Further pharmacological analysis of the orphan 5-HT receptors mediating feline vasodepressor responses: close resemblance to the 5-HT 7 receptor

Abstract

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 NC-IUPHAR subcommittee on the classification of 5-HT receptors. Intravenous (i.v.) bolus injections of 5-CT (0.003-0.3 microg/kg), 5-HT (1-100 microg/kg) and 5-methoxytryptamine (5-MeO-T; 1-100 microg/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 microg/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(IB/ID); 30 microg/kg), tropisetron (5-HT3/4; 3000 microg/kg), (+/-)-pindolol (beta-adrenergic and 5-HT1A; 4000 microg/kg) or equivalent volumes of physiological saline. In contrast, the above vasodepressor responses were markedly and specifically antagonised by i.v. methiothepin (100 microg/kg), lisuride (30 microg/kg and 100 microg/kg), mesulergine (300 microg/kg and 1000 microg/kg) or LY215840 (300 microg/kg and 1000 microg/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).

Mediation of 5-HT-induced internal carotid vasodilatation in GR127935- and ritanserin-pretreated dogs by 5-HT 7 receptors

“…Accordingly, the above rank order of agonist potency (tryptamine fingerprint) parallels that reported at both the cloned 5-HT 7 receptor (e.g. Lovenberg et al 1993;Shen et al 1993) and the functional 5-HT 7 receptors mediating: (1) external carotid vasodilatation in dogs (Villalón et al 1997a); (2) hypotension in rats (De Vries et al 1997); and (3) tachycardia (Villalón et al 1997b) and hypotension (Villalón et al 2000) in cats. In contrast, the above tryptamine fingerprint differs from that reported at cloned 5-ht 6 receptors (5-MeO-T > 5-HT > 5-CT; Monsma et al 1993).…”

“…Apart from the implications discussed below, these data indicate that the pharmacological profile of the canine internal carotid vasodilator 5-HT receptors is similar to that reported for the 5-HT 7 receptors mediating cardiovascular responses in vivo (e.g. Hoyer et al 1994;Martin 1994;De Vries et al 1997;Villalón et al 1997bVillalón et al , 2000.…”

“…Indeed, the rank order of agonist potency of 5-CT >> 5-HT ≥ 5-MeO-T to produce vasodilatation in the dog parallels that reported at mouse Plassat et al 1993), rat (Ruat et al 1993;Shen et al 1993) and human (Bard et al 1993) 5-HT 7 receptors. Notably, the above tryptamine fingerprint is practically identical to that reported in other preparations where musculotropic 5-HT 7 receptors mediate relaxation; some of these preparations include: the rabbit femoral vein (Martin and Wilson 1995), the Cynomolgus monkey isolated jugular vein (Leung et al 1996), the guinea-pig ileum (Carter et al 1995), the human colon (Prins et al 1999), the canine external carotid bed (Villalón et al 1997a), and the systemic vasculature in rats (De Vries et al 1997) and cats (Villalón et al 2000).…”

“…In the light of the above lines of pharmacological evidence, the involvement of 5-HT 7 receptors mediating the vasodilator responses to 5-HT in the canine internal carotid bed is substantiated, as shown for other cardiovascular 5-HT receptors, both in vitro (Carter et al 1995;Martin and Wilson 1995;Leung et al 1996) and in vivo (De Vries et al 1997;Villalón et al 1997aVillalón et al , 1997bVillalón et al , 2000. Admittedly, the present study cannot categorically exclude the possible involvement of additional mechanisms (e.g.…”

[3H]-Serotonin Release from Bovine Iris-ciliary Body: Pharmacology of Prejunctional Serotonin (5-HT7) Autoreceptors

“…In the guinea pig hippocampus, Thomas et al (1999) reported that 5-HT agonists displaced [ 3 H]-5-CT binding to membranes with the following rank order of af®nity: 5-CT 4 5-HT 4 8-OH-DPAT, indicating that 5HT 7 receptors were present in this tissue. A similar rank order of potency of 5-HT receptor agonists have been described in tissues containing 5-HT receptors by Villalon et al (2000) and Bacon and Beck (2000). In the present study, effects of the abovenamed selective agonists for 5-HT 7 receptors (in addition to agonists activating the other 5-HT receptor subtypes) were tested.…”