Randomized, double-blind, placebo-controlled study of the preventive effect of supplemental oral vitamin C on attenuation of development of nitrate tolerance

J Am Coll Cardiol. 1998 May;31(6):1323-9. doi: 10.1016/s0735-1097(98)00085-0.


Objectives: This study sought to evaluate the preventive effect of vitamin C, an antioxidant, on the development of nitrate tolerance.

Background: Decreased intracellular production of cyclic guanosine monophosphate (cGMP) is a mechanism of nitrate tolerance, and increased superoxide levels and reduced activation of guanylate cyclase have been observed in vitro.

Methods: In this double-blind, placebo-controlled study, 24 normal volunteers and 24 patients with ischemic heart disease (IHD) were randomized to receive either vitamin C (2 g three times daily [vitamin C group, n=12]) or placebo (placebo group, n=12). The vasodilator response to nitroglycerin was assessed with forearm plethysmography by measuring the change in FBF before and 5 min after sublingual administration of 0.3 mg of nitroglycerin. Blood samples were simultaneously obtained to measure platelet cGMP levels. FBF was measured, and blood sampling was performed serially at baseline (day 0), 3 days after administration of vitamin C or placebo (day 3) and 3 days after application of a 10-mg/24-h nitroglycerin tape concomitantly with oral vitamin C or placebo (day 6).

Results: There were no differences between the vitamin C and placebo groups in percent increases in FBF (%FBF) or platelet cGMP levels (%cGMP) after administration of sublingual nitroglycerin on day O (%FBF: normal volunteers 31+/-8 vs. 32+/-10; patients with IHD 32+/-9 vs. 32+/-8; %cGMP: normal volunteers 37+/-9 vs. 39+/-10; patients with IHD 38+/-10 vs. 39+/-10 [vitamin C group vs. placebo group]) or day 3 (%FBF: normal volunteers 32+/-9 vs. 33+/-9; patients with IHD 31+/-10 vs. 31+/-10; %cGMP: normal volunteers 36+/-8 vs. 37+/-9; patients with IHD 39+/-11 vs. 38+/-10 [vitamin C group vs. placebo group]). The %FBF and %cGMP in the placebo group were significantly lower on day 6 than in the vitamin C group (%FBF: normal volunteers 30+/-8 vs. 19 4, p < 0.01; patients with IHD 29+/-9 vs. 17+/-6, p < 0.01; %cGMP: normal volunteers 36 10 vs. 17+/-6, p < 0.01; patients with IHD 37+/-11 vs. 15+/-5, p < 0.01 [vitamin C group vs. placebo group]).

Conclusions: These results indicate that combination therapy with vitamin C is potentially useful for preventing the development of nitrate tolerance.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Antioxidants / pharmacology*
  • Ascorbic Acid / pharmacology*
  • Cyclic GMP / blood
  • Double-Blind Method
  • Drug Therapy, Combination
  • Drug Tolerance
  • Female
  • Humans
  • Male
  • Middle Aged
  • Myocardial Ischemia / blood
  • Myocardial Ischemia / drug therapy*
  • Nitroglycerin / therapeutic use*
  • Plethysmography
  • Vasodilator Agents / therapeutic use*


  • Antioxidants
  • Vasodilator Agents
  • Nitroglycerin
  • Cyclic GMP
  • Ascorbic Acid