Figure 1. Causes and consequences of ionic imbalances during ischemia.

Ischemia results in a cessation of aerobic metabolism and a reliance on anaerobic metabolism, resulting in cellular and tissue acidosis. Accumulation of intracellular H⁺ stimulates NHE, resulting in accumulation of intracellular Na⁺. Accumulation of intracellular NA⁺, in turn, stimulates reverse activity of the NCX, resulting in intracellular Ca⁺² accumulation. If ischemia is sustained, cellular Ca²⁺ overload may develop, resulting in activation of degradative enzymes (e.g., proteases, phosphatases and endonucleases), and stimulation of MPT, culminating in myocyte death. NHE, Na⁺/H⁺ exchanger; NCX, Na⁺/Ca²⁺ exchanger; MPT, mitochondrial permeability transition.