ACTION OF PEPTIDOLEUKOTRIENES ON ION-TRANSPORT IN RABBIT DISTAL COLON INVITRO

Serosal but not mucosal addition of the peptidoleukotriences, leukotriene (LT) C4 (LTC4), LTD4 and LTE4 transiently (maximal response within 2 min) increased short-circuit current (I(sc)) and transepithelial conductance across stripped rabbit colonic mucosa mounted in Ussing chambers. All three peptidoleukotrienes elicited their responses in the presence of amiloride (10-mu-M) and were inhibited by serosal addition of the NaCl cotransport inhibitors bumetanide (100-mu-M) and furosemide (1 mM). The effects of the peptidoleukotriences on I(sc) and transepithelial conductance were concentration-dependent with maximal effects occurring at 10-mu-M. 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-mu-M SK&F 104353 and half-maximal effects were achieved at 0.6 nM SK&F 104353. At 10-mu-M SK&F 104353 only 50% inhibition of the LTC4-induced increase in I(sc) 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.