Stimulation of mucosal secretion by lubiprostone (SPI-0211) in guinea pig small intestine and colon

Guijun Fei, Yu Zhong Wang, Sumei Liu, Hong Zhen Hu, Guo Du Wang, Mei Hua Qu, Xi Yu Wang, Yun Xia, Xiaohong Sun, Laura M. Bohn, Helen J. Cooke, Jackie D. Wood

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26 Scopus citations

Abstract

Actions of lubiprostone, a selective type-2 chloride channel activator, on mucosal secretion were investigated in guinea pig small intestine and colon. Flat-sheet preparations were mounted in Ussing flux chambers for recording short-circuit current (Isc) as a marker for electrogenic chloride secretion. Lubiprostone, applied to the small intestinal mucosa in eight concentrations ranging from 1-3000 nM, evoked increases in Isc in a concentration-dependent manner with an EC50 of 42.5 nM. Lubiprostone applied to the mucosa of the colon in eight concentrations ranging from 1-3000 nM evoked increases in Isc in a concentration-dependent manner with an EC50 of 31.7 nM. Blockade of enteric nerves by tetrodotoxin did not influence stimulation of Isc by lubiprostone. Antagonists acting at prostaglandin (PG)E2, EP1-3, or EP4 receptors did not suppress stimulation of Isc by lubiprostone but suppressed or abolished PGE2-evoked responses. Substitution of gluconate for chloride abolished all responses to lubiprostone. The selective CFTR channel blocker, CFTR(inh)-172, did not suppress lubiprostone-evoked I sc. The broadly acting blocker, glibenclamide, suppressed (P < 0.001) lubiprostone-evoked Isc. Lubiprostone, in the presence of tetrodotoxin, enhanced carbachol-evoked Isc. The cholinergic component, but not the putative vasoactive intestinal peptide component, of neural responses to electrical field stimulation was enhanced by lubiprostone. Application of any of the prostaglandins, E2, F2, or I2, evoked depolarization of the resting membrane potential in enteric neurons. Unlike the prostaglandins, lubiprostone did not alter the electrical behavior of enteric neurons. Exposure to the histamine H2 receptor agonists increased basal Isc followed by persistent cyclical increases in Isc. Lubiprostone increased the peak amplitude of the dimaprit-evoked cycles.

Original languageEnglish
Pages (from-to)G823-G832
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number4
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

Keywords

  • ClC-2 channels
  • Cystic fibrosis transmembrane conductance regulator
  • Enteric nervous system
  • Gastrointestinal tract
  • Irritable bowel syndrome
  • Mucosal chloride secretion
  • Prostaglandins

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    Fei, G., Wang, Y. Z., Liu, S., Hu, H. Z., Wang, G. D., Qu, M. H., Wang, X. Y., Xia, Y., Sun, X., Bohn, L. M., Cooke, H. J., & Wood, J. D. (2009). Stimulation of mucosal secretion by lubiprostone (SPI-0211) in guinea pig small intestine and colon. American Journal of Physiology - Gastrointestinal and Liver Physiology, 296(4), G823-G832. https://doi.org/10.1152/ajpgi.90447.2008