PHARMACOLOGICAL PROFILE OF THE RECEPTORS THAT MEDIATE EXTERNAL CAROTID VASOCONSTRICTION BY 5-HT IN VAGOSYMPATHECTOMIZED DOGS

1 5-Hydroxytryptamine (5-HT) can produce vasodilatation or vasoconstri ction of the canine external carotid bed depending upon the degree of carotid sympathetic tone. Hence, external carotid vasodilatation to 5- HT in dogs with intact sympathetic tone is primarily mediated by preju nctional 5-HT1-like receptors similar to the 5-HT1D subtype, which inh ibit the carotid sympathetic outflow. The present investigation is dev oted to the pharmacological analysis of the receptors mediating extern al carotid vasoconstriction by 5-HT in vagosympathectomized dogs. 2 In tracarotid (i.c.) infusions for 1 min of 5-HT (0.3, 1, 3, 10, 30 and 1 00 mu g) resulted in dose-dependent decreases in both external carotid blood how and the corresponding conductance; both mean arterial blood pressure and heart rate remained unchanged during the infusions of 5- HT. These responses to 5-HT were resistant to blockade by antagonists at 5-HT2 (ritanserin) and 5-HT3/5-HT4 (tropisetron) receptors, but wer e partly blocked by the 5-HT1-like and 5-HT2 receptor antagonist, meth iothepin (0.3 mg kg(-1)); higher doses of methiothepin (1 and 3 mg kg( -1)) caused little, if any, further blockade. These methiothepin (3 mg kg(-1))-resistant responses to 5-HT were not significantly antagonize d by MDL 72222 (0.3 mg kg(-1)) or tropisetron (3 mg kg(-1)). 3 The ext ernal carotid vasoconstrictor effects of 5-HT were mimicked by the sel ective 5-HT1-like receptor agonist, sumatriptan (3, 10, 30 and 100 mu g during 1 min, i.c.), which produced dose-dependent decreases in exte rnal carotid blood flow and the corresponding conductance; these effec ts of sumatriptan were dose-dependently antagonized by methiothepin (0 .3, 1 and 3 mg kg(-1)), but not by 5-HT1D-like receptor blocking doses of metergoline (0.1 mg kg(-1)). 4 The above vasoconstrictor effects o f 5-HT remained unaltered after administration of phentolamine, propra nolol, atropine, hexamethonium, brompheniramine, cimetidine and halope ridol, thus excluding the involvement of alpha- and beta-adrenoceptors , muscarinic, nicotinic, histamine and dopamine receptors. Likewise, i nhibition of either 5-HT-uptake (with fluoxetine) or cyclo-oxygenase ( with indomethacin), depletion of biogenic amines (with reserpine) or b lockade of calcium channels (with verapamil) did not modify the effect s of 5-HT. 5 Taken together, the above results support our contention that the external carotid vasoconstrictor responses to 5-HT in vagosym pathectomized dogs are mainly mediated by activation of sumatriptan-se nsitive 5-HT1-like receptors. It must be emphasized, notwithstanding, that other mechanisms of 5-HT, including an interaction with a novel 5 -HT receptor (sub)type and/or an indirect action that may lead to the release of a known (or even unknown) neurotransmitter substance cannot be categorically excluded.