Blood Pressure Responses to Small Doses of Amiloride and Spironolactone in Normotensive Subjects

Abstract

Abstract-The epithelial sodium channel (ENaC) is a principal site for sodium reabsorption and as such may participate importantly in blood pressure (BP) regulation. Amiloride, a direct inhibitor of ENaC, characteristically has mild antihypertensive properties, consistent with ENaC having more minor influences on BP regulation. Counter-regulatory influences may, however, prevent amiloride from effectively lowering BP. Aldosterone secretion is known to increase in response to the reduced sodium reabsorption that follows amiloride inhibition of ENaC, and because aldosterone upregulates ENaC function, we considered the possibility that secondary hyperaldosteronism mitigates the ability of amiloride to reduce BP. In the present study, the BP responses to amiloride (5 mg per day), spironolactone (25 mg per day), the combination of the 2 drugs, and placebo were studied in healthy normotensive subjects. Over 4 weeks of treatment, the combination of amiloride and spironolactone lowered systolic BP by 4.6Ϯ1.6 (meanϮSEM) mm Hg (Pϭ0.022) and diastolic BP by 2.2Ϯ1.2 mm Hg (Pϭ0.30), whereas either drug alone had no significant effect on BP.The findings suggest that the 2 drugs with different modes of action-amiloride, a direct inhibitor of ENaC, and spironolactone, a mineralocorticoid receptor antagonist-may compliment each other's ability to inhibit ENaC and thereby reduce sodium reabsorption to a point at which BP decreases. On the other hand, we cannot rule out that the BP response resulted from the greater dose of total drug. 4 -6 or the life-threatening decrease in blood pressure (BP) that occurs in the neonatal period known as pseudohypoaldosteronism type 1. 7 More minor but common molecular variations in ENaC may also affect risk for hypertension. 8,9 If, indeed, ENaC is important for maintaining BP or contributing to the high BP of some individuals, then giving amiloride, a direct inhibitor of ENaC, should effectively lower BP, but in general, it is weakly antihypertensive 10 -13 and used primarily in combination with a thiazide diuretic for its potassium-sparing actions. 11In the patients described by Liddle et al, 4 triamterene, also an inhibitor of ENaC, lowered BP but only after sodium intake was severely restricted. Sodium has been shown to interfere with the ability of amiloride to inhibit sodium conductance in vitro, 14 and thus amiloride may not lower BP because modern diets are high in sodium. An alternative theory is that the secondary increase in aldosterone secretion that occurs in response to amiloride abrogates the ability of amiloride to prevent sodium reabsorption. In the present study, we examined the effect on BP of combining amiloride and spironolactone, a mineralocorticoid antagonist. Using a 2ϫ2 factorial study design, the BP responses to amiloride alone, spironolactone alone, the combination of amiloride and spironolactone, and placebo were compared in normotensive subjects. Methods SubjectsThe study used 20 whites and 20 blacks, age 18 to 30, from a cohort followed as part of a study of BP reg...

Epithelial Sodium Channel Stiffens the Vascular Endothelium In Vitro and in Liddle Mice

“…This finding highlights the potential of the combined administration of amiloride and spironolactone as a new therapeutic endeavor suggested by Pratt et al 43 It might aim at correcting both the high blood pressure and the endothelial dysfunction. The latter was found to often precede essential hypertension.…”

“…Previous studies also state that endothelial function determined in the aorta also applies to smaller resistance vessels. 37 Under aldosterone-treated conditions, endothelial cells of Liddle mouse aorta displayed a significantly higher αENaC surface abundance (+34%; 43 …”

Improvement in Blood Pressure With Inhibition of the Epithelial Sodium Channel in Blacks With Hypertension

“…However, their concomitant use could conceivably improve blood pressure control even further by reducing the secondary increase in aldosterone secretion that accompanies inhibition of ENaC. The increase in renin secretion that accompanies treatment with amiloride 13 (or triamterene 12 ) may be greater than would be predicted from the degree of volume contraction. 18 In the present study, after 1 week, the levels of PRA in the amiloride-treated patients exceeded those in the spironolactone-treated patients by several-fold, although with time, the levels became similar.…”

“…Participants were black hypertensives with elevated blood pressures while receiving treatment that included a diuretic targeted to the proximal nephron and a calcium channel blocker. Because aldosterone levels secondarily increase with amiloride treatment 12,13 but are antagonized by spironolac-tone treatment, we also explored the relationship of both drugs to the effects of aldosterone on nonepithelial tissues by measuring endothelin-1 (ET-1), a potent vasopressor that was shown in vitro to be stimulated by aldosterone. 14 …”

Epithelial Na+ Channel (ENaC), Hormones, and Hypertension

“…In fact, elevation of serum potassium is considered the most powerful agonist for aldosterone secretion (24). Pratt et al (31) showed that, over time, plasma potassium concentrations and plasma aldosterone levels precisely matched, with aldosterone concentrations rising and falling with increases and decreases in the serum potassium concentration.…”