PHARMACOLOGICAL CHARACTERIZATION OF A NOVEL HISTAMINE-RECEPTOR ON HUMAN EOSINOPHILS

There is increased recognition that lung mast cell mediators not only produce the symptoms of acute asthma, but also result in the recruitment and activation of additional proinflammatory cells, such as eosinophils. Histamine, one of the major mast cell mediators, is known to have numerous effects on eosinophil function. These effects of histamine are mediated by distinct receptors on the surface of eosinophils, only some of which have been characterized. Prior studies have suggested that eosinophils have non-H-1, non-H-2 histamine receptors which mediate the chemotactic effects of histamine. We observed previously that the histamine-induced increase in cytosolic calcium in human eosinophils could not be blocked by classic H-1 or H-2 antagonists, but could be inhibited by the H-3 antagonist thioperamide. The purpose of this study was to further characterize the pharmacologic properties of this calcium-linked histamine receptor. Using Fura-2 loaded eosinophils to measure the concentration of cytosolic calcium, we examined the effect of additional histamine receptor antagonists and agonists. We found that the pKb for the H-3 antagonists thioperamide, impromidine, and burimamide (8.1, 7.6, and 7.2, respectively), were similar to those reported for H-3 receptors in the central nervous system, suggesting that the eosinophil histamine receptor was similar to H-3 receptors. However, when the known H-3 agonists were tested for activity ([R]-alpha-methylhistamine, N-alpha-methylhistamine), the potencies of these compounds were much less than the potency of histamine itself, indicating a significant difference between H-3 receptors and this eosinophil histamine receptor. In addition, we found that burimamide, previously known only as an antagonist at H-3 and H-2 receptors, acted to increase the intracellular calcium concentration in eosinophils when used at high concentrations. This agonist effect of burimamide was specific for eosinophils (not active on neutrophils or HL-60 cells), and was antagonized by thioperamide, but not H-1 or H-2 antagonists. These data and additional data support the existence of a novel histamine receptor on the surface of human eosinophils.