HYDROPEROXIDE-INDUCED BRONCHOCONSTRICTION AND VASOCONSTRICTION IN THE ISOLATED RAT LUNG

The effects of different hydroperoxides on lung mechanics and perfusate flow rate and their mechanisms of action were studied in isolated perfused rat lungs. The administration of hydrogen peroxide, t-butyl hydroperoxide, cumene hydroperoxide, linoleic acid hydroperoxide, and linoleic acid ethylester hydroperoxide (0.1-2 mM) to the perfusate caused a marked decreased in lung compliance, conductance, and perfusate flow rate, with constriction strength of t-butyl hydroperoxide > hydrogen peroxide > cumene hydro-peroxide > linoleic acid ethylester hydroperoxide > linoleic acid hydroperoxide. Although the hydroperoxides probably had to enter lung cells to exert their effects, no relationship was found between constriction strength and amount of hydroperoxide taken up by the lung. Reduced sensitivity was apparent after repeated dosing, depending on the length of time between dosing. The addition of the iron chelator Desferal (1 mM) had no effect on the hydroperoxide-induced broncho- and vasoconstriction, although free iron was reduced by 50% in the lungs. The administration of the antioxidants diphenyl-p-phenylenediamine (50-mu-M) or butylated hydroxyanisole (200-mu-M) to the perfusate 20 min prior to the hydroperoxide attenuated the hydroperoxide-induced effects as well as arachidonic acid-induced broncho- and vasoconstruction. Our findings have shown that hydroperoxides that can enter the lung cells will also induce both vaso- and bronchoconstriction in the isolated perfused rat lung

VASOCONSTRICTION AND BRONCHOCONSTRICTION INDUCED BY 2,5-DI-(TERT-BUTYL)1,4-BENZOHYDROQUINONE, AN ENDOPLASMIC RETICULAR CA2+-ATPASE INHIBITOR, IN ISOLATED AND PERFUSED RAT LUNG

The microsomal Ca2+-ATPase inhibitor 2,5-di-(tert-butyl)-1,4-benzohydroquinone (tBuBHQ) induced bronchoconstriction and vasoconstriction in the isolated perfused and ventilated rat lung. Thes effects were accompanied by increased levels of thromboxane and prostacyclin in the effluent perfusate. The effect of tBuBHQ was inhibited by L-655,240, a thromboxane receptor antagonist, indicating thromboxane-A2-mediated bronchoconstriction and vasoconstriction. Accordingly, the cyclooxygenase inhibitor indomethacin largely blocked the effects of tBuBHQ. The involvement of a phospholipase in the generation of thromboxane A2 (TXA2) was supported by dibucaine protection on tBuBHQ effects. The results from this study indicate that tBuBHQ, probably by inhibiting the microsomal Ca2+-ATPase, can trigger the arachidonic acid cascade leading to the formation of TXA2, which in turn causes bronchoconstriction and vasoconstriction in rat lung

SULFUR DIOXIDE-INDUCED BRONCHOCONSTRICTION IN THE ISOLATED PERFUSED AND VENTILATED GUINEA-PIG LUNG

SO2 exposure (50-500 ppm) of isolated, perfused and ventilated guinea pig lungs, via the air passages, caused a concentration-related reduction in dynamic compliance and conductance. No changes in pulmonary perfusion flow was noted at any SO2 concentration. Formed sulfite was detected in lung lavage fluid as well as in the perfusate. Pretreatment of the lungs with a low concentration of SO2 (10 ppm) for 30 min protected against bronchoconstriction by a high concentration of SO2 (250 ppm). A similar protective effect was noted by pretreatment with sodium sulfite (3 mM) in the lung perfusate

Adrenal suppression with intranasal betamethasone drops

Intranasal betamethasone sodium phosphate drops (Betnesol) are frequently used to relieve nasal congestion due to polyposis. We report a case of significant hypothalamic-pituitary-adrenal suppression secondary to the long-term use of intranasal betamethasone drops. This case emphasizes that the topical application of potent corticosteroids may produce systemic effects

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