Mechanisms by which opening the mitochondrial ATP- sensitive K(+) channel protects the ischemic heart.

Abstract

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.

• Authors: Pierre Dos Santos, Alicia J Kowaltowski, Muriel N Laclau, Subramanian Seetharaman, Petr Paucek, Sihem Boudina, Jean-Benoit Thambo, Liliane Tariosse, Keith D Garlid
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 283 Issue 1 Pg. H284-95 (Jul 2002) ISSN: 0363-6135 [Print] United States
• PMID: 12063301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Potassium Channel Blockers
• Potassium Channels
• Adenosine Diphosphate
• Adenosine Triphosphate
• Creatine
• Diazoxide

Topics

• Adenosine Diphosphate (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Cell Respiration (drug effects, physiology)
• Creatine (metabolism)
• Diazoxide (pharmacology)
• Hemodynamics
• In Vitro Techniques
• Intracellular Membranes (drug effects, metabolism)
• Male
• Mitochondria, Heart (drug effects, metabolism, ultrastructure)
• Muscle Fibers, Skeletal (drug effects, metabolism)
• Myocardial Ischemia (drug therapy, metabolism)
• Myocardium (metabolism)
• Osmolar Concentration
• Oxidative Phosphorylation (drug effects)
• Perfusion
• Permeability (drug effects)
• Potassium Channel Blockers (pharmacology)
• Potassium Channels (metabolism)
• Rats
• Rats, Sprague-Dawley