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?

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)