Inhibition of Pulmonary Thromboxane A2 Synthase Activity and Airway Responses by CGS 13080

Overview

Journal Mol Cell Biochem

Publisher Springer

Specialty Biochemistry

Date 1989 Jan 23

PMID 2725478

Citations 1

Authors

D B McNamara

J K Harrington

J A Bellan

G B Graybar

D C Underwood

P J Kadowitz

Affiliations

Soon will be listed here.

Abstract

The effects of CGS 13080, a thromboxane (TXA2) synthase inhibitor, on airway responses to arachidonic acid (AA) were investigated in the anesthetized cat. Feline and human lung microsomal fraction exhibited prostaglandin I2 (PGI2, prostacyclin), and TXA2 synthase activities, and human platelet microsomal fractions exhibited TXA2 synthase activity. Cat and human lung microsomal fractions, but not human platelets, exhibited the presence of GSH-dependent PGE2 isomerase activity. CGS 13080 inhibited TXA2 synthase activity in all three microsomal fractions in a concentration-dependent manner. The increases in transpulmonary pressure and lung resistance and decreases in dynamic compliance in response to AA were decreased significantly by CGS 13080. These data suggest that the bronchoconstrictor actions of AA are mediated in large part by the formation of TXA2. The data further indicate that cyclooxygenase products other than TXA2 are involved in the bronchoconstrictor response to AA since meclofenamate had greater inhibitory activity than did CGS 13080. Moreover, the effects of CGS 13080 were due to inhibition of TXA2 synthase rather than an effect on TXA2 receptors, since airway responses to the TXA2 mimic, U46619, were not altered. The present data show that CGS 13080 inhibits TXA2 synthase activity without altering cyclooxygenase, PGI2 synthase, or GSH-dependent PGE2 isomerase activities. The data further indicate that in vivo administration of CGS 13080 may selectively increase PGI2 synthase activity.

Citing Articles

Actions of SQ 29,548 on contractile responses and arachidonic acid metabolism of intrapulmonary arteries, in vitro.

Boyd V, Kvamme P, Harbison R, Kadowitz P, McNamara D Agents Actions. 1992; 35(3-4):280-8.

PMID: 1529803 DOI: 10.1007/BF01997512.

References

Dusting G, Moncada S, Vane J . Prostaglandins, their intermediates and precursors: cardiovascular actions and regulatory roles in normal and abnormal circulatory systems. Prog Cardiovasc Dis. 1979; 21(6):405-30. DOI: 10.1016/0033-0620(79)90024-0. View

Moncada S, Vane J . Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev. 1978; 30(3):293-331. View

Spannhake E, Levin J, Mellion B, Gruetter C, HYMAN A, Kadowitz P . Reversal of 5HT-induced bronchoconstriction by PGI2: distribution of central and peripheral actions. J Appl Physiol Respir Environ Exerc Physiol. 1980; 49(3):521-7. DOI: 10.1152/jappl.1980.49.3.521. View

Ogino N, Miyamoto T, Yamamoto S, HAYAISHI O . Prostaglandin endoperoxide E isomerase from bovine vesicular gland microsomes, a glutathione-requiring enzyme. J Biol Chem. 1977; 252(3):890-5. View

Demling R, Smith M, Gunther R, Flynn J, Gee M . Pulmonary injury and prostaglandin production during endotoxemia in conscious sheep. Am J Physiol. 1981; 240(3):H348-53. DOI: 10.1152/ajpheart.1981.240.3.H348. View

Sun F . Biosynthesis of thromboxanes in human platelets. I. Characterization and assay of thromboxane synthetase. Biochem Biophys Res Commun. 1977; 74(4):1432-40. DOI: 10.1016/0006-291x(77)90602-7. View

Dahlen S . Pulmonary effects of leukotrienes. Acta Physiol Scand Suppl. 1983; 512:1-51. View

Bertele V, de Gaetano G . Potentiation by dazoxiben, a thromboxane synthetase inhibitor, of platelet aggregation inhibitory activity of a thromboxane receptor antagonist and of prostacyclin. Eur J Pharmacol. 1982; 85(3-4):331-3. DOI: 10.1016/0014-2999(82)90220-5. View

Wasserman M, DUCHARME D, Griffin R, DeGraaf G, Robinson F . Bronchopulmonary and cardiovascular effects of prostaglandin D2 in the dog. Prostaglandins. 1977; 13(2):255-69. DOI: 10.1016/0090-6980(77)90007-7. View

10.

Rush D, Kerstein M, Bellan J, Knoop S, Mayeux P, HYMAN A . Prostacyclin, thromboxane A2, and prostaglandin E2 formation in atherosclerotic human carotid artery. Arteriosclerosis. 1988; 8(1):73-8. DOI: 10.1161/01.atv.8.1.73. View

11.

Burke S, DiCola G, Lefer A . Protection of ischemic cat myocardium by CGS-13080, a selective potent thromboxane A2 synthesis inhibitor. J Cardiovasc Pharmacol. 1983; 5(5):842-7. DOI: 10.1097/00005344-198309000-00021. View

12.

Kadowitz P, Chapnick B, Feigen L, HYMAN A, Nelson P, Spannhake E . Pulmonary and systemic vasodilator effects of the newly discovered prostaglandin, PGI2. J Appl Physiol Respir Environ Exerc Physiol. 1978; 45(3):408-13. DOI: 10.1152/jappl.1978.45.3.408. View

13.

Bhagwat S, Hamann P, STILL W, Bunting S, Fitzpatrick F . Synthesis and structure of the platelet aggregation factor thromboxane A2. Nature. 1985; 315(6019):511-3. DOI: 10.1038/315511a0. View

14.

Raz A, Aharony D . Prostaglandin biosynthesis in platelets: demonstration and role of prostaglandin H2 leads to E2 isomerase. Res Commun Chem Pathol Pharmacol. 1978; 21(3):507-15. View

15.

Coleman R, Humphrey P, Kennedy I, Levy G, Lumley P . Comparison of the actions of U-46619, a prostaglandin H2-analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations. Br J Pharmacol. 1981; 73(3):773-8. PMC: 2071689. DOI: 10.1111/j.1476-5381.1981.tb16814.x. View

16.

She H, McNamara D, Spannhake E, HYMAN A, Kadowitz P . Metabolism of prostaglandin endoperoxide by microsomes from cat lung. Prostaglandins. 1981; 21(4):531-9. DOI: 10.1016/0090-6980(81)90002-2. View

17.

Spannhake E, Colombo J, Craigo P, McNamara D, HYMAN A, Kadowitz P . Evidence for modification of pulmonary cyclooxygenase activity by endotoxin in the dog. J Appl Physiol Respir Environ Exerc Physiol. 1983; 54(1):191-8. DOI: 10.1152/jappl.1983.54.1.191. View

18.

Hamberg M . On the formation of thromboxane B2 and 12l-hydroxy-5,8,10,14-eicosatetraenoic acid (12 ho-20:4) in tissues from the guinea pig. Biochim Biophys Acta. 1976; 431(3):651-4. DOI: 10.1016/0005-2760(76)90232-0. View

19.

Kadowitz P, HYMAN A . Analysis of responses to leukotriene D4 in the pulmonary vascular bed. Circ Res. 1984; 55(5):707-17. DOI: 10.1161/01.res.55.5.707. View

20.

Underwood D, Kriseman T, McNamara D, HYMAN A, Kadowitz P . Blockade of thromboxane responses in the airway of the cat by SQ 29,548. J Appl Physiol (1985). 1987; 62(6):2193-200. DOI: 10.1152/jappl.1987.62.6.2193. View