Serotonin and norepinephrine produced concentration-dependent contractions of helical strips of canine saphenous veins. The contractile responses to both agonists were inhibited by the alpha adrenergic receptor blocking agent phentolamine. Tolazoline inhibited the contractile responses of canine saphenous veins to norepinephrine but augmented those to serotonin. Blockade of adrenergic neuronal reuptake with cocaine enhanced the sensitivity of the canine saphenous vein to serotonin, but did not suppress the inhibition by phentolamine of the contractile responses to this indolealkylamine. Serotonin-mediated venoconstriction was not secondary to release of norepinephrine since it was not accompanied by an increased release of [7-3H]-norepinephrine. These findings suggest that serotonin does not contract canine saphenous veins by stimulation of typical serotonergic receptors. The binding sites for serotonin and norepinephrine in cutaneous venous smooth muscle may share part of a common receptor complex, which triggers the contractile process. Alternatively, serotonin and norepinephrine may act at two different receptors to elicit contraction of canine saphenous veins.