Background Experiments were carried out using the new Na sup + -H sup + exchange inhibitor (3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate (HOE 694) to assess the role of Na sup + -H sup + exchange in myocardial ischemic and reperfusion injury.Methods and Results Three groups of rabbit hearts (n=5 in each) were perfused with blood and were subjected to 45 minutes of global normothermic (37 degrees C) ischemia, followed by 1 hour of reperfusion. Group 1 was the control group (vehicle only); in group 2, HOE 694 (1 micromole/L) was administered before ischemia (pretreatment group); and in group 3, HOE 694 was given only during reperfusion to separate actions exerted during ischemia from those specifically obtained during reperfusion. End-diastolic pressure rise at 1 hour of reperfusion was reduced by administration of HOE 694 starting before ischemia (from 52.2+-8.5 mm Hg in group 1 to 17.6+-4.5 mm Hg in group 2, P<.01) or starting on reperfusion (28.8+-5.4 mm Hg in group 3, P<.05 versus group 1). Left ventricular developed pressure (LVDP) and its derivative (dP/dt) recovered better in HOE 694-pretreated hearts (LVDP, 79+-9.9 mm Hg in group 2 versus 24.8+-10 mm Hg in group 1; dP/dt, 1580+-198 mm Hg/s versus 340+-221 mm Hg/s, P<.01). In hearts treated only on reperfusion, some improvement was observed, which, however, did not reach statistical significance. Coronary flow on reperfusion was higher in groups 2 and 3 compared with controls, and no "no-reflow" was observed. Two additional groups of hearts were perfused with phosphate-free Krebs-Henseleit solution to enable studies with Phosphorus-31 nuclear magnetic resonance (NMR). ATP was better preserved in HOE 694-pretreated (62+-4.9% of preischemic value) than in control hearts (44+-3.3%) at the end of 30 minutes of reperfusion, and phosphocreatine resynthesis was higher (109+-3.7% versus 86+-5.4%). HOE 694 did not affect the time course of intracellular acidosis during ischemia but suppressed a small alkaline overshoot occurring early in reperfusion (pH 6.96+-0.02 in HOE 694-pretreated hearts versus 7.14+-0.05 in control hearts). Electron microscopy with Ca2+ staining of the blood-perfused hearts showed that clumping of Ca2+ aggregates in mitochondria was prevented by HOE 694.Conclusions Postischemic dysfunction was associated with a rise in end-diastolic pressure. This rise was effectively blocked by HOE 694. The drug was most effective when hearts were treated before ischemia, although partial protection was observed when administration was started on reperfusion. The action of HOE 694 strengthens the idea that Na sup + -H sup + exchange during both ischemia and reperfusion contributes to contractile dysfunction. (Circulation. 1994;89:2787-2798.)