Leptin, a product of the ob gene, plays an important role in the regulation of body fat and has been suggested to cause vasodilation in rats. The purpose of this study was to evaluate whether leptin also has a vasodilating effect in humans. Using a strain-gauge plethysmography, we evaluated forearm blood flow (FBF) during intra-arterial infusion of leptin (1, 10 or 100 ng/kg/min for 5 min) in the absence and presence of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 8 micromol/min for 5 min) in ten healthy men (mean age, 23.0+/-1.2 years). Leptin infusion significantly increased the FBF (8.5+/-3.8, 20.3+/-7.0 and 17.7+/-5.4% at 1, 10 and 100 ng/kg/min of leptin, respectively; p<0.05) and the forearm vascular resistance (FVR; -6.9+/-3.1, -14.6+/-4.3 and -13.4+/-3.9% at 1, 10 and 100 ng/kg/min of leptin, respectively; p<0.05). No significant changes in blood pressure or heart rate were detected during infusion of leptin. The intra-arterial infusion of L-NMMA did not alter the FBF response (6.6+/-4.9, 22.1+/-7.5, 13.3+/-3.2% at 1, 10 and 100 ng/kg/min of leptin, respectively) or the FVR response (-4.3+/-4.6, -15.2+/-5.4, -11.1+/-2.5% at 1, 10 and 100 ng/kg/min of leptin, respectively) to leptin. These findings suggest that leptin per se directly causes vasodilation and that leptin-induced vasodilatation is nitric oxide-independent in healthy men.