Persistent beneficial effect of postconditioning against infarct size: role of mitochondrial K(ATP) channels during reperfusion.
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.
Mykytenko
James
J
Carlyle Fraser Heart Center, Emory Crawford Long Hospital, Emory University, Atlanta, GA 30308-2225, USA.
Reeves
James G
JG
Kin
Hajime
H
Wang
Ning-Ping
NP
Zatta
Amanda J
AJ
Jiang
Rong
R
Guyton
Robert A
RA
Vinten-Johansen
Jakob
J
Zhao
Zhi-Qing
ZQ
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
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