Effects of a serotonin 5-HT4 receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans

Bharucha, Adil E.; Camilleri, Michael; Haydock, Stephen; Ferber, Irene; Burton, Duane D.; Cooper, Stephen‐Mark; Tompson, Debra J.; Fitzpatrick, Kevin; Higgins, Rosemary; Zinsmeister, Alan R.

doi:10.1136/gut.47.5.667

Cited by 83 publications

(68 citation statements)

References 34 publications

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“…The time dependence is identical with that found in rats and humans after treatment with two chemically distinct 5-HT 4 receptor antagonists (4,12,34,35). Additionally, chronic Lys nutritional deficiency increased stress-induced defecation during the second, but neither the first nor the third hour of wrap-restraint stress (24).…”

Section: Discussionsupporting

confidence: 65%

“…Agonists on the 5-HT 4 receptor increase cholinergic transmission (9) and thus contract the smooth muscle in the rat and guinea pig ileum † and the human colon (11). Antagonists on the 5-HT 4 receptor do not affect normal, healthy gut function (12) but prevent the disturbances caused by stress (4) or high 5-HT activity (13). Thus, 5-HT 4 receptor antagonists are promising targets for the treatment of diarrhea-predominant irritable bowel syndrome (12).…”

mentioning

confidence: 99%

“…Antagonists on the 5-HT 4 receptor do not affect normal, healthy gut function (12) but prevent the disturbances caused by stress (4) or high 5-HT activity (13). Thus, 5-HT 4 receptor antagonists are promising targets for the treatment of diarrhea-predominant irritable bowel syndrome (12). In addition to their effect on the gastrointestinal tract, 5-HT 4 antagonists block corticosteroid secretion in the adrenal cortex (14), 5-HTinduced tachycardia (15,16), and stress-induced anxiety (17).…”

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confidence: 99%

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l -Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats

Smriga

Torii

2003

Proc. Natl. Acad. Sci. U.S.A.

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S tress and stress-induced anxiety play a major role in functional intestinal disorders (1). The stimulation of intestinal contraction and colonic transit are the most consistent patterns in the motility response of the intestinal tract to acute stress (2, 3); however, the stress-gut interactions are enormously complex (1). Both stress-induced anxiety and intestinal disorders are traced, from among other molecular pathologies, to the inappropriate responses of the central and͞or peripheral serotonin (5-HT) system (4, 5). Among the 5-HT receptors, the 5-HT 4 receptor plays a ''prostress'' role in the gut and throughout the body by mobilizing energy and facilitating behavioral, gastrointestinal, and cardiovascular stress responses (6, 7).5-HT 4 receptors are located within the cells and neurons of the gastrointestinal tract (6,8). Agonists on the 5-HT 4 receptor increase cholinergic transmission (9) and thus contract the smooth muscle in the rat and guinea pig ileum † and the human colon (11). Antagonists on the 5-HT 4 receptor do not affect normal, healthy gut function (12) but prevent the disturbances caused by stress (4) or high 5-HT activity (13). Thus, 5-HT 4 receptor antagonists are promising targets for the treatment of diarrhea-predominant irritable bowel syndrome (12). In addition to their effect on the gastrointestinal tract, 5-HT 4 antagonists block corticosteroid secretion in the adrenal cortex (14), 5-HTinduced tachycardia (15, 16), and stress-induced anxiety (17).However, the 5-HT receptor system is heterogeneous (18), and direct receptor targeting often causes side effects, such as diarrhea, gastric bleeding, and anxiety (19). Therefore, it is not surprising that few satisfying pharmacological treatments of stress-triggered, 5-HT-mediated intestinal disorders exist and that other therapeutic approaches, namely nutritional ones, are sought (20)(21)(22)). An interesting candidate to include in ''nutritional management'' of stress-related gastrointestinal disorders would be an essential amino acid, L-lysine (Lys). Lys blunted stress-induced anxiety in rats (23), whereas a dietary deficiency of Lys increased stress-induced colonic transit and anxiety, because of an enhanced transmission of 5-HT in the amygdala (24).Because the effects of Lys overlap with the ''antistress'' effects of the 5-HT 4 receptor antagonists (4), we hypothesized that dietary Lys could act as a partial antagonist on the 5-HT 4 receptors. The present study examined whether the provision of oral L-lysine might result in the blockage of 5-HT-mediated pathologies linked to stress exposure and͞or 5-HT sensitization in rats. Ileum contractions, stress-induced fecal excretion, diarrhea, anxiety, and tachycardia were monitored. The fractions obtained were washed once by centrifugation with 10-fold volume of the buffer, and the microsomal fraction was stored as receptor at Ϫ80°C until use. To determine the binding degree, the inhibition rate of Lys and a positive reference substance were calculated from binding of a tracer to a receptor. D...

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

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confidence: 99%

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l -Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats

Smriga

Torii

2003

Proc. Natl. Acad. Sci. U.S.A.

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“…The recently introduced 5-HT 4 receptor agonist tegaserod accelerates colonic transit but does not consistently affect sensory function in humans (Coffin et al, 2003;Lacy and Yu, 2002). Although a peripherally acting 5-HT 4 receptor antagonist has been reported to blunt somatic and visceral pain in mice, sensory thresholds to colorectal distension were not affected by inhibition of the 5-HT 4 receptor in humans (Espejo and Gil, 1998;Bharucha et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

TRPV1 Function in Mouse Colon Sensory Neurons Is Enhanced by Metabotropic 5-Hydroxytryptamine Receptor Activation

Sugiuar

Bielefeldt²,

Gebhart³

2004

J. Neurosci.

125

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Using whole-cell patch-clamp methods, we examined the hypothesis that serotonin [5-hydroxytryptamine (5-HT)] receptor activation enhances TRPV1 function in mouse colon sensory neurons in lumbosacral dorsal root ganglia, which were identified by retrograde labeling with DiI (1,1Ј-dioctadecyl-3,3,3Ј,3-tetramethlindocarbocyanine methanesulfonate) injected into multiple sites in the wall of the descending colon. 5-HT increased membrane excitability at a temperature below body temperature in response to thermal ramp stimuli in colon sensory neurons from wild-type mice, but not from TRPV1 knock-out mice. 5-HT significantly enhanced capsaicin-, heat-, and proton-evoked currents with an EC 50 value of 2.2 M. 5-HT (1 M) significantly increased capsaicin-evoked (100 nM) and proton-evoked (pH 5.5) currents 1.6-and 4.7-fold, respectively, and significantly decreased the threshold temperature for heat current activation from 42 to 38°C.

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“…Selective antagonism at this receptor has been postulated to provide symptomatic relief in patients suffering from IBS-D. In a study of 52 healthy subjects, Piboserod (SB207266), a selective 5-HT4 antagonist, was shown to block the effects of cisapride (5-HT4 agonist) and it tended to delay colonic transit times (P = 0.06) [56] . In a placebo-controlled study of 15 patients with IBS-D, Houghton and colleagues reported that 20 mg of SB207266 significantly improved orocecal transit times and demonstrated a non-statistical trend toward improved rectal sensitivity [57] .…”

Section: -Ht4 Antagonistsmentioning

confidence: 99%

Updates on treatment of irritable bowel syndrome

Hammerle¹,

Surawicz²

2008

WJG

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Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder characterized by abdominal pain and discomfort in association with altered bowel habits. It is estimated to affect 10%-15% of the Western population, and has a large impact on quality of life and (in)direct healthcare costs. IBS is a multifactorial disorder involving dysregulation within the brain-gut axis, and it is frequently associated with gastrointestinal motor and sensory dysfunction, enteric and central nervous system irregularities, neuroimmune dysregulation, and postinfectious inflammation. As with other functional medical disorders, the treatment for IBS can be challenging. Conventional therapy for those with moderate to severe symptoms is largely unsatisfactory, and the development of new and effective drugs is made difficult by the complex pathogenesis, variety of symptoms, and lack of objective clinical findings that are the hallmark of this disorder. Fortunately, research advances over the past several decades have provided insight into potential mechanisms responsible for the pathogenesis of IBS, and have led to the development of several promising pharmaceutical agents. In recent years there has been much publicity over several of these new IBS medications (alosetron and tegaserod) because of their reported association with ischemic colitis and cardiovascular disease. While these agents remain available for use under restricted prescribing programs, this highlights the need for continued development of safe and effective medication for IBS. This article provides a physiologicallybased overview of recently developed and frequently employed pharmaceutical agents used to treat IBS, and discusses some non-pharmaceutical options that may be beneficial in this disorder.

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Effects of a serotonin 5-HT4 receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans

Abstract: (Gut 2000;47:667-674)

Cited by 83 publications

References 34 publications

l -Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats

l -Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats

TRPV1 Function in Mouse Colon Sensory Neurons Is Enhanced by Metabotropic 5-Hydroxytryptamine Receptor Activation

Updates on treatment of irritable bowel syndrome

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