Locally deposited but not inhaled frusemide reduces nasal potential difference in healthy subjects

Summary

Previous publications suggest that prolonged inhalation of frusemide (F) does not cause a fall in the nasal transepithelial potential difference (PD) whereas locally deposited F does. In an attempt to reconcile these observations, we have measured the effect of inhalation through the nose and local deposition of F, amiloride (A), bumetanide (B) and salbutamol (S) on nasal PD in 7 healthy male volunteers in a randomised, double blind study. Solutions of drugs ranging from 10⁻⁶ M to 10⁻³ M (3.10⁻⁸ M to 3.10⁻⁵ M for B) in phosphate buffered saline 0.5 ml (PBS) were sequentially deposited in both nostrils, and nasal PD was measured 5 min after each dose. In 10 further volunteers, 10⁻² M solutions of A, F and S (3.10⁻⁴ M for B) 5 ml were nebulised through the nose for 15 min, when nasal PD was measured.

Resting PD was similar in the left and right nostrils averaging −17.1 mV (lumen negative). Placebo, inhaled of deposited B and S, and inhaled F did not change nasal PD. Topically deposited F significantly lowered PD_max in a dose-dependent manner [10⁻⁴ M, −12% from baseline; 10⁻³ M, −24%] as did the more potent A [10⁻⁵ M, −19%; 10⁻⁴ M, −31%; 10⁻³ M, −47%]. Nebulised A (10⁻² M) had the same effect on nasal PD as deposited A (10⁻⁴ M). The effects of locally deposited F and A (10⁻³ M) on nasal PD were additive.

Our results suggest first that, aerosol administration is less effective than local application in assessing the effect of a drug on nasal PD. And second, F cannot act primarily at the cotransporter level to reduce nasal PD, as B and F share the same inhibitory effect of the basolateral Na/K/Cl cotransporter and B does not reduce nasal PD.