title: Critical timing of mitochondrial K(ATP) channel opening for enhancement of myocardial tolerance against infarction.
abstract: OBJECTIVE
  The present study was designed to assess the relationship between the timing of a mitoK(ATP) channel opener, diazoxide, and its infarct size-limiting effect.
  
  
  METHODS
  In isolated rabbit hearts, infarction was induced by 30 min of global ischemia and 2 h of reperfusion, and infarct size was determined by tetrazolium staining and expressed as a percentage of the left ventricle (%IS/LV). Diazoxide, a mitoK(ATP) channel selective opener, and/or 5-hydroxydecanoate (5-HD), a mitoK(ATP) channel blocker, were infused before or after the onset of ischemia. When these agents were infused during the ischemic period, they were dissolved in a hypoxic buffer at concentrations 10-fold higher than those in the pre-ischemic period, and the infusion rate was set at 2% of the pre-ischemic coronary flow.
  
  
  RESULTS
  In untreated controls, %IS/LV was 53.2+/-4.1 (SE). Pretreatment with diazoxide (100 microM) with a 10-min washout period reduced %IS/LV to 7.8+/-2.4 and this protection was abolished by co-infusion of 5-HD (50 microM). Pre-ischemic infusion of diazoxide without a washout period reduced %IS/LV to 7.3+/-1.4, and infusion of diazoxide from 10 min after the onset of ischemia also limited %IS/LV to 14.9+/-4.6. However, diazoxide infusion from 25 min after the onset of ischemia failed to reduce infarct size (%IS/LV = 54.5+/-7.2). Furthermore, pretreatment with 5-HD (50 microM) also completely abolished the protection afforded by early post-ischemic diazoxide infusion (%IS/LV = 48.3+/-6.5). Neither infusion of 5-HD nor the anoxic vehicle alone during ischemia modified %IS/LV.
  
  
  CONCLUSIONS
  These findings suggest that opening of mitoK(ATP) channels before ischemia and during early ischemia, but not that upon reperfusion, is important for enhancement of myocardial tolerance against infarction.
authors.affiliation: Second Department of Internal Medicine, Sapporo Medical University, School of Medicine, Japan. atutida@sapmed.ac.jp
authors.forename: A
authors.initials: A
authors.lastname: Tsuchida
authors.forename: T
authors.initials: T
authors.lastname: Miura
authors.forename: T
authors.initials: T
authors.lastname: Miki
authors.forename: A
authors.initials: A
authors.lastname: Kuno
authors.forename: M
authors.initials: M
authors.lastname: Tanno
authors.forename: Y
authors.initials: Y
authors.lastname: Nozawa
authors.forename: S
authors.initials: S
authors.lastname: Genda
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Shimamoto
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D019194:Ischemic Preconditioning; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000819:agonists / Q000378:metabolism*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014665:Vasodilator Agents; C052853:5-hydroxydecanoic acid; D003981:Diazoxide; D005905:Glyburide