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-hydroxytryptamine; 5-HT) in vagosympathectomised cats, being potently mimicked by 5-carboxamidotryptamine (5-CT), not modified by ketanserin and blocked by methiothepin or methysergide, is mediated by '5-HT1-like' receptors. Nevertheless, current guidelines for 5-HT receptor classification refer to this receptor as an orphan receptor. Thus, the present study set out to reanalyse the above suggestion in terms of the classification schemes proposed in 1994 and 1998 by the NCIUPHAR subcommittee on the classification of 5-HT receptors. Intravenous (i.v.) bolus injections of 5-CT (0.003-0.3 μg/kg), 5-HT (1-100 μg/kg) and 5-methoxytryptamine (5-MeO-T; 1-100 μg/kg) produced dose-dependent vasodepressor responses with a rank order of agonist potency of 5-CT >> 5-HT = 5-MeO-T with sumatriptan (10-300 μg/kg) virtually inactive. The vasodepressor responses to 5-HT, 5-CT and 5-MeO-T were not attenuated following i.v. administration of the antagonists GR127935 (5- HT(1B/1D); 30 μg/kg), tropisetron (5-HT(3/4); 3000 μg/kg), (±)-pindolol (β-adrenergic and 5-HT(1A); 4000 μg/kg) or equivalent volumes of physiological saline. In contrast, the above vasodepressor responses were markedly and specifically antagonised by i.v. methiothepin (100 μg/kg), lisuride (30 μg/kg and 100 μg/kg), mesulergine (300 μg/kg and 1000 μg/kg) or LY215840 (300 μg/kg and 1000 μg/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 receptors mediating vascular and non-vascular responses (e.g. relaxation of the canine external carotid artery and guinea-pig ileum as well as feline tachycardia).

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