Vascular 5‐HT₁‐like receptors mediating vasoconstriction and vasodilatation: their characterization and distribution in the intact canine cardiovascular system

Abstract

1 In anaesthetized dogs, intra-left atrial administration of 5-hydroxytryptamine (5-HT) and selected tryptamine analogues (5-carboxamidotryptamine, 5-CT; 5-methyl tryptamine, 5-MT; a-methyl 5-hydroxytryptamine, a-HT; sumatriptan, Sum) in the presence of ketanserin and MDL72222 (5-HT2 and 5-HT3 receptor antagonists, respectively), produced dose-related changes in carotid, coronary 5 The coronary (and carotid) vasodilator responses to 5-CT were antagonized by the 5-HTI-like receptor antagonists, spiperone (1 mg kg-') and methiothepin (0.1 mg kg-'), whereas the renal vasoconstrictor responses to this tryptamine analogue were antagonized only by methiothepin. 6 It is concluded from these studies that agonist finger-printing in vivo, using tryptamine analogues, identifies and confirms the functional presence of at least two pharmacologically distinct subtypes of the 5-HTI-like receptor in the intact canine cardiovascular system. These two subtypes are located on the vascular smooth muscle and mediate direct vasoconstriction and vasodilatation responses in vivo. 7 In addition, these studies confirm that the distribution of these subtypes within the major vascular beds, shows a marked heterogeneity. The carotid vascular responses to the tryptamine analogues indicate the presence of both the vasodilator and the vasoconstrictor subtypes. The coronary vascular responses to these analogues are, however, consistent with presence of the vasodilator subtype, only. By contrast, the renal vascular responses to these analogues indicates only the presence of the vasoconstrictor subtype.

Canine renovascular responses to sumatriptan and 5‐carboxamidotryptamine: modulation through endothelial 5‐HT1‐like receptors by endogenous nitric oxide

“…By contrast, in the renal vascular beds, sumatriptan and 5-carboxamidotryptamine both produced marked vasoconstrictor responses, which were characterized by a very rapid recovery and evidence of a secondary vasodilatation (Cambridge et al, 1991a,b;1995). It had been previously concluded that the renal vascular beds possessed very few, if any, of the vasodilator subtype of the 5-HTI-like receptor, at which 5-carboxamidotryptamine is a potent agonist.…”

“…The vasoconstrictor 5-HTI-like receptors are selectively stimulated by the 5-HT,-like agonist, sumatriptan (Humphrey et al, 1988;Feniuk et al, 1989;Cambridge et al, 1995), whilst the tryptamine analogue, 5-carboxamidotryptamine, is a potent agonist at the vasodilator 5-HT,-like receptors (Saxena & Verdouw, 1985;Connor et al, 1986;Leff et al, 1987;Martin et al, 1987;Cambridge et al, 1995).…”

“…As in previous studies (see Cambridge et al, 1991b;1995) In preliminary dose-ranging studies using closed-chest, anaesthetized animals (n = 3), the haemodynamic effects of the NO-synthase inhibitor, N0-nitro-L-arginine methyl ester (L-NAME) or the substrate for NO formation, L-arginine, were assessed, in order to identify a suitable single dose of each of these compounds for use in the main part of the study. Ascending doses of either L-NAME (1-30mgkg-', i.v.…”

“…It was concluded that there was a heterogeneous distribution of these receptor subtypes such that, the coronary vasculature contained only the vasodilator subtype, the renal vasculature contained only the vasoconstrictor subtype, whilst the carotid vasculature contained both subtypes (Whiting & Cambridge, 1990;Cambridge et al, 1991a,b;1995).…”

“…and MDL72222 (0.5 mg kg-', i.v. ), respectively (see Cambridge et al, 1995). Groups of at least 4 animals were then used for the construction of a limited dose-response curve to i.l.a.…”