Arterial tone in muscular conduit arteries may influence pressure wave reflection through changes in diameter and pulse wave velocity. We examined the relative specificity of vasodilator drugs for radial artery and forearm resistance vessels during intrabrachial arterial infusion. The nitric oxide (NO) donors, nitroglycerine and nitroprusside, and brain natriuretic peptide were compared with the α-adrenergic antagonist phentolamine, calcium-channel antagonist verapamil, and hydralazine. Radial artery diameter was measured by high resolution ultrasound, forearm blood flow by strain gauge plethysmography, and pulse wave velocity by pressure recording cuffs placed over the distal brachial and radial arteries. Norepinephrine was used to constrict the radial artery to generate a greater range of vasodilator tone when examining pulse wave velocity. Despite dilating resistance vasculature, phentolamine and verapamil had little effect on radial artery diameter (mean dilation <9%). By contrast, for comparable actions on resistance vessels, nitroglycerine and nitroprusside but not brain natriuretic peptide had powerful actions to dilate the radial artery (dilations of 31.3 ± 3.6%, 23.6 ± 3.1%, and 9.8 ± 2.0% for nitroglycerine, nitroprusside, and brain natriuretic peptide, respectively). Changes in pulse wave velocity followed those in arterial diameter irrespective of the signaling pathway used to modulate arterial tone (R=-0.89, P<0.05). Basal tone in human muscular arteries is relatively unaffected by α-adrenergic or calcium-channel blockade, but is functionally or directly antagonized by NO donors. The differential response to NO donors suggests that there is potential to manipulate the downstream pathway to confer greater specificity for large arteries with a resultant decrease in pressure wave reflection and systolic blood pressure.