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Characterization of histamine H2-receptors in human neutrophils with a series of guanidine analogues of impromidine

Are cell type-specific H2-receptors involved in the regulation of NADPH oxidase?

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Summary

Human neutrophils possess an NADPH oxidase which catalyzes superoxide (O sup−inf2 ) formation and is activated by chemotactic peptides. Histamine inhibits O sup−1inf2 formation via H2-receptors (Burde et al. 1989). We characterized the neutrophil H2-receptor with a series of new guanidine-type H2-agonists structurally derived from impromidine. Histamine inhibited O sup−inf2 formation with an IC50 value of 6.7 ± 1.2 μM. Five aryloxy- and arylthioalkylguanidines were less potent and effective than histamine. Several arpromidine-like phenyl(pyridylalkyl)guanidines were either full or partial H2-agonists. Some guanidines possess a three-membered carbon chain connecting the aromatic rings and the guanidine group; they were similarly potent and effective as histamine. Shortening or elongation of the carbon chain substantially decreased the potency and intrinsic activity of the guanidines. Halogenation of the phenyl ring did not substantially affect the potency and intrinsic activity of the compounds in comparison to the non-substituted parent compound. The H2-antagonist, famotidine, competitively antagonized inhibition of O sup−inf2 formation caused by the guanidine, arpromidine, with a pA2 value of 6.84. The H2-antagonist, cimetidine, differentially counteracted inhibition caused by partial and full H2-agonists. Partial H2-agonists antagonized the effects of histamine. The inhibitor of phosphodiesterases, 3-isobutyl-lmethylxanthine, additively enhanced the inhibitory effects of histamine and guanidines. The properties of the neutrophil H2-receptor were compared with literature data concerning properties of the H2-receptor of the guinea pig atrium. In the latter system, guanidines are full H2-agonists with potencies of up to 125-fold of that of histamine. Our data indicate that guanidines inhibit O sup−inf2 formation in human neutrophils via H2-receptors. The structure/activity relationship for the neutrophil H2-receptor substantially differs from the one for the H2-receptor in the guinea pig atrium, suggesting that the neutrophil H2-receptor has cell type-specific properties. Other possibilities to explain the differences between H2-receptors in these systems are discussed.

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Authors and Affiliations

  1. Institut für Pharmakologie, Freie Universität Berlin, Thielallee 69/73, D-1000, 33, Berlin

    Rahel Burde & Roland Seifert

  2. Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2-4, D-1000, 33, Berlin

    Armin Buschauer

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  1. Rahel Burde
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  2. Armin Buschauer
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Burde, R., Buschauer, A. & Seifert, R. Characterization of histamine H2-receptors in human neutrophils with a series of guanidine analogues of impromidine. Naunyn-Schmiedeberg's Arch Pharmacol 341, 455–461 (1990). https://doi.org/10.1007/BF00176340

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  • DOI: https://doi.org/10.1007/BF00176340

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