The glutathione redox cycle as a defense system against hydrogen-peroxide-induced prostanoid formation and vasoconstriction in rabbit lungs.
Leukocyte-derived oxidants have been described as causing vasoconstriction and edema formation in isolated lungs. In the present study, dose-dependent and reversible pressor responses were achieved reproducibly by injection of hydrogen peroxide (H2O2) into the pulmonary artery of blood-free, perfused, isolated rabbit lungs in a dose-dependent manner. The pressor responses were accompanied by an instantaneous release of thromboxane A2 and a more delayed but quantitatively larger release of prostaglandin I2 into the recirculating perfusion fluid. There was no release of potassium or LDH, indicating the absence of overt cell damage. The H2O2-induced pressor responses were blocked by indomethacin (cyclooxygenase inhibitor), imidazole (inhibitor of thromboxane synthetase), mepacrine (phospholipase inhibitor), and W7 and trifluoperazine (agents that interfere with calcium-calmodulin function). Treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) dose-dependently inhibited the lung glutathione reductase activity and augmented the metabolic (prostanoid release) and functional (vasoconstriction) responsiveness of the pulmonary vascular bed to H2O2. Application of 1-(2-chloroethyl)-1-nitrosourea (CCNU), a control to BCNU, and inhibition of catalase activity by aminotriazole did not increase the sensitivity to externally applied H2O2. We conclude that calcium-calmodium function and thromboxane generation may be involved in the pulmonary vasoconstrictive response to H2O2 and that the lung glutathione redox cycle is active in limiting the responsiveness of the pulmonary vascular bed to externally generated H2O2.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002374:Catalase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D066298:In Vitro Techniques; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D011453:Prostaglandins / Q000096:biosynthesis*; D011651:Pulmonary Artery / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*
D001095:Arachidonic Acids; D011453:Prostaglandins; D016718:Arachidonic Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D005980:Glutathione Reductase; D005978:Glutathione; D002118:Calcium