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

Abstract

Human neutrophils possess an NADPH oxidase which catalyzes superoxide (O2-) formation and is activated by chemotactic peptides. Histamine inhibits O2- 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 O2- formation with an IC50 value of 6.7 +/- 1.2 microM. 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 O2- 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-1-methylxanthine, 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 O2- formation in human neutrophils via H2-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine H1-receptors in HL-60 monocytes are coupled to Gi-proteins and pertussis toxin-insensitive G-proteins and mediate activation of Ca2+ influx without concomitant Ca2+ mobilization from intracellular stores

“…1989Seifert etal. , 1992Burde et al 1989Burde et al , 1990Wenzel-Seifert and Seifert 1990;Krautwurst et al 1992).…”

“…It is well known that human phagocytes, i.e., neutrophils and monocytes, possess Hz-receptors which mediate activation of adenylyl cyclase with subsequent increase in cAMP Gespach et al , 1985. The HA-induced increase in cAMP results in inhibition of formyl peptideinduced superoxide anion (O~-) formation and in the induction of differentiation (Seligman et al 1983;Burde et al , 1990Nonaka et al 1992).…”

Current Knowledge and Perspectives on Histamine H1 and H2 Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

“…Histamine dihydrochloride (Ceplene; Immune Pharmaceuticals, New York, NY) has been approved for the treatment of patients suffering from AML, and H 2 R agonists are being extensively studied as promising drug candidates for the treatment of AML and inflammatory diseases (Burde et al, 1989(Burde et al, , 1990Jutel et al, 2009;Martner et al, 2010). By inhibiting ROS production, H 2 R ligands allow agents that stimulate the immune system (e.g., interleukin-2) to effectively activate cytotoxic cells, improving tumor cell death (Hellstrand, 2002).…”

Mutations of Cys-17 and Ala-271 in the Human Histamine H2Receptor Determine the Species Selectivity of Guanidine-Type Agonists and Increase Constitutive Activity

“…H 2 R of human neutrophils than at the H 2 R of the guinea pig right atrium (Burde et al, 1989(Burde et al, , 1990. In a membrane steady-state GTPase activity assay with fusion proteins of H 2 R and the short splice variant of G s␣ , G s␣S , these compounds are considerably more potent and efficacious at gpH 2 R-G s␣S than at hH 2 R-G s␣S (Kelley et al, 2001).…”