Aerosolized hypertonic saline is currently being investigated as a new agent for the treatment of impaired mucociliary clearance which occurs in many respiratory diseases. Mannitol aerosols, in particular dry powder inhalers, have been proposed as an alternative treatment to saline, offering the same osmotic load with other benefits. However, the effects of these hypertonic aerosols on airway epithelial ion transport processes have not been tested in human subjects in vivo. This report examines the effect of these solutions on airway ion transport using the nasal potential difference (PD) technique.Seven healthy nonsmoking adult volunteers were studied. On different days, a doseresponse curve was constructed for the saline added to Krebs N-[2-hydroxyethyl] piperazine-N9-[2-ethanesulphonic acid] (HEPES) diluent. The reversibility of this saline effect was measured, and the response to additional saline (500 mM) and mannitol (1 M) compared.Hypertonic saline decreased nasal PD in a dose-related manner, with mean (SEM) decreases in PD (less negative) of 6.6 (1.5), 7.6 (1.6), 10.0 (2.0), 13.1 (2.9) and 14.8 (3.2) mV (n~4) for addition of 150 mM, 250 mM, 500 mM, 1,200 mM and 2,000 mM NaCl to the Krebs HEPES diluent, respectively. The effect of hypertonic saline was fully reversible with washout for 3 min (presaline 15.9 (0.5) mV, postwashout 15.8 (1.1) mV, (n~4)). The hypertonic saline response was rapid in onset, sustained for at least 4 min, and decreased PD from 13.7 (1.7) mV to 5.1 (1.3) mV (n~7, pv0.001). In contrast, addition of mannitol to the perfusate did not significantly alter nasal PD, with a nonsignificant trend towards an increase (more negative) in the PD, (premannitol 13.9 (1.6) mV, postmannitol 15.3 (2.0) mV, n~7).As the osmotic stimulus of the 1 M mannitol is similar to that of the 500 mM sodium chloride, the divergent nasal potential difference responses suggest that the response to the saline was specific to the sodium chloride itself and not the simultaneous change in osmolarity. This demonstrates that the human airway epithelium in vivo can respond to topical hypertonic saline independent of the altered osmolarity.

Patients with cystic fibrosis (CF) demonstrate a characteristic defect in epithelial chloride movement, which can be demonstrated in vivo by the nasal potential difference technique. After amiloride pretreatment, the CF airway exhibits only a transient response to perfusion with low-chloride solution, contrasting with the sustained hyperpolarization seen in control subjects. This study further investigated the response to low-chloride solution in the CF airway, examining the interaction between surface divalent ions and the low-chloride response. Sequential perfusion with amiloride, low chloride, and isoproterenol was tested in groups of subjects with CF, with the diluent containing different concentrations of calcium and magnesium, on different days. When the low-chloride response was measured with the nominally calcium-free diluents, the subjects with CF had mean (SEM) responses of 8.0 (0.7), 8.6 (2.4), and 9.6 (1.6) mV in the presence of 0, 1, and 3 mM Mg2+, respectively, significantly different from the response in the presence of divalent ions. However, the subsequent response to isoproterenol was not different in the presence or absence of divalent ions. We hypothesize that perfusion of the CF airway with nominally calcium-free solutions reduces tonic inhibition of chloride secretion.