OXYGEN RADICALS STIMULATE THROMBOXANE AND PROSTACYCLIN SYNTHESIS AND INDUCE VASOCONSTRICTION IN PIG LUNGS

Reactive oxygen species have earlier been shown to induce vasoactive c hanges. In the present investigation we hypothesized that active oxyge n intermediates would stimulate arachidonic acid metabolism and thereb y influence the pulmonary circulation. Four groups of 8-week old pigs were studied after infusion of an oxygen radical generator. Haemodynam ic changes were recorded, and thromboxane (TX)B2 (the stable metabolit e Of TXA2) and 6-keto-prostaglandin (PG)F1alpha (the stable metabolite of prostacyclin, PGI2) Measured by a radioimmunoassay technique after infusion of xanthine oxidase (XO) alone or in combination with pharma cological inhibitors. In the XO group pulmonary vascular resistance in creased rapidly compared to baseline levels. Maximum resistance increa se was 118.4 +/- 27.5%, 25 min after the XO infusion (p < 0.05 compare d to baseline). The vasoconstriction was significantly attenuated afte r pretreatment with the cyclo-oxygenase inhibitor indomethacin. In thi s group the pulmonary resistance increase was 21.2 +/- 24.3% at 25 min (p < 0.01 vs. XO group). In a group given allopurinol (xanthine oxida se inhibitor), the resistance increased by 44.3 +/- 28.8% (p < 0.02 vs . XO group), and during catalase infusion (hydrogen peroxide scavenger ), the increase was 52.9 +/- 24.2% (p < 0.01 vs. XO group). Along with the pulmonary vascular pressure augmentation, we measured 1.9 fold TX B2 and 2.2 fold O-keto-PGF1alpha concentration increases in the XO gro up. However, both TXB2 and 6-keto-PGF1alpha formation was significantl y inhibited by indomethacin (p < 0.01 respectively vs. XO group), allo purinol (p < 0.01 and p < 0.05 respectively vs. XO group) and catalase (p < 0.01 and p < 0.02 respectively vs. XO group). We conclude that r eactive oxygen metabolites markedly constrict the pulmonary circulatio n in young pigs, and that the observed vasoactive effects may be media ted through the generation of TXA2.