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  • Title: Mitochondrial ATP-dependent potassium channels. Viable candidate effectors of ischemic preconditioning.
    Author: Liu Y, Sato T, Seharaseyon J, Szewczyk A, O'Rourke B, Marbán E.
    Journal: Ann N Y Acad Sci; 1999 Jun 30; 874():27-37. PubMed ID: 10415518.
    Abstract:
    Pharmacological evidence has implicated ATP-dependent potassium (KATP) channels in the mechanism of ischemic preconditioning; however, the effects of sarcolemmal KATP channels on excitability cannot account for the protection. KATP channels also exist in mitochondrial inner membrane. To test whether such channels play a role in cardioprotection, we simultaneously measured flavoprotein fluorescence, an index of mitochondrial redox state, and sarcolemmal KATP currents in intact rabbit ventricular myocytes. Our results show that diazoxide, a KATP channel opener, induced reversible oxidation of flavoproteins, but did not activate sarcolemmal KATP channels. This effect of diazoxide was blocked by 5-hydroxydecanoic acid (5-HD). We further verified that 5-HD is a selective blocker of the mitochondrial KATP channels. These methods have enabled us to demonstrate that the activity of mitochondrial KATP channels can be regulated by protein kinase C. In a cellular model of simulated ischemia, inclusion of diazoxide decreased the rate of cell death to about half of that in control. Such protection is inhibited by 5-HD. In conclusion, our results demonstrate that diazoxide targets mitochondrial but not sarcolemmal KATP channels, and imply that mitochondrial KATP channels may mediate preconditioning.
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