Autonomic Modulation of Lethal Arrhythmias.Susceptibility to sudden death in dogs with healed myocardial infarction can be defined by the response to transient ischemia during treadmill exercise and can often be predicted by the baroreceptor slope, which is determined from least squares regression of the RR interval, or heart rate, response to increasing systolic pressure during a phenylephrine infusion. We used standard microelectrode techniques to study isolated Purkinje fiber bundles as well as subendocardial Purkinje fibers overlying the infarcted myocardium of dogs classified by treadmill testing as resistant or susceptible to sudden death. We determined the response to isoproterenol (Iso) alone and in the presence of acetylcholine (ACh). Control action potential (AP) characteristics for both groups were similar except for the following: in normal Purkinje fibers, susceptible dogs had a significantly lower AP overshoot and Vmaxthan resistant dogs. In addition, fibers from the in arct zones of susceptible dogs had lower maximal diastolic potentials than those from the normal Purkinje fibers of susceptible dogs. Iso significantly shortened AP duration in normal and infarct zone fibers of both groups. ACh alone had no effect on AP duration. In the infarct zone, ACh 10−7M did not antagonize Iso‐induced shortening of AP duration in susceptible or resistant dogs; but ACh 10−5M completely blocked Iso effects in resistant dogs. In normal Purkinje fibers, ACh antagonism of Iso effects was seen in susceptible and resistant animals. Iso and ACh had no significant effect on other transmembrane potential characteristics. The differences between resistant and susceptible dogs in control transmembrane characteristics and accentuated antagonism may contribute to the substrate that increases the likelihood of sudden death in this