BACKGROUND The effects of inhibition of the Na+/H+ exchanger (NHE) on postischemic recovery of the injured neonatal rabbit heart were examined. The NHE may be an important mechanism for reperfusion injury in the neonate heart. The effects of two NHE inhibitors, HOE 642 (HOE) and 5-(N,N-dimethyl)-amiloride (DMA), given during hypothermic cardioplegic arrest, were evaluated. METHODS Isolated working crystalloid-perfused neonatal rabbit hearts were subjected to 10 min of normothermic ischemia to cause injury before undergoing 4 h of hypothermic (10 degrees C) cardioplegic arrest with a single dose of crystalloid solution (controls, n=21) or with the addition of 0.5 micromol/L HOE (n=24) or 30 micromol/L DMA (n=15). RESULTS Hearts subjected to HOE had improved recoveries of aortic flow when compared with controls at 15 min and 30 min of reperfusion (35.7+/-1.3 mL/min versus 26.2+/-1.4 mL/min, respectively, at 15 min, P<0.0001; 36.5+/-1.5 mL/min versus 23.6+/-1.6 mL/min, respectively, at 30 min, P<0.0001) and with DMA at 30 min (36.5+/-1.5 mL/min versus 29.9+/-1.9 mL/min, P=0.0214). Cardiac output and systolic pressure were also improved at 30 min in HOE hearts versus controls (P<0.0001). CONCLUSIONS NHE inhibition with HOE during cardioplegic arrest resulted in improved functional recovery of injured hearts. Further studies in blood-perfused neonatal preparations are warranted.