To characterize the responses of the canine coronary artery to serotonin, rings with and without endothelium were suspended in organ chambers for isometric tension recording. Serotonin evoked an endothelium-dependent relaxation of prostaglandin F2 alpha-contracted rings which was inhibited by antagonists with affinity for 5-hydroxytryptamine (5-HT)1 and 5-HT2 receptors, methiothepin and metergoline, but was not mimicked or antagonized by the 5-HT1A-selective ligand, 8-hydroxy-2-di-n-propylamino tetralin. This relaxation is not mediated by 5-HT1B receptors as it was not antagonized by cyanopindolol; similarly, lack of inhibition by ketanserin and MDL 72222 rule out contributions of 5-HT2 receptors or 5-HT3 receptors. Rings without endothelium contracted to serotonin; this contraction was not blocked by cyanopindolol and was only weakly inhibited by ketanserin, but was antagonized in an apparently competitive fashion by methiothepin and was mimicked by 8-hydroxy-2-di-n-propylamino tetralin (although at higher concentrations than would be expected for its action at a 5-HT1A receptor). At high concentrations, serotonin evoked a relaxation of endothelium-denuded rings, which was blocked by very low concentrations of methiothepin but was unaffected by ketanserin or cyanopindolol. Thus, there appear to be three different serotonergic receptors in the coronary artery. Although available agents do not allow their precise classification as yet, none of them is of the 5-HT2 type.