SK&F 104353, a selective leukotriene receptor antagonist, inhibits leukotriene D4- and antigen-induced bronchoconstriction in cynomolgus monkeys.
The ability of SK&F 104353 to prevent and reverse leukotriene (LT) D4- and antigen (Ag)-induced bronchoconstriction was examined in anesthetized, spontaneously breathing cynomolgus monkeys. Aerosol administration of LTD4 (10 micrograms/ml; 20 breaths) produced a sustained increase in pulmonary resistance and decrease in dynamic lung compliance. Aerosolized SK&F 104353 (150 breaths, 0.3 or 4.4 mg/ml) administered 15 min prior to LTD4 challenge antagonized these changes in a dose-dependent manner. When given intravenously 6 min after LTD4, SK&F 104353 (5 mg/kg) rapidly and completely reversed the ongoing bronchoconstriction. In mepyramine-pretreated (2 mg/kg i.v.) monkeys sensitive to aerosolized Ascaris suum Ag, intravenously administered SK&F 104353 (5 mg/kg) substantially reversed, but did not abolish, Ag-induced bronchoconstriction when administered 12 min after the Ag challenge. In contrast, SK&F 104353 (5 mg/kg i.v.) did not reverse Ag-induced bronchoconstriction in animals that had not been pretreated with mepyramine. Similar results were obtained when SK&F 104353 (20 mg/kg i.v.) was administered (as a pretreatment) 5 min prior to Ag under these conditions. Thus, SK&F 104353 reduced Ag-induced bronchoconstriction in mepyramine-pretreated monkeys, but had little effect in the absence of mepyramine. The data suggest that LTs, in addition to histamine, play a role in allergic bronchoconstriction in cynomolgus monkeys.
Osborn
R R
RR
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Hay
D W
DW
Wasserman
M A
MA
Torphy
T J
TJ
D000280:Administration, Inhalation; D000336:Aerosols; D000758:Anesthesia; D000818:Animals; D000941:Antigens / Q000008:administration & dosage*; D016084:Bronchoconstriction / Q000187:drug effects*; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D011738:Pyrilamine / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors*
D000336:Aerosols; D000941:Antigens; D003998:Dicarboxylic Acids; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D011738:Pyrilamine; C052393:pobilukast