Effects of the (R) and (S) enantiomers of sulpiride, a potent dopamine (DA) antagonist, on ganglionic transmission were studied in anesthetized dogs. The pre- and postganglionic nerves of cardiac sympathetic ganglia were stimulated electrically, and heart rate was monitored as a measure of ganglionic transmission and sympathetic nerve activity. The heart rate was free from influence of the central nervous system. (R)- And (S)-sulpiride injected i.a. close to the blood supply of the ganglia did not alter basal heart rate, but facilitated ganglionic transmission as demonstrated by an increase in the tachycardia induced by preganglionic nerve stimulation. The (R) enantiomer was 4 times more active than the (S) enantiomer in this respect. Neither enantiomer affected the tachycardia induced by postganglionic nerve stimulation. Norepinephrine and DA injected i.a. caused inhibition of the tachycardia induced by preganglionic nerve stimulation. The inhibitory effect of both catecholamines was antagonized by the sulpiride enantiomers (R)-sulpiride was about 4-fold more potent than (S)-sulpiride in antagonizing DA, whereas (S)-sulpiride was more active against norepinephrine. The sulpiride enantiomers affected neither the tachycardia induced by i.a. administration of acetylcholine nor the bradycardia induced by vagal nerve stimulation. Thus, cholinesterase inhibition and ganglionic stimulation were excluded. These data are, therefore, consistent with the hypothesis that the facilitatory action of the sulpiride enantiomers is related to the antagonism of catecholamines. Positive correlation between the activity of the (R) enantiomer to facilitate ganglionic transmission and to antagonize DA suggests that DA is a physiologically released catecholamine modulating transmission in the cardiac sympathetic ganglia of the dog.