The modulation of serotonin receptor (5-_HT1B/1D)-induced vascular contractility by histamine and U46619 was compared in the rabbit basilar artery and saphenous vein. In the saphenous vein, histamine (5 X 10^-7 M) significantly increased sumatriptan’s potency (from pEC₅₀ of 6.0 to 6.8) and efficacy (from 52.3 to 88.2%). Likewise, U46619 (5 X 10^-9 M) also increased sumatriptan’s potency (from pEC₅₀ of 5.9 to 6.6) and efficacy (from 51.8 to 92.1%) in the saphenous vein. In contrast, equieffective concentrations of histamine (10^-7 M) and U46619 (3 X 10^-9 M) failed to amplify contraction to sumatriptan in the basilar artery. Contraction to sumatriptan was inhibited by nitrendipine (10^-7M) in the basilar artery but not in the saphenous vein, suggesting that different contractile signaling mechanisms are operating in these tissues. Furthermore, U46619 - 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 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.