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EXPERIMENTAL STUDY

Infarct size limitation by nicorandil

Roles of mitochondrial K_ATP channels, sarcolemmal K_ATP channels, and protein kinase C

^a Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

Manuscript received May 31, 2001; revised manuscript received June 3, 2002, accepted July 2, 2002.

^* 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 060-8543, Japan.
miura{at}sapmed.ac.jp

OBJECTIVES: This study aimed to examine: 1) whether nicorandil protects the ischemic myocardium by activating sarcolemmal adenosine triphosphate (ATP)-sensitive K⁺ (sarcK_ATP) channels or the mitochondrial K_ATP (mitoK_ATP) channels, and 2) whether protein kinase C (PKC) activity is necessary for cardioprotection afforded by nicorandil.

BACKGROUND: Nicorandil is a hybrid of nitrate and a K_ATP channel opener that activates the sarcK_ATP and mitoK_ATP channels. Both of these K_ATP channels are regulated by PKC, and this kinase may be activated by nitric oxide and also by oxygen free radicals (OFR) generated after mitoK_ATP channel opening.

METHODS: In isolated rabbit hearts, infarction was induced by 30-min global ischemia/2-h reperfusion with monitoring of the activation recovery interval (ARI), an index of action potential duration. Protein kinase C translocation was assessed by Western blotting.

RESULTS: Nicorandil did not change ARI before ischemia, but it accelerated ARI shortening after the onset of ischemia and reduced infarct size by 90%. A sarcK_ATP channel selective blocker, HMR1098, abolished acceleration of ischemia-induced ARI-shortening by nicorandil and eliminated 40% of nicorandil-induced infarct size limitation. A mitoK_ATP channel selective blocker, 5-hydroxydecanoate, abolished the protection afforded by nicorandil without affecting ARI. Cardioprotection by nicorandil was inhibited neither by an OFR scavenger, N-2-mercaptopropionylglycine nor by a PKC inhibitor, calphostin C, at a dose that was capable of inhibiting PKC- translocation after preconditioning.

CONCLUSIONS: Both the sarcK_ATP and mitoK_ATP channels are involved in anti-infarct tolerance afforded by nicorandil, but PKC activation induced by nitric oxide or OFR generation, if any, does not play a crucial role.

Abbreviations and Acronyms   ARI   activation recovery interval   KATP channel   adenosine triphosphate-sensitive K+ channel   LVEDP   left ventricular end-diastolic pressure   LVDP   left ventricular developed pressure   mitoKATP channel   mitochondrial adenosine triphosphate-sensitive K+ channel   MPG   N-2-mercaptopropionylglycine   NO   nitric oxide   PC   ischemic preconditioning   PKC   protein kinase C   sarcKATP channel   sarcolemmal adenosine triphosphate-sensitive K+ channel   SNAP   S-nitroso-N-acetyl-DL-penicillamine   SUR   sulfonylurea receptor   5-HD   5-hydroxydecanoate   %IS/LV   infarct size as a percentage of the left ventricle

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