Cyclooxygenase inhibition during phorbol-induced granulocyte stimulation in awake sheep.
In vitro, phorbol myristate acetate (PMA) causes sheep granulocytes to release superoxide. Infused into sheep, PMA causes leukopenia, hypoxemia, pulmonary hypertension, and increased flow of protein-rich lung lymph. Lung lymph thromboxane B2 and 6-ketoprostaglandin F1 alpha levels rise markedly after PMA infusion. To see whether cyclooxygenase products of arachidonic acid mediate the lung vascular responses to PMA, we infused 5 micrograms/kg PMA twice in each of six sheep, once in the presence of sodium meclofenamate and once alone. We varied the order of paired experiments and allowed 4-7 days between experiments. Meclofenamate (5 mg/kg loading dose + 3 mg X kg-1 X h-1 infusion) given alone had no effect on base-line variables. Meclofenamate inhibited or delayed the initial pulmonary hypertension and hypoxemia after PMA but exaggerated the later increase in pulmonary arterial pressure; it prevented any increase in thromboxane B2 and 6-ketoprostaglandin F1 alpha after PMA. Meclofenamate did not affect the degree of leukopenia or the severity of the later hypoxemia nor did it prevent accumulation of granulocytes in the lung. Lung lymph flow was higher with meclofenamate + PMA than with PMA alone, but lymph-to-plasma protein concentration ratio was lower, suggesting that the main effect of meclofenamate on lymph production after PMA was related to the degree of pulmonary hypertension. We conclude that the early increase in pulmonary arterial pressure caused by PMA is mediated by a cyclooxygenase product of arachidonic acid, possibly thromboxane A2, but the later pulmonary hypertension and the increase in pulmonary vascular permeability are not the result of cyclooxygenase products.
D000818:Animals; D003243:Consciousness; D016861:Cyclooxygenase Inhibitors; D006098:Granulocytes / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000150:complications; D000860:Hypoxia / Q000150:complications; D007249:Inflammation / Q000139:chemically induced; D008171:Lung Diseases / Q000139:chemically induced; D008196:Lymph / Q000187:drug effects; D008469:Meclofenamic Acid / Q000494:pharmacology; D010704:Phorbols / Q000494:pharmacology*; D012756:Sheep; D013268:Stimulation, Chemical; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D010704:Phorbols; D008469:Meclofenamic Acid; D013755:Tetradecanoylphorbol Acetate