MCC-134, a single pharmacophore, opens surface ATP-sensitive potassium channels, blocks mitochondrial ATP-sensitive potassium channels, and suppresses preconditioning.

Abstract

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 (EC(50)=27 micro mol/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.

• Authors: Norihito Sasaki, Mitsushige Murata, Yiru Guo, Su-Hyun Jo, Andreas Ohler, Masaharu Akao, Brian O'Rourke, Rui-Ping Xiao, Roberto Bolli, Eduardo Marbán
• Journal: Circulation (Circulation) Vol. 107 Issue 8 Pg. 1183-8 (Mar 04 2003) ISSN: 1524-4539 [Electronic] United States
• PMID: 12615799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cardiotonic Agents
• Flavoproteins
• Imidazoles
• MCC 134
• Potassium Channel Blockers
• Potassium Channels
• Thioamides
• Adenosine Triphosphate
• Diazoxide

Topics

• Adenosine Triphosphate (pharmacology)
• Animals
• Cardiotonic Agents (antagonists & inhibitors)
• Cell Membrane (drug effects, physiology)
• Cells, Cultured
• Diazoxide (antagonists & inhibitors)
• Electric Conductivity
• Female
• Flavoproteins (chemistry)
• Fluorescence
• Heart (drug effects, physiology)
• Imidazoles (pharmacology)
• Ischemic Preconditioning, Myocardial
• Male
• Mice
• Mitochondria, Heart (chemistry, drug effects, physiology)
• Myocardial Infarction (pathology, therapy)
• Patch-Clamp Techniques
• Potassium Channel Blockers (pharmacology)
• Potassium Channels (agonists, physiology)
• Rabbits
• Thioamides (pharmacology)