Antihypertensive drugs can have different effects on central and brachial blood pressures and it has been suggested that these differences are relevant to outcomes. In particular, nitric oxide donors have marked acute effects on central blood pressure but have not been assessed when administered acutely with renin-angiotensin system blockade. Thirteen patients with high-normal to mild hypertension were randomized to a sequence of 5 single-dose treatments using a double-blind, balanced crossover study design. Treatments consisted of angiotensin receptor blocker (ARB) losartan 100 mg, isosorbide mononitrate (ISMN) 60 mg, losartan 100 mg + ISMN 15 mg, losartan 100 mg + ISMN 60 mg, and placebo. Central and brachial blood pressures were measured throughout 10 hours after the single-dose treatments. Treatment periods were separated by ≥4 days. Mean placebo-subtracted decrease from baseline in augmentation index (AIx), a parameter of central pressure, was approximately 1% for losartan 100 mg, 26% for ISMN 60 mg, 19% for losartan 100 mg + ISMN 15 mg, and 24% for losartan 100 mg + ISMN 60 mg. Whether administered with losartan 100 mg or alone, ISMN lowered mean AIx demonstrating that acute effects of a nitrate donor are much larger than those of an ARB even when administered with an ARB. Differences from placebo were statistically significant except for losartan 100 mg. A single dose of ISMN alone or when added to losartan 100 mg markedly lowered AIx indicating AIx is a good biomarker of acute hemodynamic effects of nitric oxide in patients with high-normal to mild hypertension.