title: A 5-HT4 agonist, mosapride, enhances intrinsic rectorectal and rectoanal reflexes after removal of extrinsic nerves in guinea pigs.
abstract: Distension-evoked reflex of rectorectal (R-R) contractions and rectointernal anal sphincter (R-IAS) relaxations can be generated in guinea pigs through an extrinsic sacral excitatory neural pathway (pelvic nerves) as well as intrinsic cholinergic excitatory and nitrergic inhibitory pathways. The aim of the present study was to create intrinsic R-R and R-IAS reflex models by pithing (destruction of the lumbar and sacral cords; PITH) and to evaluate whether the prokinetic benzamide mosapride, a 5-HT(4) receptor agonist, enhances these reflexes. The mechanical activities of the R-R and R-IAS were recorded in the anesthetized guinea pig on days 2-9 after PITH. Although the basal rectal pressure at distension after PITH was significantly lower than control, the reflex indexes of R-R contractions and synchronous R-IAS relaxations were unchanged between days 4 and 9 after PITH. The frequency of spontaneous rectal and IAS motility were also unchanged. Immunohistochemical studies revealed that the distribution of myenteric and intramuscular interstitial cells of Cajal (ICC) were not altered after PITH. Mosapride (0.1-1.0 mg/kg iv) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indexes (maximum: 2.76) from control (1.0) 6-9 days after PITH. The 5-HT(4) receptor antagonist, GR-113808 (1.0 mg/kg iv) decreased the R-R and R-IAS reflex indexes by approximately 50% and antagonized the effect of mosapride (1.0 mg/kg iv). The present results indicate that mosapride moderately enhanced intrinsic R-R and R-IAS reflexes functionally compensated after deprivation of extrinsic nerves, mediated through endogenously active intrinsic 5-HT(4) receptors.
authors.affiliation: Dept. of Physiology II, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kojima
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Renta
authors.initials: R
authors.lastname: Katsui
authors.forename: Hisao
authors.initials: H
authors.lastname: Fujii
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Miyako
authors.initials: M
authors.lastname: Takaki
mesh_terms: D000208:Acute Disease; D001003:Anal Canal / Q000294:innervation / Q000502:physiology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002908:Chronic Disease; D003714:Denervation; D004195:Disease Models, Animal; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D012007:Rectum / Q000294:innervation / Q000502:physiology*; D012018:Reflex / Q000187:drug effects*; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000503:physiopathology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D001549:Benzamides; D005765:Gastrointestinal Agents; D007211:Indoles; D009025:Morpholines; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists; D013449:Sulfonamides; C062720:mosapride; C082871:GR 113808