Inhibition of cyclooxygenase and nitric oxide synthase in hypoxic vasoconstriction and oleic acid-induced lung injury.
Cyclooxygenase (COX) products and nitric oxide (NO) inhibit hypoxic pulmonary vasoconstriction (HPV), and their release could contribute to alterations in gas exchange in lung injury. We tested the hypothesis that combined blockade of COX and NO synthase (NOS) could further increase HPV and better protect gas exchange in lung injury than could blockade of either COX or NOS alone. We determined pulmonary vascular pressure-flow relationships in pentobarbital-anesthetized and ventilated dogs submitted to hypoxic challenges before and after administration of solvent (n = 4), indomethacin alone (2 mg/kg intravenously, n = 8), Nomega-nitro-L-arginine (L-NA) alone (10 mg/kg intravenoulsy, n = 8), indomethacin followed by L-NA (n = 8), and L-NA followed by indomethacin (n = 8). All of the dogs so treated then received oleic acid (0.06 ml/kg intravenously) to induce lung injury. Blood flow was manipulated by establishing a femoral arteriovenous bypass or by inflating an inferior vena caval balloon. Gas exchange was evaluated by measuring arterial PO2 and intrapulmonary shunt (using the inert gas sulfur hexafluoride) at identical cardiac outputs. The magnitude of HPV was not affected by solvent. Indomethacin and L-NA given separately enhanced HPV. L-NA added to indomethacin further enhanced HPV, as did indomethacin added to L-NA. After oleic acid-induced lung injury, gas exchange deteriorated less in dogs pretreated with indomethacin than in dogs pretreated with solvent or with L-NA alone. These results suggest that in pentobarbital-anesthetized dogs: (1) the magnitude of HPV is limited by the corelease of COX metabolites and of NO; and (2) inhibition of COX, but not of NOS, attenuates the deterioration of gas exchange in oleic acid-induced lung injury.
Leeman
M
M
Laboratory of Physiology, Erasme University Hospital, Brussels, Belgium. marc.leeman@ulb.ac.be
de Beyl
V Z
VZ
Biarent
D
D
Maggiorini
M
M
Mélot
C
C
Naeije
R
R
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology*; D008171:Lung Diseases / Q000139:chemically induced / Q000503:physiopathology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D019301:Oleic Acid; D011652:Pulmonary Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019301:Oleic Acid; D019001:Nitric Oxide Synthase; D007213:Indomethacin