title: Inhibitory effect of the selective serotonin 5-HT₃ receptor antagonist ramosetron on duodenal acidification-induced gastric hypersensitivity in rats.
abstract: Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are both functional gastrointestinal disorders and frequently co-occur in patients. While one cause of FD appears to be gastric hypersensitivity, whether the hypersensitivity is affected by IBS treatments remains unclear, given the lack of appropriate animal models for testing. Here, we established an experimental model of duodenal acidification-induced gastric hypersensitivity in conscious rats. The model involved duodenal acidification induced by the infusion of hydrochloric acid into the proximal duodenum, with the nociceptive response being determined as the change in mean arterial pressure (MAP) during gastric distension via an indwelling latex balloon. Using our model we evaluated the effects of duodenal acidification, increased distension pressure, and orally administered therapeutic agents for IBS with diarrhea (IBS-D). Duodenal acidification enhanced the pressor response during gastric distension, and pretreatment with the opioid κ-receptor agonist fedotozine (10mg/kg, intra-arterial) inhibited the pressor response. Pressure levels of 15-60 mm Hg increased MAP in response to gastric distension. The serotonin 5-HT3 receptor antagonist ramosetron (30 μg/kg) inhibited MAP increase induced by duodenal acidification, with no other IBS-D therapeutic agents showing any effect. In contrast, the serotonin 5-HT3 receptor agonist m-chlorophenylbiguanide (1mg/kg) significantly enhanced the pressor response during gastric distension. These findings indicate that the serotonin 5-HT3 receptor plays a key role in duodenal acidification-induced gastric hypersensitivity in rats, suggesting that ramosetron may reduce FD symptoms by ameliorating sensitized gastric perception.
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan; Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: mari.nakata@astellas.com.
authors.forename: Mari
authors.initials: M
authors.lastname: Nakata-Fukuda
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Hirata
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Keto
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamano
authors.affiliation: Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001645:Biguanides / Q000494:pharmacology; D004386:Duodenum / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D043183:Irritable Bowel Syndrome / Q000188:drug therapy; D008297:Male; D059225:Nociception / Q000187:drug effects; D011807:Quinolizines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D013270:Stomach / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D001562:Benzimidazoles; D001645:Biguanides; D011807:Quinolizines; D058831:Serotonin 5-HT3 Receptor Antagonists; C030950:thiaton; C071315:ramosetron; C065734:1-(3-chlorophenyl)biguanide
keywords: Duodenal acidification; Gastric hypersensitivity; Ramosetron; Rat; Serotonin 5-HT(3) receptor