The production of arrhythmias in the isolated heart by perfusion with lysophosphatidylcholine has been well documented. However, the role of the lysophospholipid as a physiological factor in the generation of cardiac arrhythmias is not clear. In this study, a pharmacological approach was used to delineate the physiological significance of lysophosphatidylcholine during this cardiac dysfunction. Lidocaine (5-20 mg/L) was found to be effective in the protection of the isolated rat heart from the lysophospholipid-induced arrhythmias at pharmacological concentrations. The effect of lidocaine in the protection of lysophospholipid-induced membrane dysfunction was studied with red blood cells. Lidocaine (2 mg/mL) protected red blood cells from hemolysis in the presence of lysophosphatidylcholine. Lidocaine did not inhibit the binding of the lysophospholipid to the red cell membrane, but inhibited hemolysis in a manner similar to cholesterol. The results are consistent with the postulate that lysophosphatidylcholine is a physiological factor in the pathogenesis of cardiac arrhythmias during myocardial ischemia.