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.
