The 1998 Nobel Prize in Physiology or Medicine
Le lauréat du Prix Nobel 1998 de physiologie ou de
recognized the biological significance of nitric oxide.
médecine a reconnu l’importance biologique de l’oxyde
Nitric oxide is derived from the amino acid arginine.
nitrique, un dérivé d’un acide aminé, l’arginine. L’oxyde
It is intimately involved with circulatory vessel dilation
nitrique intervient dans la dilatation des vaisseaux; par
where, for example, it protects against heart attacks,
exemple, il protège le cœur contre les infarctus et il est à
and is the basis for new medications such as Sildenafil
la base de nouveaux médicaments comme le sildénafil
(Viagra). Nitric oxide acts as a neurotransmitter and can
(Viagra). Il agit également comme neurotransmetteur et
modulate many neurological reactions. The immune
peut modifier de nombreuses réactions neurologiques.
system uses nitric oxide to destroy pathogens by
Par ailleurs, le système immunitaire utilise l’oxyde
interfering with key enzymes. Nitric oxide is responsible
nitrique pour détruire des agents pathogènes en agissant
for both osteoclastic and osteoblastic responses in bone
sur des enzymes clés. Il est aussi responsable des
and is a key player in the degenerative aspects of
réactions ostéoclastiques et ostéoblastiques et joue un
arthritis. The process of apoptosis employs nitric oxide
rôle important dans la dégénérescence des tissus
in the orderly removal of unneeded cells. There is clear
observée dans l’arthrite. En outre, l’oxyde nitrique sert
evidence that major signaling and control mechanisms
dans l’apoptose pour la destruction programmée des
exist in the body apart from the nervous system.
cellules inutiles. Voilà une preuve évidente qu’il existe, à
Chiropractic is thus faced with the challenge of how to
part le système nerveux, des mécanismes importants de
incorporate this new knowledge which conflicts with
transmission de signaux et de commande dans
traditional chiropractic concepts.
l’organisme. La chiropratique fait face maintenant à un
dilemme : comment intégrer ces nouvelles connaissancesqui entrent en contradiction avec les conceptstraditionnels de la chiropratique?
(JACC 2000; 44(1):40–48)
K E Y W O R D S : nitric oxide, chiropractic.
M O T S C L É S : oxyde nitrique, chiropratique.
* 2352 North Tangent Avenue, Meridian, ID. 83642.
Phone: (208) 884-0719, Fax: (208) 884-1053.
Requests for reprints should be made to the above author.
No outside sources of support or conflicts of interest exist.
Pursuing the macrophage issue further it was discov-
Numerous chemical bio-messaging and signaling mecha-
ered that macrophage defense required the amino acid
nisms have been found necessary for human function.
arginine to produce nitrates. Macrophages use an inter-
While beyond the scope of this paper these mechanisms
mediary enzyme to convert the arginine into nitric oxide
include integrin transmembrane signaling,1 sequential
and citruline. The nitric oxide resulting from the conver-
protein kinase reactions,2 and antigen receptor signaling.3
sion of arginine permits macrophages to kill foreign invad-
This paper is intended as an overview of the remarkable
ers by its toxic, free radical activity.5
bio-messaging role played by nitric oxide (NO). Amedline search found more than 18,000 peer-reviewed,
Biochemical synthesis of NO
indexed papers have been published on the topic of nitric
Nitric oxide is formed by oxidation of the amino acid
oxide in the past four years. Thus, a comprehensive review
L-arginine. The catalyst nitric oxide synthase (NOS)
is not possible in this paper. Instead, those references were
drives this process. NOS may be either constitutive (con-
chosen that provided a summary of current nitric oxide
stant production) or inducible (iNOS) in form. Each form
research, and which held potential implications for chiro-
reflects differing origins, chemical makeup, and function.
Constitutive NOS I is found in nerve cells and is involved
An October 12, 1998 press release announced the Nobel
in nervous system signal transduction. Constitutive NOS
Prize in Physiology or Medicine for 1998 was awarded to
III is found in endothelial cells and regulates blood flow
Robert F. Furchgott, Louis J. Ignarro, and Ferid Murrad
and platelet function. Constitutive NOS levels are regu-
for their discoveries concerning “nitric oxide as a signal-
lated by activating or inhibiting enzymes.8,9
ling molecule in the cardiovascular system.”4
The constitutive forms of NOS are a key regulator of
In 1980 Furchgott revealed that the vasodilative action
homeostasis, whereas iNOS is involved in inflammation,
of acetylcholine no longer worked if the inner endothelial
lining of blood vessels was removed. The presence in the
iNOS is expressed as needed by nearly all body cells,
lining of an endothelium-derived relaxing factor (EDRF)
particularly white blood cells and hepatocytes. Cytokines
was needed for vaso-dilation to occur. EDRF was neces-
such as tumour necrosis factor alpha (TNF–a), interferon
sary for the formation of cyclic guanosine monophosphate
gamma (IFN–l), and certain interleukins (esp. IL–1, IL–2)
(GMP), a messenger for neurotransmitters and hormones.5
Further research identified EDRF as being identical withthe gas nitric oxide (NO).6
Recognizing its future potential the journal Science
Physiological effects of NO
named nitric oxide ‘Molecule of the Year’ in 1992.5
Nitric oxide’s short half-life of 5–10 seconds limits itsactions to the immediate vicinity. After entering a cell,
From humble origins
nitric oxide commonly targets the enzyme guanylate cy-
NO was first discovered in 1772 by Joseph Priestly who
. This in turn catalyzes the formation of cyclic GMP.
also discovered oxygen. NO, a colorless, highly reactive
Cyclic GMP then activates a intracellular signal to evoke
gas, normally exists for only a few seconds before combin-
the cell’s ultimate response.11 Other molecules targeted by
ing with oxygen to form nitrates. Possessing an extra elec-
NO include haem proteins and superoxide anions in vascu-
tron, it is a highly reactive free radical in the body. Its
lar and cardiac tissue.12,13 NO further reacts with oxygen
toxic-like behavior initially gave no clues that it might play
free radicals to produce peroxynitrite, a powerful oxi-
a crucial role as a mediator of body function.7
It was initially observed that subjects fed low-nitrate
The physiologic effects of NO are highly dose depend-
diets still excreted considerable amounts of nitrates. Rats
ent, with toxic effects generally increasing with higher
subjected to bacterial endotoxin injections also showed
doses.13,15 The ultimate effects of NO are dependent not
increased nitrate excretion. Further experimentation re-
only upon dosage levels, but also on the rate and timing of
vealed an association between the level of macrophage
NO release, and on the level of reactive oxygen concentra-
NO as a neurotransmitter and blocker
It is counterintuitive to consider a toxic, highly reactive
NO mediated inflammation causes neural conduction
gas such as nitric oxide as a crucial neurotransmitter.
block in multiple sclerosis and Guillain-Barré syndrome.25
Neurotransmitters are normally stored as stable chemicals
Exposed to inflammatory levels of NO peripheral nerves
in synaptic vesicles of nerve terminals. Upon release they
can experience a total loss of compound action potential in
fuse with receptor proteins on adjacent neurons and com-
both myelinated and unmyelinated fibers.26
mence signaling cascades. In contrast, nitric oxide does
While excessive levels of NO cause neural injury, nor-
not rely on vesicle storage. NO is synthesized as needed
mal levels play a key role in neural development, regen-
whereupon it promptly diffuses in all directions into
eration, and regulation of gene expression.18 Nitric oxide’s
nearby neurons, bypassing conventional neural receptors.5
ability to modulate synaptic gap junctions is a probable
The signaling action of NO is both intra- and intercellu-
mechanism whereby cortical modulation and subcortical
Nitric oxide may exhibit either a up- or downregulatory
mode in the spinal cord depending upon the types of fibers
The vascular connection
activated and the intensity of signal input.17
It is recognized that reduced nitric oxide is a factor in the
In addition to its role in neurotransmission NO is also
development of cardiovascular disease. This may occur
involved in neural development, neural regeneration, and
from abnormal signal transduction, insufficient L-ar-
regulation of genetic expression. Nitric oxide is further
ginine, and lowered enzyme expression.28,29 It has also
considered to mediate both nociceptive and proprioceptive
long been recognized that cardiovascular dysfunction of-
ten results in male impotence due to penile vascular
In the gastrointestinal tract NO is likely a transmitter for
perfusion deficits.30 The presence of cardiovascular dis-
inhibitory motor neurons, but not in enteric sensory neu-
ease interferes with the prerequisite smooth muscle relaxa-
rons. NO modulates intestinal reflexes by inhibiting trans-
tion.31 This realization led to investigations of a possible
mission in the descending reflex pathway. The site of
role for NO in erectile dysfunction.
activity appears to be between sensory neurons and
It was soon discovered that release of NO from either
interneurons. In this location NO acts as a retrograde trans-
the vascular endothelium or from non-cholinergic, non-
mitter inhibiting transmission of sensory neurons.20
adrenergic nerves would increase intracellular levels of
Observations indicate that NO modulates intestinal re-
cGMP (cyclic guanosine monophosphate). Increased lev-
flexes by direct action on intestinal neurons of the enteric
els of cGMP in turn modulated intracellular calcium pro-
nervous system. NO released by interneurons act as nega-
tive feedback system on sensory synapses inhibiting trans-
Certain phosphodiesterase compounds appeared to play
a crucial down regulatory role in the levels of cGMP.33
Additional research has established that electrical vagal
Thus a search for compounds to inhibit the action of phos-
stimulation produces stomach relaxation through NO re-
phodiesterase, thus increasing levels of cGMP, led to the
lease.21 NOS expression, and thus NO release, in the rat
discovery of Sildenafil citrate (Viagra).34 Sildenafil inhib-
gastric myenteric plexus is under vagal control.22
its phosphodiesterase allowing increased cGMP thereby
In a rat model of diabetes gastric relaxation is impaired.
releasing intracellular calcium. The calcium binds to
The impaired relaxation results from diabetes related re-
calmodulin activating nitric oxide synthase (NOS). NOS
duction in NOS-immunoreactive cells with corresponding
releases nitric oxide producing smooth muscle relaxation
loss of NOS expression and decreased gastric relaxation.23
NO may also serve as a neurological amplifier by
This research also explains why nitroglycerin, the active
strengthening a postulated feedback loop between postsy-
ingredient in dynamite, is effective as a treatment for cer-
naptic and presynaptic cells. NO can serve as an amplifier
tain heart problems. Nitroglycerine is metabolically con-
of calcium signals in neuronal cells. In the presence of NO
verted to nitric oxide which dilates the coronary arteries.5
weak input signals that might otherwise be unnoticed bythe cell can undergo amplification and result in significant
Immune system modulation
The immune system depends upon the ability of thymus-
NO has been termed the ‘mediator of lethal processes’
derived (T) lymphocytes to recognize foreign antigens. T
from its close association with apoptosis. One common
cells are further divided into helper T cells (Th) and cyto-
mechanism involves NO reaction with superoxide anions.
toxic (Tc) cells. Upon activation, Th cells produce
When the NO concentration reaches critical levels, deter-
lymphokines that regulate other cells of the immune sys-
mined by cell type and the local environment, regulated
tem. The types of lymphokines produced further catego-
rize Th cells. Th1 cells produce IL-2 and gamma
NO mediated apoptosis is implicated in many
interferon while Th2 cells produce IL-4 and IL-5.35
neurodegenerative diseases, including Alzheimer’s, Par-
It has been demonstrated that cytokines from T helper 1
kinson’s, and cell death in cerebral ischemia.39,40 Combin-
cells (Th1) increases NO production. Conversely, T helper
ing with certain cytokines NO is a primary mediator of
2 cell (Th2) derived cytokines inhibit NO production sug-
gesting immune helper cells regulate NO production.36
NO at sufficient levels depresses myocardial con-
Levels of NO must be carefully regulated within narrow
tractility and is toxic to cardiac myocytes.14 NO induces
parameters. Abnormal levels of NO are closely associated
apoptosis in cortical neuronal cells.41 By causing enter-
with numerous autoimmune pathologies. These include
ocyte apoptosis NO produces “bare areas” in the intestinal
rheumatoid arthritis, surgical graft rejection, diabetes, lu-
epithelium which are then susceptible to bacterial invasion
pus, and multiple sclerosis. NO levels are regulated, in
and a subsequent systemic inflammatory response.42
part, by opposing cytokines from Th1 and Th2 cells. NO
Conversely, NO demonstrates a protective effect
may in turn prevent excess numbers of Th1 cells that are
against actinomycin induced liver apoptosis in mice.43
Thus, depending upon the local tissue environment, NO
A variety of studies have demonstrated the NO role in
may act as either a pro- or anti-apoptotic molecule.44
antimicrobial defense against such intracellular pathogensas Leishmania, Toxoplasma, Trypanosoma, Listeria,
Inflammation and arthritis
in rodents.38 In humans the NO produced by
In the body NO lasts only a few seconds before being
neutrophils, macrophages, and other cells inactivate bacte-
oxidized to nitrite and ultimately excreted as nitrate. Moni-
toring urinary nitrate gives a measure of NO activity. Lowamounts of NO in the body are protective against inflam-
mation damage by maintaining tissue perfusion. As will be
Living cells eventually die from either necrosis or
demonstrated later, increased levels of NO are destructive,
apoptosis. In necrotic death cells passively swell, mito-
giving NO a ‘double-edged sword’ reputation.8
chondria are disrupted, the cell membrane is lysed, and
Cerinic investigated the potential role of the nervous
cellular contents are released into surrounding tissues
system in arthritis and determined that inflammation can
modulate efferent and afferent portions of the peripheral
The other form of cell death, apoptosis (Gr. “a falling
nervous system (PNS).45 Further, afferent (nociceptive)
off”), is the process of controlled cell suicide whereby
terminal fibers may have an efferent effect by releasing
cells no longer needed by the body are eliminated. In
local neuropeptides and proinflammatory mediators.45
apoptotic death an active process of cell shrinkage occurs,
NO not only reveals, but also mediates the progression
followed by phagocytosis preventing nearby tissue inflam-
of arthritis. Numerous studies have confirmed that NO is a
marker for, and a pro-inflammatory mediator of, arthritis.
Controlled apoptosis is crucial to normal health. The
Adjuvant induced arthritis results in nitrate excretion, re-
process of embryonic growth and differentiation requires
flecting the action of NO that corresponds with arthritis
that surplus cells die and be removed. In later adult life,
progression. A similar pattern exists for systemic inflam-
disrupted apoptosis allows development of neoplastic cells
matory joint disease. Increased nitrite levels are found in
and certain autoimmune diseases. Excessive apoptosis,
the joints of patients with rheumatoid arthritis (RA),
however, is likely involved in neurodegenerative diseases
osteoarthritis (OA), and in the spondylarthropathies. NO
further appears to be involved in the pathogenesis of sys-
NO likely plays a key role in the joint swelling and vasodi-
temic lupus erythematosus (SLE) and chronic inflamma-
lation characteristic of RA. When inhibitors of NOS are
used they suppress the development of inflammatory joint
A variety of cells are sources of NO in arthritis, includ-
ing macrophages, synoviocytes, endothelial cells and
The data suggest that certain synoviocytes, the cells of
chondrocytes. Not only is this NO a likely factor in arthri-
the synovial membrane, are derived from monocytes.
tis and related inflammation, it appears to also help
These synoviocytes, known as CD14+, express iNOS and
develop and maintain the associated hyperalgesia. NO
produce NO. The number of CD14+ cells present cor-
thus joins substance P and other neuropeptides in the
relates closely with subsequent production of NO.52 The
NO released by the synoviocytes accumulates at a point of
It has been demonstrated that articular symptoms and
injury activating nociceptors directly and causing vasodi-
joint degeneration in animal models can be reduced by use
Further investigation into the pathogenesis of inflam-
The actions of many arthritis drugs are directed at NO
matory arthritis suggests NO, in concert with certain
activity. Prednisolone reduces joint nitrite levels, sali-
cytokines, suppresses proteoglycan signaling and induces
cylates act to scavenge NO, cyclosporin drugs inhibit NOS
expression, and methotrexate blocks cofactors of NOS.8
In human osteoarthritis the synovial fluid contains few
neutrophils or leukocytes, common sources of NO. Instead
Bone resorption by osteoclasts is a complex process in-
osteoarthritis involves a change in the balance of catabolic
volving cytokines, hormones, and other components. Os-
and anabolic activities in the collagen matrix. It is believed
teoblastic production of NO serves as an intercellular
that articular chondrocytes have the capacity to express
inhibitor of osteoclastic action. Conversely, osteoclasts
sufficient NOS to cause cartilage degeneration and is
can produce NO in response to inflammation. Osteoclastic
likely a factor in the pathogenesis of osteoarthritis.10
NO serves to dampen excessive bone resorption.56
In osteoarthritis (OA) fundamental alterations occur in
The effects of NO on bone remodeling are extremely
the cartilage tissue itself, different from that found in rheu-
dose sensitive. Osteoblasts can release NO which in turn
matoid arthritis (RA). In OA inflammation mediators are
regulates osteoblast growth. When levels of NO pass a
found in the chondrocytes themselves. Chondrocyte stain-
certain threshold, as in inflammatory conditions, new bone
ing of cartilage from patients with OA or traumatic arthri-
formation is reduced. Beyond this threshold NO becomes
tis revealed elevated levels of the cytokines interleukin
inhibitory to osteoblasts and possibly toxic. Excess levels
(IL–1ß) and tumor necrosis factor (TNFa) and marked
of NO are likely involved in other bone depleting diseases
elevations of iNOS, considerably more than in the inflam-
including osteopenia, postmenopausal osteoporosis,
matory arthritides. The coordinated autocrine involvement
tumor-associated osteolysis, and periodontal disease.57,58
of these three substances appears to be involved in the
NO thresholds for osteoclast and osteoblast activity may
not be identical, however. Thus a given level of NO may
It is presumed that trauma and/or repeated micro-
upregulate or downregulate either osteoblasts or osteo-
traumas provide the trigger to initiate degenerative NO
clasts, or both, depending on local conditions.55,58
and cytokine activity.48 One study suggested a role for
Estrogen has been shown to protect against cardiovas-
collagenase production in the development of osteo-
cular disease and osteoporotic bone loss in postmenopau-
sal women. The benefits from estrogen therapy derive
In rheumatoid arthritis (RA) expression of iNOS is
from estrogenic stimulation of osteoclasts to generate NO,
highest in the joint synovium, the synovial lining, blood
which in turn upregulates osteoclast activity.57,59
vessels, and somewhat in the cartilage. This is in contrast
Disruption of normal bone homeostasis by excessive
to OA where no iNOS expression occurs in the synovium.
NO results in not only joint deterioration but also in loos-
The early feature of RA is local bone loss. This results
ening of joint prostheses. As polyethylene components of
from the inhibitory action of NO on osteoblast formation.
the prostheses flake off macrophages are attracted to these
debris particles. Phagocytosis of these particles is fol-
regulation of body functions has been a simplistic and
lowed by expression of iNOS and subsequent release of
straightforward one. D. D. Palmer expressed the basic con-
NO. The resulting bone resorption around the implant
causes aseptic loosening and eventual failure of the hipprosthesis.60,61
“The cause of disease is a mechanical obstruction tonatural functions.”
The multifunctional molecule
Nitric oxide’s role as a multifaceted biological mediator is
Palmer’s hypothesis of nerve interference causing dis-
pervasive. From near obscurity fifteen years ago nitric ox-
ease reflects his understanding of the limited scientific
ide is now considered one of the major players in physi-
knowledge of his time. However, Palmer’s concept of
ological function. Nitric oxide is involved in the dilation of
nervous system blockage as the basic cause of disease still
blood vessels, helps defend against infection and tumors,
serves as a neurotransmitter in the nervous system, and asa contributor to remodeling of bone. It is an essential agent
“Because the nerves work as a conduit of the life force,
of apoptosis, and is involved with numerous cytokines in
interference to the normal quantity flow causes mal-
the regeneration and degeneration of many body tissues.
function. This is the fundamental basis of dis-ease.”
Nitric oxide mediates biochemical cascades of events thatserve to control or effect any of a number of bodily func-
Dramatic advances in scientific understanding of hu-
tions. It effects this control in response to local biochemi-
man physiology bring these classical chiropractic explana-
tions of human function into question. Developing
Many biological responses are initiated in response to
knowledge of human biological messaging systems, as
local events. Severing of blood vessels starts a biochemi-
noted in this review of the role of nitric oxide, lends little or
cal cascade of events leading to the clotting of blood. This
no support to traditional chiropractic concepts. Quadriple-
biochemical cascade is subject to control by nitric oxide.
gics, with massive ‘nerve interference’, continue to dem-
NO can inhibit platelet aggregation62 and can reduce the
onstrate normal immune system function in the complete
clotting action of factor XIII.63 Hemoglobin itself is being
increasingly seen as a carrier and distributor of nitric oxide
As illustrated previously, many regulatory functions
of the body take place with limited or no input from the
The immune response is triggered when an antigen en-
nervous system. Indeed, nitric oxide is itself a potent
ters the body and is chemically recognized as being for-
modulator of the nervous system. Local conditions in the
eign. Activated lymphocytes converge and eliminate the
body have the capacity to exert a controlling influence
invader by producing NO which deactivates key enzymes
back on the nervous system via nitric oxide and cytokine
It is known that anxiety disorders can affect the immune
This should not be seen as minimizing the importance of
system by reducing lymphocyte cytokine and NO produc-
the nervous system. Rather it is an attempt to gain a ra-
tion.64 Likewise, NO can modulate the firing of neural
tional perspective that recognizes body systems work as a
synapses, influence the proliferation of nerve terminals,
coordinated whole. One example of this broadened per-
produce retrograde synaptic firing from afferent fiber ter-
spective notes: “The skin, the nervous system and immu-
minals in an efferent manner, and support nociceptive
nity are not independent systems but are closely associated
and use the same language of cytokines and neuro-
Nitric oxide’s role is so pervasive that it even plays a
transmitters.”68 Another researcher notes that the immune
key role in disease resistance in plants by inducing genes
system is itself a sensory organ, that bi-directional com-
munication pathways exist with the nervous system, andthat the immune system influences other elements of
Implications for chiropractic
Chiropractic’s classical position regarding health and the
This broader and more egalitarian view sees physiologi-
cal function as a seamless interlocking process with no one
11 Alberts B, Bray D, Johnson A, et al. General principles of
system necessarily superior. It is increasingly clear that
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chiropractic notions about human health and function be-
ing dependent upon removing ‘nerve interference’ are in-
12 Stoclet J, Muller B, Gyorgy K, Andriantsiothaina R,
adequate, misleading and hopelessly simplistic.
Kleschyov A. The inducible nitric oxide synthase in
The challenge to chiropractic is to adapt its perspectives
vascular and cardiac tissue. Eur J Pharmacol 1999;
to the latest in scientific understanding. The chiropractic
profession could choose to continue limiting itself to the
13 Veeramachaneni N, Harken A, Cairns C. Clinical
implications of hemoglobin as a nitric oxide carrier.
dictates of its archaic and arbitrary tradition. The other
choice is to deal with the implications of new knowledge
14 Ing D, Zang J, Dzau V, Webster K, Bishopric N.
about the body’s sophisticated systems of signal transduc-
Modulation of cytokine-induced cardiac myoctye
tion and control. These bio-chemical signaling systems are
apoptosis by nitric oxide, bak, and bcl-x.
Circ Res 1999;
clearly at odds with traditional chiropractic theory.
15 Damoulis P, Hauschka P. Nitric oxide acts in conjunction
To create an inclusive model of care chiropractic must
with proinflammatory cytokines to promote cell death in
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16 Huang S, Kerschbaum H, Hermann A. Nitric oxide-
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Comunicado de prensa Actos públicos y símbolos religiosos Ante el actual debate acerca de la presencia de los símbolos religiosos en los actos oficiales, así como el inminente debate en el Congreso de los diputados de los acuerdos entre el Estado español y el Estado del Vaticano, como Alianza Evangélica Española queremos aportar nuestro punto de vista dentro de la perspecti
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