MK-571 SODIUM HYDRATE

MK-571 (L660,711) is a potent and selective competitive inhibitor of [ ³ H]leukotriene D4 binding in guinea pig (K _i value, 0.22 nM) and human (K _i value, 2.1 nM) lung membranes. MK-571 is essentially inactive versus [ ³ H]LTC4 binding with IC ₅₀ values of 23±11 μM (n=16) and 32 μM (n=1) in guinea pig and human lung, respectively. MK-571 competitively antagonizes contractions of guinea pig trachea and ileum induced by leukotriene (LT) D ₄ (respective pA ₂ values, 9.4 and 10.5) and LTE4 (respective pA ₂ values, 9.1 and 10.4) and contractions of human trachea induced by LTD ₄ (pA ₂ value, 8.5). MK-571 (58 nM) antagonizes contractions of guinea pig trachea induced by LTC ₄ in the absence (dose ratio=28) but not in the presence of 45 mM L-serine borate (dose ratio less than 2). MK-571 (19μM) does not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF ₂ alpha, U-44069, or PGD ₂ . In the presence of atropine, mepyramine, and indomethacin, MK-571 (19 μM) inhibits a small component of the response to antigen on guinea pig trachea but completely blocked anti-IgE-induced contractions of human trachea.

MK-571 (L-660,711; i.v.) antagonizes bronchoconstriction induced in anesthetized guinea pigs by i.v. LTC ₄ , LTD ₄ , and LTE ₄ but does not block bronchoconstriction to arachidonic acid, U-44069, 5-hydroxytryptamine, histamine, or acetylcholine. Intraduodenal MK-571 antagonizes LTD ₄ (0.2-12.8 μg/kg)-induced bronchoconstriction in guinea pigs, and p.o. MK-571 blockes LTD ₄ - and Ascaris-induced bronchoconstriction in conscious squirrel monkeys and ovalbumin-induced bronchoconstriction in conscious sensitized rats treated with methysergide (3 μg/kg). Hypoxia-exposed WT mice are treated with either saline or MK-571 (5 mg/kg/d or 25 mg/kg/d) for 2 more weeks while being maintain in hypoxic conditions. Saline-treated mice display all the hallmarks of PH (i.e., an increase in RVSP, Fulton index, and arterial wall thickness). However, following hypoxia, MK-571-treated mice display lower RVSP and Fulton index and a decrease in the medial thickening of small pulmonary arteries and arterioles.