The 5‐HT1‐like receptor mediating the increase in canine external carotid blood flow: close resemblance to the 5‐HT1D subtype

Abstract

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. One‐minute intracarotid (i.c.) infusions of 5‐HT (0.3, 1, 3 and 10 μg), 5‐CT (0.01, 0.03, 0.1 and 0.3 μg), 5‐methoxytryptamine (1, 3, 10 and 30 μg) and sumatriptan (1, 3, 10, 30 and 100 μg) 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 ≤ sumatriptan. Interestingly, sumatriptan‐induced vasodilatation was followed by a more pronounced vasoconstriction. 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 μg 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. 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. 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. 1994 British Pharmacological Society