Characterization of LTC4 effects on rabbit ileal mucosa in vitro.
The effects of peptidoleukotriene C4 (LTC4) on electrical properties and Na+ and Cl- fluxes in the presence or absence of the LTD4/LTE4 antagonist, 2(S)-hydroxy-3-(R)-carboxyethylthio)-3-[2-(8-phenyloctyl)phe nyl] propanoic acid (SK&F 104353) were investigated in stripped ileal mucosa from rabbits placed in Ussing chambers. Results from this study demonstrate that serosal addition of LTC4 produced a dose-dependent increase in short-circuit current (Isc) which is not affected by pretreatment of the tissue with SK&F 104353 (0.1 microM). The concentration of LTC4 which produced an increase in Isc of 4 mu Eq/h.cm2 was 181 nM in the absence of SK&F 104353 and this value did not differ significantly from the value of 212 nM in the presence of SK&F 104353 (0.1 microM). SK&F 104353 (0.1 microM) reduced the increase in Isc elicited by LTD4 and LTE4 by greater than 95%. Mucosal addition of LTC4 failed to alter Isc. The time course of the increase in Isc in response to LTC4 is qualitatively similar to that seen with both LTD4 and LTE4. Increases in Isc produced by LTC4 are not inhibited by removal of Ca2+ from the serosal bathing solution but are inhibited by pretreatment of the tissue with indomethacin (1 microM). The histamine receptor antagonist, mepyramine, reduced the change in Isc resulting from stimulation with LTC4 by 20% while the cholinergic antagonist, atropine, and the excitable tissue Na+ channel blocker, tetrodotoxin, were without effect. Measurement of unidirectional and net Na+ and Cl- fluxes revealed that LTC4 reduces Na+ and Cl- absorption and that subsequent addition of PGE1 produced no further decrease.(ABSTRACT TRUNCATED AT 250 WORDS)
Smith
P L
PL
Department of Drug Delivery, Smith Kline and French Laboratories, King of Prussia, PA 19406-0939.
Chiossone
D C
DC
McCafferty
G P
GP
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004594:Electrophysiology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017999:Leukotriene E4; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011817:Rabbits; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
D002712:Chlorides; D003998:Dicarboxylic Acids; D013189:SRS-A; D013779:Tetrodotoxin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D017999:Leukotriene E4; D001285:Atropine; D012964:Sodium; D011738:Pyrilamine; C052393:pobilukast; D002118:Calcium; D007213:Indomethacin