Aldosterone receptor blockade and thiazide therapy effectively lower blood pressure in geriatric hypertension. Their impact on sympathetic nervous system function has not been evaluated. In a double-blind, randomized study, 36 patients with stage 1 hypertension underwent 6 months of therapy with either aldosterone receptor blockade (spironolactone, n=19; 68+/-1 years) or hydrochlorothiazide (n=17; 68+/-2 years). Arterial blood pressure, [(3)H]-norepinephrine (NE) kinetics (extravascular NE release rate), and alpha-adrenergic responsiveness (forearm vasoconstriction to graded intrabrachial artery NE infusions) were evaluated at baseline, after a 4-week antihypertensive medication withdrawal, and after spironolactone or hydrochlorothiazide treatment. Arterial blood pressure decreased significantly with both spironolactone (160+/-3 to 134+/-2 mm Hg; 77+/-2 to 68+/-2 mm Hg) and hydrochlorothiazide (161+/-4 to 145+/-4 mm Hg; 78+/-2 to 73+/-2 mm Hg) treatment. Sympathetic nervous system activity was significantly reduced after spironolactone (plasma NE: 378+/-40 to 335+/-20 pg/mL, P=0.04; [(3)H]-NE release rate: 2.74+/-0.3 to 1.97+/-0.2 microg/min per meter squared, P=0.04) but not hydrochlorothiazide (plasma NE: 368+/-25 to 349+/-23 pg/mL, P=0.47; [(3)H]-NE release rate: 2.63+/-0.4 to 2.11+/-0.2 mg/min per meter squared, P=0.21). alpha-Adrenergic responsiveness was unchanged with either drug treatment. These findings demonstrate a beneficial effect of aldosterone receptor blockade on reducing sympathetic nervous system activity and blood pressure in hypertensive older patients.