Biochemical, hemodynamic, and vascular evidence concerning the free radical hypothesis of nitrate tolerance.

Tolerance to nitroglycerin (NTG) may be due to increased superoxide anion production. Hemodynamic parameters and biochemical markers of free radical production were measured in 20 healthy male subjects at baseline, 3 h after acute transdermal NTG (0.6 mg/h), and after 5 days of continuous therapy. Transdermal NTG therapy was continued, and 2 days later all subjects received 2 g of oral vitamin C, or placebo, in a double-blind, randomized, crossover fashion. In another study of eight male subjects, forearm plethysmography was used to assess the venous responses to sublingual NTG at baseline, after 5 days of sustained transdermal NTG therapy (0.6 mg/h), and after 2 g of oral vitamin C or placebo. Systolic blood pressure decreased in response to acute transdermal NTG therapy but returned to normal after sustained NTG therapy, indicating the development of tolerance. The venous volume responses to sublingual NTG were significantly diminished after sustained therapy with transdermal NTG. Plasma lipid peroxidation products, 8-iso-PGF2 alpha, and vitamin C were unchanged by acute and sustained therapy with transdermal NTG. Vitamin C failed to restore either the hemodynamic or venous effects of NTG. These results do not support the hypothesis that nitrate therapy and tolerance is associated with increased free radical production.