PREVENTION OF ENDOTOXIN-INDUCED PULMONARY-HYPERTENSION IN PRIMATES BY THE USE OF A SELECTIVE THROMBOXANE SYNTHETASE INHIBITOR, OXY 1581

  • 1 January 1982
    • journal article
    • research article
    • Vol. 222  (2) , 441-446
Abstract
Endotoxin-induced pulmonary hypertension can be attenuated by nonsteroidal anti-inflammatory drugs and is associated with increased plasma levels of thromboxane (Tx) B2, prostaglandin (PG)F2, PGE and PGI2. Because nonsteroidal anti-inflammatory drugs block prostacyclin production and may also shift arachidonic acid into the lipoxygenase pathway, a selective Tx synthetase inhibitor (OKY 1581) was evaluated for preventing endotoxin-induced pulmonary hypertension. A 70% LD of Escherichia coli endotoxin (6 mg/kg) was given i.v. to 2 groups of unanesthetized baboons. Group 1 received endotoxin alone and group 2 was pretreated with i.v. OKY 1581 (2 mg/kg) 10 min before endotoxin. OKY 1581 produced a significant decrease in the basal plasma TxB2 from 0.432 .+-. 0.82 to 0.147 .+-. 0.032 ng/ml (P < 0.01), but no significant change in plasma 6-keto PGF1.alpha.. After administration of endotoxin, group 1 developed pulmonary hypertension (from 11 .+-. 1 to 19 .+-. 2 mm Hg, P < 0.005) and an 8-fold increase in plasma TxB2 (P < 0.02); group 2 did not develop pulmonary hypertension or an increase in plasma TxB2. Group 2 had a 26-fold increase in plasma 6-keto PGF1.alpha. (P < 0.05). Thus, OKY 1581 is an effective Tx synthetase inhibitor in vivo, endotoxin-induced pulmonary hypertension is mediated largely by increased Tx and the inhibition of Tx synthetase results in shunting of endoperoxides into the prostacyclin pathway.

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