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 recruitme nt and activation of additional proinflammatory cells, such as eosinop hils. Histamine, one of the major mast cell mediators, is known to hav e 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 t hat eosinophils have non-H-1, non-H-2 histamine receptors which mediat e the chemotactic effects of histamine. We observed previously that th e 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 stud y was to further characterize the pharmacologic properties of this cal cium-linked histamine receptor. Using Fura-2 loaded eosinophils to mea sure 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 burima mide (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, w hen the known H-3 agonists were tested for activity ([R]-alpha-methylh istamine, N-alpha-methylhistamine), the potencies of these compounds w ere much less than the potency of histamine itself, indicating a signi ficant 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 intr acellular calcium concentration in eosinophils when used at high conce ntrations. This agonist effect of burimamide was specific for eosinoph ils (not active on neutrophils or HL-60 cells), and was antagonized by thioperamide, but not H-1 or H-2 antagonists. These data and addition al data support the existence of a novel histamine receptor on the sur face of human eosinophils.