MECHANISMS OF HYDROPEROXIDE-INDUCED BRONCHOCONSTRICTION AND VASOCONSTRICTION IN ISOLATED AND PERFUSED RAT LUNG

The mechanisms of hydroperoxide-induced broncho- and vasoconstriction were investigated in the perfused and ventilated rat lung. Hydrogen peroxide (500 mu-M), tertiary butylhydroperoxide (500 mu-M) and arachidonic acid (100 mu-M) induced similar profiles of broncho- and vasoconstriction which could be prevented by the inhibitor of cyclooxygenase, diclofenac (100 mu-M) but not by nordihydroguaiaretic acid (5 and 25 mu-M), an inhibitor of lipoxygenase. The hydroperoxides also caused a time-dependent increase in the levels of thromboxane and prostacycline, products of cyclooxygenase. Furthermore, the thromboxane agonist, U44069 (100 pmoles), caused a very rapid broncho- and vasoconstriction that was preventable by the thromboxane antagonist L655.240 (1 mu-M). L655.240 also inhibited hydrogen peroxide-induced broncho- and vasoconstriction. The phospholipase A2 inhibitors, quinacrine (100 mu-M) and dibucaine (100 mu-M), did not prevent hydroperoxide-induced broncho- and vasoconstriction. The Ca2+ chelator, EGTA, prevented hydroperoxide and arachidonic acid-induced lung constriction, although it did not inhibit the release of thromboxane. The infusion of arachidonic acid and hydroperoxides resulted in edema in the lung which was prevented by prior administration of diclofenac, indomethacin or L655.240. These results indicate that hydroperoxide-induced broncho- and vasoconstriction and lung edema are mediated by thromboxane, a product of cyclooxygenase. The mechanism of hydroperoxide-induced release of arachidonic acid is not clear but does not seem to involve Ca2+ nor the activation of phospholipase A2.