Mechanisms by which opening the mitochondrial ATP- sensitive K+channel protects the ischemic heart
- 1 July 2002
- journal article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 283 (1) , H284-H295
- https://doi.org/10.1152/ajpheart.00034.2002
Abstract
Diazoxide opening of the mitochondrial ATP-sensitive K+(mitoKATP) channel protects the heart against ischemia-reperfusion injury by unknown mechanisms. We investigated the mechanisms by which mitoKATPchannel 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 mitoKATPchannel inhibitor 5-hydroxydecanoate. We hypothesize that an open mitoKATPchannel 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.Keywords
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