Chronic preconditioning: a novel approach for cardiac protection.
Ischemic preconditioning is the most powerful protective mechanism known against lethal ischemia. Unfortunately, the protection lasts for only a few hours. Here we tested the hypothesis that the heart can be kept in a preconditioned state for constant protection against ischemia. In this study we chose BMS-191095 (BMS), a highly selective opener of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels. BMS (1 mg/kg ip) was administered to rats every 24 h until 96 h. In other groups, BMS plus wortmannin (WTN, 15 microg/kg ip), an inhibitor of the phosphatidylinositol 3-kinase (PI3-K), or BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoK(ATP), or BMS plus N(omega)-nitro-L-arginine methyl ester (L-NAME) (30 microg/kg ip), an inhibitor of nitric oxide (NO) synthase, were administered to rats. Rats were then subjected to 30-min left anterior descending coronary artery occlusion and 120-min reperfusion. Cardiac function, infarct size, pathological changes, and apoptosis were assessed at the end of treatments. Saline-treated hearts displayed marked contractile dysfunction and underwent pathological changes. BMS-treated rats showed significant improvement in cardiac function, and infarct size was significantly reduced in BMS-treated hearts. However, protection by BMS was abolished by 5-HD, WTN, or L-NAME. These data demonstrate that hearts can be chronically preconditioned and retain their ability to remain resistant against lethal ischemia and that this protection is mediated by activation of mitoK(ATP) via NO and PI3-K/Akt signaling pathways.
Wang
Yigang
Y
Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, USA.
Ahmad
Nauman
N
Wang
Boyu
B
Ashraf
Muhammad
M
D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use*; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D016896:Treatment Outcome
C428117:BMS 191095; D001578:Benzopyrans; D002316:Cardiotonic Agents; D007093:Imidazoles