The Biochemical Pathways of Nitric Oxide Formation from Nitrovasodilators

Summary: The endogenous formation of nitric oxide (NO) plays a key role in many bioregulatory systems including the control of vascular tone, platelet aggregation, neurotransmission, and macrophage cytotoxicity. Due to the instability and inconvenient handling of aqueous solutions of authentic NO, there is increasing interest in using compounds capable of generating NO in situ. Nitrova-sodilators are prodrugs of NO and thus principally suited to mimic endogenous NO activities. As each class of compound offers distinct biochemical properties, this allows one to choose a compound that best meets the demands of the respective investigations. Several studies in which nitrovasodilator compounds were applied as donors of NO have been performed under experimental conditions that appear to be unsuitable for maintaining a reproducible supply of NO. Potential problems may arise during the preparation of aqueous solutions, their application to biological systems, and during sample processing prior to chemical analysis. The objective of this review is to outline the different pathways and biochemical mechanisms that ultimately lead to the release of NO from organic nitrates and nitrites, S-nitrosothiols, sydnonimines, furoxans, and inorganic compounds such as nitrite and sodium nitroprusside. The influence of changes in pH and oxygen tension on the rate of NO generation as well as the requirement for cofactors to form NO are discussed. In addition, crucial steps in the preparation and use of NO solutions are presented. This overview will help researchers to recognize and avoid experimental traps that can lead to an inappropriate NO supply and/or the misinterpretation of experimental results.