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Figure 1 Potential mechanism through which Na⁺/H⁺ exchanger (NHE) inhibition preserves intracellular ion homeostasis and thereby myocardial integrity and function after ischemia and reperfusion. (A) Under basal conditions, NHE is relatively quiescent, the Na⁺/K⁺ ATPase (Na⁺ pump) utilizes ATP to extrude Na⁺, and the bidirectional Na⁺/Ca²⁺ exchanger (NCX) works predominantly in forward (Ca²⁺ efflux) mode. (B) During ischemia, NHE becomes activated in response to intracellular acidosis and possibly by other NHE-stimulatory factors (26). The resulting influx of Na⁺, occurring in the presence of ischemia-induced attenuation of Na⁺ pump activity, causes the intracellular accumulation of Na⁺. Such a rise in the intracellular Na⁺ concentration during ischemia alters the reversal potential of the NCX in a manner that inhibits its operation in forward mode but favors its operation in reverse (Ca²⁺ influx) mode, thus producing intracellular Ca²⁺ accumulation (Ca²⁺ overload) during both ischemia and subsequent reperfusion. (C) NHE inhibitors are likely to afford a cardioprotective effect during ischemia and reperfusion by inhibiting this sequence at an early stage, through the limitation of Na⁺ influx during ischemia. Note that the illustration has been simplified for clarity, and that mechanisms other than NHE activity are also likely to contribute to the intracellular accumulation of Na⁺ and consequently Ca²⁺ during ischemia and reperfusion.

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