Intrapericardial administration of 5-hydroxytryptamine (5-HT) induced reflex effects consisting in an inhibition of renal sympathetic nerve activity (RSNA), bradycardia and a fall in blood pressure. Nicotine caused the same reflex effects as 5-HT. The reflex effects of both 5-HT and nicotine were abolished by vagotomy. MDL 72222, an antagonist at 5-HT M-receptors, abolished or attenuated the decreases in RSNA, heart rate and blood pressure induced by 5-HT, leaving the reflex effects of nicotine unchanged. In the absence of MDL 72222 the reflex bradycardia partially concealed a positive chronotropic response to 5-HT. After blockade of the bradycardia response by MDL 72222, 5-HT elicited a significant tachycardia, which was not altered by propranolol and phentolamine, but was prevented by phenoxybenzamine. 5-HT probably reaches the sinoatrial node and activates 5-HT receptors that mediate directly the increase in heart rate. The nicotine receptor antagonist hexamethonium selectively abolished or attenuated the reflex effects of nicotine without interfering with those of 5-HT. We conclude that 5-HT and nicotine elicit similar reflex effects in epicardial vagal nerve endings by stimulation of M-receptors or nicotine receptors, respectively.