Induction of gastric histamine synthesis by H2-receptor antagonists: potentiation of their antisecretory activity by histidine decarboxylase inhibitors.
The activation of histamine (HA) formation in rat stomach was measured after repeated administration of histamine H2-receptor antagonists and the potentiation of their antisecretory activity was examined in histidine decarboxylase inhibitor (HDI)-pretreated rats. 40 mg/kg of metiamide, given intraperitoneally (i.p.) 24, 16 and 2 h prior to the examination, produced approximately 50% increase in the amount of 14C-histamine, formed from 14C-histidine in the stomach, and an almost equal enhancement in the gastric histidine decarboxylase (HD) activity. An equal dose of the compound did not influence the endogenous histamine level in the glandular stomach whereas it caused a significant increase in the serum histamine content. By similar treatment, 10 mg/kg of cimetidine enhanced the newly formed histamine in the rat stomach by 57%. The potent HDI, 2-hydroxy-5-carbomethoxy-benzyloxyamine (GYKI-11 121) suppressed the metiamide- and cimetidine-induced increases in histamine synthesis to slightly above or below the control values. In pharmacological studies, the antisecretory activity of histamine H2-receptor blockers could markedly be potentiated by HDI. In GYKI-11 121 and NSD-1055-pretreated rats, the inhibiting potency of metiamide and cimetidine on pentagastrin-stimulated gastric acid secretion, increased to approximately twice that of the original effect. Neither GYKI-11 121 nor NSD-1055 produced significant inhibition on pentagastrin-stimulated gastric acid secretion in the applied doses. These findings provided evidence for the feedback stimulation of gastric HA synthesis by H2-receptor blockers and confirmed the role of HA in the gastric acid secretion. Potentiation of the antisecretory activity of H2-receptor antagonists by HDI would be useful in the therapeutic application of these compounds.
D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D002927:Cimetidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D006632:Histamine / Q000096:biosynthesis*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors*; D008297:Male; D008785:Metiamide / Q000494:pharmacology; D010418:Pentagastrin / Q000494:pharmacology; D051381:Rats
D006635:Histamine H2 Antagonists; D008785:Metiamide; D002927:Cimetidine; D006632:Histamine; D002262:Carboxy-Lyases; D006640:Histidine Decarboxylase; D010418:Pentagastrin