title: Rapid desensitization of the histamine H2 receptor on the human monocytic cell line U937.
abstract: In the present study we have subjected the histamine H2 receptor on the monocytic cell line U937 to a thorough pharmacological characterization using a series of selective histamine H1, H2 and H3 receptor agonists and antagonists. Recent reports have demonstrated the existence of a histamine H2 receptor on HL-60 and HGT-1 cells with a pharmacological profile distinct from the commonly described histamine H2 receptor. U937 cells, however, seem to express classical histamine H2 receptors. Histamine and dimaprit dose dependently induce the formation of cAMP, whereas dimaprit's inactive analogues, nordimaprit and homodimaprit, show reduced potencies. Histamine H1 and H3 receptor agonists do not show histamine H2 receptor activity. Various histamine H2 receptor antagonists are able to block the histamine induced production of cAMP with an antagonistic profile comparable to that observed in the guinea-pig right atrium. Furthermore, endogenous histamine H2 receptors in U937 cells are found to be susceptible to receptor desensitization, a mechanism which may become apparent under pathophysiological conditions or during drug therapy. A 30-min pre-exposure of U937 cells to histamine (100 microM) results in a 50% attenuation of the production of cAMP to a subsequent application of an agonist. Desensitization of the histamine H2 receptor in U937 cells is found to be homologous as the beta-adrenoceptor mediated response remained unaffected.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Smit
authors.forename: R
authors.initials: R
authors.lastname: Leurs
authors.forename: S R
authors.initials: SR
authors.lastname: Shukrula
authors.forename: A
authors.initials: A
authors.lastname: Bast
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
mesh_terms: D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017259:Dimaprit / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000473:pathology; D009000:Monocytes / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D017442:Histamine Agonists; D006633:Histamine Antagonists; D011970:Receptors, Histamine H2; D006632:Histamine; D000242:Cyclic AMP; D017259:Dimaprit