Effect of Oral Digoxin, Topical Ouabain and Salbutamol on Transepithelial Nasal Potential Difference in Patients with Cystic Fibrosis
Authors: Peckham D. G. , Conn A. , Chotai C. , Lewis S. , Knox A. J. 
Published: August 2015

1. Airway epithelium in cystic fibrosis is characterized by a defect in chloride secretion across the apical membrane and an increase in sodium absorption. The increased rate of sodium absorption can be inhibited in vitro by ouabain, a Na+-K+-ATPase inhibitor, and in cystic fibrosis patients the number and activity of nasal epithelial Na+-K+-ATPase pumps is increased.

2. We have performed a series of studies to determine whether drugs which modify airway epithelial Na+-K+-ATPase activity in vitro can modify nasal potential in cystic fibrosis patients in vivo. As transepithelial nasal potential difference measurements were used to study the effect of drug modulation of airway epithelial ion transport in vivo, the repeatability of the technique was first evaluated. In order to assess the effectiveness of the technique used for measuring nasal potential difference, a pilot study was carried out using topical amiloride, a drug which has previously been shown to inhibit airway epithelium sodium transport in vivo. We then studied the effects of ouabain and digoxin, two inhibitors of Na+-K+-ATPase, and salbutamol, a drug which activates Na+-K+-ATPase, on nasal potential difference.

3. In study 1, nasal potential difference measurements were repeated on non-consecutive days in 20 patients with cystic fibrosis and 20 healthy individuals. Healthy subjects had a mean (SEM) potential difference value of −19.5 (0.9) mV, with a 95% range for a single estimate of 75–133%. In patients with cystic fibrosis, the mean (SEM) potential difference was −40.4 (2.1) mV, with a 95% range for a single estimate of 74–136%.

4. In an initial pilot study, the effect of topical amiloride on nasal potential difference was investigated on two consecutive days in four cystic fibrosis patients and four healthy control subjects, in a double-blind, placebo-controlled, randomized cross-over study. Nasal transepithelial potential was measured before and at 5, 15, 30, 45 and 60 min after the intranasal administration of 0.4 ml of a fine spray of 1 mmol/l amiloride or 0.9% saline placebo to both nostrils. Amiloride was associated with a maximal reduction in nasal potential difference at 15 min of 49% and 41% in cystic fibrosis patients and control subjects, respectively. Compared with saline, the amiloride response was significant in both groups (P &lt; 0.025).

5. In study 2, the effect of topical ouabain and salbutamol on nasal potential difference was investigated in ten cystic fibrosis patients and ten healthy control subjects, in a double-blind, placebo-controlled, randomized cross-over study. Nasal transepithelial potential was measured before and at 5, 15, 30, 45 and 60 min after the intranasal administration of either 0.4 ml of a fine spray of 5 mg/ml salbutamol, 0.25 mg/ml ouabain or 0.9% saline placebo to both nostrils. There was no significant change in nasal potential difference with either ouabain, salbutamol or placebo in either healthy control subjects or patients with cystic fibrosis.

6. In study 3, we performed a randomized, double-blind, placebo-controlled cross-over study of oral digoxin on nasal potential difference, spirometry and sweat electrolytes for 2 weeks in 11 patients with cystic fibrosis. During the treatment period, patients had a mean (range) serum digoxin level after the first and second week of therapy of 0.9 (0.3–1.4) μg/l and 1.1 (0.4–2.2) μg/l, respectively. There was no significant difference in the change in nasal potential difference measurements, forced expiratory volume in 1 s and sweat Na/Cl concentrations between the digoxin and placebo trial periods.

7. In conclusion, neither topical ouabain nor systemic digoxin had any effect on nasal potential difference in cystic fibrosis. Inhibitors of Na+-K+-ATPase are therefore unlikely to find a role in the treatment of cystic fibrosis. The lack of a detrimental effect of salbutamol on nasal potential difference is reassuring, as β-agonists are widely used in patients with cystic fibrosis.