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CELLULAR AND MOLECULAR

Evans Blue Is a Specific Antagonist of the Human Epithelial Na⁺ Channel -Subunit

Department of Molecular Morphology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan

The epithelial Na⁺ channel (ENaC) regulates Na⁺ homeostasis in cells and across epithelia. Four homologous ENaC subunits (, , , and ) have been isolated in mammals. Combination of -, -, and -subunits or -, -, and -subunits forms fully functional channels. Amiloride is a well known blocker of the ENaC family that inhibits both channel complexes. However, no specific antagonists are currently known that distinguish them. Here, we show that Evans blue, a diagnostic aid for the measurement of blood volume and vascular permeability, inhibits the activity of the -subunit expressed in Xenopus oocytes. The inward currents at a holding potential of -60 mV in human ENaC-expressing oocytes were inhibited by the application of Evans blue in a concentration-dependent manner with an IC₅₀ value of 143 µM. Evans blue markedly inhibited the -subunit current but did not block the -subunit current. In conclusion, Evans blue is the first known -subunit-specific antagonist of ENaC. This finding provides us with a key compound for elucidating the physiological and pathological functions of ENaC in humans and for drug development in the ENaC family.

Address correspondence to: Dr. Hisao Yamamura, Department of Molecular Morphology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi Mizuhocho Mizuhoku, Nagoya 467-8601, Japan. E-mail: yamamura{at}med.nagoya-cu.ac.jp