Itraconazole antagonizes store‐operated influx of calcium into chemoattractant‐activated human neutrophils

SUMMARY We have investigated the effects of itraconazole (0·1–10  µ m ), an antimycotic which is often used prophylactically in primary and secondary immunodeficiency disorders, including chronic granulomatous disease, on mobilization of Ca 2+ and restoration of Ca 2+ homeostasis following activation of neutrophils with FMLP or PAF. Transmembrane fluxes of Ca 2+ , as well as cytosolic concentrations of the cation were measured using a combination of spectrofluorimetric and radiometric procedures. The abruptly occurring increases in cytosolic Ca 2+ following activation of the cells with either FMLP (1  µ m ) or PAF (200 n m ) were unaffected by itraconazole. However, the subsequent store‐operated influx of the cation was attenuated by itraconazole at concentrations of 0·25  µ m and higher. The itraconazole‐mediated inhibition of uptake of Ca 2+ was not associated with detectable alterations in the intracellular concentrations of cyclic AMP, ATP or inositol triphosphate, and appeared to be compatible with antagonism of store‐operated Ca 2+ channels. Although a secondary property, this anti‐inflammatory activity of itraconazole, if operative in vivo , may be beneficial in conditions associated with dysregulation of neutrophil Ca 2+ handling such as CGD.