Toxic doses of digitalis can induce severe arrhythmias in the sinus node. Since digitalis is known to induce electrical uncoupling in heart tissues, it is possible that the arrhythmias may be mediated by cell-to-cell uncoupling leading to desynchronization of pacemaker cells. We investigated this possibility using intracellular recordings and two different preparations of isolated rabbit sinus node. First, the whole sinus node region with the crista terminalis and a portion of right atrium were exposed to 2 microM ouabain in the presence of atropine (0.09 microM) and propranolol (0.77 microM). With ouabain superfusion, there was a gradual increase in spontaneous discharge, conduction delay, pacemaker shifts, and arrhythmias associated with multiple pacemaker sites. Interaction between pacemakers rapidly decreased, and finally atrial arrest was observed. Second, thin strips of sinus node were placed in a three-compartment bath. Superfusion of the central segment (1.0-1.5 mm) with 1-5 microM ouabain led to tachycardia and apparent conduction delay, followed by asynchronous firing and phasic interactions between pacemakers across the central segment. These interactions diminished in the course of intoxication, indicating a gradual increase of electrical uncoupling induced by the drug. All effects were reversible on washout. We conclude that digitalis-induced arrhythmias in the sinus node result from cell-to-cell uncoupling and loss of synchrony between pacemaker cells. The pattern of arrhythmias can be predicted by the phasic interactions between the pacemakers.