Effects of trimetazidine on the calcium transport and oxidative phosphorylation of isolated rat heart mitochondria.
Trimetazidine (TMZ) added in vitro to isolated cardiac mitochondria at concentrations 10-100 microM in the presence of 25-100 nM extramitochondrial Ca2+ increased Ca2+ uptake and matrix Ca2+ concentration. This effect was less evident in the presence of physiologically Na+ and Mg2+ extramitochondrial concentrations since only 100 microM TMZ was able to increase mitochondrial Ca2+ entry in the presence of 100 nM Ca2+. The drug stimulated a Ca(2+)-cooperative effect on mitochondrial Ca2+ transport, but did not modify the rate of Ca2+ egress stimulated by 10 mM NaCl. An increase in mitochondrial Ca2+ level produced by TMZ enhanced oxoglutarate dehydrogenase activity and then ATP synthesis, particularly when 50 nM extramitochondrial Ca2+ was used. These data suggest that a possible cardiac mechanism of action of TMZ at mitochondrial level could support ATP synthesis by elevating the mitochondrial Ca2+ level.
Guarnieri
C
C
Department of Biochemistry "G. Moruzzi" Bologna, Italy.
Finelli
C
C
Zini
M
M
Muscari
C
C
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000494:pharmacology; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D007656:Ketoglutaric Acids; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; D012964:Sodium; D007655:Ketoglutarate Dehydrogenase Complex; D008274:Magnesium; D014292:Trimetazidine; D002118:Calcium