Effect of FLAP antagonist MK-0591 on leukotriene production and ozone-induced airway responses in dogs.
We used the 5-lipoxygenase-activating protein (FLAP) antagonist MK-0591 to investigate the importance of leukotrienes (LT) in causing ozone-induced bronchoconstriction, airway inflammation, and airway hyperresponsiveness in dogs. Six random source dogs were studied. On one day, dogs were treated with MK-0591 (2 mg/kg iv) followed by a continuous intravenous infusion of 8 micrograms.kg-1.min-1. On the other day, the diluent was infused. Acetylcholine airway responsiveness was measured before and 1 h after ozone inhalation (3 ppm for 30 min). On each day, whole blood and bronchoalveolar lavage (BAL) cells were challenged with calcium ionophore to stimulate LTB4 production. Urinary LTE4 levels were measured before and after ozone. MK-0591 inhibited LTB4 production in whole blood by 96% (P = 0.001) and that from BAL cells by 91% (P = 0.001). By contrast, MK-0591 had no effect on ozone-induced bronchoconstriction, airway hyperresponsiveness, or influx of neutrophils into BAL. The mean log difference of the pre- to post-acetylcholine provocative concentration was 0.64 +/- 0.40 during MK-0591 treatment and 0.68 +/- 0.40 during diluent treatment (P = 0.71). These results indicate that peptidoleukotrienes are produced during ozone inhalation and that MK-0591 inhibits LT production in dogs. However, LTs do not play a role in ozone-induced bronchoconstriction, airway inflammation, or airway hyperresponsiveness in dogs.
Stevens
W H
WH
Asthma Research Group, McMaster University, Hamilton, Ontario, Canada.
Lane
C G
CG
Woolley
M J
MJ
Ellis
R
R
Tagari
P
P
Black
C
C
Ford-Hutchinson
A
A
O'Byrne
P M
PM
D058927:5-Lipoxygenase-Activating Proteins; D000109:Acetylcholine; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004285:Dogs; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D020024:Leukotriene Antagonists; D007975:Leukotriene B4 / Q000096:biosynthesis; D017999:Leukotriene E4 / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D010126:Ozone / Q000633:toxicity*; D011804:Quinolines / Q000494:pharmacology*; D012137:Respiratory System / Q000187:drug effects*
D058927:5-Lipoxygenase-Activating Proteins; D002352:Carrier Proteins; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011804:Quinolines; C078266:MK 0591; D007975:Leukotriene B4; D010126:Ozone; D017999:Leukotriene E4; D000109:Acetylcholine