Oxygen radicals stimulate thromboxane and prostacyclin synthesis and induce vasoconstriction in pig lungs

Abstract

Sanderud J, Bjøro K, Saugstad OD. Oxygen radicals stimulate thromboxane and prostacyclin synthesis and induce vasoconstriction in pig lungs. Scand J Clin Lab Invest 1993; 53: 447-455.

Reactive oxygen species have earlier been shown to induce vasoactive changes. In the present investigation we hypothesized that active oxygen intermediates would stimulate arachidonic acid metabolism and thereby influence the pulmonary circulation. Four groups of 8-week old pigs were studied after infusion of an oxygen radical generator. Haemodynamic changes were recorded, and thromboxane (TX)B₂ (the stable metabolite of TXA₂) and 6-keto-prostaglandin (PG)F_lα (the stable metabolite of prostacyclin, PGI2) measured by a radioimmunoassay technique after infusion of xanthine oxidase (XO) alone or in combination with pharmacological inhibitors. In the XO group pulmonary vascular resistance increased rapidly compared to baseline levels. Maximum resistance increase was 118.4 ± 27.5%, 25min after the XO infusion (p < 0.05 compared to baseline). The vasoconstriction was significantly attenuated after pretreatment with the cyclo-oxygenase inhibitor indomethacin. In this group the pulmonary resistance increase was 21.2 ± 24.3% at 25min (p < 0.01 vs. XO group). In a group given allopurinol (xanthine oxidase 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 TXB2 and 2.2 fold 6-keto-PGF_1α concentration increases in the XO group. However, both TXB₂ and 6-keto-PGF_lα formation was significantly inhibited by indomethacin (p < 0.01 respectively vs. XO group), allopurinol (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 reactive oxygen metabolites markedly constrict the pulmonary circulation in young pigs, and that the observed vasoactive effects may be mediated through the generation of TXA₂.

Key Words:

• hypoxanthine
• lung
• prostanoids
• vascular resistance
• xanthine oxidase