Lubiprostone stimulates duodenal bicarbonate secretion in rats.
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.


OBJECTIVE
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.
Mizumori
Misa
M
Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Akiba
Yasutada
Y
Kaunitz
Jonathan D
JD
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors; D004386:Duodenum / Q000378:metabolism*; D054368:Laxatives / Q000494:pharmacology*; D000068238:Lubiprostone; D051381:Rats
D001639:Bicarbonates; D001713:Biphenyl Compounds; D054368:Laxatives; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000068238:Lubiprostone; C046926:AH 23848; D000527:Alprostadil