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 externa l carotid bed of anaesthetized dogs with intact sympathetic tone are m ediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and p ostjunctional 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 vasoc onstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 1 27935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the phar macological profile of this postjunctional vasodilator 5-HT receptor i n the external carotid bed of vagosympathectomized dogs pretreated wit h GR 127935 (20 mu g kg(-1), i.v.). 2 One-minute intracarotid (i.c.) i nfusions 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 hea rt rare) with a rank order of agonist potency of 5-CT > > 5-HT greater than or equal to 5-methoxytryptamine > lisuride, whereas cisapride (1 00-1000 mu g min(-1), i.c.) was practically inactive. Interestingly, l isuride (mean dose of 85+/-7 mu g kg(-1), i.c.), but not cisapride (me an dose of 67+/-7 mu g kg(-1), i.c.), specifically abolished the respo nses 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. infusio ns of 8-OH-DPAT (3-3000 mu g min(-1)) produced dose-dependent decrease s, not increases, in external carotid blood flow and failed to antagon ize (mean dose of 200+/-33 mu g kg(-1), i.c.) the agonist-induced vaso dilator responses. 3 The external carotid vasodilator responses to 5-H T, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v. ) pretreatment with either saline, (+/-)-pindolol (4 mg kg(-1)) or rit anserin (100 mu g kg(-1)) plus granisetron (300 mu g kg(-1)), but were dose-dependently blocked by i.v. administration of methiothepin (10 a nd 30 mu g kg(-1), given after ritanserin plus granisetron), mesulergi ne (10 and 30 mu g kg(-1)), metergoline (1 and 3 mg kg(-1)), methyserg ide (1 and 3 mg kg(-1)) or clozapine (0.3 and 1 mg kg(-1)). Neverthele ss, the blockade of the above responses, not significant after treatme nt with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of me thysergide and clozapine. 4 Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing hi gh affinity for the cloned 5-HT7 receptor, our results indicate that t he 5-HT receptor mediating external carotid vasodilatation in GR 12793 5-pretreated vagosympathectomized dogs is operationally similar to the putative 5-HT7 receptor mediating relaxation of vascular and non-vasc ular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea-pig ileum) as well as tachycardia in the cat.