We tested the hypothesis that Na+/H+ exchange contributes to reperfusion stunning and arrhythmias. The effects of amiloride, an established inhibitor of Na+/H+ exchange, were compared with those of a new inhibitor (HOE 694). Working hearts, subjected to 20-min global ischemia and reperfused for 30 min, were pretreated (for 5 min before ischemia) or reperfused (initial 2 min) with HOE 694 or amiloride. Pretreatment with 10(-7) M HOE increased recovery of aortic output (AO) after 30-min reperfusion: As a percentage of the preischemic controls, values were 38.5 +/- 3.6% (n = 7) for controls versus 50.6 +/- 3.9% (n = 5) for the treated group (p < 0.05). Pretreatment with HOE (10(-6) M) increased AO recoveries from 38.2 +/- 2.0% (n = 5) to 52.9 +/- 2.7% (n = 5) (p < 0.05). Amiloride (10(-5) M) pretreatment improved AO recoveries from 41.6 +/- 2.7% (n = 6) to 55.8 +/- 4.0% (n = 6) (p < 0.05). Thus, pretreatment by both HOE 694 and amiloride decreased reperfusion stunning. Adding HOE (10(-7) M) only in the reperfusion period increased AO recoveries from 36.4 +/- 1.2% (n = 6) to 62.4 +/- 3.2% (n = 11) (p < 0.002). Amiloride (10(-5) or 10(-3) M) added only during reperfusion did not improve recovery of AO. HOE 694, active in much lower concentrations than amiloride, was the only compound active against stunning when added only during reperfusion. In addition, both compounds inhibited reperfusion arrhythmias when added at reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)