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

Tolerance to nitroglycerin (NTG) may be due to increased superoxide anion p roduction. Hemodynamic parameters and biochemical markers of free radical p roduction 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. T ransdermal NTG therapy was continued, and 2 days later all subjects receive d 2 g of oral vitamin C, or placebo, in a double-blind, randomized, crossov er fashion. In another study of eight male subjects, forearm plethysmograph y was used to assess the venous responses to sublingual NTG at baseline, af ter 5 days of sustained transdermal NTG therapy (0.6 mg/h), and after 2 g o f 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 respon ses to sublingual NTG were significantly diminished after sustained therapy with transdermal NTG. Plasma lipid per oxidation products, 8-iso-PGF(2 alp ha), and vitamin C were unchanged by acute and sustained therapy with trans dermal NTG. Vitamin C failed to restore either the hemodynamic or venous ef fects of NTG. These results do not support the hypothesis that nitrate ther apy and tolerance is associated with increased free radical production.