Cyclic nucleotide-gated non-selective cation (CNG) channels, first described in sensory neuroepithelia, have recently been identified in the lung. These channels are expressed both at the mRNA level and functionally in rat alveolar and airway epithelial cells (Ding et al. 1997; Schwiebert et al. 1997; Xu et al. 1999) and appear to contribute to lung liquid clearance in rats and sheep (Junor et al. 1999; Norlin et al. 2001). Although mRNA for CNG channels has been detected in a human airway cell line, it is not known whether CNG channels are functionally expressed in human airway epithelium. We therefore investigated the effect of pimozide, a CNG channel blocker, on transepithelial airway ion transport using nasal potential difference measurements.

Potential difference was measured across the nasal mucosa between an exploring electrode, sited under the inferior nasal turbinate, and a subcutaneous reference electrode. Measurements were made using a high impedance voltmeter and recorded continuously on a chart recorder. The exploring electrode was a double lumen catheter that allowed simultaneous measurement of potential difference and perfusion of ion channel blockers onto the nasal mucosa. Nasal potential difference measurements were made in seven healthy human volunteers (4 males, 3 females) before and after nasal perfusion firstly with 1.5 Ω 10^-4 M pimozide then with 1 Ω 10^-4 M amiloride, which blocks epithelial sodium channels (ENaC). The measurements were repeated 1 week later, applying the blockers in reverse order. Amiloride was used to determine whether observed effects of pimozide were independent of and additive to ENaC blockade. The study was approved by the Local Research Ethics Committee and all subjects gave informed consent.

Baseline nasal potential difference was -16.6 ± 2.5 mV (mean ± S.E.M., lumen negative with respect to interstitium) and was depolarised by 3.0 ± 0.3 mV (95 % CI 2.2-3.7 mV, P < 0.0001, paired t test) following perfusion of pimozide. Application of amiloride caused an additional depolarisation of 10.5 ± 1.2 mV (95 % CI 7.4-13.5 mV, P < 0.0001). The effect of the blockers was not significantly different when applied in reverse order. Amiloride perfusion depolarised the nasal mucosa by 9.4 ± 0.8 mV (95 % CI 7.3-11.5 mV, P < 0.0001). Application of pimozide caused an additional depolarisation of 2.5 ± 0.4 mV (95 % CI 1.4-3.6 mV, P < 0.001).

Pimozide causes a significant depolarisation of nasal mucosa, which is independent of and additive to depolarisation resulting from epithelial sodium channel blockade. This effect is consistent with inhibition of cation absorption through CNG channels by pimozide. CNG channels in airway epithelium could form an important alternative route for sodium, and hence water, absorption contributing to regulation of the volume and composition of airway surface liquid. Further studies are required to confirm their functional expression in human airways.

Ding, C., Potter, E.D., Qiu, W., Coon, S.L., Levine, M.A. & Guggino, S.E. (1997). Am. J. Physiol. 272, C1335-1344.

Junor, R.W., Benjamin, A.R., Alexandrou, D., Guggino, S.E. & Walters, D.V. (1999). J. Physiol. 520, 255-260. abstract

Norlin, A., Lu, L.N., Guggino, S.E., Matthay, M.A. & Folkesson, H.G. (2001). J. Appl. Physiol. 90, 1489-1496.

Schwiebert, E.M., Potter, E.D., Hwang, T.-H., Woo, J.S., Ding, C., Qiu, W., Guggino, W.B., Levine, M.A. & Guggino, S.E. (1997). Am. J. Physiol. 272, C911-922.

Xu, W., Leung, S., Wright, J. & Guggino, S.E. (1999). J. Membr. Biol. 171, 117-126.