D-penicillamine inhibits the action of reactive oxygen species in the pig pulmonary circulation.
Oxygen radicals produced by the hypoxanthine-xanthine oxidase (Hyp-XO) system potently constrict the pulmonary circulation of pigs. D-penicillamine (DPA) is thought to be a free radical scavenger. In the present work we have studied if DPA may influence the vasoactive action of Hyp-XO in pig lungs. Further, we have measured how this drug influences the output of cyclooxygenase and lipoxygenase products from the left atrium in pigs infused with XO into the pulmonary circulation. Twelve young pigs were divided into two groups. Group 1, the XO group, was infused 1 U/kg XO into right atrium. Group 2, the DPA group, was pretreated with DPA, 100 mg/kg intravenously before XO infusion as in group 1. Pulmonary artery pressure, left atrial pressure, pulmonary artery blood flow and systemic blood flow and pressure were recorded continuously. Plasma tromboxane B2 and prostaglandin (6-keto-PGF1 alpha) were determined with a radioimmunoassay method. Cysteinyl containing leukotrienes LTC4, LTD4, and LTE4, were measured together by RIA analyses of plasma samples, using a monoclonal antibody. There was a significant parallel decrease in paO2 and saO2 during the 130 minutes duration of the experiments in both groups without differences between the groups. Pulmonary vascular pressure and resistance increased sharply with a peak found after 25 minutes in the XO group. DPA attenuated the hemodynamic response. DPA inhibited the XO induced pulmonary blood pressure changes with 80% and inhibited the increase in pulmonary vascular resistance 68%. Plasma TXB2 increased two folds in the XO group reaching a maximum after 40 minutes, this effect was completely inhibited by DPA (92% inhibition). DPA also inhibited the XO induced increase in 6-keto-PGF1 alpha, however, not as efficient as with TXB2 (40% inhibition). Plasma cysteinyl leukotrienes increased after XO infusion reaching a peak at 20 minutes. DPA completely abolished this effect (100% inhibition). The study demonstrates that DPA attenuates or even abolishes the hemodynamic effects of XO on the pulmonary circulation in pigs. It seems that DPA inhibits the production of both lipoxygenase and cyclooxygenase products per se, and it is tempting to speculate that the observed DPA effect is caused by its action as an oxygen radical scavenger. It is further speculated that the vasoconstricting effect of XO is due to the fact that oxygen radicals may inactivate nitric oxide (NO), and that DPA stabilizes NO so it more efficiently possess its vasorelaxant activity. We conclude that DPA is an extremely potent inhibitor of XO induced pulmonary vascular effects. The mechanism of action is not fully understood, although its action as an oxygen radical scavenger may explain part of it.
Sanderud
J
J
Institute for Surgical Research, National Hospital, Oslo, Norway.
Oroszlàn
G
G
Bjøro
K
K
Kumlin
M
M
Saugstad
O D
OD
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers; D008084:Lipoxygenase / Q000378:metabolism; D008297:Male; D010100:Oxygen / Q000097:blood; D010396:Penicillamine / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D013552:Swine; D013929:Thromboxane B2 / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013929:Thromboxane B2; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D014969:Xanthine Oxidase; D010396:Penicillamine; D010100:Oxygen