Pharmacological control of the human gastric histamine H2 receptor by famotidine: comparison with H₁, H₂ and H₃ receptor agonists and antagonists

Abstract

Histamine 0.1 microM-0.1 mM increased adenylate cyclase activity five- to ten-fold in human fundic membranes, with a potency Ka = 3 microM. The histamine dose-response curve was mimicked by the H3 receptor agonist (R) alpha-MeHA, but at 100 times lower potency, Ka = 0.3 mM. Histamine-induced adenylate cyclase activation was abolished by H2, H1 and H3 receptor antagonists, according to the following order of potency IC50: famotidine (0.3 microM) greater than triprolidine (0.1 mM) thioperamide (2 mM), respectively. Famotidine has no action on membrane components activating the adenylate cyclase system, including the Gs subunit of the enzyme stimulated by forskolin and cell surface receptors sensitive to isoproterenol (beta 2-type), PGE2 and VIP. The Schild plot was linear for famotidine (P less than 0.01) with a regression coefficient r = 0.678. The slope of the regression line was 0.64 and differs from unity. Accordingly, famotidine showed a slow onset of inhibition and dissociation from the H2 receptor in human cancerous HGT-1 cells. The results demonstrate that famotidine is a potent and selective H2 receptor antagonist with uncompetitive actions in human gastric mucosa. Consequently, famotidine might be a suitable drug with long-lasting actions in the treatment of Zollinger-Ellison syndrome. The results also confirm and extend the previous observations that (R) alpha-MeHA and thioperamide are two selective ligands at histamine H3 receptor sites. In the human gastric mucosa, these drugs are respectively 330 and 6700 times less potent than histamine and famotidine on the adenylate cyclase system. The possible involvement of histamine H3 receptors in the regulation of gastric secretion is proposed.

Histamine H₃ Receptors Are Not Involved in the Regulation of Rat Gastric Secretion

“…This leads to the conclusion that apparently H3 receptors are not involved in the control of gastric secretion in this species. Our data are therefore in agreement with those obtained by Sandvik et al [6] in the iso lated vascularly perfused stomach and by Gespach et al [7] in human fundic glands, where H3 receptor activation or blockade did not modify adenylate cyclase activity.…”

“…gave approxi mately the same results. On the other hand, experiments performed in isolated prepara tions from rats [6] and humans [7] seem to indicate a lack of interference of this hista mine receptor subtype on gastric secretion. Taking into account the above discrepancies we wanted to investigate the possible regula tory role of histamine H i receptors in rat gas tric secretion by the use of different in vivo and in vitro techniques.…”

The effects of histamine, pyrilamine, cimetidine, and ranitidine on secretion of lingual lipase and amylase from rat von Ebner's glands

“…HI and H2 receptors act through different signal transduction pathways. The H z receptor stimulates the adenylate cyclase system [2,5,32] and the H t receptor acts primarily through the phosphatidyl inositol system [1,2,33]. Increased cytosolic Ca 2 + was found in the cytosol of the exocrine pancreas after stimulation with histamine [12].…”

Drug Repurposing in Dentistry: Towards Application of Small Molecules in Dentin Repair

“…Famotidine is a competitive inhibitor of the histamine (H2) receptor, the dominant receptor involved in gastric acid secretion that abolishes the activation of adenylate cyclase induced by histamines. Famotidine is able to effectively suppress meal-stimulated acid secretion with higher efficiency than Ranitidine [29][30][31]. Olanzapine is an atypical antipsychotic agent used for treatment of schizophrenia.…”