Involvement of gastrin in gastric secretory and protective actions of N-alpha-methyl histamine.
N alpha-methylhistamine (N alpha-MH) is one of an unusual metabolite of histamine that was found in Helicobacter pylori-infected stomachs and is believed to interact with specific histamine H(1), H(2) and H(3)-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 exogenous N alpha-MH with that of standard histamine on gastric secretion and plasma gastrin levels in rats equipped with gastric fistula (series A); and (2) to assess the action of N alpha-MH on gastric lesions induced by 100% ethanol (series B) in rats with or without removal of antral portion of the stomach (antrectomy). Rats of series B were pretreated intragastrically (i.g.) or intraperitoneally (i.p.) with N alpha-MH or histamine (0.1-2 mg/kg) 30 min prior to 100% ethanol (1.5 ml, i.g.) with or without: (1) vehicle (saline); (2) RPR 102681 (30 mg/kg i.p.), to block CCK-B/gastrin receptors; and (3) ranitidine (40 mg/kg s.c.) to inhibit histamine H(2)-receptors. The area of gastric lesions was determined planimetrically, gastric blood flow (GBF) was assessed by H(2)-gas clearance method and venous blood was collected for determination of plasma gastrin levels by radioimmunoassay (RIA). N alpha-MH and histamine dose-dependently increased gastric acid output (series A); the dose increasing this secretion by 50% (ED(50)) being 2 and 5 mg/kg i.g or i.p., respectively, and this effect was accompanied by a significant rise in plasma gastrin levels. Both, N alpha-MH and histamine attenuated dose-dependently the area of gastric lesions induced by 100% ethanol (series B) while producing significant rise in the GBF and plasma immunoreactive gastrin increments. These secretory, protective, hipergastrinemic and hyperemic effects of N alpha-MH and histamine were completely abolished by antrectomy, whereas pretreatment with RPR 102681 attenuated significantly the N alpha-MH and histamine-induced protection against ethanol damage and accompanying hyperemia. Ranitidine, that produced achlorhydria and a further increase in plasma gastrin levels, failed to influence the N alpha-MH- and histamine-induced protection and accompanying rise in the GBF. We conclude that (1) N alpha-MH stimulates gastric acid secretion and exhibit gastroprotective activity against acid-independent noxious agents in the manner similar to that afforded by histamine; and (2) this protection involves an enhancement in the gastric microcirculation and release of gastrin acting via specific CCK-B/gastrin receptors but unexpectedly, appears to be unrelated to histamine H(2)-receptors.
Brzozowski
T
T
Department of Physiology, Jagiellonian University School of Medicine, ul. Grzegorzecka 16, 31-531 Cracow, Poland.
Konturek
P C
PC
Konturek
S J
SJ
Kwiecień
S
S
Pajdo
R
R
Drozdowicz
D
D
Ptak
A
A
Pawlik
M
M
Hahn
E G
EG
D000818:Animals; D019610:Cytoprotection / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D006632:Histamine / Q000494:pharmacology; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology*; D011706:Pyloric Antrum / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013270:Stomach / Q000098:blood supply / Q000187:drug effects / Q000473:pathology
D005755:Gastrins; D008761:Methylhistamines; D000431:Ethanol; C069357:alpha-methylhistamine; D006632:Histamine