alpha-fluoromethylhistidine depletes histamine from secreting but not from non-secreting rat stomach ECL cells.
Histamine in the oxyntic mucosa of the rat stomach occurs in mast cells (10%) and ECL cells (90%). Unlike the mast cells, the ECL cells operate under the control of gastrin. alpha-Fluoromethylhistidine, an irreversible inhibitor of the histamine-forming enzyme, histidine decarboxylase depletes ECL-cell but not mast-cell histamine. This report shows that the effectiveness by which histidine decarboxylase inhibition depletes ECL-cell histamine depends on the rate of histamine secretion. Rats received alpha-fluoromethylhistidine by continuous subcutaneous infusion for 24 h. Maximally effective doses (>/=3 mg/kg/h) inhibited histidine decarboxylase and reduced oxyntic mucosal histamine in fed rats by 80-90%. In fasted rats, the reduction was 50%. alpha-Fluoromethylhistidine greatly reduced the number of histamine-immunoreactive ECL cells (immunocytochemistry) and of secretory vesicles in the ECL cells (electron microscopy) in fed but not in fasted rats. The half-life of oxyntic mucosal histamine (determined upon histidine decarboxylase inhibition) was 2.6 h in fed rats and 19.4 h in fasted rats. The amount of histamine secreted in response to gastrin (monitored by gastric submucosal microdialysis) was greatly reduced by alpha-fluoromethylhistidine in fed rats but not in fasted rats. ECL cells were isolated from rat stomach by elutriation (80% purity). Their histamine content was determined after culture, with or without alpha-fluoromethylhistidine, in the presence of varying concentrations of gastrin. In a medium containing 10 nM gastrin, ECL cells responded to a maximally effective concentration of alpha-fluoromethylhistidine (0.1 nM) with 80% reduction in histamine content. In the absence of gastrin, ECL cells responded to alpha-fluoromethylhistidine with 45% reduction of histamine; the releasable histamine pool was unaffected. In conclusion, the combination of histidine decarboxylase inhibition and a high rate of histamine secretion will promptly exhaust the ECL-cell histamine pool, while histidine decarboxylase inhibition and a low secretion rate will affect the histamine pool much less.
Norlén
P
P
Department of Pharmacology, Institute of Physiological Sciences, University of Lund, Lund, Sweden.
Lindström
E
E
Zhao
C
C
Kitano
M
M
Chen
D
D
Andersson
K
K
Håkanson
R
R
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors*; D008297:Male; D008762:Methylhistidines / Q000494:pharmacology*; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D008762:Methylhistidines; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D006640:Histidine Decarboxylase