Opening of mitochondrial K+ channels increases ischemic ATP levels by preventing hydrolysis.
Mitochondrial ATP-sensitive K+ channels (mitoK(ATP)) have been proposed to mediate protection against ischemic injury by increasing high-energy intermediate levels. This study was designed to verify if mitochondria are an important factor in the loss of cardiac ATP associated to ischemia, and determine the possible role of mitoK(ATP) in the control of ischemic ATP loss. Langendorff-perfused rat hearts subjected to ischemia were found to have significantly higher ATP contents when pretreated with oligomycin or atractyloside, indicating that mitochondrial ATP hydrolysis contributes toward ischemic ATP depletion. MitoK(ATP) opening induced by diazoxide promoted a similar protection against ATP loss. Diazoxide also inhibited ATP hydrolysis in isolated, nonrespiring mitochondria, an effect accompanied by a drop in the membrane potential and Ca2+ uptake. In hearts subjected to ischemia followed by reperfusion, myocardial injury was prevented by diazoxide, but not atractyloside or oligomycin, which, unlike diazoxide, decreased reperfusion ATP levels. Our results suggest that mitoK(ATP)-mediated protection occurs due to selective inhibition of mitochondrial ATP hydrolysis during ischemia, without affecting ATP synthesis after reperfusion.
Belisle
Eduardo
E
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brazil.
Kowaltowski
Alicia J
AJ
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration; D006868:Hydrolysis; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000737:chemistry / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology; D017202:Myocardial Ischemia; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010539:Permeability; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D024101:Mitochondrial Proteins; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D002118:Calcium