Pulmonary actions of LY255283, a leukotriene B4 receptor antagonist.
The actions of LY255283, a leukotriene (LT) B4 receptor antagonist, were examined on guinea pig lung. LTB4 and LY255283 displaced [3H]LTB4 from its binding site on lung membranes with pKi values of 9.9 and 7.0, respectively. In the functional correlate of the binding studies, LY255283 competitively reduced contractile responses of lung parenchyma to LTB4 (pA2 = 7.2). LTB4 produced airway obstruction which was reduced by LY255283 administered i.v. (ED50 = 2.8 mg/kg) or orally (ED50 = 11.0 mg/kg). Contractile responses to histamine, LTD4 and the thromboxane mimetic, U46619, were not reduced by LY255283. The compound also did not inhibit cyclooxygenase or 5-lipoxygenase enzymes. We conclude that LY255283 selectively antagonized pharmacologic responses to LTB4 on lung tissue and appears to be a useful tool to investigate the role of LTB4 in pulmonary disease.
Silbaugh
S A
SA
Pulmonary Research Department, Eli Lilly and Company, Indianapolis, IN 46285.
Stengel
P W
PW
Cockerham
S L
SL
Roman
C R
CR
Saussy
D L
DL
Spaethe
S M
SM
Goodson
T
T
Herron
D K
DK
Fleisch
J H
JH
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000402:Airway Obstruction / Q000503:physiopathology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D015232:Dinoprostone / Q000097:blood; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D008168:Lung / Q000187:drug effects*; D008176:Lung Volume Measurements; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011869:Radioligand Assay; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000097:blood
D000700:Analgesics; D011450:Prostaglandin Endoperoxides, Synthetic; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D007975:Leukotriene B4; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C063823:LY 255283; D015232:Dinoprostone