Effect of procaine on the SA node of the dog heart was studied in situ using a selective perfusion technique of the SA node artery. Procaine in doses from 100 mug to 1 mg produced a sinus depression followed by a prolonged phase of the increased heart rate. The depression became more prominent with increasing the dose. The threshold dose for inducing the tachycardiac response was lower, but the sinus acceleration was not proportional to the dose. The initial depression was not affected by atropine, whereas the occurrence of the stimulatory phase was inhibited by prior administration of propranolol or tetrodotoxin into the SA node artery or in the reserpine-treated dogs. The results indicate that the biphasic response is induced by a direct negative chronotropic action of procaine on the SA node and by an indirect effect mediated by an interaction with the postganglionic adrenergic nerves.