Sarcoplasmic ATP-sensitive potassium channel blocker HMR1098 protects the ischemic heart: implication of calcium, complex I, reactive oxygen species and mitochondrial ATP-sensitive potassium channel.
The aim of this study was to investigate the effects of HMR1098, a selective blocker of sarcolemmal ATP-sensitive potassium channel (sarcK(ATP)), in Langendorff-perfused rat hearts submitted to ischemia and reperfusion. The recovery of heart hemodynamic and mitochondrial function, studied on skinned fibers, was analyzed after 30-min global ischemia followed by 20-min reperfusion. Infarct size was quantified on a regional ischemia model after 2-h reperfusion. We report that the perfusion of 10 microM HMR1098 before ischemia, delays the onset of ischemic contracture, improves recovery of cardiac function upon reperfusion, preserves the mitochondrial architecture, and finally decreases infarct size. This HMR1098-induced cardioprotection is prevented by 1 mM 2-mercaptopropionylglycine, an antioxidant, and by 100 nM nifedipine, an L-type calcium channel blocker. Concomitantly, it is shown that HMR1098 perfusion induces (i) a transient and specific inhibition of the respiratory chain complex I and, (ii) an increase in the averaged intracellular calcium concentration probed by the in situ measurement of indo-1 fluorescence. Finally, all the beneficial effects of HMR1098 were strongly inhibited by 5-hydroxydecanoate and abolished by glibenclamide, two mitoK(ATP) blockers. This study demonstrates that the HMR1098-induced cardioprotection occurs indirectly through extracellular calcium influx, respiratory chain complex inhibition, reactive oxygen species production and mitoK(ATP) opening. Taken together, these data suggest that a functional interaction between sarcK(ATP) and mitoK(ATP) exists in isolated rat heart ischemia model, which is mediated by extracellular calcium influx.
Pasdois
Philippe
P
INSERM U. 828, France.
Beauvoit
Bertrand
B
Costa
Alexandre D T
AD
Vinassa
Béatrice
B
Tariosse
Liliane
L
Bonoron-Adèle
Simone
S
Garlid
Keith D
KD
Dos Santos
Pierre
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism*; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism*
D001549:Benzamides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; C410297:HMR 1098; D042967:Electron Transport Complex I