Nitrates and NO release: contemporary aspects in biological and medicinal chemistry

Free Radic Biol Med. 2004 Oct 15;37(8):1122-43. doi: 10.1016/j.freeradbiomed.2004.06.013.

Abstract

Nitroglycerine has been used clinically in the treatment of angina for 130 years, yet important details on the mechanism of action, biotransformation, and the associated phenomenon of nitrate tolerance remain unanswered. The biological activity of organic nitrates can be said to be nitric oxide mimetic, leading to recent, exciting progress in realizing the therapeutic potential of nitrates. Unequivocally, nitroglycerine and most other organic nitrates, including NO-NSAIDs, do not behave as NO donors in the most fundamental action: in vitro activation of sGC to produce cGMP. The question as to whether the biological activity of nitrates results primarily or exclusively from NO donation will not be satisfactorily answered until the location, the apparatus, and the mechanism of reduction of nitrates to NO are defined. Similarly, the therapeutic potential of nitrates will not be unlocked until this knowledge is attained. Aspects of the therapeutic and biological activity of nitrates are reviewed in the context of the chemistry of nitrates and the elusive efficient 3e- reduction required to generate NO.

Publication types

  • Review

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Biotransformation
  • Cations / pharmacokinetics
  • Cyclic GMP / metabolism
  • Drug Design
  • Drug Tolerance
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Free Radicals
  • Guanylate Cyclase / metabolism
  • Humans
  • Molecular Structure
  • Nitrates / chemistry
  • Nitrates / metabolism*
  • Nitrates / pharmacokinetics
  • Nitrates / therapeutic use
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / chemistry
  • Nitric Oxide Donors / pharmacokinetics
  • Nitric Oxide Donors / therapeutic use
  • Nitrites / chemistry
  • Nitrites / pharmacokinetics
  • Nitroglycerin / metabolism
  • Nitroglycerin / pharmacology
  • Oxidation-Reduction
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacokinetics
  • Sulfhydryl Compounds / therapeutic use
  • Vasodilator Agents / chemistry
  • Vasodilator Agents / pharmacokinetics
  • Vasodilator Agents / therapeutic use

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cations
  • Free Radicals
  • Nitrates
  • Nitric Oxide Donors
  • Nitrites
  • Sulfhydryl Compounds
  • Vasodilator Agents
  • Nitric Oxide
  • Guanylate Cyclase
  • Nitroglycerin
  • Cyclic GMP