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-059 1 to investigate the importance of leukotrienes (LT) in causing ozone- induced bronchoconstriction, airway inflammation, and airway hyperresp onsiveness in dogs. Six random source dogs were studied. On one day, d ogs were treated with MK-0591 (2 mg/kg iv) followed by a continuous in travenous infusion of 8 mu g.kg(-1).min(-1). On the other day, the dil uent was infused. Acetylcholine airway responsiveness was measured bef ore and 1 h after ozone inhalation (3 ppm for 30 min). On each day, wh ole blood and bronchoalveolar lavage (BAL) cells were challenged with calcium ionophore to stimulate LTB(4) production. Urinary LTE, levels were measured before and after ozone. MK-0591 inhibited LTB, productio n 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 bronchoc onstriction, airway hyperresponsivenesss or influx of neutrophils into BAL. The mean log difference of the pre- to postacteylcholine provoca tive 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 ro le in ozone-induced bronchoconstriction, airway inflammation, or airwa y hyperresponsiveness in dogs.