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INTRODUCTION

Nitric oxide (NO) is a gaseous signaling molecule that readily diffuses across cell membranes and regulates a wide range of physiologic and pathophysiologic processes including cardiovascular, inflammatory, and neuronal functions. Nitric oxide should not be confused with nitrous oxide (N2O), an anesthetic gas, or with nitrogen dioxide (NO2), a toxic pulmonary irritant gas.

DISCOVERY OF ENDOGENOUSLY GENERATED NITRIC OXIDE

The understanding that NO is an endogenously synthesized signaling molecule came from a series of discoveries that began with Italian chemist Ascanio Sobrero, who synthesized nitroglycerin in 1846 and found it to be unstable and explosive. Nevertheless, upon tasting the chemical, which was not an unusual practice at the time, he noted profound headache, which was soon understood to be caused by cerebral vasodilation. Based on this early observation, nitroglycerin was used to treat angina and hypertension within 20 years.

These and other early studies demonstrated that human cells have the capacity to detect and respond to nitroglycerin, as well as its metabolite, NO. However, the first indication that NO could be produced in the body came from studies of cultured macrophages. Treatment of these cells with inflammatory mediators such as bacterial endotoxin resulted in increased levels of nitrate and nitrite in the culture media, which are known byproducts of NO breakdown. Similarly, injection of endotoxin in animals elevated urinary nitrite and nitrate.

The second indication came from studies of vascular tissue, the well-known target of nitroglycerin. Several molecules, such as acetylcholine, were known to cause relaxation of blood vessels. Acetylcholine was thought to act by stimulating the endothelial cells that cover the smooth muscle of the vessel wall since removal of these cells prevents acetylcholine-induced vasodilation (see Figure 7–5). Subsequent studies showed that endothelial cells respond to vasorelaxants by releasing a soluble endothelial-derived relaxing factor (EDRF). EDRF acts on vascular muscle to elicit relaxation. These findings prompted an intense search for the identity of EDRF.

NO was suspected to be EDRF because they have similar vasorelaxation effects. Systematic comparison of the biochemical and pharmacologic properties of EDRF and NO provided initial evidence that NO is the major bioactive component of EDRF. These findings also made it clear that exogenously applied NO and NO-releasing compounds (nitrates, nitrites, nitroprusside; see Chapters 11 and 12) elicit their effects by recruiting many of the physiologic signaling pathways that normally mediate the actions of endogenously generated NO.

NITRIC OXIDE SYNTHESIS, SIGNALING MECHANISMS, & INACTIVATION

Synthesis

NO, written as NO to indicate an unpaired electron in its chemical structure, or simply NO, is a highly reactive signaling molecule that is synthesized in cells by any of three closely related NO synthase (NOS, EC 1.14.13.49) isoenzymes, each of which is encoded by a separate gene and named for the initial cell ...

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