title: Roles of mitochondrial ATP-sensitive K channels and PKC in anti-infarct tolerance afforded by adenosine A1 receptor activation.
abstract: OBJECTIVE
  This study intended to assess the role of mitochondrial ATP-sensitive potassium (mitoK ATP) channels and the sequence of signal transduction with protein kinase C (PKC) and adenosine A1 receptors in rabbits.
  
  
  BACKGROUND
  To our knowledge, the link between trigger receptors of preconditioning, PKC and mitoK ATP channels has not been examined in a whole heart model of infarction.
  
  
  METHODS
  In the first series of experiments, myocardial infarction was induced in isolated buffer-perfused rabbit hearts by 30-min global ischemia and 2-h reperfusion. Infarct size in the left ventricle was determined by tetrazolium staining and expressed as a percentage of area at risk (i.e., the whole left ventricle) (%IS/AR). In the second series of experiments, mitochondria were isolated from the heart, and their respiratory function was examined using glutamate as a substrate.
  
  
  RESULTS
  Pretreatment with R-phenylisopropyladenosine (R-PIA, 1 micromol/liter), an A1-receptor agonist, reduced %IS/AR from 49.8 +/- 6.5% to 13.4 +/- 2.9%. This protection was abolished by calphostin C, a PKC inhibitor, and by 5-hydroxydecanoate (5-HD), a selective inhibitor of mitoK ATP channels. A selective mitoK ATP channel opener, diazoxide (100 micromol/liter), mimicked the effect of R-PIA on infarct size (%IS/AR = 11.6 +/- 4.0%), and this protective effect was also abolished by 5-HD. However, calphostin C failed to block the infarct size-limiting effect of diazoxide. Neither calphostin C nor 5-HD alone modified %IS/AR. State III respiration (QO2) and respiratory control index (RCI) were reduced after 30 min of ischemia (QO2 = 147.3 +/- 5.3 vs. 108.5 +/- 12.3, RCI = 22.3 +/- 1.1 vs. 12.1 +/- 1.8, p < 0.05). This mitochondrial dysfunction was persistent after 10 min of reperfusion (QO2 = 96.1 +/- 15.5, RCI = 9.5 +/- 1.9). Diazoxide significantly attenuated the respiratory dysfunction after 30 min of ischemia (QO2 = 142.8 +/- 9.7, RCI = 16.2 +/- 0.8) and subsequent 10-min reperfusion (QO2 = 135.3 +/- 7.2, RCI = 19.1 +/- 0.8).
  
  
  CONCLUSIONS
  These results suggest that mitoK ATP channels are downstream of PKC in the mechanism of infarct-size limitation by A1-receptor activation and that the anti-infarct tolerance afforded by opening of mitoK ATP channels is associated with preservation of mitochondrial function during ischemia/reperfusion.
authors.affiliation: Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan. miura@sapmed.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Miura
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Kita
authors.forename: T
authors.initials: T
authors.lastname: Ogawa
authors.forename: K
authors.initials: K
authors.lastname: Shimamoto
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D004579:Electron Transport / Q000502:physiology; D008297:Male; D008929:Mitochondria, Heart / Q000473:pathology / Q000502:physiology*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology; D015221:Potassium Channels / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D011817:Rabbits; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015221:Potassium Channels; D018047:Receptors, Purinergic P1; D000255:Adenosine Triphosphate; D011493:Protein Kinase C