, Nanjing, 210029 [corrected] China. dmeng@sibs.ac.cn
Feng
Lin
L
Chen
Xiang-Jian
XJ
Yang
Di
D
Zhang
Ji-Nan
JN
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D004338:Drug Combinations; D007545:Isoproterenol; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D014292:Trimetazidine / Q000008:administration & dosage*; D014665:Vasodilator Agents / Q000008:administration & dosage
D002316:Cardiotonic Agents; D004338:Drug Combinations; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; D007545:Isoproterenol; D014292:Trimetazidine; D002118:Calcium