Activation of the hypothalamo-hypophyseal-adrenocortical system as an important gastroprotective component of the stress reaction

  • L. P. Filaretova


This article presents an analysis of data providing evidence of the important contribution of the hypothalamo-hypophyseal-adrenocortical system (HHACS) to the processes maintaining the integrity of the gastric mucosa. According to these data, glucocorticoid hormones produced during stress-induced activation of the HHACS are gastroprotective hormones rather than ulcerogenic factors, as is widely believed. The gastroprotective influence of glucocorticoids has been demonstrated on exposure to ulcerogenic stimuli of different modalities. The gastroprotective action of glucocorticoid hormones is mediated via type II glucocorticoid receptors and may be associated with the maintenance of the blood glucose level, their calming effects on pathogenetic factors, and their favorable effects on protective factors for the gastric mucosa. Glucocorticoid hormones can compensate for the absence of the gastroprotective action of prostaglandins, nitric oxide, and capsaicin-sensitive neurons. The data lead to the conclusion that activation of the HHACS is an important gastroprotective component of the stress reaction.

Key words

hypothalamo-hypophyseal-adrenocortical system glucocorticoid hormones stress ulcerogenic stimuli gastric erosions and ulcers gastroprotection 


  1. 1.
    T. T. Podvigina, A. I. Bogdanov, and L. P. Filaretova, “The role of glucocorticoids in the healing of indomethacin-induced gastric mucous erosions in rats,” Ros. Fiziol. Zh. im. I. M. Sechenova, 86, No. 6, 720–727 (2000).Google Scholar
  2. 2.
    G. Sel’e, At the Level of the Whole Body [in Russian], Nauka, Moscow (1972).Google Scholar
  3. 3.
    A. A. Filaretov, T. T. Podvigina, and L.P. Filaretova, Adaptation as a Function of the Hypophyseal-Adrenocortical System (Monograph) [in Russian], Nauka, St. Petersburg (1994).Google Scholar
  4. 4.
    L. P. Filaretova, “The role of the paraventricular nucleus of the hypothalamus in the inhibition of the hypophyseal-adrenocortical system,” Dokl. Akad. Nauk., 273, No. 1, 247–250 (1983).Google Scholar
  5. 5.
    L. P. Filaretova, “Relationship between the formation of gastric stress ulcers and the state of the hypothalamo-hypophyseal-adrenocortical system,” Ros. Fiziol. Zh. im. I. M. Sechenova, 76, No. 11, 1594–1600 (1990).Google Scholar
  6. 6.
    L. P. Filaretova, “Gastric stress ulcers: the protective role of hypothalamo-hypophyseal-adrenocortical system hormones,” Ros. Fiziol. Zh. im. I. M. Sechenova, 81, No. 3, 52–62 (1995).Google Scholar
  7. 7.
    L. P. Filaretova, “Glucocorticoid hormones as important protective factors for the gastric mucosa,” in: St. Petersburg Fragments of the Scientific World View [in Russian], E. A. Ivanova, Yu. A. Petrosyan, and É. A. Tropp (eds.), St. Petersburg Scientific Center, Russian Academy of Sciences, St. Petersburg, No. 2, pp. 169–177 (2003).Google Scholar
  8. 8.
    L. P. Filaretova, “The role of endogenous glucocorticoids in maintaining the integrity of the gastric mucosa,” Ros. Fiziol. Zh. im. I. M. Sechenova, 86, No. 11, 1548–1558 (2000).Google Scholar
  9. 9.
    L. P. Filaretova and Yu. I. Levkovich, “The antiulcer effect of corticosteroids and the blood supply of the gastric mucosa,” Ros. Fiziol. Zh. im. I. M. Sechenova, 82, No. 2, 63–72 (1996).Google Scholar
  10. 10.
    L. P. Filaretova and A. A. Filaretov, “The effects of large doses of corticosteroids on ulcer formation in the stomach: a new hypothesis,” Ros. Fiziol. Zh. im. I. M. Sechenova, 78, No. 10, 77–83 (1992).Google Scholar
  11. 11.
    L. P. Filaretova, T. R. Bagaeva, T. T. Podvigina, and O. Yu. Morozova, “Deficiency of glucocorticoid production in rats increases the ulcerogenic effects of stimuli of different modalities and intensities,” Ros. Fiziol. Zh. im. I. M. Sechenova, 88, No. 5, 602–611 (2002).Google Scholar
  12. 12.
    L. P. Filaretova, T. R. Bagaeva, T. T. Podvigina, and O. Yu. Morozova, “Deficiency of glucocorticoid production slows the healing of acute erosions and chronic ulcers of the gastric mucosa in rats,” Ros. Fiziol. Zh. im. I. M. Sechenova, 89, No. 9, 1137–1146 (2003).Google Scholar
  13. 13.
    H. E. Black, “The effects of steroids upon the gastrointestinal tract,” Toxicol. Pathol., 16, No. 2, 213–222 (1988).PubMedCrossRefGoogle Scholar
  14. 14.
    A. Dembinski, Z. Warzecha, P. Ceranowicz, T. Brzozowski, M. Dembinski, S. J. Konturek, and W. W. Pawlik, “Role of capsaicin-sensitive nerves and histamine H1, H2, and H3 receptors in the gastroprotective effect of histamine against stress ulcers in rats,” Eur. J. Pharmacol., 508, No. 1–3, 211–221 (2004).PubMedGoogle Scholar
  15. 15.
    K. Ehrlich, C. Sicking, M. Respondek, and B. Peskar, “Interaction of cyclooxygenase isoenzymes, nitric oxide, and afferent neurons in gastric mucosal defence in rats,” J. Pharmacol. Exptl. Ther., 256, No. 1, 441–447 (2004).Google Scholar
  16. 16.
    A. A. Filaretov and L. P. Filaretova, “Role of the paraventricular and ventromedial hypothalamic nuclear areas in the regulation of the pituitary-adrenocortical system,” Brain Res., 342, No. 1, 135–140 (1985).PubMedCrossRefGoogle Scholar
  17. 17.
    L. P. Filaretova, “The hypothalamic-pituitary-adrenocortical system: hormonal brain-gut interaction and gastroprotection,” Autonom. Neurosci. (2005) (in press).Google Scholar
  18. 18.
    L. P. Filaretova, T. R. Bagaeva, and G. B. Makara, “Aggravation of nonsteroidal antiinflammatory drug gastropathy by glucocorticoid deficiency or blockade of glucocorticoid receptor in rats,” Life Sci., 71, No. 21, 2457–2468 (2002).PubMedCrossRefGoogle Scholar
  19. 19.
    L. P. Filaretova, T. R. Bagaeva, and T. T. Podvigina, “Role of endogenous glucocorticoids in the healing of gastric erosions and chronic gastric ulcers in rats,” Inflammopharmacology, 10, No. 4–6, 401–412 (2002).CrossRefGoogle Scholar
  20. 20.
    L. P. Filaretova, A. A. Filaretov, and G. B. Makara, “Corticosterone increase inhibits stress-induced gastric erosions in rats,” Amer. J. Physiol., 274, No. 37, G1024–G1030 (1998).Google Scholar
  21. 21.
    L. P. Filaretova, T. R. Bagaeva, T. T. Podvigina, and G. B. Makara, “Various ulcerogenic stimuli are potentiated by glucocorticoid deficiency in rat,” J. Physiol. (Paris), 95, No. 1–6, 59–65 (2001).CrossRefGoogle Scholar
  22. 22.
    L. P. Filaretova, A. N. Maltcev, A. I. Bogdanov, and A. I. Levkovich, “Role of gastric microcirculation in the gastroprotection by glucocorticoids released during water-restraint stress in rats,” Clin. J. Physiol., 42, No. 3, 145–152 (1999).Google Scholar
  23. 23.
    L. P. Filaretova, T. T. Podvigina, T. R. Bagaeva, and G. B. Makara, “Gastroprotective action of glucocorticoids during the formation and the healing of indomethacin-induced gastric erosions in rats,” J. Physiol. (Paris), 95, No. 1–6, 201–208 (2001).CrossRefGoogle Scholar
  24. 24.
    L. Filaretova, A. Tanaka, S. Kato, and K. Takeuchi, “The mechanisms of gastroprotective action of glucocorticoids against indomethacin-induced gastric mucosal injury,” Ulcer Res. (Japan), 29, No. 2, 159–162 (2002).Google Scholar
  25. 25.
    L. Filaretova, A. Tanaka, Y. Komoike, and K. Takeuchi, “Selective cyclooxygenase-2_inhibitor induces gastric mucosal damage in adrenalectomized rats,” Inflammopharmacology, 10, No. 4–6, 413–422 (2002).CrossRefGoogle Scholar
  26. 26.
    L. Filaretova, P. Bobryshev, T. Bagaeva, T. Podvigina, and K. Takeuchi, “Compensatory role of glucocorticoid hormones in gastric mucosal defense under inhibition of prostaglandin and nitric oxide production or desensitization of capsaicin-sensitive afferent neurons in rats,” Gastroenterology, 128, No. 4, Supplement 2, A–343 (2005).Google Scholar
  27. 27.
    L. P. Filaretova, T. T. Podvigina, T. R. Bagaeva, G. Makara, and K. Tekeuchi, “Hormonal mechanisms of gastroprotection: Role of the hypothalamic-pituitary-adrenocortical axis,” in: Mediators in Gastrointestinal Protection and Repair, K. Takeuchi and G. Mozsik (eds.), Res. Signpost, Kerala (2004), pp. 17–41.Google Scholar
  28. 28.
    L. P. Filaretova, T. T. Podvigina, T. R. Bagaeva, A. Tanaka, and K. Takeuchi, “Mechanisms underlying gastroprotective action of glucocorticoids released in response to ulcerogenic stress factors,” Ann. N.Y. Acad. Sci., 1018, No. 1–5, 288–293 (2004).PubMedCrossRefGoogle Scholar
  29. 29.
    L. P. Filaretova, T. T. Podvigina, T. R. Bagaeva, A. Tanaka, and K. Takeuchi, “Gastroprotective action of glucocorticoid hormones during NSAID treatment,” Inflammopharmacology, 13, No. 1–3, 27–43 (2005).PubMedCrossRefGoogle Scholar
  30. 30.
    L. Filaretova, A. Tanaka, S. Kato, T. Miyazawa, and K. Takeuchi, “Mechanisms underlying protective action of endogenous glucocorticoids against indomethacin induced gastric injury in rats,” Amer. J. Physiol., 283, No. 5, G1082–G1089 102.Google Scholar
  31. 31.
    L. Filaretova, T. Podvigina, T. Bagaeva, P. Bobryshev, A. Tanaka, and K. Takeuchi, “Cooperative interaction between glucocorticoids and prostaglandins in gastroprotection,” in: International Proceedings of the llth International Conference on Ulcer Research, P. Sikiric (ed.), Monduzzi, Italy (2003), pp. 169–173.Google Scholar
  32. 32.
    S. J. Gray, C. Ramsey, R. W. Reifenstein, and J. A. Benson, “The significance of hormonal factors in the pathogenesis of peptic ulcer,” Gastroenterology, 25, No. 2, 156–172 (1953).PubMedGoogle Scholar
  33. 33.
    K. Gyires, “Gastric mucosal protection: from prostaglandins to gene therapy,” Curr. Med. Chem., 12, No. 2, 203–215 (2005).PubMedGoogle Scholar
  34. 34.
    C. J. Hawkey, “Nonsteroidal anti-inflammatory drug gastropathy,” Gastroenterology, 119, No. 2, 521–535 (2000).PubMedCrossRefGoogle Scholar
  35. 35.
    P. Holzer, “Neural emergency system in the stomach,” Gastroenterology, 114, No. 4, 823–839 (1998).PubMedCrossRefGoogle Scholar
  36. 36.
    F. Lechin, B. van der Dijs, I. Rada, J. Jara, A. E. Lechin, A. Cabrera, M. E. Lechin, C. Jimenez, F. Gomez, and S. Villa, “Plasma neurotransmitters and cortisol in duodenal ulcer patients. Role of stress,” Dig. Dis. Sci., 35, No. 11, 1313–1319 (1990).PubMedCrossRefGoogle Scholar
  37. 37.
    R. Murison, J. B. Overmier, D. H. Hellhammer, and M. Carmona, “Hypothalamo-pituitary-adrenal manipulations and stress ulcerations in rats,” Psychoneuroendocrinology, 14, No. 5, 331–338 (1989).PubMedCrossRefGoogle Scholar
  38. 38.
    H. M. Murphy, C. H. Wideman, and T. S. Brown, “Plasma corticosterone levels and ulcer formation in rats with hippocampal lesions,” Neuroendocrinology, 28, No. 2, 123–130 (1979).PubMedGoogle Scholar
  39. 39.
    M. Perretti, K. G. Mugridge, J. L. Wallace, and L. Parente, “Reduction of aspirin-induced gastric damage in rats by interleukin-1 beta: possible involvement of endogenous corticosteroids,” J. Pharmacol. Exptl. Ther., 261, No. 3, 1238–1247 (1992).Google Scholar
  40. 40.
    D. J. Sandweiss, “Effects of adrenocorticotrophic hormone (ACTH) and of cortisone on peptic ulcer. I. Clinical review,” Gastroenterology, 27, No. 5, 604–616 (1954).PubMedGoogle Scholar
  41. 41.
    M. J. Spirt, “Stress-related mucosal disease: Risk factors and prophylactic therapy,” Clin. Ther., 26, No. 2, 197–213 (2004).PubMedCrossRefGoogle Scholar
  42. 42.
    N. Stollman and D. C. Metz, “Pathophysiology and prophylaxis of stress ulcer in intensive care unit patients,” J. Crit. Care, 20, No. 1, 35–45 (2005).PubMedCrossRefGoogle Scholar
  43. 43.
    S. Szabo, G. T. Gallagher, H. C. Horner, P. W. Frankel, R. H. Underwood, S. J. Konturek, T. Brzozowski, and J. S. Trier, “Role of the adrenal cortex in gastric mucosal protection by prostaglandins, sulfhydryls, and cimetidine in the rat,” Gastroenterology, 85, No. 6, 1384–1390 (1983).PubMedGoogle Scholar
  44. 44.
    K. Takeuchi, A. Tanaka, K. Suzuki, and H. Mizoguchi, “Gastrointestinal sparing anti-inflammatory drugs-effects on ulcerogenic and healing responses,” Curr. Pharm. Des., 7, 49–69 (2001).PubMedCrossRefGoogle Scholar
  45. 45.
    J. R. Vane, “Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs, ” Nat New Biol., 231, No. 25, 232–235 (1971).PubMedGoogle Scholar
  46. 46.
    J. R. Vane and R. M. Botting, “The mechanism of action of aspirin,” Thromb. Res., 110, No. 5–6, 255–258 (2003).PubMedCrossRefGoogle Scholar
  47. 47.
    J. L. Wallace, “Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years, ” Gastroenterology, 112, No. 3, 1000–1016 (1997).PubMedCrossRefGoogle Scholar
  48. 48.
    J. M. Weiss, “Effects of coping behavior in different warning signal conditions on stress pathology in rats,” J. Comp. Physiol. Psychol., 77, No. 1, 1–13 (1971).PubMedCrossRefGoogle Scholar
  49. 49.
    B. L. Weusten, J. W. Jacobs, and J. M. Bijlsma, “Corticosteroid pulse therapy in active rheumatoid arthritis,” Semin. Arthr. Rheum., 23, No. 3, 183–192 (1993).CrossRefGoogle Scholar
  50. 50.
    B. J. R. Whittle, J. Lopez-Belmonte, and S. Moncada, “Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat,” Brit. J. Pharmacol., 99, No. 3, 606–611 (1990).Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2007

Authors and Affiliations

  • L. P. Filaretova
    • 1
  1. 1.I. P. Pavlov Institute of PhysiologyLaboratory for Experimental EndocrinologySt. PetersburgRussia

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