The main catecholamine end-metabolites have been considered biologically inactive, but accumulated evidence indicates a variety of pharmacological actions after exogenous administration. We examined the dose-related haemodynamic effects of vanillylmandelic acid in the in vivo rat-model. One hundred and sixteen Wistar rats (250±20 g) were studied under continuous electrocardiographic monitoring; invasive blood pressure was recorded for 60 min through a catheter in the right common carotid artery. Measurements were performed at baseline and after vanillylmandelic acid (1, 10, 100 mg/kg) and homovanillic acid (10 mg/kg) intra-arterial administration. To examine the underlying mechanisms, the haemodynamic effects were compared with those (a) after trimetazidine administration, which has similar structure due to a tri-methylated phenolic ring; (b) after epinephrine and isoprenaline administration following vanillylmandelic acid pretreatment; (c) after vanillylmandelic acid administration post-bilateral vagotomy. Vanillylmandelic acid, homovanillic acid and (to a lesser extent) trimetazidine decreased heart rate and mean arterial blood pressure. This effect was blunted in vagotomized animals. Comparable effects were noted in heart rate and blood pressure after adrenaline and isoprenaline infusion, with and without vanillylmandelic acid-pretreatment. In conclusion, vanillylmandelic acid administration decreases heart rate dose-dependently, mediated by increased vagal tone, without α- or β-adrenergic-receptor blocking effects. The pharmacological properties of compounds with a mono- and tri-methylated phenolic ring merit further investigation.