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 (KATP) channels but inhibits pancreatic KATP channels. However, the effects of MCC-134 on cardiac surface KATP channels and mitochondrial KATP (mitoKATP) channels are unknown. A mixed agonist/blocker with differential effects on the two channel types would help to clarify the role of KATP channels in cardioprotection. Methods and Results - To index mitoKATP 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 KATP currents with some delay (>10 minutes). These results indicate that MCC-134 is a mitoKATP channel inhibitor and a surface KATP 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 KATP channels but blocks mitoKATP channels; the fact that this drug inhibits preconditioning reaffirms the primacy of mitOKATP rather than surface KATP, channels in the mechanism of cardioprotection.
|Number of pages||6|
|Publication status||Published - 2003 Mar 4|
- Myocardial infarction
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)