Blockade of human atrial 5‐HT 4 receptors by GR 113808

In human isolated detrusor strips, submaximal contractile responses evoked by electrical stimulation were resistant to hexamethonium (30 tiM) and abolished by tetrodotoxin (0.6 ELM) and hyoscine (1 fM), indicating the activation of postganglionic cholinergic nerves. In methysergide (1 tM) and ondansetron (3 ,iM) pretreated tissues, 5-hydroxytryptamine (5-HT) (0.3 nM-1ILM) caused a concentration-dependent increase in the amplitude of contractions (pEC_ = 8.1), which was antagonized by the selective 5-HT4 receptor antagonist GR 113808 (3, 10 and 30 nM) in a competitive manner. Schild analysis yielded a pA2 estimate of 8.9, a value comparable to that reported for GR 113808 in other animal and human peripheral tissues (8.8-9.7). Our findings indicate that neuromuscular cholinergic transmission in human isolated detrusor muscle is facilitated by neural 5-HT receptors belonging to the 5-HT4 subtype. The human urinary bladder can thus be regarded as an additional site in which 5-HT4 receptors are distributed.

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confidence: 68%

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confidence: 99%

Characterization of the 5‐HT receptor potentiating neuromuscular cholinergic transmission in strips of human isolated detrusor muscle

Tonini

Messori

Franceschetti

et al. 1994

“…Indeed, the observation that the selective 5-HT 4 receptor antagonist GR 113808 (Gale et al, 1994) was able to antagonize the enhancement induced by 5-HT in both preparations, strongly suggested involvement of 5-HT 4 receptors, as was also corroborated by the blockade of the e ect of prucalopride by GR 113808. GR 113808 expresses 5-HT 4 receptor antagonist a nity at nanomolar concentrations (pK B estimates in human and canine tissues ranging from 8.8 to 9.4; Gale et al, 1994;Kaumann, 1993;Prins et al, 1999; and does not produce signi®cant binding to all other 5-HT receptors up to 0.3 mM (Gale et al, 1994). Thus, the GR 113808-induced antagonism of the 5-HT-and prucalopride-induced responses indicates involvement of 5-HT 4 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…In bioassays, it was demonstrated that 5-HT 4 receptors are abundantly present in the gut (for review: Hegde & Eglen, 1996), but were also found in human brain (Reynolds et al, 1995; by means of binding studies), heart (Kaumann, 1993), adrenal cortex (Lefebvre et al, 1998) and bladder (Candura et al, 1996). 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).…”

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.

“…As only one concentration of GR 113808 could be tested due to the finite number of tissues available, the existence of an equilibrium condition cannot be assumed. This non equilibrium condition probably accounts for the slightly lower potency of GR 113808 (apparent pKB values 8.3 and 8.4 with 5-HT and 5-methoxytryptamine respectively) as compared to 9.2 in guineapig proximal colon, 9.5 in rat oesophagus (Grossman et al, 1993), 8.8-9 in rat terminal ileum (Tuladhar et al, 1994) and 8.8 in human atrium (Kaumann, 1993).…”

Section: Discussionmentioning

confidence: 99%

5‐HT₃ and 5‐HT₄ receptor‐mediated facilitation of the emptying phase of the peristaltic reflex in the marmoset isolated ileum

Tuladhar

Costall

Naylor

1996

1 The patterns of intestinal motility and the effect of an increase in intraluminal pressure were studied in vitro on segments obtained from the marmoset small intestine. 2 Segments obtained from the distal half of the marmoset small intestine exhibited segmentation, consisting of narrow annular contractions (lasting for 2-3 s) interposed between the relaxed segments of varying length. The subsequent contractions occurred slightly distal to the previous contraction, with ring-like contractions appearing to move in the aboral direction. Such segmentation was infrequent or absent in the segments obtained from the proximal half of the small intestine. An increase in intraluminal pressure inhibited segmentation and finally produced peristalsis in most of the tissues. 3 The influence of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on the threshold of the peristaltic reflex was investigated in the segments obtained from the distal half of the intestine after segmentation had subsided. The effect of drug application to the serosal surface was measured as a change in threshold pressure required to trigger the peristaltic reflex. A facilitation was defined in two ways (a) as a reduction in the threshold pressure required to trigger the reflex and (b) in those tissues that failed to respond with peristalsis on raising intraluminal pressure to the maximum attainable (1 kPa), as a reduction in threshold pressure compared to this value. 4 5-HT (7.85+0.19), 5-methoxytryptamine (7.79+0.24), 5-carboxamidotryptamine (6.66+0.13) and 2-methyl-5-HT (6.24+0.16) caused a concentration related facilitation of the peristaltic reflex, the pD2 values (mean+s.e.mean) being shown in parentheses. 5 The concentration-response curves to both 5-HT and 5-methoxytryptamine were dextrally shifted in a surmountable manner in the presence of GR 113808 (30 nM). pD2 values for 5-HT and 5-methoxytryptamine were significantly decreased to 6.98 + 0.24 and 6.83 + 0.36 respectively in the presence of GR 113808 (30 nM).6 In the presence of a high concentration of (10 jgM) 5-methoxytryptamine the subsequent addition of 2-methyl-5-HT (3-10 -OM) but not 5-methoxytryptamine (10 gM) facilitated peristalsis; the effect of 3 pM 2-methyl-5-HT was significantly decreased by 2 pM ondansetron. 7 It is concluded that the facilitation of the peristaltic reflex in the marmoset intestine induced by 5-HT at submicromolar concentrations involves a 5-HT4 receptor stimulation with an additional 5-HT3 receptor activation at higher concentrations.