Mechanisms by which opening the mitochondrial ATP- sensitive K(+) channel protects the ischemic heart.
Diazoxide opening of the mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel protects the heart against ischemia-reperfusion injury by unknown mechanisms. We investigated the mechanisms by which mitoK(ATP) channel opening may act as an end effector of cardioprotection in the perfused rat heart model, in permeabilized fibers, and in rat heart mitochondria. We show that diazoxide pretreatment preserves the normal low outer membrane permeability to nucleotides and cytochrome c and that these beneficial effects are abolished by the mitoK(ATP) channel inhibitor 5-hydroxydecanoate. We hypothesize that an open mitoK(ATP) channel during ischemia maintains the tight structure of the intermembrane space that is required to preserve the normal low outer membrane permeability to ADP and ATP. This hypothesis is supported by findings in mitochondria showing that small decreases in intermembrane space volume, induced by either osmotic swelling or diazoxide, increased the half-saturation constant for ADP stimulation of respiration and sharply reduced ATP hydrolysis. These effects are proposed to lead to preservation of adenine nucleotides during ischemia and efficient energy transfer upon reperfusion.
Dos Santos
Pierre
P
Unité 441 Athérosclérose and IFR 4, Institut National de la Santé et de la Recherche Médicale, 33600 Pessac, France.
Kowaltowski
Alicia J
AJ
Laclau
Muriel N
MN
Seetharaman
Subramanian
S
Paucek
Petr
P
Boudina
Sihem
S
Thambo
Jean-Benoit
JB
Tariosse
Liliane
L
Garlid
Keith D
KD
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D003401:Creatine / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D006439:Hemodynamics; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009994:Osmolar Concentration; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010477:Perfusion; D010539:Permeability / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003401:Creatine; D003981:Diazoxide