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Prolonged ischemia results in a variety of cellular metabolic and ultrastructural changes. Ischemia induced decreases in cellular oxidative phosphorylation results in a failure to resynthesize energy-rich phosphates, including adenosine 5'-triphosphate (ATP) and phosphocreatine. Membrane ATP-dependent ionic pump function is thus altered, favoring the entry of calcium, sodium, and water into the cell. Furthermore, adenine nucleotide catabolism during ischemia results in the intracellular accumulation of hypoxanthine, which is subsequently converted into toxic reactive oxygen species (ROS) upon the reintroduction of molecular oxygen see below). Within the endothelium, ischemia promotes expression of certain proinflammatory gene products (e.g., leukocyte adhesion molecules, cytokines) and bioactive agents (e.g., endothelin, thromboxane A2), while repressing other “protective” gene products (e.g., constitutive nitric oxide synthase, thrombomodulin) and bioactive agents (e.g., prostacyclin, nitric oxide). Thus, ischemia induces a proinflammatory state that increases tissue vulnerability to further injury on reperfusion.