Blood pressure responses to small doses of amiloride and spironolactone innormotensive subjects

The epithelial sodium channel (ENaC) is a principal site for sodium reabsor ption and as such may participate importantly in blood pressure (BP) regula tion. Amiloride, a direct inhibitor of ENaC, characteristically has mild an ti hypertensive properties, consistent with ENaC having more minor influenc es on BP regulation. Counter-regulatory influences may, however, prevent am iloride from effectively lowering BP. Aldosterone secretion is known to inc rease 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 t o 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 4.6 +/-1.6 (mean +/- SEM) mmHg (P=0.022) and diasto lic BP by 2.2 +/-1.2 mm Hg (P=0.30), whereas either drug alone had no signi ficant effect on BP. The findings suggest that the 2 drugs with different m odes 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 re sulted from the greater dose of total drug. The lowering of BP with small d oses of inhibitors of ENaC serves as additional evidence for the importance of ENaC to the tonic maintenance of BP.