Abstract
The amiloride-sensitive epithelial sodium channel (ENaC) contributes to the regulation of the sodium balance and blood pressure because it mediates a rate-limiting step in sodium transport across the epithelium of the distal nephron. The activity of ENaC is regulated by hormones, such as aldosterone and vasopressin, and by other intracellular or extracellular factors, but the mechanisms of these regulations are not yet well understood. It has been proposed that ENaC may be regulated by an associated ATP-binding cassette protein such as the cystic fibrosis conductance regulator or the K channel-associated sulfonylurea receptor. Glibenclamide, a known inhibitor of sulfonylurea receptor and cystic fibrosis conductance regulator, induced a dose-dependent and reversible stimulation (of the order of 40–50%) of the amiloride-sensitive current in oocytes expressingXenopus ENaC, with aK1/2 of 45 ± 5 μM. A similar effect was observed in oocytes expressing human ENaC, but not rat ENaC. Measurements performed with various combinations of rat andXenopus subunits indicated that several subunits are involved in this effect. Glibenclamide also increased the transepithelial Na transport by the A6 Xenopus kidney cell line. Single-channel current recordings showed a doubling of the number of the open channels when glibenclamide was applied locally to the extracellular surface of the cell membrane. These results support the hypothesis of the existence of an associated ATP-binding cassette-type regulatory protein associated with the epithelial sodium channel.
Footnotes
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Send reprint requests to: Jean-Daniel Horisbeger, M.D., Institut de Pharmacologie et de Toxicologie, Bugnon 27, CH-1005 Lausanne, Switzerland. E-mail: Jean-Daniel.Horisberger{at}ipharm.unil.ch
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↵1 This work was supported by the Human Frontier Science Program, Grant RG-0464 (to J.-D.H.).
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↵2 Present address: Université Sidi Mohamed Ben Abdellah, Faculté des Sciences Dhar El Mahraz, Laboratoire de Physiologie Animale, Fes, Morocco.
- Abbreviations:
- ENaC
- epithelial sodium channel
- SUR
- sulfonylurea receptor
- CFTR
- cystic fibrosis conductance regulator
- ABC
- ATP-binding cassette
- N · Po
- number of channels × open probability
- Received November 30, 1998.
- Accepted March 17, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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