Page 353 - Basic _ Clinical Pharmacology ( PDFDrive )

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Nitric Oxide

Samie R. Jaffrey, MD, PhD

Nitric oxide (NO) is a gaseous signaling molecule that readily NO was suspected to be EDRF because they have similar
diffuses across cell membranes and regulates a wide range of physi- vasorelaxation effects. Systematic comparison of the biochemical
ologic and pathophysiologic processes including cardiovascular, and pharmacologic properties of EDRF and NO provided initial
inflammatory, and neuronal functions. Nitric oxide should not evidence that NO is the major bioactive component of EDRF.
be confused with nitrous oxide (N O), an anesthetic gas, or with These findings also made it clear that exogenously applied NO
2
nitrogen dioxide (NO ), a toxic pulmonary irritant gas. and NO-releasing compounds (nitrates, nitrites, nitroprusside; see
2
Chapters 11 and 12) elicit their effects by recruiting physiologic
signaling pathways that normally mediate the actions of endog-
■ DISCOVERY OF enously generated NO.
ENDOGENOUSLY GENERATED
NITRIC OXIDE
■ NITRIC OXIDE SYNTHESIS,

The understanding that NO is an endogenously synthesized SIGNALING MECHANISMS, &
signaling molecule came from a series of discoveries that began INACTIVATION
with Italian chemist Ascanio Sobrero, who synthesized nitroglyc-
erin in 1846 and found it to be unstable and explosive. Never- Synthesis
theless, upon tasting the chemical, which was not an unusual
•
practice at the time, he noted profound headache, which was NO, written as NO to indicate an unpaired electron in its
soon understood to be caused by cerebral vasodilation. Based on chemical structure, or simply NO, is a highly reactive signaling
this early observation, nitroglycerin was used to treat angina and molecule that is synthesized in cells by any of three closely related
hypertension within 20 years. NO synthase (NOS, EC 1.14.13.49) isoenzymes, each of which
These and other early studies demonstrated that human cells is encoded by a separate gene and named for the initial cell type
have the capacity to detect and respond to nitroglycerin, as well from which it was isolated (Table 19–1). These enzymes, neuronal
as its metabolite, NO. However, the first indication that there NOS (nNOS or NOS-1), macrophage or inducible NOS (iNOS
may be an endogenous source of NO came from studies of cul- or NOS-2), and endothelial NOS (eNOS or NOS-3), despite
tured macrophages, which release byproducts of NO breakdown, their names, are each expressed in a wide variety of cell types, often
including nitrate and nitrite, after treatment with inflammatory with an overlapping distribution.
mediators such as bacterial endotoxin. Similarly, injection of These NOS isoforms generate NO from the amino acid
endotoxin in animals elevated urinary nitrite and nitrate. l-arginine in an O 2 - and NADPH-dependent reaction (Figure 19–1).
The second indication came from studies of vascular tissue, the This enzymatic reaction involves enzyme-bound cofactors, includ-
well-known target of nitroglycerin. Several molecules, such as ace- ing heme, tetrahydrobiopterin, and flavin adenine dinucleotide
tylcholine, were known to cause relaxation of blood vessels. This (FAD). In the case of nNOS and eNOS, NO synthesis is trig-
effect occurred only when the vessels were prepared so that the gered by agents and signaling events that increase cytosolic cal-
luminal endothelial cells covering the smooth muscle of the vessel cium concentrations. Cytosolic calcium forms complexes with
wall were retained (see Figure 7–5). Subsequent studies showed calmodulin, an abundant calcium-binding protein, which then
that these endothelial cells respond to vasorelaxants by releasing a binds and activates eNOS and nNOS. On the other hand, iNOS
soluble endothelial-derived relaxing factor (EDRF). EDRF acts is not regulated by calcium, but after synthesis is constitutively
on vascular muscle to elicit relaxation. These findings prompted active. In macrophages and several other cell types, iNOS is nor-
an intense search for the identity of EDRF. mally not readily detectable until inflammatory mediators induce

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