Influence of steroidal and nonsteroidal anti-inflammatory agents on the accumulation of arachidonic acid metabolites in plasma and lung lymph after endotoxemia in awake sheep. Measurements of prostacyclin and thromboxane metabolites and 12-HETE.
The influence of methylprednisolone and meclofenamate on endotoxin-induced release of 3 arachidonic acid metabolites was studied in unanesthetized sheep. Concentrations in plasma and lung lymph of prostacyclin and thromboxane (Tx) A2 metabolites (6-keto-PGF1 alpha and TxB2, respectively) were measured by radioimmunoassay. Concentrations of 12-HETE in lung lymph were measured by stable isotope dilution assay employing gas chromatography-mass spectroscopy. Thromboxane B2 concentrations increased quickly to peak values during the first hour after endotoxin infusion, then decreased to baseline by 1.5 hr. 6-keto-PGF1 alpha concentrations increased more gradually to peak values between 1 and 2 h after endotoxin infusion and remained elevated at 2.5 h. Lymph concentrations of both cyclooxygenase metabolites exceeded those in blood plasma. Methylprednisolone significantly inhibited accumulation of 6-keto-PGF1 alpha in lymph and plasma, but did not significantly inhibit accumulation of TxB2 in lymph or plasma. The combination of meclofenamate and methylprednisolone completely inhibited accumulation of TxB2 and 6-keto-PGF1 alpha in lymph and plasma. The concentration of 12-HETE in lung lymph increased significantly to peak values by 2.5 h after endotoxemia, and methylprednisolone, with or without meclofenamate, inhibited accumulation of 12-HETE in lung lymph. These data support participation of TxA2 in acute pulmonary hypertension after endotoxemia. That methylprednisolone treatment inhibited accumulation of 6-keto-PGF1 alpha and prevented the increase in lung vascular permeability suggests that prostacyclin production is a consequence of lung vascular injury. Increased lung lymph concentrations of the lipoxygenation product, 12-HETE, were coincident with physiologic evidence of increased lung vascular permeability, but whether release of lipoxygenase products after endotoxemia contributes to or results from lung vascular injury remains to be established.
Ogletree
M L
ML
Begley
C J
CJ
King
G A
GA
Brigham
K L
KL
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001427:Bacterial Toxins / Q000633:toxicity*; D004357:Drug Synergism; D004731:Endotoxins / Q000633:toxicity*; D004926:Escherichia coli; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008196:Lymph / Q000378:metabolism*; D008469:Meclofenamic Acid / Q000008:administration & dosage / Q000494:pharmacology; D008775:Methylprednisolone / Q000008:administration & dosage / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects; D012756:Sheep; D013929:Thromboxane B2 / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014851:Wakefulness
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D001427:Bacterial Toxins; D004731:Endotoxins; D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; D008469:Meclofenamic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D008775:Methylprednisolone