Anti-leukotriene effects of WY-50,295 tromethamine in isolated guinea pig pulmonary tissues.
The abilities of WY-50,295 tromethamine, a 5-lipoxygenase inhibitor, to inhibit antigen-induced leukotriene (LT) release from guinea pig lung fragments, and to prevent LTD4 or antigen-induced contraction of isolated guinea pig tracheal muscle were compared with the activities of zileuton and MK-886 (two selective 5-lipoxygenase inhibitors), and LY171883 (a LTD4 receptor antagonist). In fragmented guinea pig lung, WY-50,295 tromethamine inhibited antigen-induced LT release with an IC50 of 0.63 microM, and was 4.6- and 5.2-fold more potent than zileuton and MK-886, respectively. WY-50,295 tromethamine differed from these 5-lipoxygenase inhibitors, however, in that WY-50,295 tromethamine competitively antagonized LTD4-induced tracheal contractions (pA2 = 6.06) at concentrations that inhibited LT release. LY171883 was an effective LTD4 receptor antagonist (pA2 = 6.96), that only inhibited antigen-induced LT release at higher concentrations (IC50 = 7.9 microM). WY-50,295 tromethamine almost completely inhibited antigen-induced leukotriene-dependent tracheal contractions, whereas high concentrations of zileuton, MK-886, or LY171883 produced only partial inhibition. This partial inhibition was likely to result from 'breakthrough' 5-lipoxygenase activity, because combinations of zileuton plus MK-886 or zileuton plus LY171883, were more effective than zileuton, MK-886, or LY171883 alone. The greater efficacy of WY-50,295 tromethamine in the antigen-challenged guinea pig trachea is likely to result from its combined abilities to prevent LT biosynthesis and block LTD4 receptors.
Heaslip
R J
RJ
Department of Experimental Therapeutics, Wyeth-Ayerst Research, Princeton, NJ 08543-8000.
Grimes
D
D
Berkenkopf
J W
JW
Ilsemann
B A
BA
Sickels
B D
BD
Weichman
B M
BM
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D006168:Guinea Pigs; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009280:Naphthaleneacetic Acids / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D013189:SRS-A / Q000037:antagonists & inhibitors; D013777:Tetrazoles / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D002722:Chlorobenzenes
D000098:Acetophenones; D006918:Hydroxyurea; D007211:Indoles; D020024:Leukotriene Antagonists; D016859:Lipoxygenase Inhibitors; D009280:Naphthaleneacetic Acids; D011804:Quinolines; D013189:SRS-A; D013777:Tetrazoles; C060893:MK-886; D002722:Chlorobenzenes; C067525:S(alpha)-methyl-6-(2-quinolinylmethoxy)-2-naphthaleneacetic acid; C044660:LY 171883; C063449:zileuton