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.