Summary: The effects of the antiarrhythmic drugs lidocaine and bretylium tosylate on myocardial necrosis were studied in anesthetized pigs subjected to 60-min coronary occlusion followed by 3-h reperfusion. Group A (n = 7) received lidocaine (average dose × SD = 1,828 × 515 mg) before and during coronary occlusion and after reperfusion; the other series (group B, n = 7) received bretylium tosylate (3,457 × 1,323 mg). Infarct size was 16.3 × 14.7% in the lidocaine group as compared with 68.6 × 12.6% (p < 0.01) in the bretylium group. In vitro release of superoxide anion from porcine granulocytes was studied using the lucigenin-dependent chemiluminescence technique. Lidocaine significantly reduced the peak chemiluminescence response to zymosan from 3.34 × 0.44 without lidocaine to 2.23 × 0.46 (p < 0.01) and 1.06 × 0.17 mV (p < 0.001), with lidocaine concentrations of 20 and 200 μg/ml, respectively. Bretylium had no effect on the chemiluminescence response. Adherence of porcine granulocytes to plastic was also reduced from 332 × 32 cells/mm2 (no lidocaine) to 247 × 35 and 206 × 26 cells/mm2 with lidocaine concentrations of 20 and 200 μg/ml, respectively (p < 0.001). Bretylium had no significant effect. Eight additional bretylium-treated pigs received either rabbit antiporcine granulocyte serum (group C, n = 4) to reduce circulating granulocytes or nonimmune serum (group D, n = 4). Infarct size in the granulocyte-depleted pigs was 26.6 × 5.6% as compared with 51.4 × 5.5% in pigs that received nonimmune serum (p < 0.01). Smaller infarct size with lidocaine as compared with bretylium tosylate therapy is associated with decreased adherence of granulocytes to vascular endothelium in the ischemic myocardium and inhibition of superoxide anion release.