title: Persistent beneficial effect of postconditioning against infarct size: role of mitochondrial K(ATP) channels during reperfusion.
abstract: This study tested the hypothesis that inhibition of myocardial injury and modulation of mitochondrial dysfunction by postconditioning (Postcon) after 24 h of reperfusion is associated with activation of K(ATP) channels. Thirty dogs undergoing 60 min of ischemia and 24 h of reperfusion (R) were randomly divided into four groups:
  
  
  METHODS
  no intervention at R; Postcon: three cycles of 30 s R alternating with 30 s re-occlusion were applied at R; 5-hydroxydecanoate (5-HD): the mitochondrial K(ATP) channel blocker was infused 5 min before Postcon; HMR1098: the sarcolemmal K(ATP) channel blocker was administered 5 min before Postcon. After 24 h of R, infarct size was smaller in Postcon relative to CONTROL (27 +/- 4%* Vs. 39 +/- 2% of area at risk), consistent with a reduction in CK activity (66 +/- 7* Vs. 105 +/- 7 IU/g). The infarct-sparing effect of Postcon was blocked by 5-HD (48 +/- 5%(dagger)), but was not altered by HMR1098 (29 +/- 3%*), consistent with the change in CK activity (102 +/- 8(dagger) in 5-HD and 71 +/- 6* IU/g in HMR1098). In H9c2 cells exposed to 8 h hypoxia and 3 h of reoxygenation, Postcon up-regulated expression of mito-K(ATP) channel Kir6.1 protein, maintained mitochondrial membrane potential and inhibited mitochondrial permeability transition pore (mPTP) opening evidenced by preserved fluorescent TMRE and calcein staining. The protective effects were blocked by 5-HD, but not by HMR1098. These data suggest that in a clinically relevant model of ischemia-reperfusion (1) Postcon reduces infarct size and decreases CK activity after prolonged reperfusion; (2) protection by Postcon is achieved by opening mitochondrial K(ATP) channels and inhibiting mPTP opening. *P < 0.05 Vs. CONTROL; P < 0.05 Vs. Postcon.
authors.affiliation: Carlyle Fraser Heart Center, Emory Crawford Long Hospital, Emory University, Atlanta, GA 30308-2225, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mykytenko
authors.forename: James G
authors.initials: JG
authors.lastname: Reeves
authors.forename: Hajime
authors.initials: H
authors.lastname: Kin
authors.forename: Ning-Ping
authors.initials: NP
authors.lastname: Wang
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Zatta
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Guyton
authors.forename: Jakob
authors.initials: J
authors.lastname: Vinten-Johansen
authors.forename: Zhi-Qing
authors.initials: ZQ
authors.lastname: Zhao
mesh_terms: D000818:Animals; D016923:Cell Death; D003326:Coronary Circulation; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D054086:KATP Channels; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009206:Myocardium / Q000473:pathology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000378:metabolism / Q000473:pathology / Q000628:therapy
chemical_list: D054086:KATP Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D003402:Creatine Kinase