NO Netting, Health and Stress

Studying Wellness from a Net Perspective
 Dina Ralt,
Med Hypotheses. 2008;70(1):85-91

On the nature of wellness, stress, netting and the radical gas nitric oxide (NO).
The multi-complex role of NO resulted in its discoverers receiving a Nobel award, its presence everywhere and volatility makes it a suitable candidate to be a main signal in an instantaneous communication network. Such network, with the capacity of tight physiological monitoring, enables assets distributions in the body.
A model is presented suggesting that an intercellular communication network coordinates the various bodily functions. Radical gases like nitric oxide (NO) are signals in this net and its usability affects health and indicates wellness. From this netting point of view, stress is the sense of flow interruption or blockage of the information stream. Such flow interruption affects also physiological functions and can explain the association between stress and many ailments.
It is suggested that netting is a prerequisite route of wellness, enabling bodily unconscious managerial decisions. This vital diffusive network is extremely labile and potentially could contain the interplay of consciousness and unconsciousness effected by activities such as yoga or guided imagery.
Vast data from studies on NO signals, health and the relaxation/stress processes have already been accumulated. Integration of these data supports this novel look of an NO network as a coordinator. Interactions between stress and health are discussed in net perspective and include basic concepts of some integrative health approaches.
Studying the nature of such communication network and of NO may suggest new ways to reduce stress and approach wellness.

Information crisis
Stress is one of the main ailments of the 21st century and we have caused it, as phrased by Robert Sapolsky "we've evolved to be smart enough to make ourselves sick" [1]. Facing wealth of opportunities, we constantly pay only partial attention (in an effort not to miss anything), a behavior that results in a feel of permanent crisis [2].
This article deals with the physiological aspects of the information crisis and with possible ways to ease it and its accompanying stress.
Information is crucial to the ability to handle complexity; thus, control mechanisms in the body might be regarded as information processing. This idea was proposed by Maturana and Varela in the concept of Autopoiesis, the process by which systems organize themselves out of disorder, forming a responsive, self-maintaining network characteristic of life [3].
As information processing is the porthole of this article, stress and wellness are referred to here as a sense of wellbeing devised from bodily information. Vast data show that stress is associated with many ailments [4-6], implying that in a way we do sense our health status. It is important to note that other factors, besides direct information processing, can contribute to stress and wellness.
Just as stress could be an indication of ill health, optimism and wellness could be markers of health and potential longevity [7, 8]. Evaluation of the stress or wellness condition requires constant data input and it is reasonable to assume that the body will utilize vital markers like nitric oxide (NO) which are found everywhere and anytime for updated evaluation.
On nitric oxide
The discovery that mammalian cells have the ability to synthesize the free radical NO has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions [9].
NO is produced by a family of enzymes, the nitric oxide synthetases (NOS), through enzymatic oxidation of the guanidine group of L-arginine [10]. NO is implicated in numerous physiological and pathophysiological processes. Its dual-natured activity [11] in almost any physiological system studied, as well as its complex regulation and intricate biochemistry [12], sometimes result in studies without current conclusive deduction such as "Is the increased NO produced in airway disease good or bad?" [13]. The suggested webby nature of NO may imply that more NO or less NO is not good or bad per se, but rather indicates its involvement in regulation.
Despite the theoretical saturation of NOS enzymes with intracellular L-arginine, cellular NO production depends on exogenous L-arginine concentration, which is known as the "arginine paradox" [14]. L-Arginine affects many physiological functions [15], at a higher dose it can even replace Viagra [16] in treating erectile dysfunction [17]. A warning against using very high concentrations of L-arginine emerged when six patients died in a study testing whether L-arginine can improve heart function after a heart attack [18].
It has also been demonstrated that nitrite, which was previously considered to be only an oxidation byproduct of NO, is the largest tissue storage form of NO [19].
Along with NO, a novel type of medication was discovered – sildenafil citrate, Viagra [16]. Its ability to treat erectile dysfunction made it the most famous drug in the world. Sildenafil citrate is a potent inhibitor of phosphodiesterase type 5, and extends the persistence of any elevated scale of NO processed via the guanylate cyclase [12]. If as suggested, increased NO signaling enables better curability, one can expect Viagra to assist not only in treating erectile dysfunction but other maladies as well. Indeed, data are accumulating and indicating that Viagra has other therapeutic use in ailments of the heart [20], lungs [21], and kidneys [22]. Such medication, which enhances the body’s own signals, is bound to have fewer side effects than many other drugs as it let the body operate naturally. It is important to note that this does not mean that Viagra has no side effects [23].
The hypothesis presented here suggests that the body relies on non-structured (sensitive and volatile) communication networks to better its maintenance. Besides major communication tools (nerves, blood, hormones), other inter-cellular communication mechanisms, such as NO signaling, can serve an important role in the wellness data bank. It is suggested that just as on top of television news or cellular phone conversations, the internet provides instant data to assist people facing demanding decisions [24], the body relies on rapid/diffusive communication nets to keep an eye on the ball.
If information processing in the body is essential for wellness, a possible cause of stress would be the blurring or obstruction of this data flow in our body. Operating under "not enough data" condition is stressful and enhancement of the relevant information flow can reduce stress and support health. It is suggested that un-obstructing the NO flow, increases the body capabilities to decide where, how and which of its own healing resources to utilize for maintenance and for repairing its maladies. It also suggests that under hectic conditions we are not enjoying our natural potential for cure. This, in other words, is what naturalists/therapists [25] claim – do not obstruct the natural way and just let the body take care of itself.
NO is a small, hydrophobic molecule that can easily pass through membranes. It persists in vivo for a few seconds, and can diffuse only several cell diameters away from its site of synthesis. Molecules containing thiol groups, such as acethylcysteine, albumin or red blood cells, can not only be NO scavengers, but can also protect it from metabolism. They are NO carriers that can release active NO or an NO-containing small molecule at a distance from the NO site of production. The reversible addition of NO to Cys-sulfur in proteins, a modifi
cation termed S-nitrosylation, has emerged as a ubiquitous signaling mechanism for regulating diverse cellular processes [26, 27].
The NO known toxicity can be a virtue when considering it as a communication signal. Implementing the "handicap principle" [28] calls to mind that toxicity of signals can be a reliable way to ensure their credibility.
As expected from a key signal, many factors can modulate the NO effect on the cells: NO concentration, time course of exposure to NO, type of NO derivative present, thiol status of the cell, glycolytic capacity, NO and NO-independent protective mechanisms, metals such as iron, other free radicals, oxygen, superoxide anion, unsaturated fatty acids and other molecules [29]. NO network has thus the capacity of tight physiological monitoring.
Implications and testing
Looking at NO as a major information signal circulating in the body [30] can theoretically explain why we are so stressful and suggest ways to reduce the stress.
NO is a very fragile molecule affected by numerous variables; its information flow depends on its neighboring carriers and many other factors and is thus slow and susceptible. In our times, where our minds as well as our senses are bombarded with stimuli, we can likely assume that many of the NO and the NO-derived reactive species messages do not reach their destination. Operating consciously or unconsciously under missing information conditions is bound to be stressful, especially when considering the centrality of the NO net. Indeed, relaxation response which is associated with NO production [31, 32] can help to explain the NO clinical effects under stress.
The proposal presented here suggests that just as our body feels good after physical activity [33] it feels good when its information flow is unobstructed and when signals reach their destinations. Though it is too early at this stage to figure out the mechanism for such data evaluation, it is possible to suggest ways to enhance the information flow and thus to lower stress. The interplay between stress, emotional behavior such as response to anxiety, and NO has been established. It has been demonstrated for example, that much of the mediated effects of the amygdala – the emotional regulatory center, exert their effects coupled to NO release [34]. Both NO and CO exert a stimulatory influence on the acute adrenocorticotropic hormone (ACTH) response to physico-emotional stressors [35]. NO plays a modulatory role on brain areas related to defensive reactions [36]. NOS inhibitor prevents anxiety-like and depression-like behavior in rats exposed to restraint stress (37). In humans, responses to mental stress test, such as elevation of arterial plasma norepinephrine, were affected by pre-infusion of the NOS inhibitor L-NMMA (38). Other studies, affecting NO in other ways (via L-arginine for example), also demonstrate that NO plays a role in stress and in depression [39-42]. A reduction in stress associated with NO, can give an additional explanation for smoking and nicotine addiction. Inhaled NO from smoke may be able to increase nicotine absorption and NO released through nicotine can reduce symptoms of stress [43]. 
How does the NO net interact with other stress systems in the body? Due to the multi-functionality of the NO [9], a complex reciprocal relation is expected. The NO net will be both affected and affecting other stress systems and thus netting rather than linear relations models should be looked for.
Data are accumulating establishing the NO interactions with variety of mediators such as acetylecholine and dopamine associated with increased parasympathetic activity [44], morphine [45], ACTH and corticosterone [46], norepinephrin [47], glucocorticoid [48], gamma-aminobutyric acid [49] glutamate or serotonin [36]. To demonstrate just the tip of the NO interactions' iceberg it has been recently shown that syndapin, a protein previously thought to have no major role in nerve communication, is the molecule that simultaneously works with dynamin to allow the transmission of messages between nerve cells [50]. Dynamin is regulated by NO via S-nitrosylation [51].
Considering communication nets, it can be assumed that signals will reach their destination if they are stable enough, distinctive above background noise and if their flow is not obstructed.
This assumption leads to novel strategies to enhance signaling and thus reduce stress and improve health.  For example, decrease the background noise, optimize timing, increase the signal or focus attention.

Lowering the background noise
Living in hectic cities and being excited by so many stimuli can lead to blurring of many central signals and to feelings of anxiety. More is not necessarily better; even the cellular phone use, meant to improve family communication, is associated with increased family distress [52]. This may explain why quieting external stimuli is associated with relaxation and why many alternative therapies are concerned with reducing stimuli: less noise, soft music, less visual mess or simply closing of the eyes. The Zen approach is a good example of attempting minimal stimuli in order to enhance peacefulness [53]. Going out of the city (away from the hectic stimuli) is another popular approach to reduce stress [54].
Lowering the "noise" can be achieved in other areas as well, for example food. Food approaches for healing are numerous, and cutting down on variety, such as the vegan diet [55] or fasting [56] can contribute to the healing power of the body in more ways than one.
Leisure-time activities can also diminish noisy interference. A population-based study in Finland showed that leisure participation predicts survival in middle-aged Finnish men. This beneficial effect emphasizes the significance of leisure activities for the promotion of men's health [57].
Regular increase in physical activity is associated with nitric oxide bioavailability and is an example of another aspect of lifestyle that affects health via NO [58]. Thus, as can be expected, NO indeed contributes to the potentially beneficial outcomes of various relaxation approaches [59].
Studies of complex networks (e.g. internet, traffic) demonstrate a universal dynamic nature that could be applied to other fields (e.g. physiology). Nodes of the network, playing different roles in the internet, can be classified into stable or alternating nodes according to the rapidity of their information flow [60]. Net traffic is characterized by a pattern of bursts of rapidly occurring events separated by long periods of inactivity [61]. Such time dependent conducts can be taken into account to improve treatments. For example, therapy might be more efficient if applied at the optimal burst time of the relevant net.
Enhancing the NO signal
Increasing the effects of NO can be achieved either by increasing NO production or by affecting parameters that influence its behavior.
One easy way to accomplish this is via nutrition. Foods like honey [62], garlic [63], olives [64] or nutrients containing the NO precursor – L-arginine (e.g peanuts [65] or L-arginine itself) will enhance NO production. Here again is a suggestion for food contribution to relaxation and not necessarily via lowered calories.
Another approach to influence the NO effect was mentioned earlier, the use of medication like Viagra [16]. It can enhance the NO resultant cGMP by lowering its breakup rate. The advantage of this approach is that it does not automatically increase the level of NO in the body, but rather allows the body to choose where and when to utilize the NO.
A well established technique is to use NO directly. Inhaled NO has been used for treatment of acute respiratory failure and pulmonary hypertension both in adult patients [66] and in newborns [67].
Gene therapy is another potential way to exert the diverse NO functions. All three NOS isoforms have been used in cardiovascular gene transfer studies with encouraging results in cardiovascular biology and pathobiology in various animal models [68].
An additional approach to increasing the level of NO is to increase its carriers’ availability by burning processes such as candle lighting or therapies like Moxa. Moxa, the Chinese heat/burn therapy, uses the ground up leaves of the plant Mugwort (Artemesia vulgaris) [69].
If indeed they enhance the NO signaling, then it is no wonder that lighting candles is an essential part of so many healing, romantic or spiritual ceremonies.
Heat can also enhance NO and may suggest another perspective for understanding the relaxing effect of a sauna [70].
Focusing while overlooking non-relevant signals
A whole range of alternative therapies and arts is concerned with focusing attention and ignoring or "letting go" of disturbing information signals. Attention to breathing is a major tool in many of these techniques, as for example guided imagery, meditation or relaxation [71, 72]. Is it related to the role of NO in signal transduction affecting oxygen transfer in the body [73]? NO has a very complex role in respiration [74] and despite the accumulated data its integrated role is not yet elucidated. It is proposed that holistic terms like the Buddhist term "within us" [75] or the Chinese term "qi" [76] may be related to the integrative role of NO netting information.
Attention focusing will result in quieting of all other areas and thus can exert well-being by enabling signals like NO to reach their destinations undisturbed. Biological studies in this field are starting to accumulate; for example, three different studies on meditation demonstrated that meditation is associated with happiness [77], health [78] and increased levels of NO [79]. It seems that the good feeling that accompanies meditation is really associated with significant better health and is not just a non-relevant feel. Another study on directed focusing showed that concentrating on the fMRI image of the brain region responsible for pain perception allowed the participants to increase or lower their pain while holding a very hot metal cube [80].
It is interesting to note that the whole range of concentration and "letting go" practices is associated with apparent time consumption. Overly busy people usually do not have the time and/or the patience required to achieve such needed attention and this may be an additional reason for stress in our western society where "time is money.”
Does this mean that enabling ("listening to") the inner NO disposition, or any communication system, requires time and space? Probably yes, but considering the recent study demonstrating that success follows happiness [81], it might be beneficial to invest in enabling  NO moves and stress reduction. As teachers in many cultures try to impart, happiness/wellness does not depend on the next success – wellness is the here and now.
Final words
Scientists in the west appreciate now the idea that information alone is sufficient to handle complex organization. This in fact was fundamental to the Chinese philosopher Lau-Tsu, who wrote in The Tao te Ching, more than two thousand years ago, that the world is ruled by letting things take their course, and cannot be controlled through interference [82].  Furthermore, It is interesting to note that documents (Dunhuang scrolls) dating to approximately 800 AD, suggest that nitrite and nitrate were used by the Chinese to relieve heart pains and cold in the hands [19].
The universal patterns of netting can be applied to maximize therapeutic potential and some possible routes have been suggested, there are of course others. Data were presented to demonstrate that NO can be a potential stimulus in such nets and explain its multi-factorial role in health.
Studying wellness from a net perspective enables applying novel approaches to therapy including known alternative therapies. This might be very relevant to the newer generation whose multitasking dexterity [83, 84] might evolve at the expense of their healing attention.
This article presents optimizing unobstructed information flow as a new approach to wellness.
"Life is too short to be in a hurry" Henry David Thoreau (1817-1862)
The author wish to thank Orit Cohen Raz, expert in inter-cellular communication, for contributing to understanding the basic concept of communication.

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