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EXPERIMENTAL STUDY

Mitochondrial ATP-sensitive K⁺ channels play a role in cardioprotection by Na⁺-H⁺ exchange inhibition against ischemia/reperfusion injury

Tetsuji Miura, MD, PhD^*, Yongge Liu, PhD, Mahiko Goto, MD, PhD^*, Akihito Tsuchida, MD, PhD^*, Takayuki Miki, MD, PhD^*, Atsushi Nakano, MD^*, Yasuhiro Nishino, MD^*, Yoshito Ohnuma, MD^* and Kazuaki Shimamoto, MD, PhD^*

^* Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
Maryland Research Laboratory, Otsuka America Pharmaceutical, Inc., Rockville, Maryland, USA

Manuscript received July 6, 2000; revised manuscript received October 20, 2000, accepted November 22, 2000.

Reprint requests and correspondence: Dr. Tetsuji Miura, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo 060-0061, Japan
miura{at}sapmed.ac.jp

OBJECTIVES

The possible role of the ATP-sensitive potassium (K_ATP) channel in cardioprotection by Na⁺-H⁺ exchange (NHE) inhibition was examined.

BACKGROUND

The K_ATP 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 K_ATP channel blockers were assessed. In another series of experiments, the effects of EIPA on mitochondrial K_ATP (mito-K_ATP) and sarcolemmal K_ATP (sarc-K_ATP) channels were examined in isolated cardiomyocytes.

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 K_ATP channel blocker. In vitro, 1 µM cariporide limited infarct size by 90%, and this effect was blocked by 5-hydroxydecanoate (5-HD), a mito-K_ATP channel blocker but not by HMR1098, a sarc-K_ATP channel blocker. Infarct size limitation by 1 µM 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-K_ATP channel nor enhanced activation of this channel by diazoxide, a K_ATP channel opener.

CONCLUSIONS

Opening of the mito-K_ATP channel contributes to cardioprotection by NHE inhibition, though the interaction between NHE and this K_ATP channel remains unclear.

Abbreviations and Acronyms   EIPA = ethylisopropyl amiloride   IK.ATP = sarc-KATP channel current   LV = left ventricle or left ventricular   LVDP = left ventricular developed pressure   LV dP/dt = the first derivative of left ventricular pressure   mito-KATP = mitochondrial KATP channel   NHE = Na+-H+ exchanger   sarc-KATP = sarcolemmal KATP channel   TTC = triphenyltetrazolium chloride   5-HD = 5-hydroxydecanoate

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