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 M. 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 M of the compounds. H₂-mediated inhibition was totally blocked by 10 M 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<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.This work was supported by grant K1 622/1-1 from the Deutsche Forschungsgemeinschaft.