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

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)E-2, EP1-3, or EP4 receptors did not suppress stimulation of I-sc by lubiprostone but suppressed or abolished PGE(2)-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, E-2, F-2, or I-2, 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 H-2 receptor agonists increased basal I-sc followed by persistent cyclical increases in I-sc. Lubiprostone increased the peak amplitude of the dimaprit-evoked cycles.