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MUCOSAL BIOLOGY

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

Departments of ¹Physiology and Cell Biology, ²Pharmacology, ³Internal Medicine, ⁴Neuroscience, and ⁵Anesthesiolgy, The Ohio State University, College of Medicine, Columbus, Ohio

Submitted 22 July 2008 ; accepted in final form 26 January 2009

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 (I_sc) 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 I_sc 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 I_sc in a concentration-dependent manner with an EC₅₀ of 31.7 nM. Blockade of enteric nerves by tetrodotoxin did not influence stimulation of I_sc by lubiprostone. Antagonists acting at prostaglandin (PG)E₂, EP_1–3, or EP₄ receptors did not suppress stimulation of I_sc 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 I_sc. Lubiprostone, in the presence of tetrodotoxin, enhanced carbachol-evoked I_sc. 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 I_sc followed by persistent cyclical increases in I_sc. Lubiprostone increased the peak amplitude of the dimaprit-evoked cycles.

gastrointestinal tract; mucosal chloride secretion; enteric nervous system; prostaglandins; irritable bowel syndrome; cystic fibrosis transmembrane conductance regulator; ClC-2 channels

This article has been cited by other articles:

				S. Baldassano, S. Liu, M.-H. Qu, F. Mule, and J. D. Wood Glucagon-like peptide-2 modulates neurally evoked mucosal chloride secretion in guinea pig small intestine in vitro Am J Physiol Gastrointest Liver Physiol, October 1, 2009; 297(4): G800 - G805. [Abstract] [Full Text] [PDF]