Skip to main content
SpringerLink
Log in

Histamine as an intermediate growth factor in genesis of gastric ECLomas associated with hypergastrinemia in mastomys

  • Original Articles
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Profound and sustained inhibition of gastric acid secretion has been associated with development of carcinoid tumors of the fundic enterochromaffin-like (ECL) cells in rodents. While ECL cell hyperplasia has been recognized in humans, the development of carcinoid tumors is rare and often confined to patients under treatment for gastrinoma related to the multiple endocrine neoplasia type I (MEN1) syndrome. The Mastomys was utilized as a model for the rapid induction of ECLomas by insurmountable acid secretory blockade induced by the pharmacologically irreversible H2-receptor antagonist, loxtidine. Loxtidine-induced ECL cell hyperplasia and neoplasia were compared in the absence of presence of cyproheptadine (0.5 mg/kg), an H1-receptor antagonist. Loxtidine administration resulted in a significant increase in ECL cell hyperplasia and neoplasia as well as an increase in ECL cell number, mucosal thickness, plasma gastrin levels, and stomach weight. Cyproheptadine ameliorated loxtidine-induced ECL cell hyperplasia and neoplasia and significantly decreased loxtidine-stimulated increases in ECL cell number. Nevertheless, cyproheptadine failed to alter the loxtid-ineinduced increase in plasma gastrin, stomach weight or mucosal height. The results indicate that cyproheptadine, an H1-receptor antagonist, inhibits loxtidine-induced ECL cell hyperplasia independent of any effects on serum gastrin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Soybel DI, Modlin IM: Implications of sustained suppression of gastric acid secretion. Am J Surg 163:613–622, 1992

    Google Scholar 

  2. Bilchik AJ, Nilsson O, Modlin IM, Sussman J, Zucker KA, Adrian TE: H2-receptor blockade induces peptide YY and enteroglucagon secreting gastric carcinoids in Mastomys. Surgery 106:1119–1127, 1989

    Google Scholar 

  3. Mattson H, Havu N, Brautigan J, Carlsson K, Lundell L, Carlsson E: Partial corpectomy results in hypergastrinemia and development of gastric enterochromaffin cell carcinoids in the rat. Gastroenterology 100:311–319, 1991

    Google Scholar 

  4. Havu N: Enterochromaffin-like cell carcinoids of gastric mucosa in rats after long-term inhibition of gastric secretion. Digestion 35:42–55, 1986

    Google Scholar 

  5. Creutzfeldt W: The achlorhydria-carcinoid sequence: Role of gastrin. Digestion 39:61–79, 1988

    Google Scholar 

  6. Eissele R, Patberg H, Koop H, Krack W, Lorenz W, McNight AT, Arnold R: Effect of gastrin receptor blockade on endocrine cells in rats during achlorhydria. Gastroenterology 103:1596–1601, 1992

    Google Scholar 

  7. Tielemans Y, Willems G: Cellular kinetics in the oxyntic mucosa of the rat with special reference to the enterochrommaffin-like (ECL) cells: Influences of circulating gastrin. Res Clin Forums 12:81–92, 1990

    Google Scholar 

  8. Borch K, Renvall H, Liedberg G: Gastric endocrine cell hyperplasia and carcinoid tumors in pernicious anemia. Gastroenterology 88:638–648, 1985

    Google Scholar 

  9. Carney JA, Go VLW, Fairbanks VF: The syndrome of gastric argyrophil carcinoid tumors and nonantral gastric atrophy. Ann Intern Med 99:761–766, 1983

    Google Scholar 

  10. Rubin W, Schwartz B: Electronmicroscopic radioautographic identification of the ECL cell as the histamine-synthesizing endocrine cell of the rat stomach. Gastroenterology 77:458–467, 1979

    Google Scholar 

  11. Soll AH: Secretagogue stimulation of14C-aminopyrine accumulation by isolated canine parietal cells. Am J Physiol 238:G366-G375, 1980

    Google Scholar 

  12. Ander F, Ander C, Cavagna S: Role of histamine in the cell turnover change associated with gastric ulceration in the Mastomys. Gastroenterology 88:452–457, 1985

    Google Scholar 

  13. Johnson CL, Johnson CG, Bazan E, Garver D, Gruenstein E, Ahluwalia M: Histamine receptors in human fibroblasts: inositol phosphates, Ca2+, and cell growth. Am J Physiol 258:C533-C543, 1990

    Google Scholar 

  14. Tilly BC, Tertoolen LG, Remorie R, Ladoux A, Verlaan I, de Laat SW, Moolenaar WH: Histamine as a growth factor and chomoattractant for human carcinoma and melanoma cells: action through Ca2+ mobilizing H1 receptors. J Cell Biol 110:1211–1215, 1990

    Google Scholar 

  15. Ekblad EBM: Histamine: The sole mediator of pentagastrinstimulated acid secretion. Acta Physiol Scand 125:135–143, 1985

    Google Scholar 

  16. Sandvik AK, Lewin MJM, Waldum HL: Histamine release in the isolated vascularly perfused stomach of the rat: Regulation by autoreceptors. Br J Pharmacol 96:557–562, 1989

    Google Scholar 

  17. Sandvik AK, Waldum HL: CCK-B (gastrin) receptor regulates gastric histamine release and acid secretion. Am J Physiol 260:G925-G928, 1991

    Google Scholar 

  18. Feldman M, Burton ME: Histamine2-receptor antagonists. Standard therapy for acid-peptic diseases. N Engl J Med 323:1672–1680, 1990

    Google Scholar 

  19. Hakanson R, Larsson LI, Liedberg G, Oscarsson J, Sundler F: Effects of antrectomy or portocaval shunting on the histamine storing endocrine-like cells in the oxyntic mucosa of rat stomach. J Physiol (London) 259:785–800, 1976

    Google Scholar 

  20. Hakanson R, Sundler F: Proposed mechanism of gastric carcinoids: The gastrin hypothesis. Eur J Clin Invest 20:S65-S71, 1990

    Google Scholar 

  21. Tielemans Y, Axelson J, Sundler F, Willems G, Hakanson R: Serum gastrin concentration affects the self-replication rate of the enterochromaffin cell in the rat stomach. Gut 31:274–278, 1990

    Google Scholar 

  22. Soga J, Tazawa K, Kanahara H, Hiraide H: Some characteristic features of spontaneous argyrophil carcinoids in glandular stomach ofPraomys (Mastomys) natalensis. Gann Monogr 8:15–38, 1969

    Google Scholar 

  23. Hosoda S, Nakamura W, Snell KC, Stewart HL: Histamine production by transplantable argyrophilic carcinoid ofPraomys (Mastomys) natalensis. Science 170:454–455, 1970

    Google Scholar 

  24. Modlin IM, Zucker KA, Zdon MJ, Sussman J, Adrian TE: Characteristics of the spontaneous gastric endocrine tumor of Mastomys. J Surg Res 44:205–215, 1988

    Google Scholar 

  25. Bilchik AJ, Nilsson O, Modlin IM, Zucker KA, Adrian TE: Significance of gastric endocrine tumor and age-related gut peptide alterations in Mastomys. Regul Pept 27:195–207, 1990

    Google Scholar 

  26. Modlin IM, Bilchik AJ, Nilsson O, Goldenring JR: Enterochromaffin-like cell tumor induction in Mastomys by insurmountable H2 receptor blockade. Res Clin Forums 12:59–74, 1989

    Google Scholar 

  27. Larsson H, Carlsson E, Hakanson R, Mattson H, Nilsson G, Seensalu R, Wallmark B, Sundler F: Time course of development and reversal of gastric endocrine cell hyperplasia after inhibition of acid secretion. Gastroenterology 95:1447–1458, 1988

    Google Scholar 

  28. Lehy T, Mignon M, Cadiot G, Elouaer-Blanc L, Ruszniewski P, Lewin MJM, Bonfils S: Gastric endocrine cell behavior in Zollinger-Ellison patients upon long-term potent antisecretory treatment. Gastroenterology 96:1029–1040, 1989

    Google Scholar 

  29. Lehy T, Cadiot M, Ruszniewski P, Bonfils S: Influence of multiple endocrine neoplasia type I on gastric endocrine cell in patients with Zollinger-Ellison syndrome. Gut 33:1275–1279, 1992

    Google Scholar 

  30. Modlin IM, Kumar R, Soroka CJ, Pasikhov D, Nangia A, Goldenring JR: Gastrin-dependent inhibitory effects of octreotide on the genesis of gastric ECLomas. Surgery 1992

  31. Woodward JK: Pharmacology of antihistamines. J Allergy Clin Immunol 86:606–612, 1990

    Google Scholar 

  32. Hosoda S, Saito T, Kumazawa H, Watanabe T, Wada H: Marked inhibition of histamine formation in transplantable histamine-producing gastric carcinoid of Mastomys natalensis by (S)-a-fluoromethylhistidine and its potent antiulcer effect on tumor-bearing hosts. Biochem Pharmacol 34:4327–4329, 1985

    Google Scholar 

  33. Chow SA, Fischer L: Postnatal changes in the insulindepleting action and disposition of cyproheptadine in rats. Dev Pharmacol Ther 16:150–163, 1991

    Google Scholar 

  34. Miller CP, Giddings SJ, Chatterjee AK, Fischer LJ: Rapid alteration of pancreatic proinsulin and preproinsulin messenger ribonucleic acid in rats treated with cyproheptadine. Endocrinology 128:3040–3046, 1991

    Google Scholar 

  35. Longnecker DS, Wold JS, Fischer LJ: Ultrastructural study of alterations in beta cells of pancreatic islets from cyproheptadine-treated rats. Diabetes 21:71–79, 1972

    Google Scholar 

  36. Leitner SP, Greenberg P, Daniel LA, Michaelson RA: Partial remission of carcinoid tumor in response to cyproheptadine. Ann Intern Med 111:760–761, 1989

    Google Scholar 

  37. Harris AL, Smith IE: Regression of carcinoid tumor with cyproheptadine. Br J Med 285–475, 1982

Download references

Author information

Author notes

  1. James R. Goldenring MD, PhD

    Present address: Institute for Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, 30912, Augusta, Georgia

Authors and Affiliations

  1. From the Gastrointestinal Surgical Pathobiology Research Group, Department of Surgery, Yale University School of Medicine, 06510, New Haven, Connecticut

    Irvin M. Modlin MD, PhD, Ravin R. Kumar MD, Carol J. Soroka PhD, Hakan Ahlman MD, PhD, Ola Nilsson MD, PhD &  James R. Goldenring MD, PhD

  2. the West Haven Department of Veterans Affairs Medical Center, 06510, New Haven, Connecticut

    Irvin M. Modlin MD, PhD, Ravin R. Kumar MD, Carol J. Soroka PhD, Hakan Ahlman MD, PhD, Ola Nilsson MD, PhD &  James R. Goldenring MD, PhD

  3. the Department of Surgery, University of Goteborg, Sweden

    Irvin M. Modlin MD, PhD, Ravin R. Kumar MD, Carol J. Soroka PhD, Hakan Ahlman MD, PhD, Ola Nilsson MD, PhD &  James R. Goldenring MD, PhD

  4. Institute for Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, 30912, Augusta, Georgia

    Irvin M. Modlin MD, PhD

Authors
  1. Irvin M. Modlin MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ravin R. Kumar MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carol J. Soroka PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hakan Ahlman MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ola Nilsson MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James R. Goldenring MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Modlin, I.M., Kumar, R.R., Soroka, C.J. et al. Histamine as an intermediate growth factor in genesis of gastric ECLomas associated with hypergastrinemia in mastomys. Digest Dis Sci 39, 1446–1453 (1994). https://doi.org/10.1007/BF02088047

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02088047

Key words

Search

Navigation