Amiloride Inhalation Therapy in Cystic Fibrosis: Influence on Ion Content, Hydration, and Rheology of Sputum

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Abstract
Amiloride inhalation as treatment for cystic fibrosis (CF) lung disease has been shown in independent studies to increase mucus clearance by ciliary and/or cough action and to retard the decline in lung function. It is hypothesized that amiloride therapy decreases the excess sodium and water absorption that is a characteristic of CF airway epithelium and that it leads to an improvement in the rheologic properties of mucus favoring airway mucus clearance. The aim of this study was to investigate whether amiloride treatment (5 × 10−3 M amiloride in one-third normal saline four times a day) would change sputum electrolyte composition in patients with CF after 25 wk of therapy as compared with placebo (one-third normal saline), and whether appropriate changes in sputum water content and rheologic properties would accompany any changes in electrolyte composition. Sputum samples were obtained from six patients with CF undergoing amiloride therapy, using the dental cotton protection technique to avoid salivary contamination. The samples were stored at −80° C until analyzed. For electrolyte analyses an aliquot of the sputum (minimum, 30 mg) was analyzed with ion-selective electrodes for sodium and potassium, and a chloride meter was used to measure chloride content. Chronic (25-wk) amiloride therapy increased significantly the sputum sodium (94.8 ± 16.4 to 121.4 ± 15.4 mmol/L, p = 0.001) and chloride (64.4 ± 11.8 to 77.2 ± 8.0 mmol/L, p = 0.10) content when compared with 25 wk of saline treatment. The sputum potassium content was not altered. Additional acute amiloride treatment increased sputum sodium and chloride contents even further than that achieved after chronic amiloride therapy (up to 143.3 ± 27.7 mmol/L for sodium and 95.1 ± 11.5 mmol/L for chloride). No differences were observed between acute and chronic saline treatments. The principal index of sputum rigidity, log G*, decreased both for the chronic and the acute/chronic treatment with amiloride. For chronic amiloride versus chronic saline treatment, log G* decreased from 2.92 ± 0.25 to 2.41 ± 0.33, which represents an approximate threefold decrease in viscoelasticity. There was, however, no corresponding change in mucus solids content. The results indicate that amiloride reduces mucus viscoelasticity and increases mucus clearance by mechanisms that involve electrolyte transport, supporting the thesis that amiloride inhalation therapy in CF represents a rational approach to drug therapy. However, the fact that sputum water content did not change measurably suggests that the mechanism for mucus improvement by amiloride is more complex than originally assumed.