Further pharmacological analysis of the orphan 5-HT receptors mediating feline vasodepressor responses: close resemblance to the 5-HT7 receptor

It has been suggested that the late hypotensive response to serotonin (5-hy droxytryptamine; 5-HT) in vagosympathectomised cats, being potently mimicke d by 5-carboxamidotryptamine (5-CT), not modified by ketanserin and blocked by methiothepin or methysergide, is mediated by '5-HT1-like' receptors. Ne vertheless, current guidelines for 5-HT receptor classification refer to th is receptor as an orphan receptor. Thus, the present study set out to reana lyse the above suggestion in terms of the classification schemes proposed i n 1994 and 1998 by the NC-IUPHAR subcommittee on the classification of 5-HT receptors. Intravenous (i.v.) bolus injections of 5-CT (0.003-0.3 mu g/kg), 5-HT (1-10 0 mu g/kg) and 5-methoxytryptamine (5-MeO-T; 1-100 mu g/kg) produced dose-d ependent vasodepressor responses with a rank order of agonist potency of 5- CT >> 5-HT = 5-MeO-T with sumatriptan (10-300 mu g/kg) virtually inactive. The vasodepressor responses to 5-HT, 5-CT and 5-MeO-T were not attenuated f ollowing i.v. administration of the antagonists GR127935 (5-HT1B/1D; 30 mu g/kg), tropisetron (5-HT3/4; 3000 mu g/kg), (+/-)-pindolol (beta-adrenergic and 5-HT1A; 4000 mu g/kg) or equivalent volumes of physiological saline. I n contrast, the above vasodepressor responses were markedly and specificall y antagonised by i.v. methiothepin (100 mu g/kg), lisuride (30 mu g/kg and 100 mu g/kg), mesulergine (300 mu g/kg and 1000 mu g/kg) or LY215840 (300 m u g/kg and 1000 mu g/kg). The above lines of evidence, therefore, indicate that the orphan receptors mediating the vasodepressor responses to 5-HT in vagosympathectomised cats are pharmacologically similar to other 5-HT7 rece ptors mediating vascular and non-vascular responses (e.g. relaxation of the canine external carotid artery and guinea-pig ileum as well as feline tach ycardia).