Effect of central and peripheral actions of histamine and its metabolite N-alpha methyl histamine on gastric secretion and acute gastric lesions.
N alpha-methylhistamine (N alpha-MH) is one of unusual metabolite of histamine that was found in Helicobacter pylori-infected stomach and is believed to interact with specific histamine H1, H2 and H3-receptors to stimulate gastric acid secretion and gastrin release from isolated G-cells but the effects of N alpha-MH on gastric mucosal integrity have been little studied. This study was designed; 1) to compare the effect of intraperitoneal (i.p.), intracerebroventricular (i.c.v.) and gastric topical (intragastric i.g.) application of exogenous N alpha-MH with that of standard histamine on gastric secretion in rats equipped with gastric fistula (series A) and 2) to compare the effect of i.c.v. administration of histamine and N alpha-MH with that of peripheral (i.p. and i.g.) application of these amines on gastric lesions induced by 100% ethanol (series B) in rats with or without capsaicin-induced deactivation of sensory nerves. The area of gastric lesions was determined planimetrically, gastric blood flow (GBF) was assessed by H2-gas clearance method and venous blood was collected for determination of plasma gastrin levels by RIA. N alpha-MH and histamine (0.1-10 mg/kg i.p. or i.g.) dose-dependently increased gastric acid output (series A); whereas i.c.v. administration of histamine or N alpha-MH inhibited dose-dependently this secretion; the dose attenuating gastric acid output by 50% (ED50) being 4 and 6 microg/kg i.c.v. Both, N alpha-MH and histamine (2 mg/kg i.p. and i.g.) attenuated significantly the area of gastric lesions induced by 100% ethanol (series B) while producing significant rise in the GBF and plasma immunoreactive gastrin increments. Central application of N alpha-MH and histamine (0.01-5 microg/kg i.c.v.) inhibited ethanol-induced gastric damage whereas higher doses ranging from 10-100 microg/kg of histamine and N alpha-MH were significantly less effective. Capsaicin-induced deactivation of sensory nerves by itself augmented significantly ethanol damage and attenuated significantly the protective and hyperemic effects of histamine and its methylated analog applied i.p. but failed to affect significantly those caused by i.c.v. administration of these amines. We concluded that: 1) central histamine and N alpha-MH inhibits gastric acid secretion and exhibits gastroprotective activity against ethanol in similar manner to that afforded by parenteral and topical histamine and N-alphaMH, 2) central N-alphaMH- and histamine-induced protection involve the enhancement in gastric microcirculation unrelated to neuropeptides released from capsaicin-sensitive afferent nerves, and 3) the major difference between central and peripheral histamine and its methylated analog is the influence on gastric acid secretion which does not appear to play any major role in gastroprotective activity of these agents.
Kwiecień
S
S
Department of Physiology, Jagiellonian University School of Medicine, Cracow, Poland.
Brzozowski
T
T
Konturek
P C
PC
Konturek
S J
SJ
Pawlik
M
M
Pajdo
R
R
Drozdowicz
D
D
Ptak
A
A
Hahn
E G
EG
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D019610:Cytoprotection; D004759:Enterochromaffin Cells / Q000502:physiology; D000431:Ethanol / Q000633:toxicity; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D008761:Methylhistamines / Q000008:administration & dosage / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000502:physiology; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects
D008761:Methylhistamines; D000431:Ethanol; C069357:alpha-methylhistamine; D006632:Histamine