Evidence for common pharmacological properties of [3H]5-hydroxytryptamine binding sites, presynaptic 5-hydroxytryptamine autoreceptors in CNS and inhibitory presynaptic 5-hydroxytryptamine receptors on sympathetic nerves

Abstract

The affinities of 16 5-hydroxytryptamine (5-HT) receptor agonists (indole derivatives) and 7 5-HT receptor antagonists for [3H]5-hydroxytryptamine [( 3H]5-HT) binding sites in rat cerebral cortex membranes were determined. In addition, the potencies of the agonists for inhibiting the electrically induced tritium overflow from rat brain cortex slices preincubated with [3H]5-HT and from canine saphenous veins preincubated with [3H]noradrenaline were measured. Furthermore, the potencies of the indole derivatives for inducing contractile responses of canine saphenous veins were recorded. In addition, the interaction of the antagonists with unlabelled 5-HT at the 5-HT autoreceptor was studied in rat brain cortex slices. There was a good correlation between the binding affinities of the indole derivatives for the [3H]5-HT sites of rat brain cortex membranes and their potencies for inhibiting the evoked tritium overflow from both rat brain cortex slices and strips of canine saphenous vein. Comparison of the inhibition constants derived from the overflow experiments in both tissues again revealed a high correlation coefficient while there was only weak correlation between the binding affinities in rat brain cortex and the contractile potencies of the drugs in canine saphenous vein strips. When 5-HT receptor antagonists were investigated, metitepin and metergoline showed moderate affinities for the 5-HT autoreceptors in rat brain cortex slices, whereas quipazine had only weak affinity, and ketanserin, metoclopramide, cinanserin and cyproheptadine exhibited no antagonistic property. In binding experiments, the competition curves of most 5-HT receptor antagonists were biphasic, suggesting that the [3H]5-HT binding sites are heterogeneous.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential classification of vascular smooth muscle and endothelial cell 5‐HT receptors by use of tryptamine analogues

“…Yet a further 5-HT receptor, which is clearly not of the 5-HT2 type (Feniuk et al, 1985), has been shown to mediate contraction of certain cutaneous and cerebral blood vessels (Apperley et al, 1980;Mfiller-Schweinitzer, 1981;Bradley et al, 1986a) and to inhibit release of noradrenaline from sympathetic nerve terminals (Feniuk et al, 1979;Engel et al, 1983;Cohen, 1985). This receptor shares in common with the endothelial and smooth muscle relaxant 5-HT receptors a susceptibility to blockade by low concentrations ofmethiothepin (Apperley & Humphrey, 1986) and a resistance to blockade by ketanserin (Cohen, 1985;Bradley et al, 1986a;Feniuk et al, 1985).…”

5‐Carboxamidotryptamine is a selective agonist at 5‐hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats

“…Leysen et al (1981) have described an order of antagonist potency of methiothepin > methysergide >> ketanserin at 5-HT, binding sites in rat frontal cortex. Furthermore, 5-CT is the most potent 5-HT receptor agonist yet identified which is capable of displacing 5-HT from the 5-HT, binding site in rat cerebral cortex (Engel et al, 1983). However, it is now clear that the 5-HT, recognition site is not a homogeneous population of binding sites and reflects the presence of at least two subtypes (Pedigo et al, 1981).…”

Effects of methysergide and 5‐hydroxytryptamine on carotid blood flow distribution in pigs: further evidence for the presence of atypical 5‐HT receptors

“…Thus, the overall response to 5-HT in the carotid vascular bed is determined by the relative magnitude of the effects in the three segments, though obviously the large artery responses are the least important in vivo. The situation is further complicated as the amine can also reduce the release of noradrenaline by a presynaptic action (Apperley et al, 1980;Engel et al, 1983). Therefore, in the presence of a substantial sympathetic neural tone, total carotid blood flow may increase due to a more marked arteriolar vasodilatation (for references, see Saxena & Verdouw, 1982).…”