The identification of nitric oxide as endothelium-derived relaxing factor

Abstract

The identification of endothelium-derived relaxing factor as nitric oxide (NO) dramatically altered the course of vascular biology, as well as other biomedical disciplines. The ubiquity of this natural product of cell metabolism and the complexity of its biochemistry provide a rich source of molecular mediators of phenotype in health and disease.

Figure 1. The entero-salivary circulation of nitrogen oxides

Nitrate in the diet is reduced by oral bacteria to nitrite, which is converted to nitric oxide upon entering the acidic environment of the stomach. Nitrate that enters the small intestine is absorbed into the bloodstream where it joins with circulating nitrate and nitrite derived from the oxidative metabolism of endogenous nitric oxide. This circulating pool of nitrate and nitrite is taken up by the salivary glands and secreted into the oral salivary pool. Excess nitrate is excreted by the kidney. [Reproduced with permission from MacMillan Publishers Ltd: (reference 10)].

Figure 2. Nitric oxide metabolism and S-nitrosothiol formation

(A) Nitric oxide (NO^.) is synthesized by the nitric oxide synthases (NOS), and can undergo oxidation to nitrite and nitrate, react with superoxide anion (^.O₂) to form peroxynitrite (ONOO⁻), or bind to transition metals (NO-M). Three different mechanisms of trans-S-nitrosylation are indicated, as well as denitrosylation steps. Detailed reaction mechanisms for key reactions highlighted in blue are provided in (B). [Reproduced with agreement by Mary Ann Liebert Publisher, Inc., which does not require formal permission to obtain approval for personal reuses (reference 14).]

Figure 2. Nitric oxide metabolism and S-nitrosothiol formation

(A) Nitric oxide (NO^.) is synthesized by the nitric oxide synthases (NOS), and can undergo oxidation to nitrite and nitrate, react with superoxide anion (^.O₂) to form peroxynitrite (ONOO⁻), or bind to transition metals (NO-M). Three different mechanisms of trans-S-nitrosylation are indicated, as well as denitrosylation steps. Detailed reaction mechanisms for key reactions highlighted in blue are provided in (B). [Reproduced with agreement by Mary Ann Liebert Publisher, Inc., which does not require formal permission to obtain approval for personal reuses (reference 14).]