Cardioprotective effect of diazoxide is mediated by activation of sarcolemmal but not mitochondrial ATP-sensitive potassium channels in mice.
BACKGROUND
We recently demonstrated that the sarcolemmal ATP-sensitive potassium (sarcK(ATP)) channel plays a key role in cardioprotection against ischemia/reperfusion injuries in Kir6.2-knockout (KO) mice. In the present study, we evaluated the effects of diazoxide, a mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel opener, on ischemia-induced myocardial stunning in sarcK(ATP) channel-deficient mice.


RESULTS
Langendorff-perfused hearts of wild-type (WT) and KO mice were subjected to global ischemia/reperfusion. Diazoxide improved the recovery of contractile function in WT hearts but not in KO hearts. Treatment with HMR1098 (a sarcK(ATP) channel blocker) but not 5-hydroxydecanoate (a mitoK(ATP) channel blocker) abolished the cardioprotective effect of diazoxide in WT hearts. In coronary-perfused WT ventricular muscle preparations, action potential shortening during ischemia was accelerated in the presence of diazoxide.


CONCLUSIONS
Diazoxide enhances action potential shortening during ischemia by activating sarcK(ATP) channels and provides cardioprotection in mouse hearts.
Suzuki
Masashi
M
Department of Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Saito
Tomoaki
T
Sato
Toshiaki
T
Tamagawa
Masaji
M
Miki
Takashi
T
Seino
Susumu
S
Nakaya
Haruaki
H
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology; D015425:Myocardial Reperfusion; D017682:Myocardial Stunning / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000235:genetics; D020127:Recovery of Function / Q000187:drug effects; D012508:Sarcolemma / Q000378:metabolism*
D001549:Benzamides; D002316:Cardiotonic Agents; D008565:Membrane Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C117780:mitochondrial K(ATP) channel; D000255:Adenosine Triphosphate; C410297:HMR 1098; D003981:Diazoxide