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Abstract

Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581.

L C Casey, J R Fletcher, M I Zmudka and P W Ramwell
Journal of Pharmacology and Experimental Therapeutics August 1982, 222 (2) 441-446;
L C Casey
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J R Fletcher
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M I Zmudka
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P W Ramwell
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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, 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.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 222, Issue 2
1 Aug 1982
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Abstract

Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581.

L C Casey, J R Fletcher, M I Zmudka and P W Ramwell
Journal of Pharmacology and Experimental Therapeutics August 1, 1982, 222 (2) 441-446;

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Abstract

Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581.

L C Casey, J R Fletcher, M I Zmudka and P W Ramwell
Journal of Pharmacology and Experimental Therapeutics August 1, 1982, 222 (2) 441-446;
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