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The activity of soluble guanylate cyclase can be increased by exposure of the enzyme to arachidonic acid or to some oxidized metabolites of the fatty acid. We have tried to determine whether activation of the enzyme by arachidonate requires that the fatty acid be converted to an oxidized metabolite, either by a possible trace contaminant of a lipoxygenase or by guanylate cyclase itself, which contains a heme moiety. Soluble guanylate cyclase purified from bovine lung was activated 4-6-fold by arachidonic acid. This activation was not dependent on the presence of oxygen in the incubation medium. No detectable metabolites of arachidonic acid were formed during incubation with soluble guanylate cyclase. Addition of soybean lipoxygenase to the incubation did not increase activation by arachidonic acid. The inhibitors of lipoxygenase activity, nordihydroguaiaretic acid and eicosatetraynoic acid, had direct effects on soluble guanylate cyclase and interfered with its activation by arachidonate, whereas another lipoxygenase inhibitor, BW 755 C, did not. The data suggest that arachidonic acid increases the activity of guanylate cyclase by direct interaction with the enzyme rather than by being converted to an active metabolite.
Products of arachidonic acid have been implicated as potential mediators of allergic airway responses in sheep and in humans. We therefore measured the release of arachidonate metabolites into sheep bronchoalveolar lavage fluid (BALF) after local instillation of Ascaris antigen, using a highly specific and sensitive approach, gas chromatography-negative ion-chemical ionization mass spectrometry. Allergen instillation caused increases in the levels of the potent bronchoconstrictors prostaglandin (PG) D2 and thromboxane (TX) A2 (as reflected by levels of TXB2) and of their enzymatic metabolites, 9 alpha, 11 beta-PGF2 and 11-dehydro-TXB2, respectively. Potential bronchodilators, PGI2 and PGE2, were also formed in increased amounts. Levels of the 5-lipoxygenase products, leukotriene (LT) B4 and C4, were not significantly increased. Pretreatment of sheep with cyclooxygenase inhibitors was associated with a decrease in the release of cyclooxygenase products and a concomitant increase in the allergen-stimulated release of LTB4 and LTC4. Eicosanoids are formed promptly in vivo in sheep after allergen instillation: inhibition of cyclooxygenase results in augmented generation of leukotrienes in the airways of sensitive sheep in response to antigen challenge.
The time course of leukotriene generation in the adult respiratory distress syndrome (ARDS) was investigated by measurement of urinary leukotriene E4 (LTE4) excretion, the major urinary LT metabolite in humans. Sequential measurements were made in nine subjects entered into the study within 48 h of the onset of ARDS, defined by an arterial/alveolar PO2 ratio of less than 0.3 and radiographic evidence of diffuse bilateral pulmonary edema. Initial urinary LTE4 excretion was significantly elevated (1.250 +/- 0.050 ng/mg creatinine sulphate; n = 7) compared with a non-ARDS postoperative group (0.254 +/- 0.114 ng/mg; n = 5) and normal control subjects (0.035 +/- 0.010 ng/mg; n = 12). LTE4 excretion in the first 24 h was estimated to be 6.9 micrograms, representing a release of 0.1 micrograms/kg/h of peptido leukotrienes into the bloodstream. These values were physiologically important based on a comparison with the increased urinary LTE4 excretion observed after antigen-induced bronchoconstriction in allergic asthmatics (baseline LTE4, 0.06 +/- 0.04 ng/mg; postantigen, 0.56 +/- 0.14 ng/mg; 0.17 micrograms LTE4/24 h; n = 8). In subjects with ARDS, this pathologic LTE4 excretion persisted during a subsequent 5-day study period. Leukotriene E4 excretion was associated with persistent abnormalities in gas exchange, pulmonary edema, and lung compliance, suggesting an important role for peptido leukotrienes in the pathophysiology of ARDS.