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Fasting improves contractile recovery and attenuates lactate production and mitochondrial permeability transition (MPT) without altering cell viability in ischemic-reperfused rat hearts. 5-hydroxydecanoate (5-HD), a mitochondrial ATP-sensitive K+ channel (K-ATPmito) blocker, abolishes the improvement of mechanical recovery elicited by fasting despite it decreases lactate production, suggesting that K-ATPmito might be involved in the preservation of contractility. This chapter assessed the contribution of K-ATPmito in the attenuation of MPT which in turn may improve mitochondrial energetics. 2. Langendorff-perfused hearts from fed and fasted rats were subjected to ischemia-reperfusion in the presence or absence of 5-HD. To assess whether 5-HD has any direct effect on glycolysis, a cell free heart extract containing all the glycolytic enzymes was used. MPT was quantitated measuring the mitochondrial 2-[3H]-deoxyglucose (3H-2-DG) entrapment. Total heart 3H-2-DG content as an estimation of necrosis was measured. As an index of mitochondrial energetic function, the rate of ATP synthesis was examined in mitochondria isolated from the ischemic-reperfused hearts. 3. Fasting increased the rate of mitochondrial ATP synthesis and attenuated MPT. 5-HD abolished these protective effects. 5-HD did not change total heart 3H-2-DG content indicating that it lacked effects on cell survival. Since 5-HD did not affect glucose consumption and lactate production in the cell-free heart-extract the inhibition of glycolysis could be due to its own oxidative metabolism. 4. It may be concluded that cardioprotection elicited by fasting in the ischemic-reperfused heart could be ascribed, at least in part, to the K-ATPmito activation which in turn inhibits MPT and induces energetic preservation.