The aim of this study was to determine the effects of a single exercise bout on luminal Cl(-) and Na(+) conductance in the respiratory epithelium of patients with cystic fibrosis (CF). In nine patients with CF and nine healthy control subjects, the transepithelial electrical potential difference (PD) of the nasal respiratory epithelium was recorded, first at rest and then during moderate-intensity exercise. Under both conditions, PD was first measured while superfusing the epithelium with isotonic saline. Then, the effects of amiloride and amiloride plus low chloride plus isoproterenol were determined. Exercise resulted in a significant lower PD compared with rest in patients with CF (-6.6 +/- 16.6 mV versus -33.6 +/- 10.0 mV, p < 0.0001) and control subjects (0.1 +/- 8.7 mV versus -7.1 +/- 5.1 mV, p < 0.01). The effects of amiloride on PD were reduced during exercise compared with rest in patients with CF (+15.8 +/- 9.5 mV versus +26.1 +/- 11.0 mV, p < 0.01) and control subjects (+5.8 +/- 4.8 mV versus +10.0 +/- 3.1 mV, p < 0.01). There was no effect of exercise on chloride conductance in patients with CF and control subjects. We conclude that moderate-intensity exercise partially blocks the amiloride-sensitive sodium conductance in the respiratory epithelium. The inhibition of luminal sodium conductance could increase water content of the mucus in the CF lung during exercise and may, in part, explain the beneficial effects of exercise in patients with CF.