The effect of the selective Na(+)/H(+) antiporter inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) on cerebral ischemia/reperfusion injury was evaluated in the Mongolian gerbil. Ischemia was induced in unanaesthetized gerbils by a 5-min period of bilateral common carotid artery occlusion followed by reperfusion for 6 days. Two groups of gerbils were injected intraperitoneally with either dimethyl sulfoxide (DMSO; 10 microl) or EIPA (5 mg/kg in 10 microl DMSO) 30 min prior to ischemia. The increase in locomotor activity in the EIPA-treated group was significantly less than that of the control group at both 24 h and 6-day post-ischemia. The extent of CA1 pyramidal neuron loss was significantly reduced in the EIPA-treated group in comparison with that of DMSO treated controls. These results suggest that EIPA can protect cerebral neurons from ischemia/reperfusion injury and implicates acidosis and Na(+)/H(+) exchange as a causative factor in such injury.