Evidence supporting abnormalities in nitric oxide synthase function induced by nitroglycerin in humans

OBJECTIVES We studied the effects of nitroglycerin (GTN) therapy on die res ponse to endothelium-dependent and independent vasoactive agents in the for earm circulation of healthy subjects. BACKGROUND Recent evidence suggests that therapy with GTN may induce specif ic changes in endothelial cell function, including increased superoxide ani on production and sensitivity to vasoconstrictors. Additionally, continuous GTN therapy worsens endothelial function in the coronary circulation of pa tients with ischemic heart disease. METHODS Forearm blood flow was measured with venous occlusion, mercury-in-s ilastic strain gauge plethysmography. RESULTS Sixteen male volunteers (26 +/- 6 years) were randomized to no ther apy (control) or GTN, 0.6 mg/h/24 h, for six days in an investigator-blind, parallel-design study. The flow responses to brachial artery infusions of acetylcholine ([Ach] 7.5, 15.0, 30.0 mug/min), N-monomethyl-L-arginine (L-N MMA) (1, 2, 4 mu mol/min) and sodium nitroprusside (SNP) (0.8, 1.6, 3.2 mug /min) were recorded. The vasodilator responses to Ach were blunted in the G TN group as compared with the control group (p < 0.05). The vasoconstrictor responses to L-NMMA were also blunted in the GTN group (p < 0.001). In the GTN group, paradoxical vasodilation was observed in response to the lowest infused concentration of L-NMMA. The vasodilator responses to SNP did not differ. between groups. CONCLUSIONS The response to Ach confirms the hypothiesis that continuous GT N causes endothelial dysfunction. The responses to L-NMMA suggest that GTN therapy causes abnormalities in nitric oxide synthase (NOS) function; the v asodilation observed at the lowest infused concentration of L-NMMA in the G TN group also suggests that continuous GTN therapy is associated with a NOS -mediated production of a vasoconstrictor. (C) 2001 by the American College of Cardiology.