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(Circulation. 2003;107:1183.)
© 2003 American Heart Association, Inc.

Basic Science Reports

MCC-134, a Single Pharmacophore, Opens Surface ATP–Sensitive Potassium Channels, Blocks Mitochondrial ATP–Sensitive Potassium Channels, and Suppresses Preconditioning

Norihito Sasaki, MD, PhD^*; Mitsushige Murata, MD, PhD^*; Yiru Guo, MD; Su-Hyun Jo, PhD; Andreas Ohler, MD; Masaharu Akao, MD, PhD; Brian O’Rourke, PhD; Rui-Ping Xiao, MD, PhD; Roberto Bolli, MD; Eduardo Marbán, MD, PhD

From the Laboratory of the Institute of Molecular Cardiobiology (N.S., M.M., A.O., M.A., B.O., E.M.), Johns Hopkins University, Baltimore, Md; Cardiovascular Sciences (S.-H.J., R.-P.X.), Gerontology Research Center, National Institute on Aging, National Institute of Health, Baltimore, Md; and the Experimental Research Laboratory (Y.G., R.B.), Division of Cardiology, University of Louisville and the Jewish Heart and Lung Institute, Louisville, Ky.

Correspondence to Eduardo Marbán, MD, PhD, Institute of Molecular Cardiobiology, Johns Hopkins University, 720 Rutland Ave/Ross 844, Baltimore, MD 21205. E-mail marban{at}jhmi.edu

Background— MCC-134 (1-[4-(H-imidazol-1-yl)benzoyl]-N-methylcyclobutane-carbothioamide), a newly developed analog of aprikalim, opens surface smooth muscle–type ATP-sensitive potassium (K_ATP) channels but inhibits pancreatic K_ATP channels. However, the effects of MCC-134 on cardiac surface K_ATP channels and mitochondrial K_ATP (mitoK_ATP) channels are unknown. A mixed agonist/blocker with differential effects on the two channel types would help to clarify the role of K_ATP channels in cardioprotection.

Methods and Results— To index mitoK_ATP channels, we measured mitochondrial flavoprotein fluorescence in rabbit ventricular myocytes. MCC-134 alone had little effect on basal flavoprotein fluorescence. However, MCC-134 inhibited diazoxide-induced flavoprotein oxidation in a dose-dependent manner (EC₅₀=27 µmol/L). When ATP was included in the pipette solution, MCC-134 slowly activated surface K_ATP currents with some delay (>10 minutes). These results indicate that MCC-134 is a mitoK_ATP channel inhibitor and a surface K_ATP channel opener in native cardiac cells. In cell-pelleting ischemia assays, coapplication of MCC-134 with diazoxide abolished the cardioprotective effect of diazoxide, whereas MCC-134 alone did not alter cell death. These results were reproducible in both rabbit and mouse myocytes. MCC-134 also attenuated the effect of ischemic preconditioning against myocardial infarction in mice, consistent with the results of cell-pelleting ischemia assays.

Conclusions— A single drug, MCC-134, opens surface K_ATP channels but blocks mitoK_ATP channels; the fact that this drug inhibits preconditioning reaffirms the primacy of mitoK_ATP rather than surface K_ATP, channels in the mechanism of cardioprotection.

Key Words: ischemia • potassium • myocardial infarction

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