Abstract

This study characterizes the sumatriptan-sensitive [5-hydroxytryptamine (5-HT)_1B/1D] receptor in rabbit saphenous vein and basilar artery. (S)-(-)-1-{2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethyl}-isochroman-6-carboxylic acid methylamide (PNU-109291), a 5-HT_1D subtype-selective agonist (human K_i = 2.5 ± 0.07 nM), did not contract either tissue, whereas o-methoxyphenylpiperazide derivative 4F (MPPA-4F), a 5-HT_1B subtype-selective antagonist (human K_i = 4.6 ± 0.6 nM) potently inhibited sumatriptan-induced contraction in the saphenous vein and basilar artery. These results suggested that sumatriptan-induced contraction was mediated via the 5-HT_1B receptor in these blood vessels. 5-HT_1B receptor-mediated contraction was then compared in endothelium-intact and denuded vessels to evaluate the role of the endothelium in regulating sumatriptan-induced contractility in these tissues. The presence of an intact endothelium inhibited 5-HT_1B-induced contraction in both tissues. Endothelial denudation or nitric-oxide synthase inhibition with N^ω nitro-l-arginine methyl ester (l-NAME) (100 μM) increased the efficacy and potency of sumatriptan in the saphenous vein and basilar artery. Surprisingly, in endothelial-denuded vascular tissues, l-NAME (100 μM) also significantly increased the maximal 5-HT_1B receptor-induced contraction in both tissues, with no effect on potency of sumatriptan. The effect of l-NAME after endothelial denudation may reflect the presence of a low density of residual endothelial cells as estimated by CD31 antibody staining combined with the modulating effect of nitric oxide released from nonendothelial cells in vascular tissue. Endothelial modulation was specific to 5-HT_1B receptors because removal of the endothelium did not significantly alter contraction to norepinephrine, histamine, prostaglandin, or potassium chloride in the saphenous vein or basilar artery.