TABLE 1

Proposed mechanisms of nitrate tolerance

Intravascular volume expansion
Neurohumoral counter-regulation
Increased vascular superoxide production due to:

  1. Increased vascular NA(D)PH oxidase activity

  2. Uncoupling of endothelial NO synthase

Increased vascular endothelin-1 production
Increased sensitivity to vasoconstrictors
Protein thionitrate formation and depletion of critical sulfhydryl groups
Decreased superoxide dismutase activity
A reduced cGMP response due to:

  1. Reduced mechanism-based biotransformation to NO

  2. Desensitization of sGC to activation by NO

  3. Increased PDE activity