Lubiprostone stimulates duodenal bicarbonate secretion in rats.

Full Abstract

BACKGROUND: Lubiprostone, a bicyclic fatty acid, is used for the treatment of chronic constipation. No published study has addressed the effect of lubiprostone on intestinal ion secretion in vivo. AIM: The aim of this study was to test the hypothesis that lubiprostone augments duodenal HCO(3) (-) secretion (DBS). METHODS: Rat proximal duodenal loops were perfused with pH 7.0 Krebs, control vehicle (medium-chain triglycerides), or lubiprostone (0.1-10 microM). We measured DBS with flow-through pH and CO(2) electrodes, perfusate [Cl(-)] with a Cl(-) electrode, and water flux using a non-absorbable ferrocyanide marker. Some rats were pretreated with a potent, selective CFTR antagonist, CFTR(inh)-172 (1 mg/kg, ip), 1 h before experiments. RESULTS: Perfusion of lubiprostone concentration dependently increased DBS, whereas net Cl(-) output and net water output were only increased at 0.1 microM, compared with vehicle. CFTR(inh)-172 reduced lubiprostone (10 microM)-induced DBS increase, whereas net Cl(-) output was also unchanged. Nevertheless, CFTR(inh)-172 reduced basal net water output, which was reversed by lubiprostone. Furthermore, lubiprostone-induced DBS was inhibited by EP4 receptor antagonist, not by an EP1/2 receptor antagonist or by indomethacin pretreatment. CONCLUSIONS: In this first study of the effect of lubiprostone on intestinal ion secretion in vivo, lubiprostone stimulated CFTR-dependent DBS without changing net Cl(-) secretion. This effect supports the hypothesis that Cl(-) secreted by CFTR is recycled across the apical membrane by anion exchangers. Recovery of water output during CFTR inhibition suggests that lubiprostone may improve the intestinal phenotype in CF patients. Furthermore, increased DBS suggests that lubiprostone may protect the duodenum from acid-induced injury via EP4 receptor activation.

Author information

Author/s: Mizumori, Misa (M); Akiba, Yasutada (Y); Kaunitz, Jonathan D (JD);

Affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Grants: P30 DK0413 (Agency:NIDDK NIH HHS) ; R01 DK54221 (Agency:NIDDK NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.

Journal: Digestive diseases and sciences (Dig Dis Sci), published in United States. (Language: eng)

Reference: 2009-Oct; vol 54 (issue 10) : pp 2063-9

Dates: Created 2009/09/03; Completed 2009/09/24;

PMID: 19657734, status: MEDLINE (last retrieved date: 9/24/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Alprostadil - analogs & derivatives; pharmacology
Animals
Bicarbonates - metabolism
Biphenyl Compounds - pharmacology

Cystic Fibrosis Transmembrane Conductance Regulator - antagonists & inhibitors
Duodenum - secretion
Laxatives - pharmacology
Rats

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Bicarbonates (0) ; Biphenyl Compounds (0) ; Laxatives (0) ; lubiprostone (0) ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Alprostadil (745-65-3) ; AH 23848 (81443-73-4)

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