Previous studies have shown a close temporal relationship between lipid abnormalities and membrane dysfunction in ischemia and that phospholipase-inhibiting drugs limit such derangements. Amiodarone is a potent phospholipase inhibitor, but its potential or that of any other inhibitor to simultaneously attenuate lipid abnormalities and electrophysiological changes in the very early phase of ischemia has never been studied. We therefore investigated simultaneously such changes in early ischemia. In isolated porcine hearts perfused with or without pure amiodarone solutions, electrophysiologic changes before and during 20 min of LAD occlusion were recorded using unipolar electrodes and Franz contact electrode catheters, and full thickness myocardial biopsies obtained for lipid analyses. In untreated hearts (n = 5), occlusion of LAD resulted in the rapid onset of TQ depression/ST elevation within 1 min and plateauing at 10 min. There were mean increases of 33% and 50% in lysophosphatidylcholine and 33% and 70% in lysophosphatidylethanolamine levels at 5-7 min and 20 min of ischemia, respectively. Non-esterified fatty acid (NEFA) content did not change significantly during the first 5-7 min, but increased by 75% after 20 min of LAD occlusion. In treated hearts (n = 5) there was a 37% increase in sinus cycle length after amiodarone administration (503 +/- 85 vs 689 +/- 115 ms, P < 0.01) but no significant change in ventricular effective refractory period (202 +/- 22 vs 204 +/- 21 ms), action potential duration (215 +/- 11 vs 217 +/- 7 ms), or amplitude (31 +/- 6 vs 28 +/- 3 mV) was observed. Also, amiodarone treatment did not alter total phospholipid content, lysophospholipids and NEFA levels of non-ischemic hearts. However, there was significant attenuation (P < 0.01) of the onset of the TQ/ST shift and preservation of action potential amplitude (P < 0.02) during the first 5-7 min of LAD occlusion with concomitant suppression of the increase in both lysophospholipids (hydrolysis products of membrane phospholipids by endogenous phospholipases) and NEFA levels observed after 5-7 and 20 min of ischemia. The results suggest that amiodarone can delay the onset and limit the extent of electrophysiologic change in early myocardial ischemia in temporal association with suppression of myocardial phospholipase activities.