The modulation of serotonin (5-HT_1B/1D) receptor-induced vascular contractility by histamine and U-46619 was compared in the rabbit basilar artery and saphenous vein. In the saphenous vein, histamine (5 × 10⁷ M) significantly increased the potency (from pEC₅₀ of 6.0 to 6.8) and efficacy (from 52.3% to 88.2%) of sumatriptan. Likewise, U-46619 (5 × 10⁹ M) also increased the potency (from pEC₅₀ of 5.9 to 6.6) and efficacy (from 51.8% to 92.1%) of sumatriptan in the saphenous vein. In contrast, equieffective concentrations of histamine (10⁷ M) and U-46619 (3 × 10⁹ M) failed to amplify contraction to sumatriptan in the basilar artery. Contraction to sumatriptan was inhibited by nitrendipine (10⁷ M) in the basilar artery but not in the saphenous vein, suggesting that different contractile signaling mechanisms are operating in these tissues. Furthermore, U-46619- and thrombin-induced contractility in the basilar artery were also not amplified by histamine, suggesting that lack of amplification of contraction in the basilar artery was not restricted to sumatriptan but was rather a characteristic of this cerebral vessel. These data suggest that in the in vivo plasma milieu sumatriptan will more markedly contract the peripheral saphenous vein than the basilar artery, a cerebral blood vessel.