Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1990 Mar;99(3):607–611. doi: 10.1111/j.1476-5381.1990.tb12977.x

Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat.

B J Whittle 1, J Lopez-Belmonte 1, S Moncada 1
PMCID: PMC1917359  PMID: 2110019

Abstract

1. The interactions between nitric oxide (NO), prostacyclin and sensory neuropeptides in the maintenance of gastric mucosal integrity have been investigated in the anaesthetized rat. 2. Administration of either NG-monomethyl-L-arginine (L-NMMA) to inhibit endothelium-derived NO formation, indomethacin to inhibit prostanoid biosynthesis or chronic capsaicin pretreatment to deplete sensory neuropeptides, did not induce acute mucosal injury. 3. In capsaicin-pretreated rats, however, L-NMMA (12.5-100 mg kg-1 i.v.) dose-dependently induced acute mucosal damage, characterized as vasocongestion and haemorrhagic necrosis. The enatiomer D-NMMA (100 mg kg-1 i.v.) did not induce any detectable mucosal damage. 4. This mucosal injury induced by L-NMMA was inhibited by concurrent administration of L-arginine (300 mg kg-1 i.v.). 5. In indomethacin (5 mg kg-1 i.v.)-pretreated rats, L-NMMA also induced mucosal damage. Furthermore, following indomethacin administration in capsaicin-pretreated rats, L-NMMA induced widespread, severe haemorrhagic necrotic damage. 6. These findings suggest a role for endogenous NO formed from L-arginine, acting in concert with prostacyclin and sensory neuropeptides, in the modulation of gastric mucosal integrity.

Full text

PDF
607

Selected References

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

  1. Amezcua J. L., Palmer R. M., de Souza B. M., Moncada S. Nitric oxide synthesized from L-arginine regulates vascular tone in the coronary circulation of the rabbit. Br J Pharmacol. 1989 Aug;97(4):1119–1124. doi: 10.1111/j.1476-5381.1989.tb12569.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brain S. D., Williams T. J., Tippins J. R., Morris H. R., MacIntyre I. Calcitonin gene-related peptide is a potent vasodilator. Nature. 1985 Jan 3;313(5997):54–56. doi: 10.1038/313054a0. [DOI] [PubMed] [Google Scholar]
  3. Ekblad E., Ekelund M., Graffner H., Håkanson R., Sundler F. Peptide-containing nerve fibers in the stomach wall of rat and mouse. Gastroenterology. 1985 Jul;89(1):73–85. doi: 10.1016/0016-5085(85)90747-4. [DOI] [PubMed] [Google Scholar]
  4. Esplugues J. V., Whittle B. J. Close-arterial administration of the thromboxane mimetic U-46619 induces damage to the rat gastric mucosa. Prostaglandins. 1988 Feb;35(2):137–148. doi: 10.1016/0090-6980(88)90082-2. [DOI] [PubMed] [Google Scholar]
  5. Esplugues J. V., Whittle B. J., Moncada S. Local opioid-sensitive afferent sensory neurones in the modulation of gastric damage induced by Paf. Br J Pharmacol. 1989 Jun;97(2):579–585. doi: 10.1111/j.1476-5381.1989.tb11988.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Furchgott R. F. Role of endothelium in responses of vascular smooth muscle. Circ Res. 1983 Nov;53(5):557–573. doi: 10.1161/01.res.53.5.557. [DOI] [PubMed] [Google Scholar]
  7. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
  8. Green T., Dockray G. J. Characterization of the peptidergic afferent innervation of the stomach in the rat, mouse and guinea-pig. Neuroscience. 1988 Apr;25(1):181–193. doi: 10.1016/0306-4522(88)90017-6. [DOI] [PubMed] [Google Scholar]
  9. Guth P. H., Paulsen G., Nagata H. Histologic and microcirculatory changes in alcohol-induced gastric lesions in the rat: effect of prostaglandin cytoprotection. Gastroenterology. 1984 Nov;87(5):1083–1090. [PubMed] [Google Scholar]
  10. Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience. 1988 Mar;24(3):739–768. doi: 10.1016/0306-4522(88)90064-4. [DOI] [PubMed] [Google Scholar]
  11. Holzer P., Sametz W. Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons. Gastroenterology. 1986 Oct;91(4):975–981. doi: 10.1016/0016-5085(86)90702-x. [DOI] [PubMed] [Google Scholar]
  12. Ignarro L. J., Buga G. M., Wood K. S., Byrns R. E., Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9265–9269. doi: 10.1073/pnas.84.24.9265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kelm M., Feelisch M., Spahr R., Piper H. M., Noack E., Schrader J. Quantitative and kinetic characterization of nitric oxide and EDRF released from cultured endothelial cells. Biochem Biophys Res Commun. 1988 Jul 15;154(1):236–244. doi: 10.1016/0006-291x(88)90675-4. [DOI] [PubMed] [Google Scholar]
  14. Kitagawa H., Takeda F., Kohei H. Endothelium-dependent increases in rat gastric mucosal hemodynamics induced by acetylcholine and vagal stimulation. Eur J Pharmacol. 1987 Jan 6;133(1):57–63. doi: 10.1016/0014-2999(87)90205-6. [DOI] [PubMed] [Google Scholar]
  15. Martling C. R. Sensory nerves containing tachykinins and CGRP in the lower airways. Functional implications for bronchoconstriction, vasodilatation and protein extravasation. Acta Physiol Scand Suppl. 1987;563:1–57. [PubMed] [Google Scholar]
  16. McCall T. B., Boughton-Smith N. K., Palmer R. M., Whittle B. J., Moncada S. Synthesis of nitric oxide from L-arginine by neutrophils. Release and interaction with superoxide anion. Biochem J. 1989 Jul 1;261(1):293–296. doi: 10.1042/bj2610293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  19. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  20. Palmer R. M., Rees D. D., Ashton D. S., Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun. 1988 Jun 30;153(3):1251–1256. doi: 10.1016/s0006-291x(88)81362-7. [DOI] [PubMed] [Google Scholar]
  21. Patthy A., Bajusz S., Patthy L. Preparation and characterization of Ng-mono-, di- and trimethylated arginines. Acta Biochim Biophys Acad Sci Hung. 1977;12(3):191–196. [PubMed] [Google Scholar]
  22. Pique J. M., Whittle B. J., Esplugues J. V. The vasodilator role of endogenous nitric oxide in the rat gastric microcirculation. Eur J Pharmacol. 1989 Dec 19;174(2-3):293–296. doi: 10.1016/0014-2999(89)90324-5. [DOI] [PubMed] [Google Scholar]
  23. Rees D. D., Palmer R. M., Hodson H. F., Moncada S. A specific inhibitor of nitric oxide formation from L-arginine attenuates endothelium-dependent relaxation. Br J Pharmacol. 1989 Feb;96(2):418–424. doi: 10.1111/j.1476-5381.1989.tb11833.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rees D. D., Palmer R. M., Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci U S A. 1989 May;86(9):3375–3378. doi: 10.1073/pnas.86.9.3375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sharkey K. A., Williams R. G., Dockray G. J. Sensory substance P innervation of the stomach and pancreas. Demonstration of capsaicin-sensitive sensory neurons in the rat by combined immunohistochemistry and retrograde tracing. Gastroenterology. 1984 Oct;87(4):914–921. [PubMed] [Google Scholar]
  26. Szabo S., Trier J. S., Brown A., Schnoor J. Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat. Gastroenterology. 1985 Jan;88(1 Pt 2):228–236. doi: 10.1016/s0016-5085(85)80176-1. [DOI] [PubMed] [Google Scholar]
  27. Wallace J. L., Cirino G., De Nucci G., McKnight W., MacNaughton W. K. Endothelin has potent ulcerogenic and vasoconstrictor actions in the stomach. Am J Physiol. 1989 Apr;256(4 Pt 1):G661–G666. doi: 10.1152/ajpgi.1989.256.4.G661. [DOI] [PubMed] [Google Scholar]
  28. Whittle B. J., Esplugues J. V. Induction of rat gastric damage by the endothelium-derived peptide, endothelin. Br J Pharmacol. 1988 Dec;95(4):1011–1013. doi: 10.1111/j.1476-5381.1988.tb11733.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Whittle B. J., Kauffman G. L., Moncada S. Vasoconstriction with thromboxane A2 induces ulceration of the gastric mucosa. Nature. 1981 Jul 30;292(5822):472–474. doi: 10.1038/292472a0. [DOI] [PubMed] [Google Scholar]
  30. Whittle B. J., Lopez-Belmonte J., Rees D. D. Modulation of the vasodepressor actions of acetylcholine, bradykinin, substance P and endothelin in the rat by a specific inhibitor of nitric oxide formation. Br J Pharmacol. 1989 Oct;98(2):646–652. doi: 10.1111/j.1476-5381.1989.tb12639.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Whittle B. J. Mechanisms underlying gastric mucosal damage induced by indomethacin and bile-salts, and the actions of prostaglandins. Br J Pharmacol. 1977 Jul;60(3):455–460. doi: 10.1111/j.1476-5381.1977.tb07522.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Whittle B. J., Oren-Wolman N., Guth P. H. Gastric vasoconstrictor actions of leukotriene C4, PGF2 alpha, and thromboxane mimetic U-46619 on rat submucosal microcirculation in vivo. Am J Physiol. 1985 May;248(5 Pt 1):G580–G586. doi: 10.1152/ajpgi.1985.248.5.G580. [DOI] [PubMed] [Google Scholar]
  33. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K., Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988 Mar 31;332(6163):411–415. doi: 10.1038/332411a0. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES