Autonomic tone may contribute to cardiac arrhythmogenesis and influence the efficacy of implantable defibrillators. Fifty-two anesthetized pigs were randomized to: (1) methacholine (n = 12); (2) nitroprusside (n = 12); (3) phenylephrine (n = 12); (4) carbachol (n = 8); and (5) saline (n = 8). Ventricular fibrillation threshold (VFT) and triplicate defibrillation thresholds (DFT) were obtained before and during each intervention. Mean (+/- SE) VFT was increased with: methacholine (76 +/- 10.6 V vs 39 +/- 7.1 V, P < 0.001); phenylephrine (68 +/- 10.5 V vs 38 +/- 6.2 V, P < 0.001); and carbachol (106 +/- 11.5 V vs 30 +/- 6.5 V, P < 0.0001). Nitroprusside and saline failed to alter VFT. Mean (+/- SE) DFT was decreased with: methacholine (7.7 +/- 0.8) vs 9.7 +/- 0.8 J, P < 0.001); phenylephrine (9.8 +/- 0.9 J vs 11.3 +/- 1.0 J, P < 0.05); and carbachol (9.2 +/- 0.7 J vs 12.2 +/- 0.8 J, P < 0.0001), remaining unchanged following nitroprusside and saline infusion. Thus, modulation of autonomic tone modified arrhythmia susceptibility and the energy necessary for defibrillation, increased parasympathetic tone, increased VFT, and decreased DFT. Evaluation of autonomic balance, particularly parasympathetic tone, may be useful with the implantation of automatic defibrillators.