Action of peptidoleukotrienes on ion transport in rabbit distal colon in vitro

MF Jett, P Marshall, JD Fondacaro and PL Smith

Department of Drug Delivery, Smithkline Beecham, King of Prussia, Pennsylvania.

Serosal but not mucosal addition of the peptidoleukotrienes, leukotriene (LT) C4 (LTC4), LTD4 and LTE4 transiently (maximal response within 2 min) increased short-circuit current (Isc) and transepithelial conductance across stripped rabbit colonic mucosa mounted in Ussing chambers. All three peptidoleukotrienes elicited their responses in the presence of amiloride (10 microM) and were inhibited by serosal addition of the NaCl cotransport inhibitors bumetanide (100 microM) and furosemide (1 mM). The effects of the peptidoleukotrienes on Isc and transepithelial conductance were concentration-dependent with maximal effects occurring at 10 microM. Half-maximal effects were produced at 30 nM for LTC4, 50 nM for LTD4 and 450 nM for LTE4. The secretory responses to both LTD4 and LTE4 were antagonized in a concentration- dependent manner by the LTD4/LTE4 receptor antagonist, SK&F 104353 (2(S)-hydroxy-3-(R)-[(2-carboxyethyl)thio]-3-[2-(8 phenyloctyl)phenyl]propanoic acid). Complete inhibition of the LTD4 and LTE4 effects were observed at 0.1 microM SK&F 104353 and half-maximal effects were achieved at 0.6 nM SK&F 104353. At 10 microM SK&F 104353 only 50% inhibition of the LTC4-induced increase in Isc was observed. These results suggest the peptidoleukotrienes stimulate colonic Cl- secretion by receptor-mediated mechanisms and that receptors for LTC4 are distinct from those mediating the action of LTD4/LTE4.

Volume 257, Issue 2, pp. 698-705, 05/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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