THE LEUKOTRIENE-D4 RECEPTOR BLOCKER, SK-AND-F 104353, INHIBITS VOLUME REGULATION IN ISOLATED CRYPTS FROM THE RAT DISTAL COLON

The effect of SK&F 104353 (2-hydroxy-3-carboxyethylthio-3-[2-(8-phenyloctyl)phenyl] propanoic acid), a specific leukotriene D4 receptor blocker, on volume regulation in isolated rat colonic crypts was studied. SK&F 104353 (10(-7) - 5 X 10(-6) Mol . l-1) concentration dependently inhibited the regulatory decrease in volume following cell swelling induced either by uptake of a short-chain fatty acid, butyrate, or by exposure to hypotonic medium. Whole-cell patch-clamp experiments revealed that SK&F 104353 suppressed the depolarization of crypt cells during the regulatory decrease in volume. Also the effect of leukotriene D4 (5 X 10(-7) mol. l-1), which has an action on the membrane potential similar to that induced by cell swelling, was suppressed nearly completely by the receptor blocker. In contrast, the precursor of leukotriene D4, leukotriene C4, had no effect on the membrane potential. These results are in accordance with the hypothesis that leukotriene D4 acts as mediator for the activation of basolateral Cl- channels in the rat colonic epithelium during regulatory decrease in volume.