The modulating role of the cholinergic system in epinephrine (EP)-induced ventricular arrhythmias (VAs) was studied in anesthetized (alpha-chloralose and pentobarbitone sodium) dogs. Unifocal VAs were produced by subepicardial infusion of EP (4 X 10(-3)M) in 2.5 X 10(-3) M CaCl2-0.9% NaCl at a rate of 10 microliter/min for a maximum period of 10 min at a time. One of the interacting drugs acetylcholine Cl (ACh), carbachol Cl (CCh), physostigmine salicylate (PHY), DL-propranolol HC1 (PROP), quindine HC1 (QD), lidocaine HC1 (LD), and atropine sulfate (AT) was given in an equimolar concentration (4 X 10(-3)M) along with EP. The effects of bilateral vagotomy (VT) were also studied. The time of onset, frequency, and duration of VAs were recorded. Reproducible cognizable VAs (less than 10%) were produced by EP in 38 of 43 experimental dogs. Focal infusion of the cholinomimetic agent ACh or CCh marketedly inhibited the arrhythmogenic activity of EP at the focal site. The effect of the anticholinesterase agent PHY was similar. These experiments showed that exogenous administration of a cholinomimetic agent or focal facilitation of endogenous cholinergic influence had an antiarrhythmic activity against EP. On the other hand, bilateral VT or focal infusion of AT markedly potentiated the arrhythmogenic potentiality of EP. Thus, it appeared that removal of endogenous influence facilitated EP-induced arrhythmias. The antiarrhythmic activities of the beta-adrenoceptor-blocking agent PROP and the membrane-stabilizing agents LD and QD against EP were confirmed using the subepicardial infusion technique. These studies show that the presence of cardiovagal tone or its facilitation inhibits, and its blockade increases, the propensity to VAs in situations in which the adrenergic system may be involved primarily or otherwise. The receptors involved appear to be muscarinic in nature.