Mitochondrial ATP-sensitive K+ channels play a role in cardioprotection by Na+-H+ exchange inhibition against ischemia/reperfusion injury.
OBJECTIVE
The possible role of the ATP-sensitive potassium (KATP) channel in cardioprotection by Na+-H+ exchange (NHE) inhibition was examined.


BACKGROUND
The KATP channel is suggested to be involved not only in ischemic preconditioning but also in some pharmacological cardioprotection.


METHODS
Infarction was induced by 30-min coronary occlusion in rabbit hearts in situ or by 30-min global ischemia in isolated hearts. Myocardial stunning was induced by five episodes of 5-min ischemia/5-min reperfusion in situ. In these models, the effects of NHE inhibitors (cariporide and ethylisopropyl-amiloride [EIPA]) and the changes caused by KATP channel blockers were assessed. In another series of experiments, the effects of EIPA on mitochondrial KATP (mito-KATP) and sarcolemmal KATP (sarc-KATP) channels were examined in isolated cardiomyocvtes.


RESULTS
Cariporide (0.6 mg/kg) reduced infarct size in situ by 40%, and this effect was abolished by glibenclamide (0.3 mg/kg), a nonselective KATP channel blocker. In vitro, 1 microM cariporide limited infarct size by 90%, and this effect was blocked by 5-hydroxydecanoate (5-HD), a mito-KATP channel blocker but not by HMR1098, a sarc-KATP channel blocker. Infarct size limitation by 1 microM EIPA was also prevented by 5-HD. Cariporide attenuated regional contractile dysfunction by stunning, and this protection was abolished by glibenclamide and 5-HD. Ethylisopropyl amiloride neither activated the mito-KATP channel nor enhanced activation of this channel by diazoxide, a KATP channel opener.


CONCLUSIONS
Opening of the mito-KATP channel contributes to cardioprotection by NHE inhibition, though the interaction between NHE and this KATP channel remains unclear.
Miura
T
T
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan. miura@sapmed.ac.jp
Liu
Y
Y
Goto
M
M
Tsuchida
A
A
Miki
T
T
Nakano
A
A
Nishino
Y
Y
Ohnuma
Y
Y
Shimamoto
K
K
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006439:Hemodynamics; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D017682:Myocardial Stunning / Q000503:physiopathology; D015221:Potassium Channels / Q000502:physiology*; D011817:Rabbits; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D015221:Potassium Channels; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide