Reduction by SEA0400 of myocardial ischemia-induced cytoplasmic and mitochondrial Ca2+ overload.
The cardioprotective effects of SEA0400, a novel Na(+)-Ca(2+) exchanger inhibitor, were examined in isolated guinea pig myocardial tissue and ventricular myocytes. In a coronary-perfused right ventricular tissue preparation, SEA0400 had no cardiosuppressive effect during normoxia and experimental ischemia, but enhanced the recovery of contractile force during reperfusion. SEA0400 had no effect on tissue ATP content during normoxia, but attenuated its decrease during ischemia. Treatment of ventricular myocytes with an ischemia mimetic solution (high K(+), glucose free, pH 6.0, gassed with N(2)) resulted in the depolarization of the mitochondrial membrane potential and an increase in cytoplasmic and mitochondrial Ca(2+) concentration, which had a similar time course. SEA0400 significantly delayed these changes. These results suggest that SEA0400 maintains mitochondrial function and tissue ATP content during ischemia through the inhibition of cytoplasmic and mitochondrial Ca(2+) overload.
Namekata
Iyuki
I
Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences, Miyama 2-2-1 Funabashi, Chiba 274-8510, Japan.
Shimada
Hideaki
H
Kawanishi
Toru
T
Tanaka
Hikaru
H
Shigenobu
Koki
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003593:Cytoplasm / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010647:Phenyl Ethers / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D000814:Aniline Compounds; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D000255:Adenosine Triphosphate; D002118:Calcium