We evaluated the effects of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), a Na+/H+ exchanger (NHE) inhibitor, on ischemia/reperfusion (I/R)-induced acute renal failure (ARF) in mice. Ischemic ARF was induced by clamping the left renal artery and vein for 40 minutes followed by reperfusion 2 weeks after the contralateral nephrectomy. Preischemic treatment with EIPA attenuated the I/R-induced renal dysfunction. Histopathological examination of the kidney of ARF mice revealed severe renal damage such as tubular necrosis and proteinaceous casts in the tubuli. Histologically evident damage was also improved by preischemic treatment with EIPA. In addition, the I/R-induced increase in renal endothelin-1 (ET-1) content was suppressed by preischemic treatment with EIPA, reflecting the difference in immunohistochemical ET-1 localization in necrotic tubular epithelium. However, the postischemic treatment with EIPA failed to improve the I/R-induced renal dysfunction and ET-1 overproduction. These findings suggest that NHE activation, followed by renal ET-1 overproduction, plays an important role in the pathogenesis of I/R-induced renal injury. The inhibition of NHE by EIPA may be considered as a therapeutic approach to protect the postischemic ARF.