title: Infarct size limitation by nicorandil: roles of mitochondrial K(ATP) channels, sarcolemmal K(ATP) channels, and protein kinase C.
abstract: OBJECTIVE
  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- epsilon 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.
authors.affiliation: Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Tsuchida
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
authors.forename: Jun
authors.initials: J
authors.lastname: Sakamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Miki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuno
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ohnuma
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimamoto
mesh_terms: D000818:Animals; D001549:Benzamides; D003652:Decanoic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D009281:Naphthalenes / Q000494:pharmacology; D020108:Nicorandil / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D011817:Rabbits; D012508:Sarcolemma / Q000502:physiology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology
chemical_list: D001549:Benzamides; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; C110658:N-(2-mercaptoproprionyl)-glycine; D009281:Naphthalenes; D015221:Potassium Channels; D013438:Sulfhydryl Compounds; D020108:Nicorandil; C052853:5-hydroxydecanoic acid; C410297:HMR 1098; D011493:Protein Kinase C; C058819:calphostin C; D005998:Glycine