Mediation of 5-HT-induced internal carotid vasodilatation in GR127935-and ritanserin-pretreated dogs by 5-HT7 receptors

The vasoconstrictor effects of 5-hydroxytryptamine (5-HT) in the internal c arotid bed of anaesthetised dogs with bilateral vagosympathectomy are mainl y mediated by both 5-HT1B and 5-HT2 receptors. The blockade of this vasocon strictor effect of 5-HT by the combined use of the antagonists, GR127935 (5 -HT1B/1D) and ritanserin (5-HT2,), unmasks a dose-dependent vasodilator eff ect of 5-HT, but not of sumatriptan. Therefore, the present study set out t o analyse the pharmacological profile of this vasodilator 5-HT receptor in the internal carotid bed of vagosympathectomized dogs systematically pretre ated with intravenous (i.v.) injections of GR127935 (30 mu g/kg) and ritans erin (100 mu g/kg). One-minute (l-min) intracarotid (i.c.) infusions of 5-H T (0.1-10 mu g/min), 5-carboxamido-tryptamine (5-CT; 0.01-0.3 mu g/min), 5- methoxytryptamine (5-MeO-T; 1-100 mu g/min) and acetylcholine (ACh; 0.003-0 .1 mu g/min) resulted in dose-dependent increases in internal carotid blood flow (without changes in blood pressure or heart rate) with a rank order o f agonist potency of ACh > 5-CT >> 5-HT greater than or equal to 5-MeO-T. T he internal carotid vasodilator responses to 5-HT, 5-CT and 5-MeO-T, which remained unaffected after saline (0.03 ml/kg and 0.1 ml/kg, i.v.), were spe cifically and dose-dependently blocked by i.v. administration of lisuride ( 10 mu g/kg and 30 mu g/kg), clozapine (1000 mu g/kg), mesulergine (300 mu g /kg and 1000 mu g/kg) and LY215840 (300 mu g/kg and 1000 mu g/kg) with the following apparent rank order of potency: lisuride >> mesulergine = LY21584 0 greater than or equal to clozapine. The above results suggest that the 5- HT receptor mediating internal carotid vasodilatation in vagosympathectomiz ed dogs pretreated with GR127935 and ritanserin is operationally similar to other 5-HT7 receptors mediating vascular and non-vascular responses.