ENAC Blockade and Arterial Stiffness

Overweight/obese males, pre- and post-menopausal females with insulin resistance, 30-70 years of age will be recruited. Following screening, eligible men and women will be randomly assigned to either amiloride (max dose 5mg) or placebo in a double-blinded design manner.

After randomization, subjects will be scheduled for an outpatient visit to the undergo baseline assessment of arterial stiffness (carotid femoral pulse wave velocity - cfPWV) and endothelial function (brachial popliteal artery flow mediated dilation). Subject assessment will be repeated at 12 weeks and at 24 weeks.

Inclusion criteria

• 30 to 70 years of age at randomization
• Body mass index (BMI) 25.1-50 kg/m2 or waist circumference > 88 cm (> 35 in) in women and >102 cm (>40 in) in men. 3, 4
• One other characteristic of metabolic syndrome (elevated triglycerides ≥150 mg/dl; HDL cholesterol <40 mg/dl in men and <50 mg/dl in women; blood pressure ≥130/85 mm Hg or treatment for hypertension; impaired fasting glucose (≥100 mg/dl)) or fasting insulin level >10 mU/L (correlates with insulin resistance).

Exclusion criteria

• History of type 1 or type 2 diabetes
• Known cardiovascular events within the last 12 months (stroke, acute coronary event, revascularization, heart failure hospitalization).
• History of uncontrolled thyroid disease, chronic liver disease (cirrhosis) or GFR <50 ml/min.
• Use of potassium sparing medications (angiotensin II receptor blockers, angiotensin converting enzymes inhibitors or mineralocorticoid receptor blockers) or use of potassium supplements.
• Active cancer (This criterion does not apply to those subjects with basal cell carcinoma or stage 1 squamous cell carcinoma of the skin)
• Excessive alcohol consumption (>14 drinks/week for men, >7 drinks/week for women)
• Current tobacco use
• Non controlled hypertension
• Participation in regular exercise > 3 days/wk per week at a moderate or vigorous intensity
• Pregnancy or lactation in women (or women not using contraceptives)
• Women who plan to become pregnant during the duration of the trial
• Chronic use of NSAIDs
• Potassium level > 5.0 mqE/L at time of screening
• Blood pressure at screening <110/70