In Liddle's syndrome, a rare inherited form of hypertension, epithelial sodium channel mutations appear to cause high blood pressure by increasing sodium reabsorption through sodium channels in the renal distal tubule. This increase in channel activity has not been confirmed previously by in vivo measurement. We have made transnasal potential difference measurements (effective in detection of increased sodium channel activity in cystic fibrosis) in three brothers with genetically proven Liddle's syndrome, their unaffected sister, and 40 normotensive controls. Maximum potential difference after 2 wk off treatment in the affected brothers was -30.4+/-1.2 mV (values mean+/-SD, lumen-negative with respect to submucosa) and was significantly more lumen-negative than that of the control group (-18.6+/-6.8 mV, P = 0.0228) or the unaffected sister (-18.25 mV, P < 0.01). The change in potential difference after topical application of 10(-)4 M amiloride was greater in the Liddle's patients, 14.0+/-2.1 mV, than in controls (7.9+/-3.9 mV, P = 0.0126) or the unaffected sister (5.5 mV, P < 0.05). This is the first in vivo demonstration of increased sodium channel activity in Liddle's syndrome. If these results are confirmed in other kindreds with this condition, then nasal potential difference measurements could provide a simple clinical test for Liddle's syndrome.