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Central Role for ENaC in Development of Hypertension

Department of Medicine, Indiana University School of Medicine, and the Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana

Address correspondence to: Dr. J. Howard Pratt, Department of Medicine, Indiana University School of Medicine, 541 Clinical Drive, Indianapolis, IN 46202-5111. Phone: 317-274-4347; Fax: 317-274-7700; E-mail: johpratt{at}iupui.edu

Na⁺ reabsorption by the epithelial Na⁺ channel (ENaC) in cortical collecting duct provides the final renal adjustment to Na⁺ balance, there being no further downstream Na⁺ transport system. This fact coupled with the responsiveness of ENaC to aldosterone, which conveys stimulation inversely proportional to the state of Na⁺ balance, places ENaC in a pivotal position to influence the risk for hypertension. Although several molecular variants of ENaC subunits have been identified, there has been no consistent demonstration of an association of any of the variants with hypertension. More compelling is the notion that ENaC activity does not fully adjust to an increase in Na⁺ reabsorption occurring elsewhere in the nephron, there being overstimulation by inappropriately elevated aldosterone levels. Additional evidence that the maintenance of hypertension can be dependent on ENaC is derived from the observed responses to the treatment of hypertensive individuals with inhibitors of ENaC. Described is a clinical trial in which black hypertensive individuals who did not fully respond to more traditional therapy were given amiloride, spironolactone, a combination of the two drugs, or placebo. Treatment with either of the active inhibitors of ENaC resulted in a substantial improvement in BP. In conclusion, evidence to date is supportive of the concept that an increase in Na⁺ transport by ENaC may be a common and requisite component of salt-dependent forms of hypertension.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673