Cardiac electrophysiologic effects of verapamil in vivo are the result of both direct and indirect actions on the heart (the latter due to augmentation of sympathetic neural tone, diminution of parasympathetic neural tone, and increased circulating catecholamines). In this study we assessed the interaction of verapamil's direct and indirect actions on electrophysiologic properties of the heart in awake, previously instrumented, unsedated dogs. After administration of intravenous verapamil (0.2 mg/kg), electrophysiologic effects were assessed serially over a 1 hr period in 10 awake dogs before (group I studies) and during pharmacologic autonomic blockade (group 2 studies), and in a subset of these dogs (n = 5) after orthotopic cardiac transplantation (group 3 studies). In group 1 dogs, sinus cycle length (SCL) initially shortened after verapamil (postverapamil 379 ± 50 msec vs baseline of 494 ± 72 msec, p < .001) and subsequently gradually prolonged. In groups 2 and 3, transient SCL shortening was absent. SCL prolonged promptly after verapamil, and sinus arrest developed in two of 10 group 2 and two of five group 3 animals. Verapamil exerted a negative dromotropic effect on atrioventricular node conduction in all three experimental groups, as assessed by drug-induced changes in minimum cycle length with sustained 1:1 atrioventricular conduction and measurements of atrioventricular node effective and functional refractory period. However, compared with findings in group 1, this negative dromotropic effect occurred more rapidly and was markedly potentiated in groups 2 and 3. The time course of drug action was also affected by experimental conditions. For instance, peak effects of verapamil on atrioventricular node electrophysiologic properties occurred later in group 1 (30 to 60 min) than in group 2 or 3 (5 to 10 min). Verapamil plasma levels did not account for differences in drug effects in the three experimental groups. Thus, in the awake unsedated subject, both the magnitude and time course of parenteral verapamil's direct negative chronotropic effect on the sinus node and its negative dromotropic effect on the atrioventricular node are substantially modified by indirect effects mediated through neural mechanisms and alterations of circulating catecholamines. Potentially, both of these direct electrophysiologic effects of verapamil may be accentuated in clinical settings in which indirect moderating influences are diminished (e.g., concomitant treatment with sympatholytic drugs; cardiac transplantation).