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The porphyrin handbook - Kadish K.M.

Kadish K.M. The porphyrin handbook - Academic press, 2000. - 368 p.
Download (direct link): kadishsmishgulilard2000.djvu
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44/Porphyrin-Based Electrochemical Sensors
241
production is blocked by administration of eNOS inhibitors, or by
pathological states such as deposition of cholesterol on the wall of the
arteries (atherosclerosis), the vascular muscles do not relax to the
appropriate degree and vasoconstriction ensues. Vasoconstriction
increases blood pressure, and decreases flow, and is responsible for
hypertension.49'50
Even though they do not have nuclei, platelets in the blood also
possess an eNOS, apparently expressed by their mitochondrial DNA. One
platelet can produce about 10"17 moles of NO in a single burst lasting a
few minutes, when all its eNOSs are activated. NO released by platelets
prevents blood coagulation, formation of thrombi and subsequent blockage
of arteries. The pathology of this process leads to coronary thrombosis
and is a major cause of stroke. The heart itself releases a significant
amount of NO, on a beat-to-beat basis, during the systolic (compression),
as well as the diastolic (decompression) period.
3. Nitric Oxide in the Nervous System
nNOS is a constitutive enzyme; that is, it is continuously present,
though not always active. nNOS like eNOS is turned on by Ca2 + currents,
but only produces NO for a few seconds before being shut off by the
binding of NO to the heme in the active site; then the nNOS rests for a
few minutes until the bound NO disassociates. NO generated by nNOS in
certain neurons in the peripheral nervous system serves as a
neurotransmitter to help control the cardiovascular, respiratory,
digestive (excretory and reproductive) systems.51-52
Neurons throughout the body transfer information by means of signaling
molecules. Neuronal activity and, therefore, all the functions attributed
to the central and peripheral nervous system are based on the synthesis
and release of neurotransmitters. In the brain, this action can lead to
an increase or decrease of electrical signals produced. Electrical
signals are due to flow of positive or negative ions into and out of
neurons which change the electrical potential on the neuron membrane. The
net effect of this process is either excitation or inhibition of neurons.
In the central nervous system, NO acts as a neurotransmitter in the
cerebellum.53-54 Its action resembles the interaction between endothelial
cells and smooth-muscle cells in a blood vessel. NO released from the
postsynaptic neurons (in response to activation of receptor molecule N-
methyl-D-aspartate) stimulates neighboring neurons to produce cyclic GMP.
NO has also been implicated in another part of the brain-the hippocampus.
The hippocampus is involved in learning and the formation of memory. NO
appears to be essential for establishing long-term potentiation memory,
but not short-term potentiation memory. In long-term potentiation, the
strength of synaptic contact increases as a consequence of the frequent
use of memory.
4. Nitric Oxide as a Part of the Immune System
The role of NO in the immune system is much different from its role in
cardiovascular or neuronal system. In humans, almost every type of cell
in the body can express
iNOS. In contrast to nNOS and eNOS, the inducible iNOS is calcium-
independent.53-54 The signal to translate the DNA sequence for the iNOS
into the amino-acid sequence for the iNOS enzyme comes from certain
cytokines that are produced by the infected cells. Any kind of infection
(including bacterium, viruses or cancer) will lead to the production of
cytokines. Cytokines carry the message of the infectious state to the
macrophages of rodents, or to the surrounding cells of humans, which will
start to produce iNOS. Immediately after translation is complete and the
prosthetic groups are in place, iNOS will continuously produce large
amounts of NO for an extended period of time (several hours). The total
NO production will be therefore much higher than that produced by
endothelial cells (few minutes) or neurons (few seconds).
iNOS produce a sufficient concentration of NO to locally inhibit
ribonucleotide reductase, the enzyme that converts ribonucleotides to the
deoxyribonucleotides necessary for DNA synthesis, hence the profound
cytostatic effect of NO on the proliferation of rapidly dividing tumor
cells or pathogens. In addition, DNA synthesis is a fundamental step in
normal cell proliferation. Even normally high NO concentrations from
constitutive NOS can inhibit the ribonucleotide reductase, thus halting
the proliferation of smooth muscles around major arteries and cardiac
myocytes. NO is not toxic even at higher biological concentration.
Therefore it is unlikely that NO can actually kill tumor cells; NO just
limits their proliferation.
5. Electrochemical Measurements of Nitric Oxide
The short life of NO and its low concentration in biological systems make
the measurement of this molecule a challenging analytical problem. Among
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