Modulation of IgE-mediated histamine release from human leukocytes by a new class of histamine H2-agonists.

A new class of phenyl (pyridylalcyl) guanidines, acting as potent histamine H2-agonists, inhibits IgE-mediated human basophil histamine release in a nanomolar range. IC30-level of three substitutes of this group (arpromidine, BUA-75, and FRA-19) were found to be 0.02, 0.015 and 0.008 microM. The inhibition appeared with a fast onset (plateau after 10 min. preincubation) and claimed its maximum (60 +/- 2.9%, 63 +/- 1.8%, and 61 +/- 3.1%, n = 7) with 10 microM of the compounds. H2-mediated inhibition was totally blocked by 10 microM famotidine, a potent histamine H2-antagonist. The amount of anti-IgE or antigen for the initiation of the immunological release influenced the strength of inhibition of H2-agonist FRA-19 (p less than 0.05). Combined preincubation of FRA-19 with zardaverine, a cAMP-specific phosphodiesterase III/IV inhibitor, produced a synergistical inhibitory effect of leukocyte histamine release, which might explained by their different sites of action on intracellular cAMP levels. The capability of histamine to inhibit its own release is mediated by H2-receptors exclusively. New, potent H2-receptor stimulating compounds with positive inotropic effects possess additional potent anti-allergic properties.