Background Since organic nitroesters and endothelium-derived nitric oxide mediate vasodilation through a final common pathway, that is, by activation of soluble guanylate cyclase in vascular smooth muscle, nitroglycerin (NTG) could specifically enhance the endothelium-dependent vasodilatory response to acetylcholine (Ach) in patients with congestive heart failure (CHF) and endothelial cell dysfunction. Accordingly, the net effects of an intra-arterial infusion of NTG (10 sup -9 mol/L) on endothelium-dependent and endothelium-independent vasodilation were assessed in the forearm circulation of patients with CHF.Methods and Results The forearm blood flow responses to intra-arterial administration of graded concentrations of Ach (10 sup -7 to 10 sup -5 mol/L) were determined by venous occlusion plethysmography (mL/min per 100 mL) in 18 patients with CHF and 5 age-matched normal subjects before and during intra-arterial infusion of NTG (10 sup -9 mol/L) for 20 minutes. In eight patients, the duration of the infusion of NTG (n=5) or vehicle control solution (n=3) was extended to 12 hours with measurement of the forearm blood flow responses to Ach at 20 minutes, 4 hours, and 12 hours. In five additional patients, forearm blood flow response to intra-arterial administration of two doses of phentolamine (0.05 and 0.5 mg) were determined before and during a 20-minute NTG infusion. Regional administration of NTG 10 sup -9 mol/L did not change resting forearm blood flow in either normal subjects or patients with CHF. Before administration of NTG 10 sup -9 mol/L, intra-arterial infusions of Ach 10 sup -7, 10 sup -6, and 10 sup -5 mol/L increased forearm blood flow to 14.7+-6.2, 20.2+-4.7, and 38.4+-7.9 mL/min per 100 mL in normal subjects and to 4.1+-0.8, 5.0+-1.1, and 10.6+-2.3 mL/min per 100 mL in patients with CHF. After administration of NTG 10 sup -9 mol/L for 20 minutes, the vasodilatory response to Ach significantly increased to 5.6+-1.0, 6.9+-1.6, and 17.7+-3.4 mL/min per 100 mL in patients with CHF but did not change in normal subjects. The enhanced forearm blood flow responses to administration of Ach observed after 20 minutes of NTG administration in patients with CHF were sustained throughout a 12-hour NTG infusion. In contrast, regional administration of NTG did not change the vasodilatory responses to phentolamine.Conclusions NTG, when administered intra-arterially for 20 minutes at a dose that does not affect resting forearm blood flow, specifically increased the vasodilatory response to intra-arterial administration of Ach in patients with CHF but not in normal subjects. The vasodilatory response to Ach was consistently enhanced by low-dose NTG throughout a 12-hour period. The vasodilating effects of organic nitroesters on the peripheral vasculature of patients with CHF may result in part from an interaction with the vascular endothelium. (Circulation. 1994;89:1609-1614.)