BACKGROUND WNK [With No K (lysine)] kinases are essential for regulation of blood pressure and potassium homeostasis. WNK4 expression was recently found not only in the distal nephron but also in chloride-transporting epithelia. To establish a physiological role for this distribution we studied patients with familial hyperkalaemia and hypertension (FHH), [pseudohypoaldosteronism type II (PHAII)], which is caused by mutations in WNK4. DESIGN Measurement of nasal potential difference (NPD) and sweat electrolytes were performed in controls, in six subjects with FHH and ten subjects with cystic fibrosis (CF). RESULTS Basal NPD was higher in FHH compared with controls (n = 20): 22.8 +/- 5.7 vs. 16.2 +/- 5.3 mV, respectively (P = 0.014). Maximal response to amiloride was also higher in FHH compared with controls: 14.8 +/- 3.5 vs. 10.0 +/- 4.8 mV, respectively (P = 0.03). In CF these values were 42.9 +/- 9.3 and 29.9 +/- 7.4 mV, respectively. The kinetics of the amiloride effect were faster in FHH, and as first reported here also in CF, compared with controls. At 30 s, amiloride-inhibitable residual PD in FHH was 50 +/- 30 vs. 81 +/- 9% in controls (P = 0.0003) and 56 +/- 7% in CF. The response to chloride-free and isoproterenol solutions, which determines chloride transport activity, was similar in FHH compared with controls [16.0 +/- 8.6 vs. 10.4 +/- 5.9 mV (P = 0.08)]. Sweat conductivity in FHH was 49.7 +/- 7.3 vs. 38.2 +/- 8.1 mmol (NaCl eq) L-1 in 16 controls (P = 0.007) and 94.0 +/- 19.3 in CF. CONCLUSIONS Mutant WNK4 increases Na+ transport in airways, and therefore it is regulated by wild-type WNK4. This may be caused by a regulation of ENaC or a K+ channel.