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1 Department of Anesthesia and Critical Care and 2 Department of Medicine, The University of Chicago, Chicago, Illinois 60637
The objective of this study was to examine the role of oxygen radicals, protein kinase C (PKC), and ATP-sensitive K+ (KATP) channels in mediating flumazenil-produced preconditioning. Chick cardiomyocyte death was quantified using propidium iodide, and oxygen radical generation was assessed using 2',7'-dichlorofluorescin oxidation. Preconditioning was initiated with 10 min of ischemia followed by 10 min of reoxygenation. Alternatively, flumazenil was infused for 10 min and removed 10 min before ischemia. Flumazenil (10 µM) and preconditioning increased oxygen radicals [1,693 ± 101 (n = 3) and 1,567 ± 98 (n = 3), respectively, vs. 345 ± 53 (n = 3) in control] and reduced cell death similarly [22 ± 3% (n = 5) and 18 ± 2% (n = 6), respectively, vs. controls 49 ± 5% (n = 8)]. Protection and increased oxygen radicals by flumazenil were abolished by pretreatment with the antioxidant thiol reductant 2-mercaptopropionyl glycine (800 µM; 52 ± 10%, n = 6). Specific PKC inhibitors Go-6976 (0.1 µM) and chelerythrine (2 µM), given during ischemia and reoxygenation, blocked flumazenil-produced protection (47 ± 5%, n = 6). The PKC activator phorbol 12-myristate 13-acetate (0.2 µM), given during ischemia and reoxygenation, reduced cell death similarly to that with flumazenil [17 ± 4% (n = 6) and 22 ± 3% (n = 5)]. Finally, 5-hydroxydecanoate (1 mM), a selective mitochondrial KATP channel antagonist given during ischemia and reoxygenation, abolished the protection of flumazenil and phorbol 12-myristate 13-acetate. Thus flumazenil mimics preconditioning to reduce cell death in cardiomyocytes. Oxygen radicals activate mitochondrial KATP channels via PKC during the process.
mitochondria; ischemia; potassium channels; GABA receptors; signal transduction
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