Lysophophatidylcholine (LysoPC) accumulates rapidly in the ischemic myocardium and is an important mediator of ischemia-induced cell injury. Na(+)-H+ exchange (NHE) inhibition has been demonstrated to protect the ischemic and reperfused myocardium. We determined whether NHE inhibition can also modulate cardiotoxicity produced by LysoPC (3 and 5 mumol/L) in isolated rat hearts. At 3 mumol/L, LysoPC produced a depression in left ventricular developed pressure (LVDP) and elevation in left ventricular end-diastolic pressure (LVEDP), which were 19 +/- 7% and 1290 +/- 205% of pre-LysoPC values, respectively, after 30 minutes of treatment. In the presence of the NHE inhibitor 4-isopropyl-3-methylsulfonylbenzoyl-guanidine methanesulfonate (HOE 642, 5 mumol/L), LVDP was reduced to only 80.8 +/- 8.6%, and LVEDP increased to 270 +/- 32% (P < .05 for both parameters). LysoPC significantly depressed tissue ATP, creatine phosphate, and glycogen contents and increased lactate levels, all of which were significantly attenuated by HOE 642. Moreover, marked LysoPC-induced ultrastructural abnormalities, including mitochondrial and myofibrillar disruption, were totally prevented by HOE 642. This protection was mimicked by another NHE inhibitor, methylisobutylamiloride (5 mumol/L). HOE 642 was also effective against injury produced by 5 mumol/L LysoPC although, generally, the protection was less marked than that observed against 3 mumol/L; LVDP depression after 30 minutes was 10.1 +/- 4.3% and 41.4 +/- 10.4% of pre-LysoPC values in control and HOE 642-treated hearts, respectively (P < .05), whereas corresponding LVEDP elevations were 1629 +/- 393% and 990 +/- 144% (P > .05). In myocytes superfused with bicarbonate-free buffer subjected to acid loading by NH4Cl pulsing, pH recovery (as measured by acid flux) was significantly stimulated by 3 mumol/L LysoPC, indicative of NHE activation. Our study shows that cardiac injury produced by low concentrations of LysoPC can be effectively attenuated by NHE inhibition. The results also suggest that the beneficial effects of NHE inhibitors on the ischemic myocardium may be, at least partially, mediated by inhibiting the deleterious effects of LysoPC.