Studies in animals suggest that nitric oxide production is increased under conditions of salt loading and that this increase protects against the development of salt-induced hypertension. To determine the effect of dietary sodium intake on nitric oxide-mediated vascular responses, we studied seven healthy male volunteers twice 4 weeks apart while they were receiving a diet containing 10 or 250 mmol Na+ per 24 hours. Methacholine (0.25 to 8 micrograms/min) and sodium nitroprusside (0.25 to 8 micrograms/min) were infused intra-arterially in incremental doses, and forearm blood flow was measured. The response of forearm blood flow to sodium nitroprusside was greater when subjects received a high sodium diet than when they received a low sodium diet (F = 7.11, P < .05); however, the response to methacholine was not altered by sodium intake (F = 0.57, P = NS). Plasma renin activity was significantly higher (3.99 versus 1.0 ng angiotensin I/mL per hour) when subjects received a low salt diet (P < .05). Systolic pressure, diastolic pressure, heart rate, and baseline forearm blood flow were not affected by sodium status. We conclude that under conditions of salt loading, vasodilation in response to sodium nitroprusside was enhanced, whereas the response to methacholine was not affected, suggesting a differential effect of sodium intake on endothelium-dependent and endothelium-independent responses after the administration of methacholine and sodium nitroprusside, respectively.