These studies identify a further abnormality in cystic fibrosis (CF). The increase in intracellular free calcium concentration ([Ca2+]i) after exposure to histamine and PGE1 is demonstrated to be abnormally low in nasal cells, studied in short-term culture, from patients with CF compared with control subjects. [Ca2+]i is measured by using the Ca(2+)-sensitive fluorescent dye fura-2 and a fluorescence microscope imaging system. The percentage of CF cells that increase [Ca2+]i in response to histamine is decreased compared with controls, and, even in those CF cells that increase [Ca2+]i, the magnitude of the increase in [Ca2+]i in response to histamine is smaller than in controls. When exposed to PGE1, a similar number of control and CF cells responded with an increase in [Ca2+]i, but again the magnitude of the response was smaller in the CF cells. The mechanism of the PGE1-induced increase in [Ca2+]i is not mediated by cAMP, since 8-bromo-cAMP failed to increase [Ca2+]i in these cells. This abnormality in [Ca2+]i response did not apply to all secretagogues, with the response to carbachol being similar in CF and normal cells. How the abnormal CF gene product accounts for the abnormality in intracellular Ca2+ response to some but not all secretagogues is unknown.