ENAC blockade reduces blood pressure and arterial stiffness in adults with obesity and insulin resistance

Obesity and insulin resistance promote arterial stiffening and hypertension, increasing cardiovascular risk. Activation of the epithelial sodium channel (ENAC) contributes to vascular stiffening in preclinical models, but the vascular effects of ENAC inhibition in adults with obesity and insulin resistance are not well defined. In this Phase II, 24-week, randomized, double-blind, single-center, placebo-controlled trial, 137 adults aged 30-70 years with overweight or obesity and at least one metabolic syndrome feature were randomized (2:1) to the ENAC inhibitor amiloride (5 mg daily) or placebo. Carotid-femoral pulse wave velocity (cfPWV), blood pressure, and vascular function were assessed at baseline, 12 weeks, and 24 weeks. Amiloride significantly reduced arterial stiffness, with decreases in cfPWV at 12 and 24 weeks, whereas no changes were observed with placebo. Systolic blood pressure was also reduced, with a mean reduction of 5.6 mmHg at 24 weeks. Older age was associated with greater reductions in cfPWV and systolic blood pressure. Amiloride increased serum potassium and lowered fasting glucose but did not significantly affect brachial artery flow-mediated dilation. No severe adverse events were observed. In conclusion, low-dose amiloride improves blood pressure and arterial stiffness in adults with overweight or obesity and features of metabolic syndrome, without major safety concerns. These findings suggest that blood pressure lowering with amiloride is associated with favorable changes in vascular stiffness in this population.