Investigation into the 5‐hydroxytryptamine receptor mediating smooth muscle relaxation in the rat oesophagus

Abstract

1 An investigation has been made into the 5-hydroxytryptamine (5-HT) receptor mediating relaxation of rat oesophagus in preparations precontracted with carbachol.2 In tissues treated with pargyline (100pM) and in the presence of corticosterone (30OUM) and cocaine (30 pM) the potency of 5-HT and 5-methoxytyramine (5-MeOT) was not changed but the maximum response to these agonists was reduced. Thus there was no evidence of metabolism and/or uptake through an amine depleting mechanism. 3 The relaxant concentration-effect curves to 5-HT were shifted to the left in a concentration-related manner by isobutylmethylxanthine (1 and 10pM), suggesting the involvement of adenosine 3':5'-cyclic monophosphate in these responses.

Development of a radioligand binding assay for 5‐HT4 receptors in guinea‐pig and rat brain

“…The use of the enantiomers of zacopride has indicated small but significant differences in the affinities of R-and S-zacopride for the [3H]-GR1 13808 binding site in homogenates of both guinea-pig hippocampus and striatum (P = 0.01 and 0.04 respectively). This compares well with functional data in guinea-pig ileum where S-zacopride has been shown to be a full agonist and R-zacopride a weak partial agonist (Eglen et al, 1990 (Dumuis et al, 1988;Craig & Clarke, 1990;Eglen et al, 1990;Elswood et al, 1991;Reeves et al, 1991) in both the guinea-pig hippocampus and the striatum pK1 (Grossman et al, 1993). Hill coefficients for 5-HT are slightly increased by the addition of GTP, however, values obtained both in the presence and absence of GTP are not significantly different from unity.…”

“…In functional studies in rat oesophagus and guinea-pig colon, renzapride and R,S-zacopride have very similar acitivity with renzapride being fractionally more potent (Reeves et al, 1991;Elswood et al, 1991). In the present binding study, renzapride also revealed a slightly higher affinity than R,Szacopride (pKi = 7.0 and 6.8 respectively in the striatum and 6.9 and 6.7 in the hippocampus).…”

“…In the central nervous system 5-HT4 receptors have been shown to mediate an activation of adenylate cyclase (Dumuis et al, 1988;Bockaert et al, 1990). In the periphery, 5-HT4 receptors produce a variety of responses including relaxation of smooth muscle (Reeves et al, 1991), neuronal cholinergically mediated contraction of guinea-pig ileum and proximal colon (Eglen et al, 1990;Elswood et al, 1991), enhancement of the 'twitch' response in electrically field stimulated guinea-pig ileum (Craig & Clarke, 1990) and induction of chloride secretion in rat distal colon . 5-HT4 receptors have also been implicated in cardiovascular effects in both pig and man (Bom et al, 1988;Villalon et al, 1990: Kaumann et al, 1990.…”

Characterization of the 5‐hydroxytryptamine receptor type involved in inhibition of spontaneous activity of human isolated colonic circular muscle

“…In the gastrointestinal tract, the 5-HT4 receptor has been identified at neuronal sites of the guinea-pig ileum (Craig & Clarke, 1990) and colon (Elswood et al, 1991;Wardle & Sanger, 1993) and at non-neuronal sites in rat oesophagus (Reeves et al, 1991;Baxter et al, 1991) and terminal ileum (Tuladhar et al, 1991a). In preparations from the guinea-pig, activation of these receptors results in a contractile response while in those from the rat, relaxation.…”

“…Additionally, substituted benzamides, including renzapride, cisapride, zacopride and metoclopramide, which are 5-HT3 receptor antagonists, are agonists at the 5-HT4 receptor. Further characterization of 5-HT4 receptors is by the weak antagonistic effect of tropisetron with pKB 5.8-6.7 (Baxter et al, 1991;Reeves et al, 1991), although this compound is a potent 5-HT3 receptor antagonist, pKB 7.8-10.6 (Richardson et al, 1985). The 5-HT4 receptor is also antagonized by DAU 6285 (Bockaert et al, 1992) and GR 113808 (Grossman et Author for correspondence.…”