(Circulation. 2000;101:2418.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Selective Pharmacological Agents Implicate Mitochondrial but Not Sarcolemmal KATP Channels in Ischemic Cardioprotection
From the Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Md. Dr Sato is now at the Department of Physiology, Oita Medical University, Oita, Japan.
Correspondence to Eduardo Marbán, MD, PhD, Director, Institute of Molecular Cardiobiology, Johns Hopkins University, Ross 844/720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}jhmi.edu
Background—Pharmacological evidence has implicated ATP-sensitive K+ (KATP) channels as the effectors of cardioprotection, but the relative roles of mitochondrial (mitoKATP) and sarcolemmal (surfaceKATP) channels remain controversial.
Methods and Results—We examined the effects of the KATP channel blocker HMR1098 and the KATP channel opener P-1075 on surfaceKATP and mitoKATP channels in rabbit ventricular myocytes. HMR1098 (30 µmol/L) inhibited the surfaceKATP current activated by metabolic inhibition, whereas the drug did not blunt diazoxide (100 µmol/L)-induced flavoprotein oxidation, an index of mitoKATP channel activity. P-1075 (30 µmol/L) did not increase flavoprotein oxidation but did elicit a robust surfaceKATP current that was completely inhibited by HMR1098. These results indicate that HMR1098 selectively inhibits surfaceKATP channels, whereas P-1075 selectively activates surface KATP channels. In a cellular model of simulated ischemia, the mitoKATP channel opener diazoxide (100 µmol/L), but not P-1075, blunted cellular injury. The cardioprotection afforded by diazoxide or by preconditioning was prevented by the mitoKATP channel blocker 5-hydroxydecanoate (500 µmol/L) but not by the surfaceKATP channel blocker HMR1098 (30 µmol/L).
Conclusions—The cellular effects of mitochondria- or surface-selective agents provide further support for the emerging consensus that mitoKATP channels rather than surfaceKATP channels are the likely effectors of cardioprotection.
Key Words: mitochondria • potassium • ischemia • preconditioning
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