Mediation of 5-HT-induced external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs by the putative 5-HT7 receptor

1 The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 mu g kg(-1), i.v.). 2 One-minute intracarotid (i.c.) infusions of 5-HT (0.3-30 mu g min(-1)), 5-carboxamidotryptamine (5-CT; 0.01-0.3 mu g min(-1)), 5-methoxytryptamine (1-100 mu g min(-1)) and lisuride (3-1000 mu g min(-1)) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rare) with a rank order of agonist potency of 5-CT > > 5-HT greater than or equal to 5-methoxytryptamine > lisuride, whereas cisapride (100-1000 mu g min(-1), i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85+/-7 mu g kg(-1), i.c.), but not cisapride (mean dose of 67+/-7 mu g kg(-1), i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (3-3000 mu g min(-1)) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200+/-33 mu g kg(-1), i.c.) the agonist-induced vasodilator responses. 3 The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (+/-)-pindolol (4 mg kg(-1)) or ritanserin (100 mu g kg(-1)) plus granisetron (300 mu g kg(-1)), but were dose-dependently blocked by i.v. administration of methiothepin (10 and 30 mu g kg(-1), given after ritanserin plus granisetron), mesulergine (10 and 30 mu g kg(-1)), metergoline (1 and 3 mg kg(-1)), methysergide (1 and 3 mg kg(-1)) or clozapine (0.3 and 1 mg kg(-1)). Nevertheless, the blockade of the above responses, not significant after treatment with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of methysergide and clozapine. 4 Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing high affinity for the cloned 5-HT7 receptor, our results indicate that the 5-HT receptor mediating external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs is operationally similar to the putative 5-HT7 receptor mediating relaxation of vascular and non-vascular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea-pig ileum) as well as tachycardia in the cat.