THE 5-HT1-LIKE RECEPTOR MEDIATING THE INCREASE IN CANINE EXTERNAL CAROTID BLOOD-FLOW - CLOSE RESEMBLANCE TO THE 5-HT1D SUBTYPE

1 It has recently been shown that the increase in external carotid blood flow induced by 5-hydroxytryptamine (5-HT) in the anaesthetized dog, being mimicked by 5-carboxamidotryptamine (5-CT), inhibited by methiothepin, vagosympathectomy and sympatho-inhibitory drugs, and resistant to blockade by ritanserin and MDL 72222, is mediated by stimulation of prejunctional 5-HT1-like receptors leading to an inhibitory action on carotid sympathetic nerves; these 5-HT1-like receptors are unrelated to either the 5-HT1A, 5-HT1B Or 5-HT1C (now 5-HT2C) receptor subtypes. Inasmuch as 5-CT, 5-methoxytryptamine, sumatriptan and metergoline display high affinity, amongst other 5-HT binding sites, for the 5-HT1D subtype, in the present study we have used these drugs in an attempt to determine whether the above inhibitory prejunctional 5-HT1-like receptors correlate with the 5-HT1D subtype. 2 One-minute intracarotid (i.c.) infusions of 5-HT (0.3, 1, 3 and 10 mu g), 5-CT (0.01, 0.03, 0.1 and 0.3 mu g), 5-methoxytryptamine (1, 3, 10 and 30 mu g) and sumatriptan (1, 3, 10, 30 and 100 Ctg) resulted in dose-dependent increases in external carotid blood flow (without changes in mean arterial blood pressure or heart rate) with the following rank order of agonist potency: 5-CT>> 5-HT> 5-methoxytryptamine greater than or equal to,sumatriptan. Interestingly, sumatriptan-induced vasodilatation was followed by a more pronounced vasoconstriction. 3 The external carotid vasodilator effects of 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan were dose-dependently and specifically antagonized by metergoline (10, 30 and/or 100 mu g kg(-1), i.v.). In addition, 5-methoxytryptamine- and sumatriptan-induced vasodilator effects were, respectively, markedly inhibited or abolished after vagosympathectomy, as previously shown for 5-CT and 5-HT. 4 Sumatriptan showed tachyphylaxis in its vasodilator component and antagonized 5-HT-induced external carotid vasodilatation in a specific manner, suggesting that a common site of action may be involved. 5 Taken together, the above results support our contention that 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan produce external carotid vasodilatation in the dog by an action that might primarily involve a prejunctional inhibition on carotid sympathetic nerves; a secondary component of this vasodilator response may be postsynaptic (endothelium-dependent and/or even directly on the vasculature). Based on the rank order of agonist potency, inhibition by vagosympathectomy and blockade by metergoline, we suggest that the inhibitory prejunctional 5-HT1-like receptors mediating external carotid vasodilatation in the dog closely resemble the 5-HT1D receptor subtype. The pharmacological profile of these receptors is similar (sympathetic nerves of the rat kidney and human saphenous vein, as well as porcine coronary endothelium) to other putative 5-HT1D receptors mediating vascular responses.