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Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581.
J Pharmacol Exp Ther 1982; 222(2):441-6JP

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.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

6896528

Citation

Casey, L C., et al. "Prevention of Endotoxin-induced Pulmonary Hypertension in Primates By the Use of a Selective Thromboxane Synthetase Inhibitor, OKY 1581." The Journal of Pharmacology and Experimental Therapeutics, vol. 222, no. 2, 1982, pp. 441-6.
Casey LC, Fletcher JR, Zmudka MI, et al. Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581. J Pharmacol Exp Ther. 1982;222(2):441-6.
Casey, L. C., Fletcher, J. R., Zmudka, M. I., & Ramwell, P. W. (1982). Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581. The Journal of Pharmacology and Experimental Therapeutics, 222(2), pp. 441-6.
Casey LC, et al. Prevention of Endotoxin-induced Pulmonary Hypertension in Primates By the Use of a Selective Thromboxane Synthetase Inhibitor, OKY 1581. J Pharmacol Exp Ther. 1982;222(2):441-6. PubMed PMID: 6896528.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prevention of endotoxin-induced pulmonary hypertension in primates by the use of a selective thromboxane synthetase inhibitor, OKY 1581. AU - Casey,L C, AU - Fletcher,J R, AU - Zmudka,M I, AU - Ramwell,P W, PY - 1982/8/1/pubmed PY - 1982/8/1/medline PY - 1982/8/1/entrez SP - 441 EP - 6 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 222 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/6896528/Prevention_of_endotoxin_induced_pulmonary_hypertension_in_primates_by_the_use_of_a_selective_thromboxane_synthetase_inhibitor_OKY_1581_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6896528 DB - PRIME DP - Unbound Medicine ER -