title: Autoregulation of enterochromaffin-like cell histamine secretion via the histamine 3 receptor subtype.
abstract: BACKGROUND
  The neuroendocrine histamine-secreting cell of the gastric fundus, the enferochromaffin-like cell, is the principal regulator of parietal cell acid secretion. We have proposed that histamine may regulate its own synthesis and release via an autocrine mechanism. The purpose of this study was to evaluate the role of the histamine receptor subtypes H1, H2 and H3 in the regulation of this phenomenon.
  
  
  METHODS
  Purified ECL cells were isolated by pronase digestion and EDTA exposure of the rat stomach, followed by particle size and density separation using counterflow elutriation and Nycodenz gradient centrifugation, 24-hr cultured cells were pretreated for 30 min with the agents; H1 receptor agonist (2-[(3-trimethyl)-diphenyl] histamine) (TMPH), H1 receptor antagonist (terfenadine); H2 receptor agonist (dimaprit) or antagonist (cimetidine or loxitidine); or H3 receptor agonist (imetit) or antagonist (thioperamide) (all tested, 10(-10)-10(-6) M). Gastrin was then used to stimulate histamine secretion. Histamine secretion was quantified by specific enzyme-immunoassay.
  
  
  RESULTS
  Basal histamine secretion was 2.7 +/- 0.14 nmol/10(3) cells. Gastrin-stimulated (10 nM) levels were 4.6 +/- 0.4 nmol/10(3) cells (p < .01). TMPH inhibited both basal and gastrin driven histamine secretion with a maximal effect (34 percent) (1.78 +/- 0.08 nmol/10(3) cells) and an IC50 of > 5 x 10(-7) M. H1 receptor antagonism did not alter histamine secretion alone or in combination with gastrin. Neither H2 receptor stimulation nor antagonism had any effect on histamine secretion alone or in combination with gastrin. Gastrin-induced histamine secretion was dose-dependently inhibited by imetit (H3 agonist) with a maximal effect (2.4 +/- 0.6 nmol/10(3) cells) (p < .05) and an IC50 of 10(-9) M. Conversely, Thioperamide (H3 antagonist) dose-dependently augmented gastrin-stimulated histamine secretion with a maximum effect (5.7 +/- 0.5 nmol/10(3) cells) (p < .05) at 10(-8) M and an EC50 of 7 x 10(-10) M.
  
  
  CONCLUSIONS
  These data are consistent with the presence of an H3 receptor on the ECL cell which modulates gastrin-stimulated histamine secretion. Our observations support the proposal that a histamine-mediated short-loop autocrine regulatory mechanism of ECL cell secretion exists.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520-8062, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kidd
authors.forename: L H
authors.initials: LH
authors.lastname: Tang
authors.forename: K
authors.initials: K
authors.lastname: Miu
authors.forename: G P
authors.initials: GP
authors.lastname: Lawton
authors.forename: A
authors.initials: A
authors.lastname: Sandor
authors.forename: I M
authors.initials: IM
authors.lastname: Modlin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002927:Cimetidine / Q000494:pharmacology; D017259:Dimaprit / Q000494:pharmacology; D004759:Enterochromaffin Cells / Q000378:metabolism*; D005748:Gastric Fundus / Q000502:physiology; D005753:Gastric Mucosa / Q000378:metabolism; D006632:Histamine / Q000031:analogs & derivatives / Q000494:pharmacology; D006636:Histamine Release / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007124:Immunoenzyme Techniques; D051381:Rats; D011968:Receptors, Histamine / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D016593:Terfenadine / Q000494:pharmacology
chemical_list: C106481:2-((3-trimethyl)diphenyl)histamine; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D016593:Terfenadine; D002927:Cimetidine; D006632:Histamine; D017259:Dimaprit