Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581.
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, we have evaluated a selective Tx synthetase inhibitor (OKY 1581) as a means for preventing endotoxin-induced pulmonary hypertension. An LD70 dose of Escherichia coli endotoxin (6 mg/kg) was given i.v. to two groups of unanesthetized baboons. Group I received endotoxin alone and Group II was pretreated with i.v. OKY 1581 (2 mg/kg) 10 min before the 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 less than .01), but no significant change in plasma 6-keto PGF1 alpha. After the administration of the endotoxin, Group I developed pulmonary hypertension (from 11 +/- 1 to 19 +/- 2 mm Hg. P less than .005) and an 8-fold increase in plasma TxB2 (P less than .02), whereas Group II did not develop pulmonary hypertension or an increase in plasma TxB2. However, Group II had a 26-fold increase in plasma 6-keto PGF1 alpha (P less than .05). From these studies, we conclude that: 1) OKY 1581 is an effective Tx synthetase inhibitor in vivo; 2) endotoxin-induced pulmonary hypertension is mediated largely by increased Tx; and 3) the inhibition of Tx synthetase results in shunting of endoperoxides into the prostacyclin pathway.
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010215:Papio; D012772:Shock, Septic / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000179:Acrylates; D008689:Methacrylates; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; D010088:Oxidoreductases; D013930:Thromboxane-A Synthase