The electrochemical defect in the bronchial epithelium in cystic fibrosis (CF) consists of defective chloride secretion and excessive sodium reabsorption. The sodium channel blocker, amiloride, has been shown to reversibly correct the sodium reabsorption in CF subjects, but long term studies of amiloride have been disappointing due to its short duration of action. Benzamil, a benzyl substituted amiloride analogue, has a longer duration of action than amiloride in cultured human nasal epithelium. The results of the first randomized, placebo controlled, double blind, crossover study are reported here comparing the effects of benzamil and amiloride on nasal potential difference (nasal PD) in CF. Ten adults with CF attended on three occasions. At each visit baseline nasal PD was recorded, the drug (amiloride 1 x 10(-3) M, benzamil 1.7 x 10(-3) M, or 0.9% sodium chloride) was administered topically via a nasal spray, and nasal PD was measured at 15, 30 min, 1, 2, 4 and 8 h. Results were expressed as maximum change in nasal PD from baseline (PDmax), time for PDmax to return to 50% of baseline (t0.5), and the area under the curve (AUC). PDmax values for benzamil (20.6+/-0.9 mV) and amiloride (20.3+/-1.6 mV), were similar. The duration of effect was much longer for benzamil as measured as either AUC or t0.5 AUC values were 11.8+/-1.6 mV for benzamil, 2.8+/-0.4 mV for amiloride and 0.6+/-0.4 mV for placebo. The AUC value for benzamil was significantly greater than amiloride (95% confidence interval (CI) for the difference 5.3-12.7 mV, p<0.0001). t0.5 values were 4.3+/-0.7 h for benzamil and 0.6+/-0.1 h for amiloride (95% CI for the difference 2.0-5.3 h, p<0.001). It is concluded that benzamil has a similar maximal effect to amiloride but a more prolonged duration of action on nasal potential difference in cystic fibrosis. Benzamil may be a useful sodium channel blocker for the long-term treatment of the biochemical defect in the lungs of patients with cystic fibrosis.