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. 1983 Jan;78(1):173–180. doi: 10.1111/j.1476-5381.1983.tb09378.x

Stimulation and inhibition of prostacyclin formation in the gastric mucosa and ileum in vitro by anti-inflammatory agents

NK Boughton-Smith, BJR Whittle
PMCID: PMC2044797  PMID: 6402044

Abstract

1 Homogenates of rat gastric mucosa, forestomach and ileum and dog gastric mucosa reproducibly generated prostacyclin from endogenous substrate.

2 Prostacyclin formation was inhibited by pre-incubation with indomethacin, flurbiprofen, naproxen, ketoprofen or meclofenamate (0.1-10 μM).

3 BW755C (3-amino-1[m-(trifluoromethyl)-phenyl]-2-pyrazoline) stimulated prostacyclin production in the rat gastric mucosa and ileum with inhibition occurring only at high concentrations (> 200 μM). The stimulation of prostacyclin production by BW755C in rat forestomach homogenates was less pronounced, with inhibition at concentrations > 20 μM.

4 BW755C thus exhibits differential activity on prostacyclin production from different gastric tissues in vitro.

5 The antioxidant-lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA, 3-15 μM) likewise augmented rat mucosal prostacyclin formation.

6 Paracetamol stimulated and, at higher concentrations, inhibited prostacyclin formation (> 1 mM), and had comparable activity in both rat gastric tissues.

7 The ability of NDGA and BW755C to enhance prostacyclin generation may reflect the removal of a modulating influence of lipoxygenase products on prostacyclin formation, the diversion of substrate to the cyclo-oxygenase pathway, or free-radical scavenging.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beetens J. R., Claeys M., Herman A. G. Antioxidants increase the formation of 6-oxo-PGF1 alpha by ram seminal vesicle microsomes. Biochem Pharmacol. 1981 Oct;30(20):2811–2815. doi: 10.1016/0006-2952(81)90419-6. [DOI] [PubMed] [Google Scholar]
  2. Bennett A., Hensby C. N., Sanger G. J., Stamford I. F. Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers. Br J Pharmacol. 1981 Oct;74(2):435–444. doi: 10.1111/j.1476-5381.1981.tb09989.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bennett A., Stamford I. F., Unger W. G. Prostaglandin E2 and gastric acid secretion in man. J Physiol. 1973 Mar;229(2):349–360. doi: 10.1113/jphysiol.1973.sp010142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cottee F., Flower R. J., Moncada S., Salmon J. A., Vane J. R. Synthesis of 6-keto-PGF1alpha by ram seminal vesicle microsomes. Prostaglandins. 1977 Sep;14(3):413–423. doi: 10.1016/0090-6980(77)90257-x. [DOI] [PubMed] [Google Scholar]
  5. Flower R. J. Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev. 1974 Mar;26(1):33–67. [PubMed] [Google Scholar]
  6. 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 Jun 22;431(3):651–654. doi: 10.1016/0005-2760(76)90232-0. [DOI] [PubMed] [Google Scholar]
  7. Higgs G. A., Flower R. J., Vane J. R. A new approach to anti-inflammatory drugs. Biochem Pharmacol. 1979 Jun 15;28(12):1959–1961. doi: 10.1016/0006-2952(79)90651-8. [DOI] [PubMed] [Google Scholar]
  8. Knapp H. R., Oelz O., Sweetman B. J., Oates J. A. Synthesis and metabolism of prostaglandins E2, F2alpha and D2 by the rat gastrointestinal tract. Stimulation by a hypertonic environment in vitro. Prostaglandins. 1978 May;15(5):751–757. doi: 10.1016/0090-6980(78)90141-7. [DOI] [PubMed] [Google Scholar]
  9. Kuehl F. A., Jr, Humes J. L., Egan R. W., Ham E. A., Beveridge G. C., Van Arman C. G. Role of prostaglandin endoperoxide PGG2 in inflammatory processes. Nature. 1977 Jan 13;265(5590):170–173. doi: 10.1038/265170a0. [DOI] [PubMed] [Google Scholar]
  10. LeDuc L. E., Needleman P. Regional localization of prostacyclin and thromboxane synthesis in dog stomach and intestinal tract. J Pharmacol Exp Ther. 1979 Oct;211(1):181–188. [PubMed] [Google Scholar]
  11. Moncada S., Gryglewski R., Bunting S., Vane J. R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976 Oct 21;263(5579):663–665. doi: 10.1038/263663a0. [DOI] [PubMed] [Google Scholar]
  12. Pace-Asciak C. R., Nashat M. Mechanistic studies on the biosynthesis of 6-ketoprostaglandin F1alpha. Biochim Biophys Acta. 1977 Jun 22;487(3):495–507. doi: 10.1016/0005-2760(77)90219-3. [DOI] [PubMed] [Google Scholar]
  13. Pace-Asciak C. R., Rangaraj G. Distribution of prostaglandin biosynthetic pathways in several rat tissues. Formation of 6-ketoprostaglandin F1alpha. Biochim Biophys Acta. 1977 Mar 25;486(3):579–582. doi: 10.1016/0005-2760(77)90112-6. [DOI] [PubMed] [Google Scholar]
  14. Pace-Asciak C. Prostaglandin synthetase activity in the rat stomach fundus. Activation by L-norepinephrine and related compounds. Biochim Biophys Acta. 1972 Sep 7;280(1):161–171. doi: 10.1016/0005-2760(72)90221-4. [DOI] [PubMed] [Google Scholar]
  15. Payne T. G., Dewald B., Siegl H., Gubler H. U., Ott H., Baggiolini M. Radical scavenging and stimulation of prostaglandin synthesis not anti-inflammatory? Nature. 1982 Mar 11;296(5853):160–162. doi: 10.1038/296160a0. [DOI] [PubMed] [Google Scholar]
  16. Peskar B. M. On the synthesis of prostaglandins by human gastric mucosa and its modification by drugs. Biochim Biophys Acta. 1977 May 25;487(2):307–314. doi: 10.1016/0005-2760(77)90007-8. [DOI] [PubMed] [Google Scholar]
  17. Peskar B. M., Weiler H., Peskar B. A. Effect of BW755C on prostaglandin synthesis in the rat stomach. Biochem Pharmacol. 1982 Apr 15;31(8):1652–1653. doi: 10.1016/0006-2952(82)90397-5. [DOI] [PubMed] [Google Scholar]
  18. Randall R. W., Eakins K. E., Higgs G. A., Salmon J. A., Tateson J. E. Inhibition of arachidonic acid cyclo-oxygenase and lipoxygenase activities of leukocytes by indomethacin and compound BW755C. Agents Actions. 1980 Dec;10(6):553–555. doi: 10.1007/BF02024164. [DOI] [PubMed] [Google Scholar]
  19. Robak J., Wieckowski A., Gryglewski R. The effect of 4-acetamidophenol on prostaglandin synthetase activity in bovine and ram seminal vesicle microsomes. Biochem Pharmacol. 1978 Feb 15;27(4):393–396. doi: 10.1016/0006-2952(78)90367-2. [DOI] [PubMed] [Google Scholar]
  20. Salmon J. A. A radioimmunoassay for 6-keto-prostaglandin F1alpha. Prostaglandins. 1978 Mar;15(3):383–397. doi: 10.1016/0090-6980(78)90122-3. [DOI] [PubMed] [Google Scholar]
  21. Salmon J. A., Smith D. R., Flower R. J., Moncada S., Vane J. R. Further studies on the enzymatic conversion of prostaglandin endoperoxide into prostacyclin by porcine aorta microsomes. Biochim Biophys Acta. 1978 Mar 14;523(1):250–262. doi: 10.1016/0005-2744(78)90028-1. [DOI] [PubMed] [Google Scholar]
  22. Siegel M. I., McConnell R. T., Abrahams S. L., Porter N. A., Cuatrecasas P. Regulation of arachidonate metabolism via lipoxygenase and cyclo-oxygenase by 12-HPETE, the product of human platelet lipoxygenase. Biochem Biophys Res Commun. 1979 Aug 28;89(4):1273–1280. doi: 10.1016/0006-291x(79)92146-6. [DOI] [PubMed] [Google Scholar]
  23. Vane J. R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971 Jun 23;231(25):232–235. doi: 10.1038/newbio231232a0. [DOI] [PubMed] [Google Scholar]
  24. Whittle B. J., Higgs G. A., Eakins K. E., Moncada S., Vane J. R. Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa. Nature. 1980 Mar 20;284(5753):271–273. doi: 10.1038/284271a0. [DOI] [PubMed] [Google Scholar]
  25. Whittle B. J. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology. 1981 Jan;80(1):94–98. [PubMed] [Google Scholar]
  26. van Kolfschoten A. A., Dembinska-Kiec A., Basista M. Interaction between aspirin and paracetamol on the production of prostaglandins in the rat gastric mucosa. J Pharm Pharmacol. 1981 Jul;33(7):462–463. doi: 10.1111/j.2042-7158.1981.tb13834.x. [DOI] [PubMed] [Google Scholar]

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