NATURE OF 5-HT1-LIKE RECEPTORS MEDIATING DEPRESSOR RESPONSES IN VAGOSYMPATHECTOMIZED RATS - CLOSE RESEMBLANCE TO THE CLONED 5-HT(7) RECEPTOR

It has been suggested that the late hypotensive response to serotonin (5-hydroxytryptamine; 5-HT) in vagosympathectomized rats is mediated b y '5-HT1-like' receptors since this effect is mimicked by 5-carboxamid otryptamine (5-CT), is not modified by cyproheptadine, ketanserin or M DL, 72222, but it is blocked by methysergide. The present study was se t out to reanalyze this suggestion in terms of the classification sche mes proposed in 1994 and 1996 by the NC-IUPHAR sub-committee on the cl assification and nomenclature of 5-HT receptors. I.v. bolus injections of 5-CT (0.01-0.3 mu g.kg(-1)), 5-HT (1-30 mu g.kg(-1)) and 5-methoxy tryptamine (5-MeO-T; 1-30 mu g.kg(-1)) produced dose-dependent hypoten sive responses with a rank order of agonist potency: 5-CT >> 5-HT grea ter than or equal to 5-methoxytryptamine with sumatriptan (30-1000 mu g.kg(-1)) inactive. The depressor responses to 5-HT and 5-CT were not attenuated by i.v. GR127935 (300-3000 mu g.kg(-1)) or equivalent volum es of saline. In contrast, lisuride, methiothepin, mesulergine, meterg oline and clozapine dose-dependently antagonized the responses to 5-HT and 5-CT: the rank order of apparent pA(2) values against 5-HT and 5- CT, respectively, was: lisuride (7.7; 7.8) > methiothepin (6.8; 7.0) g reater than or equal to mesulergine (6.4; 6.6) > clozapine (5.7; 5.8); metergoline displayed variable potencies (5.6; 6.4). Except for lisur ide, which also affected isoprenaline-induced hypotension, the antagon ism by the other drugs was selective. Based upon the above rank order of agonist potency, the blockade by a series of drugs showing high aff inity for the cloned 5-ht(7) receptor and the lack of blockade by GR12 7935, our results indicate that the 5-HT receptor mediating hypotensio n in vagosympathectomized rats is operationally similar to other putat ive 5-ht(7) receptors mediating vascular and non-vascular responses (e .g. relaxation of the rabbit femoral vein, canine coronary and externa l carotid arteries and guinea-pig ileum as well as feline tachycardia) .