Post-synaptic 5-HT4 receptor modulation of tachykinergic excitation of rat oesophageal tunica muscularis mucosae

Goldhill, J; Porquet, Marie‐France; Angel, Itzchak

doi:10.1016/s0014-2999(97)00046-0

Cited by 10 publications

(3 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the earliest serotonergic‐modulating drugs introduced into widespread clinical practice was cisapride, a drug that acts presynaptically via 5HT 4 receptors [46], enhancing acetylcholine release in response to nerve stimulation [47]. Cisapride is a 5HT 4 agonist with partial 5HT 3 antagonist effects.…”

Section: Clinical Applications (Table 1)mentioning

confidence: 99%

Serotonergic modulating drugs for functional gastrointestinal diseases

Spiller

2002

Brit J Clinical Pharma

View full text Add to dashboard Cite

After many years of basic research we have now begun to learn how to manipulate the serotonergic mechanisms within the gut. This has lead to a number of significant advances including 5HT3 antagonists for the treatment of functional diarrhoea, 5HT4 agonists for the treatment of constipation and 5HT1 agonists for the treatment of impaired fundal relaxation. Initial enthusiasm has been somewhat dented by the withdrawal of alosetron because of ischaemic colitis, but it remains to be seen whether this adverse event will be seen with other 5HT3 antagonists. Finally it should be recognized that, in a substantial proportion of patients attending clinics complaining of functional symptoms, anxiety is a major component. The drugs so far described are by and large devoid of CNS effects. It remains possible therefore that a drug which combines both peripheral and central effects would likely to be beneficial.

show abstract

Section: Clinical Applications (Table 1)mentioning

confidence: 99%

Serotonergic modulating drugs for functional gastrointestinal diseases

Spiller

2002

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Contraction and potentiation of the electrical field twitch response in the guinea‐pig ileum ( Kajita et al ., 2001 ) and colon ( Jin et al ., 1999 ) have also been described, as has facilitation of fast excitatory synaptic transmission ( Galligan et al ., 2003 ). In the rat oesophagus, 5‐HT 4 receptors mediate relaxation of smooth muscle ( Leung et al ., 1996 ; Goldhill et al ., 1997 ).…”

Section: Introductionmentioning

confidence: 99%

A comparison of the pharmacological properties of guinea‐pig and human recombinant 5‐HT₄ receptors

Vickery

Mai

Kaufman

et al. 2007

British J Pharmacology

View full text Add to dashboard Cite

Background and purpose: 5-HT 4 receptor agonists are used therapeutically to treat disorders of reduced gastrointestinal motility. Since such compounds are evaluated in guinea-pigs, we cloned, expressed and pharmacologically characterized the guinea-pig 5-HT 4 and human 5-HT 4(b) splice variant, which share 95% homology. The functional properties of guinea-pig 5-HT 4(b) receptors were compared with native receptors in guinea-pig colon. Experimental approach: Membrane radioligand binding and whole cell cAMP accumulation assays were used to determine the affinities, potencies and intrinsic activities (IA). Contraction of the guinea-pig distal colon longitudinal muscle myenteric plexus preparation (LMMP) was monitored to evaluate functional activity. Key results: pK i values for guinea-pig and human recombinant receptors, and guinea-pig striatum 5-HT 4 receptors, were in agreement, as were the potency and IA values for guinea-pig and human 5-HT 4 receptors expressed at a similar density (B0.2 pmol mg À1 protein). Tegaserod was a potent (pEC 50 ¼ 8.4 and 8.7, respectively), full agonist at both guinea-pig and human 5-HT 4 receptors. In contrast, in the LMMP preparation, tegaserod was a potent, partial agonist (pEC 50 ¼ 8.2; IA ¼ 66%). Conclusions and implications:Close agreement between the pharmacological properties of guinea-pig and human 5-HT 4 receptors support the use of guinea-pig model systems for the identification of 5-HT 4 receptor therapeutics. However, the mechanisms underlying the different agonist properties of tegaserod in recombinant and isolated tissue preparations, and the extent to which these impact the clinical efficacy of tegaserod as a prokinetic agent, remain to be determined.

show abstract

“…Higher concentrations of serotonin produced a transient contraction of the muscularis mucosae which was abolished by the pretreatment with tetrodotoxin or atropine, indicating an indirect action via the stimulation of intramural cholinergic nerves (Bartlet, 1968b;Kamikawa and Shimo, 1983a). In the rat esophageal muscularis mucosae, however, serotonin did not produce a contraction but relaxed the cholinergically-induced tone via the stimulation of postjunctional 5-HT4 receptor which was coupled to the adenylate cyclase-cyclic AMP pathway (Baxter et al, 1991;Moummi et al, 1992;Ford et al, 1992;Ohia et al, 1992;Yang et al, 1993;Leung et al, 1996;Goldhill et al, 1997). Adenosine and related purine nucleotides also enhanced cholinergic neurotransmission by the postjunctional mechanism, since the purine nucleotides produced a contraction of the muscularis mucosae via the production of endogenous PGs, probably PGE2 (Kamikawa et al, 1977;.…”

Section: Responsiveness To Drugsmentioning

confidence: 99%

Muscularis mucosae - the forgotten sibling

Uchida

Kamikawa

2007

J. Smooth Muscle Res.

View full text Add to dashboard Cite

Lamina muscularis mucosae sitting beneath mucosal surface of the digestive tract has received little attention to date compared with external smooth muscle layers. Motor activity of the muscularis mucosae shows a great regional and species difference. Autonomic innervation profile is also different from esophagus to colon or between animal species. Intracellular transduction mechanisms for motor activity of the muscularis mucosae are also different from those of external longitudinal and circular muscles or from vascular and airway smooth muscles. Since the submucosal area is a major source for eicosanoid production, abnormality of muscularis mucosae motor activity may link with abnormality of mucosal absorption and secretion functions. Inflammatory bowel diseases such as diarrhea, irritable bowel syndrome and Crohn's disease accompanied with altered motor activity of the muscularis mucosae. Much attention should be attracted to the human muscularis mucosae as a new therapeutic target for inflammatory bowel diseases.

show abstract

Post-synaptic 5-HT4 receptor modulation of tachykinergic excitation of rat oesophageal tunica muscularis mucosae

Cited by 10 publications

References 17 publications

Serotonergic modulating drugs for functional gastrointestinal diseases

Serotonergic modulating drugs for functional gastrointestinal diseases

A comparison of the pharmacological properties of guinea‐pig and human recombinant 5‐HT₄ receptors

Muscularis mucosae - the forgotten sibling

Contact Info

Product

Resources

About

Post-synaptic 5-HT4 receptor modulation of tachykinergic excitation of rat oesophageal tunica muscularis mucosae

Cited by 10 publications

References 17 publications

Serotonergic modulating drugs for functional gastrointestinal diseases

Serotonergic modulating drugs for functional gastrointestinal diseases

A comparison of the pharmacological properties of guinea‐pig and human recombinant 5‐HT4 receptors

Muscularis mucosae - the forgotten sibling

Contact Info

Product

Resources

About

A comparison of the pharmacological properties of guinea‐pig and human recombinant 5‐HT₄ receptors