Introduction Cystic fibrosis (CF), first described just 50 yr ago, is today the most common lethal inherited disease among Caucasians (1). This autosomal recessive disorder has a carrier rate ranging from approximately 1: 20 in most of Europe and among white Americans to 1: 60 in US blacks and 1: 150in the Japanese of Hawaii. The basic defect relates to regulation of ion transport by the secretory epithelia. A reduced chloride conductance occurs in both airway and sweat ductal epithelia in CF (2). In addition, in airway epithelium, but not in sweat gland, the sodium absorption is abnormally elevated (2, 3). Thus, if augmented volume absorption and/or reduced water secretion playa role in the pathogenesis of CF airway disease, then modalities to either induce CI-secretion or block the excess Na'absorption may be beneficial. Because no established drug activates the defective CI-channels in CF airway epithelia, the alternative concept, ie, blocking Na" absorption, appears to be the most rational approach to develop a useful therapy in CF. Investigations have shown that bronchial clearance is impaired in patients with CF (4). This may be due to rheologic abnormalities in the CF mucus, which could arise from dysfunction of transepithelial electrolyte movement (5). In CF, the respiratory secretions exhibit decreased sodium and chloride contents (6), only partially compensated by increased potassium and other electrolytes, which appear to reflect the altered ion transport mechanisms. Whether this results in a decreased water content and hence increased viscosity or rigidity is not yet certain, although the water content of CF sputum (~ 89010) has been reported to be lower than in other lung diseases (~ 95010)(7) or than that of normal canine tracheal mucus (~ 93070)(8, 9). Thus, alterations in electrolyte content might correlate with alterations in sputum rheology, which in tum might relate to impairments in ciliary and/or cough clearability of mucus.

These suggestions led us to study amiloride (pyrazinecarbonylguanidine) as a novel therapeutic approach to this disease. Boucher and coworkers (3) and Knowles and colleagues (10) had previously shown that amiloride applied directly to the luminal side of the respiratory epithelium is able to" normalize" the increased transepithelial potential difference in patients with CF, and they proposed its use as a therapy in CF lung disease. Amiloride as a diuretic drug acts on the nephron in the kidney by blocking sodium reabsorption while preventing potassium excretion. For this to occur the amiloride must first be filtered in the glomerulus and act on the luminal side of the epithelium (11). A similar mechanism could result from the inhalation of amiloride with a reduction of the transepithelial potential difference and an in-