Abstract
Ischemic preconditioning is a phenomenon in which brief intermittent periods of ischemia are paradoxically protective against subsequent ischemic injury. To characterize the memory of ischemic preconditioning, we studied pretreatment effects of 2, 4-dinitrophenol, a protonophore that uncouples mitochondrial respiration from ATP synthesis, on both flavoprotein oxidation, an index of mitochondrial uncoupling, and sarcolemmal KATP channel activation in isolated rat ventricular myocytes. Effects of 5-hydroxydecanoic acid, a mitochondrial KATP channel inhibitor, on the pretreatment effects were also studied. Major findings of this study were that pretreatment of mitochondrial uncoupler sensitizes flavoprotein oxidation and sarcolemmal KATP activation. In the presence of 5-hydroxydecanoic acid, the sensitizing effects were completely abolished. Without metabolic inhibition, sensitized myocardium represents almost normal flavoprotein oxidation and sarcolemmal KATP activity. These results suggest that, if we assume a memory molecule, direct effects of the memory molecule on mitochondrial uncoupling and sarcolemmal KATP are negligible, but the memory molecule potentiates mitochondrial uncoupling and sarcolemmal KATP in the face of metabolic impairment. In addition, the production of the memory molecule is 5-hydroxydecanoic acid-sensitive.
