We studied the effect of extracellular
sodium concentration on histamine release (HR) from human basophils initiated by immunologic and nonimmunologic stimuli. We found that lowering extracellular
sodium markedly enhances HR induced by an immunologic stimulus from these cells. In
buffer in which
sodium had been replaced with univalent
ions of strong bases, enhancement of HR increased as extracellular
sodium decreased. Enhancement was the result of increased duration of release. When
sucrose was used for replacement of
sodium, we also observed that enhancement of HR increased as extracellular
sodium decreased, but there was some lessening of enhancement at [Na+]e between 5 and 10 mmol/L.
Ouabain, which is an inhibitor of the Na+/K+
adenosine triphosphatase, and
bumetanide and
furosemide, which are inhibitors of Cl(-)-dependent Na(+)-K+ cotransport, caused small increases in enhancement of HR by
sodium-deficient
buffers; 4,4'-diisothiocyanostilbene-2-2'-disulfonic
acid, an
anion transport inhibitor, caused some inhibition of enhancement of HR. Analogues of
amiloride, such as 5-(N-N-hexamethylene)
amiloride (HMA) and 5-(N-4-chlorobenzyl)-2'-4'dimethylbenzamil (
CBDMB), inhibit Na+/H+ exchange, Na+/Ca++ exchange, and Na+ channels. Interestingly, at higher doses, HMA and
CBDMB caused marked enhancement of HR in both normal and
sodium-deficient
buffers. These results suggest that several cellular regulatory mechanisms potentially are important for normal basophil secretion. The most likely are pH regulatory mechanisms that include Na+/H+ exchange and
anion exchangers that transport alkaline equivalents. Our findings enhancement of basophil HR by HMA and
CBDMB is particularly noteworthy in light of the recent interest in use of
amiloride by inhalation for
therapy of
lung disease in patients with
cystic fibrosis.