TY - JOUR
T1 - MCC-134, a single pharmacophore, opens surface ATP-sensitive potassium channels, blocks mitochondrial ATP-sensitive potassium channels, and suppresses preconditioning
AU - Sasaki, Norihito
AU - Murata, Mitsushige
AU - Guo, Yiru
AU - Jo, Su Hyun
AU - Ohler, Andreas
AU - Akao, Masaharu
AU - O'Rourke, Brian
AU - Xiao, Rui Ping
AU - Bolli, Roberto
AU - Marbán, Eduardo
PY - 2003/3/4
Y1 - 2003/3/4
N2 - 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.
AB - 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.
KW - Ischemia
KW - Myocardial infarction
KW - Potassium
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U2 - 10.1161/01.CIR.0000051457.64240.63
DO - 10.1161/01.CIR.0000051457.64240.63
M3 - Article
C2 - 12615799
AN - SCOPUS:0037418249
SN - 0009-7322
VL - 107
SP - 1183
EP - 1188
JO - Circulation
JF - Circulation
IS - 8
ER -