(by interacting with the heme moiety of soluble guanylyl cyclase to increase cGMP
levels), precipitating a cascade of intracellular biochemical processes. Once in the
interneuronal region, NO may even function as a retrograde messenger, influencing
the metabolism and release of neurotransmitters from presynaptic terminals. Also,
unlike conventional neurotransmitters, NO is not inactivated by enzymatic processes
but decays to nitrite after 30 seconds.
It is possible that biosynthesis from L-arginine is not the only synthetic route for the
generation of NO. NO may also be generated nonenzymatically by reduction of nitrate ion
to NO. This process occurs under the reducing conditions that evolve in the brain during
the ischemia of stroke. Furthermore, there is an excess release of NO associated with
NMDA receptor stimulation during a stroke. Coupled to this realization that NO plays a
role in the neurotoxic cascade of stroke has been an attempt to pharmacologically manip-
ulate NO as a stroke therapy. Regrettably, as with the glutamate story (discussed above),
NO-based drugs have failed to provide a “magic bullet” for the treatment of stroke.
4.11.3 Role of NO in the Central and Peripheral Nervous SystemsNO plays a significant role in the CNS, where it functions as both a neurotransmitter
and a neuromodulator. As a neuromodulator, NO can influence ligand-gated ion chan-
nels within the brain. In the brain, NO plays a role in memory and learning. Moreover,
as discussed above, NO is a participant in the molecular cascade that leads to brain
damage during stroke.
NO exerts an equally important role in the PNS. Nonadrenergic, noncholinergic
(NANC) neurons are distributed throughout both the gastrointestinal and reproductive
tracts. NO is a neurotransmitter/neuromodulator within many of these NANC neurons.
Penile erection, for example, is caused by NO release from NANC neurons. Accordingly,
impotence is a clinical indication for the use of an NO donor such as nitroglycerin oint-
ment. NO enables penile engorgement by activating guanylyl cyclase, which increases
the concentration of cGMP, which in turn stimulates the dephosphorylation of myosin
light chains in the smooth muscles within the penile arterial walls. In fact, any drug that
increases cGMP might be of value in the treatment of erectile dysfunction. Sildenafil
(4.227) (more famously known by its trade name Viagra) is an enzyme inhibitor that
increases cGMP levels by blocking cGMP’s catabolic breakdown as catalyzed by the
phosphodiesterase (PDE isoform 5) enzyme located in the corpora cavernosa of the
penis.
NEUROTRANSMITTERS AND THEIR RECEPTORS 293