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J Am Coll Cardiol, 2002; 40:1523-1530
© 2002 by the American College of Cardiology Foundation
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EXPERIMENTAL STUDY

Infarct size limitation by nicorandil

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

Akihito Tsuchida, MD, PhD*, Tetsuji Miura, MD, PhD, FACC*,*, Masaya Tanno, MD*, Jun Sakamoto, MD, PhD*, Takayuki Miki, MD, PhD*, Atsushi Kuno, MD*, Tomoaki Matsumoto, MD*, Yoshito Ohnuma, MD*, Yoshihiko Ichikawa, MD* and Kazuaki Shimamoto, MD, PhD*

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+ (sarcKATP) channels or the mitochondrial KATP (mitoKATP) 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 KATP channel opener that activates the sarcKATP and mitoKATP channels. Both of these KATP channels are regulated by PKC, and this kinase may be activated by nitric oxide and also by oxygen free radicals (OFR) generated after mitoKATP 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 sarcKATP channel selective blocker, HMR1098, abolished acceleration of ischemia-induced ARI-shortening by nicorandil and eliminated 40% of nicorandil-induced infarct size limitation. A mitoKATP 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-{varepsilon} translocation after preconditioning.

CONCLUSIONS: Both the sarcKATP and mitoKATP 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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