5-Hydroxytryptamine4 receptors mediate relaxation of the rat oesophageal tunica muscularis mucosae

1 The pharmacological properties of RS 23597-190 (3-(piperdine-1-yl)-propyl-4-amino-5-chloro-2-methoxy benzoate hydrochloride) have been studied in vitro and in vivo.2 RS 23597-190 competitively antagonized 5-HT4 receptor-mediated relaxations of rat, carbachol precontracted oesophageal muscularis mucosae, (pA2 = 7.8 ± 0.1; Schild slope = 1.2 ± 0.2). Affinity estimates (-log KB) at 5-HT4 receptors using either renzapride or SC-53116 as agonists yielded a -log KB value of 8.0 ± 0.01. In contrast, RS 23597-190 failed to antagonize contractile responses to 5-HT of guinea-pig ileal 5-HT3 receptors, even at concentrations up to 10 tiM. 3 Increases in short-circuit current, induced by 5-HT, were studied in guinea-pig ileal mucosal sheets. Concentration-response curves to 5-HT were biphasic, with the high potency phase to 5-HT inhibited by RS 23597-190 and mimicked by 5-methoxytryptamine. The -log KB value for RS 23597-190 at the high potency phase was 7.3 confirming that 5-HT4 receptors mediated the high potency phase. min. Transient arrhythmic effects were noted after administration of the compound. 7 In conclusion, RS 23597-190 acts as a high affinity, selective competitive antagonist at 5-HT4 receptors. Thus, the compound appears to be a useful tool for 5-HT4 receptor identification in vitro. In vivo, the compound is rapidly metabolized in pigs such that 5-HT4 blockade is not maintained. However, in the rat, when given by infusion, RS 23597-190 antagonizes 5-HT3 mediated responses, at doses consistent with a low affinity 5-HT3 receptor. These data suggest that, under appropriate experimental conditions, RS 23597-190 may also be used in vivo to characterize further 5-HT4 receptor function.

Section: In Vitro Studiesmentioning

confidence: 99%

Section: In Vitro Studiesmentioning

confidence: 99%

RS 23597‐190: a potent and selective 5‐HT₄ receptor antagonist

Eglen¹,

Bley²,

Bonhaus³

et al. 1993

“…In the gut, rat oesophagus muscularis mucosae contains smooth muscle 5-HT 4 receptors mediating relaxation (Baxter et al, 1991), an e ect suggested to be absent in the guinea-pig and dog (Cohen et al, 1994). In the human lower oesophageal sphincter, there is evidence for the presence of excitatory 5-HT 4 receptors on the cholinergic nerves (Tomita et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

5‐HT₄ receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle

Prins

Akkermans

Lefebvre

et al. 2000

1 5-HT 4 receptors mediate circular muscle relaxation in both human and canine large intestine, but this phenomenon alone can not explain the improvement in colonic motility induced by selective 5-HT 4 receptor agonists in vivo. We set out to characterize 5-HT 4 receptor-mediated e ects in longitudinal muscle strips of canine and human large intestine. 2 Electrical ®eld stimulation (EFS) was applied providing submaximal isotonic contractions. L-NOARG (0.1 mM) was continuously present in the organ bath to preclude nitric oxide-induced relaxation to EFS. 3 The selective 5-HT 4 receptor agonist prucalopride (0.3 mM) enhanced EFS-evoked contractions, that were antagonized in both preparations by the selective 5-HT 4 receptor antagonist GR 113808 (0.1 mM). The prucalopride-induced increase was present in canine ascending and descending colon, but absent in rectum. Regional di erences in response to prucalopride were not observed in human ascending and sigmoid colon and rectum. Incubation with atropine (1 mM) or tetrodotoxin (0.3 mM) inhibited EFS-induced contractions, which were then una ected by prucalopride (0.3 mM) in both tissues. 4 In the presence of methysergide (3 mM; both tissues) and granisetron (0.3 mM; only human tissues), 5-HT (0.3 mM) enhanced EFS-induced contractions, an e ect that was antagonized by GR 113808 (0.1 mM). In the presence of atropine or tetrodotoxin, EFS-induced contractions were inhibited, leaving 5-HT (0.3 mM) ine ective in both preparations. 5 This study demonstrates for the ®rst time that in human and canine large intestine, 5-HT 4 receptors are located on cholinergic neurones, presumably mediating facilitating release of acetylcholine, resulting in enhanced longitudinal muscle contractility. This study and previous circular muscle strip studies suggest that 5-HT 4 receptor agonism facilitates colonic propulsion via a coordinated combination of inhibition of circumferential resistance and enhancement of longitudinal muscle contractility.

“…Rat isolated oesophageal muscularis mucosal studies 5-HT4 agonist activity was studied in the rat isolated oesophagus (Baxter et al, 1991), in which relaxation is mediated by 5-HT4 receptor activation. Thoracic oesophagus was isolated from male Sprague-Dawley rats (Charles River,) and placed in Tyrode solution (composition, mM: NaCl 139.0, KCl 2.7, MgCl2.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological characterization of two novel and potent 5‐HT₄ receptor agonists, RS 67333 and RS 67506, in vitro and in vivo

Eglen¹,

Bonhaus²,

Johnson³

et al. 1995

1 The pharmacology of two novel 5-HT4 receptor agonists, RS 67333 (1-(4-amino-5-chloro-2-methoxy phenyl)-3-[1(n-butyl)-4-piperidinyl]-1-propanone HCl) and RS 67506 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone HCl) have been assessed in vitro and in vivo.2 RS 67333 and RS 67506 exhibited affinities (pKi=8.7 and 8.8, respectively) for the 5-HT4 binding sites, labelled with [3H]-GR 113808, in guinea-pig striatum. The Hill coefficients from these displacement curves were not significantly different from unity. The compounds exhibited lower affinities (< 6.0) at several other receptors including 5-HTA, 5-HTID, 5-HT2A, 5-HT2c, dopamine D,, D2 and muscarinic M,-M3 receptors. However, RS 67333 and RS 67506 did exhibit affinities for the a, (pKi=8.9 and 7.9, respectively) and Ca2 (pK,=8.0 and 7.3, respectively) binding sites. 3 At the 5-HT4 receptor mediating relaxation of the carbachol-precontracted oesophagus, RS 67333 and RS 67506 acted as potent (pECm 8.4 and 8.6, respectively), partial agonists (intrinsic activities, with respect to 5-HT were 0.5 and 0.6, respectively) with respect to 5-HT. Relaxant responses to RS 67333 or RS 67506 were surmountably antagonized by GR 113808 (10 nM), with apparent affinities (pKB) of 9.1 and 9.0, respectively. RS 67333 and RS 67506 induced dose-dependent increases in heart rate of the anaesthetized micropig (ED50 4.9 and 5.4 pg kg-',i.v.), with maximal increases of 35 and 47 beats min-', respectively. 4 RS 67333 and RS 67506, therefore, acted as potent, partial 5-HT4 receptor agonists in vitro and in vivo. These compounds, by virtue of their high potency and selectivity, may have some utility in elucidating the physiological role of 5-HT4 receptors.