How can the Epithelial Sodium Channel (ENaC) mechanism be antagonized?

From the Guidelines

The ENaC mechanism can be antagonized primarily through the use of blockers such as amiloride, which is preferable to spironolactone in certain conditions like nephrotic syndrome, as it directly blocks the ENaC channels independent of the mineralocorticoid receptor 1. When considering the antagonism of the ENaC mechanism, it's crucial to understand the role of diuretics and their potential impact on patients, especially those with conditions like congenital nephrotic syndrome.

• The use of diuretics like furosemide is recommended with caution, as they can induce or increase hypovolemia and promote thrombosis, but they can improve edema and fluid control in most children with CNS when given in conjunction with albumin infusions 1.
• In patients with severe edema, commencing furosemide at 0.5–2 mg/kg per dose intravenously or orally up to six times daily may be necessary, with adequate monitoring of fluid status, electrolytes, blood pressure, and kidney function 1.
• Experimental evidence suggests that proteases in the urine directly activate the ENaC, contributing to salt retention and edema formation in patients with nephrotic syndrome, which will not be inhibited by mineralocorticoid receptor blockers like spironolactone 1.
• Therefore, the use of amiloride as an ENaC blocker is preferable to spironolactone in certain conditions, as it directly blocks the ENaC channels, reducing sodium reabsorption and promoting sodium and water excretion while conserving potassium 1.

From the FDA Drug Label

Triamterene has a unique mode of action; it inhibits the reabsorption of sodium ions in exchange for potassium and hydrogen ions at that segment of the distal tubule under the control of adrenal mineralocorticoids (especially aldosterone). The Epithelial Sodium Channel (ENaC) mechanism can be antagonized by inhibiting the reabsorption of sodium ions.

• The drug triamterene has been shown to have this effect, although the text does not explicitly state that it directly antagonizes ENaC. 2

From the Research

ENaC Mechanism Antagonism

The Epithelial Sodium Channel (ENaC) mechanism can be antagonized through various methods, including:

• Blockage by amiloride and its analogs, as described in 3, 4, 5
• Inhibition by other small molecules, such as quaternary amines, as reported in 6
• Regulation by proteases, including furin, prostasin, elastase, plasmin, and trypsin, as discussed in 4
• Endogenous substances that block the activity of these proteases, such as aprotinin, bikunin, and nexin-1, as mentioned in 4

ENaC Blockers

ENaC blockers, including amiloride and its derivatives, have been shown to be effective in inhibiting the channel, as described in 3, 4, 6, 5. These blockers can be used to treat various diseases, including hypertension and cardiovascular disease, as discussed in 3.

ENaC Regulation

ENaC activity is regulated by several factors, including:

• The number of channels inserted in the membrane, as mentioned in 4
• The open probability of the channels, which depends on the proteolysis of specific segments in the α and γ subunits of ENaC, as discussed in 4
• Hormones, such as aldosterone, which can regulate ENaC activity, as mentioned in 3, 4