Ischemic preconditioning in rats: role of mitochondrial K(ATP) channel in preservation of mitochondrial function.
We examined the role of the sarcolemmal and mitochondrial K(ATP) channels in a rat model of ischemic preconditioning (IPC). Infarct size was expressed as a percentage of the area at risk (IS/AAR). IPC significantly reduced infarct size (7 +/- 1%) versus control (56 +/- 1%). The sarcolemmal K(ATP) channel-selective antagonist HMR-1098 administered before IPC did not significantly attenuate cardioprotection. However, pretreatment with the mitochondrial K(ATP) channel-selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before IPC partially abolished cardioprotection (40 +/- 1%). Diazoxide (10 mg/kg iv) also reduced IS/AAR (36.2 +/- 4.8%), but this effect was abolished by 5-HD. As an index of mitochondrial bioenergetic function, the rate of ATP synthesis in the AAR was examined. Untreated animals synthesized ATP at 2.12 +/- 0.30 micromol x min(-1) x mg mitochondrial protein(-1). Rats subjected to ischemia-reperfusion synthesized ATP at 0.67 +/- 0.06 micromol x min(-1) x mg mitochondrial protein(-1). IPC significantly increased ATP synthesis to 1.86 +/- 0.23 micromol x min(-1) x mg mitochondrial protein(-1). However, when 5-HD was administered before IPC, the preservation of ATP synthesis was attenuated (1.18 +/- 0.15 micromol x min(-1) x mg mitochondrial protein(-1)). These data are consistent with the notion that inhibition of mitochondrial K(ATP) channels attenuates IPC by reducing IPC-induced protection of mitochondrial function.
Fryer
R M
RM
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Eells
J T
JT
Hsu
A K
AK
Henry
M M
MM
Gross
G J
GJ
D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology*; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D009994:Osmolar Concentration; D015221:Potassium Channels; D051381:Rats; D017208:Rats, Wistar
D003652:Decanoic Acids; D006880:Hydroxy Acids; D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D003981:Diazoxide