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The effects of different extracellular Na+ and Ca2+ concentrations on histamine release from human basophils were investigated. Isosmotic replacement of extracellular Na+ either with choline+, a non-permeant Na+ analogue, or glucose significantly increased spontaneous and anti-IgE-induced histamine release. Basophils from 12 of 49 normal subjects, which were found not to release histamine upon challenge with an optimal dose of anti-IgE in a 135 mM NaCI buffer, were converted into releasing basophils when stimulation with anti-IgE was performed in a low-Na medium. The increase in Na+ concentration in the extracellular medium was accompanied by a reduction in the magnitude of basophil response to anti-IgE, which was significantly more pronounced in non-releasers than in releasers (per cent inhibition by 70 mM NaCI 75.5 ±3.2 vs 43.5 + 9.0, P<0.01). At higher Na+ concentrations a progressive and almost complete abrogation of histamine release was observed in non-releasers, but not in releasers (maximal per cent inhibition at 140 mM NaCI 97.3± 1.3 vs 50.4±8.6). The Na+/H+ exchanger monensin had a dose-dependent inhibitory effect on anti-IgE-induced histamine release, and the concentration inhibiting 50% of histamine release was 1.5 × 10-7M. When basophils were challenged in the presence of different Na+ and Ca2+ concentrations, it was shown that the two cations have antagonistic effects, which is to say that they down-regulate and upregulate histamine release, respectively. Moreover, the requirement of extracellular Ca2+ was lowered in a low-Na+ medium. These results suggest that Na+ and Ca2+ ions contribute with opposite effects to the modulation of basophil response to anti-IgE and that non-releasing basophils are converted into releasing basophils in a low-Na+ medium. [ABSTRACT FROM AUTHOR]