Mitochondrial damage during ischemia determines post-ischemic contractile dysfunction in perfused rat heart.

Abstract

Possible mechanisms underlying sodium overload-induced ischemia/reperfusion injury in perfused rat hearts were examined. Massive accumulation of myocardial Na(+) occurred during ischemia, suggesting cytosolic sodium overload in cardiac cells. Treatment of the pre-ischemic heart with 0.3 micromol/l tetrodotoxin or 3 micromol/l ethyl-isopropyl amiloride enhanced post-ischemic contractile recovery (72 or 82% of initial vs 24% for untreated group), which was associated with suppression of tissue Na(+) accumulation (138 or 141% of initial vs 270% for untreated group), restoration of tissue high-energy phosphates, and preservation of the ability of mitochondria to produce ATP in the ischemic/reperfused heart. The release of cytochrome c from the ischemic heart was observed, which was blocked by treatment of the pre-ischemic heart with these agents. The improvement of post-ischemic contractile recovery by these agents was closely correlated with the ability of mitochondria to produce ATP during ischemia. To examine the effects of sodium overload on mitochondrial function, isolated mitochondria were incubated in the presence of various concentrations of Na(+). Na(+) induced mitochondrial membrane perturbations such as depolarization of the membrane potential, mitochondrial swelling, cytochrome c release from isolated mitochondria, and a reduction in oxidative phosphorylation. These events in the isolated mitochondria were not blocked by the presence of the above agents. The results suggest that cytosolic sodium overload in cardiac cells may induce deterioration of the mitochondrial function during ischemia and that this mitochondrial damage may determine post-ischemic contractile dysfunction in perfused rat hearts.