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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.
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Introduction
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 clase. 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, and Inflammation and arthritis
Rickettsia 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- Apoptosis
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 Bone remodeling
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.”66 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.”67 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 cell signaling, in Essential Cell Biology: an introduction tothe molecular biology of the cell. New York: Garland 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 expand its views to include the body’s complex signaling osteoblasts. J Bone Miner Res 1997; 12:412–22.
systems. Such a move would allow better definition of 16 Huang S, Kerschbaum H, Hermann A. Nitric oxide- those conditions most amenable to our therapeutic inter- mediated cGMP synthesis in Helix neural ganglia. Brain ventions. For chiropractic to lay claim to being a bona fide health science we must incorporate the latest in scientific 17 Callsen C, Hoheisel U, Kaske A, Mense S, Tenschert S.
The controversy about spinal neuronal nitric oxide knowledge, even when it means abandoning old traditions.
synthase: under which conditions is it up- ordownregulated? Cell Tissue Res 1999; 295:183–194.
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