Mechanisms of Hydroperoxide‐Induced Broncho‐ and Vasoconstriction in Isolated and Perfused Rat Lung

Abstract: The mechanisms of hydroperoxide‐induced broncho‐ and vasoconstriction were investigated in the perfused and ventilated rat lung. Hydrogen peroxide (500 μM), tertiary butylhydroperoxide (500 μM) and arachidonic acid (100 μM) induced similar profiles of broncho‐ and vasoconstriction which could be prevented by the inhibitor of cyclooxygenase, diclofenac (100 μM) but not by nordihydroguaiaretic acid (5 and 25 μM), 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 μM). L655.240 also inhibited hydrogen peroxide‐induced broncho‐ and vasoconstriction. The phospholipase A₂ inhibitors, quinacrine (100 μM) and dibucaine (100 μM), 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. 1991 Nordic Pharmacological Society