Acute myocardial ischemia reduces tolerance of the heart to arrhythmogenic actions of digitalis glycosides. Because both ischemia and the glycoside produce profound changes in activity of the autonomic nervous system and because sympathetic discharge or catecholamines enhance toxic actions of the cardiac glycosides, the possibility that alterations in digitalis sensitivity of ischemic heart involve changes in sympathetic nerve activity was examined using alpha-chloralose-anesthetized cats. Left anterior descending coronary artery (LAD) was completely occluded by ligation and, 40 min later, a slow i.v. infusion of digoxin was started at a rate of 1 microgram/kg/min. LAD ligation alone did not produce arrhythmias in that condition, but shortened the time to onset of digoxin-induced arrhythmias and thereby reduced the amount of digoxin required to produce the toxic manifestation. Concomitantly, digoxin concentration in plasma and nonischemic areas of the heart were lower in LAD-ligated cats at the onset of arrhythmias than those in sham-operated cats. Myocardial digoxin content in the ischemic area of the LAD-occluded heart was lower than that in nonischemic areas of the same heart. At the onset of digoxin-induced arrhythmias, Na,K-adenosine triphosphatase activity of ischemic myocardium was significantly higher than that in the nonischemic area, reflecting a lower digoxin occupancy of the glycoside binding sites on the sodium pump. Spinal cord (C1) transection or propranolol treatment prolonged the time to arrhythmias in both control and LAD-ligated cats, but failed to abolish the effect of LAD ligation to augment digoxin toxicity. Bilateral vagotomy also did not alter the enhancement of digoxin toxicity caused by ligation of LAD.(ABSTRACT TRUNCATED AT 250 WORDS)