Inhibition of permeability edema with imidazole.
Acute respiratory failure (ARF) with permeability edema and increased physiologic shunting (QS/QT) occurs after complement activation. Leukocytes aggregate, become entrapped in the lungs, and release vasotoxic agents. This study of 31 sheep infused with zymosan-activated plasma (ZAP) tests the hypothesis tha thromboxane (Tx) A2, a proaggregator and bronchoconstrictor, is an intermediate in complement-induced ARF. Group I animals (n = 11) were untreated controls. An imidazole infusion, 25 mg/kg . hr was started 1 hour before a ZAP infusion in group II (n = 10). Prostacyclin (PGi2) was given to group III sheep (n = 10) in a dose of 100 ng/kg . min 3- minutes before the ZAP infusion. Within 5 minutes ZAP led to a decrease in the leukocyte count to 2900/mm3 (P less than 0.001), a rise in plasma TxB2 concentration (the stable degradation product of TxA2) from 14 to 246 pg/ml (P less than 0.001), a rise in lymph TxB2 from 24 to 609 pg/ml (P less than 0.001), a rise in QS/QT from 13% to 31% (P less than 0.01), and a rise in mean pulmonary arterial pressure from 17 to 43 mm Hg. Both imidazole and PGI2 prevented the increase in TxB2 and QS/QT and limited the increases in MPAP to 25 and 30 mm Hg, respectively--values below those of untreated controls (P less than 0.05). Imidazole, but not PGI2, prevented the increase in lymph flow, which in controls increased from 2.8 +/- 8.5 ml/30 min (P less than 0.01), and lymph albumin clearance, which increased from 2.2 to 6.0 ml/30 min (P less than 0.01). The high lymph concentrations of TxA2 suggest a pulmonary site of production, and its bronchoconstrictive action may account for the increase in QS/QT. However, TxA2 is only partially responsible for the pulmonary hypertension and is apparently unrelated to changes in permeability. The protective action of infused imidazole against increased permeability appears to be independent of its inhibition of Tx synthetase.
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D003167:Complement Activation; D011464:Epoprostenol / Q000378:metabolism / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use*; D007958:Leukocyte Count / Q000187:drug effects; D008168:Lung / Q000032:analysis; D008196:Lymph / Q000032:analysis; D010974:Platelet Aggregation / Q000187:drug effects; D011654:Pulmonary Edema / Q000188:drug therapy* / Q000503:physiopathology; D012131:Respiratory Insufficiency / Q000188:drug therapy / Q000503:physiopathology; D013928:Thromboxane A2 / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
D007093:Imidazoles; D013928:Thromboxane A2; C029899:imidazole; D015054:Zymosan; D011464:Epoprostenol