Epithelial Sodium Channel Inhibition in Cardiovascular Disease. A Potential Role for Amiloride

Justin Teiwes, Robert D. Toto

Research output: Contribution to journalReview article

58 Scopus citations

Abstract

Amiloride was originally described in 1967 as a potassium-sparing diuretic, the mechanism of action of which is to block the epithelial sodium channel (ENaC) within the distal tubule of the kidney. In addition, higher doses of amiloride were found to be capable of inhibiting the Na+/H+ exchangers (NHE) and the Na+/Ca2+ exchangers. In time, several amiloride analogs have been synthesized to have a marked increase in their specificity to inhibit the ENaC, the NHE or the Na+/Ca2+ exchangers. Although the NHE inhibitors have received the most recent attention, large-scale clinical trials using NHE inhibitors in ischemic cardiac states have shown them to be either ineffective or associated with an unacceptable risk profile. Aldosterone excess in animal models is known to cause cardiovascular injury, and blockade of mineralocorticoid receptors in human beings with heart disease improves outcomes. However, the exact mechanisms of aldosterone injury in animal models of hypertensive disease and protection with mineralocorticoid receptor antagonists in human trials of heart failure remain unknown. These effects are unexplained by changes in BP, potassium, or sodium balance. An additional possibility is that aldosterone action and mineralocorticoid receptor blockade is conferred by alterations in ENaC activity. Emerging experimental evidence suggests the possibility that systemic or central ENaC inhibition or both may be an alternative to the treatment of hypertension and cardiovascular disease states. Clinical trials to evaluate further the potential beneficial cardiovascular effects of ENaC blockade are needed. This article reviews the case for ENaC inhibition as a potential target for cardiovascular and renal protection in human beings.

Original languageEnglish (US)
Pages (from-to)109-117
Number of pages9
JournalAmerican Journal of Hypertension
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • Hypertension
  • amiloride
  • cardiovascular disease
  • epithelial sodium channel

ASJC Scopus subject areas

  • Internal Medicine

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