Randomized, Double-Blind, Placebo-Controlled Study of Supplemental Vitamin E on Attenuation of the Development of Nitrate Tolerance

Abstract

Background The attenuation of intracellular production of cGMP has been known to be a mechanism of nitrate tolerance. A recent in vitro study showed an increase in superoxide levels and a reduced activation of guanylate cyclase in tolerant vessels. We investigated the preventive effect of an antioxidant, vitamin E, on the development of nitrate tolerance. Methods and Results In this double-blind, placebo-controlled study, 24 normal volunteers and 24 patients with ischemic heart disease (IHD patients) were randomized to receive either vitamin E (200 mg TID vitamin E group) or placebo (placebo group). Vasodilator response to nitroglycerin was assessed with forearm plethysmography by measurement of the change in the forearm blood flow before and 5 minutes after sublingual administration of 0.3 mg nitroglycerin, and at the same time, blood samples were taken from veins to measure the platelet cGMP level. Measurements of the forearm blood flow and blood sampling were obtained serially at baseline (day 0), 3 days after vitamin E or placebo alone was taken (day 3), and 3 days after application of a 10-mg/24-h nitroglycerin tape concomitantly with oral vitamin E or placebo (day 6). The responses of forearm blood flow (%FBF) and cGMP (%cGMP) after sublingual nitroglycerin on day 0 (%FBF: normal volunteers, 32±12 versus 31±11; IHD patients, 35±15 versus 34±15; %cGMP: normal volunteers, 38±10 versus 35±11; IHD patients, 37±11 versus 38±12, vitamin E group versus placebo group) and day 3 (%FBF: normal volunteers, 33±9 versus 32±12; IHD patients, 35±12 versus 33±13; %cGMP: normal volunteers, 38±10 versus 37±11; IHD patients, 36±14 versus 37±10, vitamin E group versus placebo group) were not different between the two groups. On day 6, %FBF and %cGMP in the placebo group were significantly lower compared with day 0, and there were significant differences in them between the two groups (%FBF: normal volunteers, 30±12 versus 17±9, P <.01; IHD patients, 28±14 versus 17±8, P <.01; %cGMP: normal volunteers, 35±11 versus 8±5, P <.01; IHD patients, 38±10 versus 12±4, P <.01, vitamin E group versus placebo group). Conclusions These results indicate that the combination therapy with vitamin E is potentially a useful method to prevent the development of nitrate tolerance.