Stikkordarkiv: oksidativt stress

Vagal tone and the inflammatory reflex

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En studie som beskriver mekanismene bak hvordan vagus nerven henger sammen med immunsystemet. Med en sterk vagusnerve (høy HRV) kan betennelser dempes.

http://www.ccjm.org/content/76/Suppl_2/S23.long

Inhibition of sympathoexcitatory circuits is influenced by cerebral structures and mediated via vagal mechanisms. Studies of pharmacologic blockade of the prefrontal cortex together with neuroimaging studies support the role of the right hemisphere in parasympathetic control of the heart via its connection with the right vagus nerve. Neural mechanisms also regulate inflammation; vagus nerve activity inhibits macrophage activation and the synthesis of tumor necrosis factor in the reticuloendothelial system through the release of acetylcholine. Data suggest an association between heart rate variability and inflammation that may support the concept of a cholinergic anti-inflammatory pathway.

The neurovisceral integration model of cardiac vagal tone integrates autonomic, attentional, and affective systems into a functional and structural network. This neural network can be indexed by heart rate variability (HRV). High HRV is associated with greater prefrontal inhibitory tone. A lack of inhibition leads to undifferentiated threat responses to environmental challenges.

The cholinergic anti-inflammatory pathway

Acetylcholine and parasympathetic tone inhibit proinflammatory cytokines such as interleukin (IL)-6. These proinflammatory cytokines are under tonic inhibitory control via the vagus nerve, and this function may have important implications for health and disease.5

The cholinergic anti-inflammatory pathway is associated with efferent activity in the vagus nerve, leading to acetylcholine release in the reticuloendothelial system that includes the liver, heart, spleen, and gastrointestinal tract. Acetylcholine interacts with the alpha-7 nicotinic receptor on tissue macrophages to inhibit the release of proinflammatory cytokines, but not anti-inflammatory cytokines such as IL-10.

Approximately 80% of the fibers of the vagus nerve are sensory; ie, they sense the presence of proinflammatory cytokines and convey the signal to the brain. Efferent vagus nerve activity leads to the release of acetylcholine, which inhibits tumor necrosis factor (TNF)-alpha on the macrophages. Cytokine regulation also involves the sympathetic nervous system and the endocrine system (the hypothalamic-pituitary axis).

Inverse relationship between HRV and CRP

In a study of 613 airplane factory workers in southern Germany, vagally mediated HRV was inversely related to high-sensitivity CRP in men and premenopausal women, even after controlling for urinary norepinephrine as an index of sympathetic activity.6

Inverse relationship between HRV and fibrinogen

In a related report from the same study, vagal modulation of fibrinogen was investigated.7 Fibrinogen is a large glycoprotein that is synthesized by the liver. Plasma fibrinogen is a measure of systemic inflammation crucially involved in atherosclerosis.

CONCLUSION

The brain and the heart are intimately connected. Both epidemiologic and experimental data suggest an association between HRV and inflammation, including similar neural mechanisms. Evidence of an association between HRV and inflammation supports the concept of a cholinergic anti-inflammatory pathway.

Supplementary oxygen for nonhypoxemic patients: O2 much of a good thing?

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Nevner alt om hvordan oksygen er skadelig i høye mengder, både i klinisk sammenheng og eller. Bl.a. fordi med høy O2 går CO2 ned og da trekker blodårene seg sammen.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218982/

Abstract

Supplementary oxygen is routinely administered to patients, even those with adequate oxygen saturations, in the belief that it increases oxygen delivery. But oxygen delivery depends not just on arterial oxygen content but also on perfusion. It is not widely recognized that hyperoxia causes vasoconstriction, either directly or through hyperoxia-induced hypocapnia. If perfusion decreases more than arterial oxygen content increases during hyperoxia, then regional oxygen delivery decreases. This mechanism, and not (just) that attributed to reactive oxygen species, is likely to contribute to the worse outcomes in patients given high-concentration oxygen in the treatment of myocardial infarction, in postcardiac arrest, in stroke, in neonatal resuscitation and in the critically ill. The mechanism may also contribute to the increased risk of mortality in acute exacerbations of chronic obstructive pulmonary disease, in which worsening respiratory failure plays a predominant role. To avoid these effects, hyperoxia and hypocapnia should be avoided, with oxygen administered only to patients with evidence of hypoxemia and at a dose that relieves hypoxemia without causing hyperoxia.

… the aim of oxygen therapy should be to increase the delivery of oxygen rather than to reach any arbitrary concentration in the arterial blood.

Hyperoxia marginally increases the arterial blood oxygen content (CaO2), theoretically increasing tissue oxygen delivery (DO2) assuming no reduction in tissue blood flow. However, oxygen causes constriction of the coronary, cerebral, renal and other key vasculatures – and if regional perfusion decreases concomitantly with blood hyperoxygenation, one would have a seemingly paradoxical situation in which the administration of oxygen may place tissues at increased risk of hypoxic stress. Any tissue damage in the course of oxygen administration would plausibly be attributed to the underlying disease process.

One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?

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Alt om hvordan melatonin virker som en antioksidant. Jo større ROS utfordring vi har, jo mer spiser det av melatoninlagrene våre. Når vi får mindre ROS, feks gjennom kostholdsendringer og stressreduksjon, så økes melatonin igjen.

http://www.ncbi.nlm.nih.gov/pubmed/17198536

Melatonin is a highly conserved molecule. Its presence can be traced back to ancient photosynthetic prokaryotes. A primitive and primary function of melatonin is that it acts as a receptor-independent free radical scavenger and a broad-spectrum antioxidant. The receptor-dependent functions of melatonin were subsequently acquired during evolution. In the current review, we focus on melatonin metabolism which includes the synthetic rate-limiting enzymes, synthetic sites, potential regulatory mechanisms, bioavailability in humans, mechanisms of breakdown and functions of its metabolites. Recent evidence indicates that the original melatonin metabolite may be N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) rather than its commonly measured urinary excretory product 6-hydroxymelatonin sulfate. Numerous pathways for AFMK formation have been identified both in vitro and in vivo. These include enzymatic and pseudo-enzymatic pathways, interactions with reactive oxygen species (ROS)/reactive nitrogen species (RNS) and with ultraviolet irradiation. AFMK is present in mammals including humans, and is the only detectable melatonin metabolite in unicellular organisms and metazoans. 6-hydroxymelatonin sulfate has not been observed in these low evolutionary-ranked organisms. This implies that AFMK evolved earlier in evolution than 6-hydroxymelatonin sulfate as a melatonin metabolite. Via the AFMK pathway, a single melatonin molecule is reported to scavenge up to 10 ROS/RNS. That the free radical scavenging capacity of melatonin extends to its secondary, tertiary and quaternary metabolites is now documented. It appears that melatonin’s interaction with ROS/RNS is a prolonged process that involves many of its derivatives. The process by which melatonin and its metabolites successively scavenge ROS/RNS is referred as the free radical scavenging cascade. This cascade reaction is a novel property of melatonin and explains how it differs from other conventional antioxidants. This cascade reaction makes melatonin highly effective, even at low concentrations, in protecting organisms from oxidative stress. In accordance with its protective function, substantial amounts of melatonin are found in tissues and organs which are frequently exposed to the hostile environmental insults such as the gut and skin or organs which have high oxygen consumption such as the brain. In addition, melatonin production may be upregulated by low intensity stressors such as dietary restriction in rats and exercise in humans.

Intensive oxidative stress results in a rapid drop of circulating melatonin levels. This melatonin decline is not related to its reduced synthesis but to its rapid consumption, i.e. circulating melatonin is rapidly metabolized by interaction with ROS/RNS induced by stress. Rapid melatonin consumption during elevated stress may serve as a protective mechanism of organisms in which melatonin is used as a first-line defensive molecule against oxidative damage. The oxidative status of organisms modifies melatonin metabolism. It has been reported that the higher the oxidative state, the more AFMK is produced. The ratio of AFMK and another melatonin metabolite, cyclic 3-hydroxymelatonin, may serve as an indicator of the level of oxidative stress in organisms.

Primitive, and protective, our cellular oxygenation status?

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Om hvordan oksygennivået i mitokondriene er nesten ingen ting, og har vært slik siden tidenes morgen for å beskytte oss mot svingende oksygennivåer i atmosfæren gjennom evlusjonen.

http://www.ncbi.nlm.nih.gov/pubmed/14499489/

The primitive atmosphere where aerobic life started on earth was hypoxic and hypercapnic. Remarkably, an adaptation strategy whereby O2 partial pressure, PO2, in the arterial blood is maintained within a low and narrow range of 1-3 kPa, largely independent of inspired PO2, has also been reported in modern water-breathers. In mammalian tissues, including brain, the most frequently measured PO2 is also in the same low range. Based on the postulate that basic cellular machinery has been established since the early stages of evolution, we propose that this similarity in oxygenation status is the consequence of an early adaptation strategy which, subsequently, throughout the course of evolution, maintained cellular oxygenation in the same low and primitive range independent of environmental changes. Specialized enzymes aimed at protecting cells against O2 toxicity are thought to have appeared very early in evolution but we suggest that preventing high PO2’s is also the simplest and most efficient tool for limiting reactive oxygen species (ROS) production. It could be a cue mechanism to widen our understanding of the ageing process.

Carbon dioxide and the critically ill—too little of a good thing?

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Omfattende studie av alle de gode egenskapene ved hyperkapni – høyt CO2 nivå. Nevner mange interessante ting, bl.a. at CO2 indusert acidose gir mye mindre fire radikaler enn om pH senkes av andre faktorer. Bekrefter også at oksygen blir sittende fast på blodcellene ved hypokapni, og at melkesyreproduksjonen begrensens når acidosen er pga CO2 men ikke når den er av andre faktorer.

Spesielt med denne artikkelen er at den beskriver forskjellene på en hyperkapni acidose og acidose av andre faktorer. Hyperkapnisk acidose har beskyttende egenskaper.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)02388-0/fulltext

Permissive hypercapnia (acceptance of raised concentrations of carbon dioxide in mechanically ventilated patients) may be associated with increased survival as a result of less ventilator-associated lung injury.
Accumulating clinical and basic scientific evidence points to an active role for carbon dioxide in organ injury, in which raised concentrations of carbon dioxide are protective, and low concentrations are injurious.
Although hypercapnic acidosis may indicate tissue dysoxia and predict adverse outcome, it is not necessarily harmful per se. In fact, it may be beneficial. There is increasing evidence that respiratory (and metabolic) acidosis can exert protective effects on tissue injury, and furthermore, that hypocapnia may be deleterious.
If hypoventilation is allowed in an effort to limit lung stretch, carbon dioxide tension increases. Such “permissive hypercapnia” may be associated with increased survival in acute respiratory distress syndrome (ARDS);2 this association is supported by outcome data from a 10-year study.3
Furthermore, hypocapnia shifts the oxyhaemoglobin dissociation curve leftwards, restricting oxygen off-loading at the tissue level; local oxygen delivery may be further impaired by hypocapnia-induced vasoconstriction.
Brain homogenates develop far fewer free radicals and less lipid peroxidation when pH is lowered by carbon dioxide than when it is lowered by hydrochloric acid.19
Finally, greater inhibition of tissue lactate production occurs when lowered pH is due to carbon dioxide than when it is due to hydrochloric acid.20
An association between hypoventilation, hypercapnia, and improved outcome has been established in human beings.2, 5, 21 In lambs, ischaemic myocardium recovers better in the presence of hypercapnic acidosis than metabolic acidosis.22 Hypercapnic acidosis has also been shown to protect ferret hearts against ischaemia,23 rat brain against ischaemic stroke,16 and rabbit lung against ischaemia-reperfusion injury.24 Hypercapnia attenuates oxygen-induced retinal vascularisation,25 and improves retinal cellular oxygenation in rats.26 “pH-stat” management of blood gases during cardiopulmonary bypass, involving administration of large amounts of additional carbon dioxide for maintenance of temperature-corrected PaCO2, results in better neurological and cardiac outcome.27
Hypercapnia results in a complex interaction between altered cardiac output, hypoxic pulmonary vasoconstriction, and intrapulmonary shunt, with a net increase in PaO2 (figure).28 Because hypercapnia increases cardiac output, oxygen delivery is increased throughout the body.28 Regional, including mesenteric, blood flow is also increased,29 thereby increasing oxygen delivery to organs. Because hypercapnia (and acidosis) shifts the haemoglobin-oxygen dissociation curve rightwards, and may increase packed-cell volume,30 oxygen delivery to tissues is further increased. Acidosis may reduce cellular respiration and oxygen consumption,31 which may further benefit an imbalance between supply and demand, in addition to greater oxygen delivery. One hypothesis32 is that acidosis protects against continued production of further organic acids (by a negative feedback loop) in tissues, providing a mechanism of cellular metabolic shutdown at times of nutrient shortage—eg, ischaemia.
Acidosis attenuates the following inflammatory processes (figure): leucocyte superoxide formation,33 neuronal apoptosis,34phospholipase A2 activity,35 expression of cell adhesion molecules,36 and neutrophil Na+/H+ exchange.37 In addition, xanthine oxidase (which has a key role in reperfusion injury) is inhibited by hypercapnic acidosis.24 Furthermore, hypercapnia upregulates pulmonary nitric oxide38 and neuronal cyclic nucleotide production,39 both of which are protective in organ injury. Oxygen-derived free radicals are central to the pathogenesis of many types of acute lung injury, and in tissue homogenates, hypercapnia attenuates production of free radicals and decreases lipid peroxidation.19 Thus, during inflammatory responses, hypercapnia or acidosis may tilt the balance towards cell salvage at the tissue level.
However, we know from several case series that human beings, and animals, can tolerate exceptionally high concentrations of carbon dioxide, and when adequately ventilated, can recover rapidly and completely. Therefore, high concentrations (if tolerated) may not necessarily cause harm.
From the published studies reviewed, and from the pathological mechanisms assessed, we postulate that changes in carbon dioxide concentration might affect acute inflammation,33—36 tissue ischaemia,16 ischaemia-reperfusion,20, 24 and other metabolic,12, 21,32 or developmental14 processes.
We argue that the recent shift in thinking about hypercapnia must now be extended to therapeutic use of carbon dioxide. Our understanding of the biology of disorders in which hypocapnia is a cardinal element would require fundamental reappraisal if hypocapnia is shown to be independently harmful.
In summary, in critically ill patients, future therapeutic goals involving PaCO2 might be expressed as:“keep the PaCO2 high; if necessary, make it high; and above all, prevent it from being low”.

Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans

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Viktig studie som nevner alt om hvordan melatonin virker som en antioksidant. Hele studien er her, men den er ikke gjennomgått enda.

http://www.actabp.pl/pdf/4_2003/1129s.pdf

Melatonin’s functions as an antioxidant include: a), direct free radical scavenging, b), stimulation of antioxidative enzymes, c), increasing the efficiency of mitochon- drial oxidative phosphorylation and reducing electron leakage (thereby lowering free radical generation), and 3), augmenting the efficiency of other antioxidants.

Melatonin induces γ- glutamylcysteine syn thetase mediated by activator protein-1 in human vascular en dothelial cells

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Det første bildet viser hvordan melatonin dobler glutathion konsentrasjon. Dette er interessant med tanke på at diafragmiske pust øker melatonin. Melatonin hemmer enzymet som bryter ned glutathion, derfor økes konsentrasjonen.

http://www.sciencedirect.com/science/article/pii/S0891584999001318

In the present study, we show that melatonin induces the expression of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting enzyme of glutathione (GSH) synthesis, in ECV304 human vascular endothelial cells.

As conclusion, induction of GSH synthesis by melatonin protects cells against oxidative stress and regulates cell proliferation.

Apnea: A new training method in sport?

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Veldig viktig studie om hva dykkeres trening i Apnea (å holde pusten) kan bidra med i annen idrett. Bekrefter det meste av det jeg har skrevet om, men oppklarer noe om blodverdier bl.a. Nevner EPO, nyrenes tilpasning, hypoxi, HIF-1, melkesyre, lungevolum

http://www.univ-rouen.fr/servlet/com.univ.utils.LectureFichierJoint?CODE=1307716204012&LANGUE=0

http://www.ncbi.nlm.nih.gov/pubmed/19850416

Breath-hold divers have shown reduced blood acidosis, oxidative stress and basal metabolic rate, and increased hematocrit, erythropoietin concentration, hemoglobin mass and lung volumes. We hypothesise that these adaptations contributed to long apnea durations and improve performance. These results suggest that apnea training may be an effective alternative to hypo- baric or normobaric hypoxia to increase aerobic and/or anaerobic performance.

Apnea durations clearly increase with training. Perhaps less well known are the findings that apnea train- ing also increases hematocrit (Hct), erythropoietin (EPO) concen- tration, hemoglobin (Hb) mass, and lung volumes [2–5]. In addition, blood acidosis and oxidative stress were shown to be re- duced after three months of apnea training [6,7]. Therefore, why not encourage apnea training for athletes?

The major determinant of aerobic performance is the capacity to deliver oxygen to the tissues [8]. An increase in the total amount of erythrocytes, as reflected by increased Hct and Hb mass, is med- iated by the glycoprotein hormone EPO, which is predominantly synthesized by the kidneys in response to chronic hypoxia [9] and to some extent (10–15% of total production) by the liver. EPO stimulates the proliferation and maturation of red blood cell precursors in bone marrow, increasing oxygen delivery to muscle and thereby enhancing sports performance [9].

(hypoxic or ischemic conditions) results in a stabilization of the transcription factor hypoxia-inducible factor (HIF)-1a, which increases EPO secretion and the expression of EPO receptor [10].

Furthermore, any training effect vanishes rapidly (two weeks), as the newly formed red cells disappear within a mat- ter of days due to neocytolysis.

The splenic contraction effect

Apnea training may well be a future training method. Splenic contraction has been described in marine mammals as improving oxygen transport, through an increase in circulating erythrocytes. Its consequence is a prolonged dive without injuries. In humans, repeated apneas (five, in general) induce splenic contraction. This increases Hct and Hb (both between 2% and 5%) independently of hemoconcentration [19] and reduces arterial oxygen desaturation, thereby prolonging the apnea duration [3,19–22].

Repeated apneas are known to induce hypoxemia in the spleen and kidney, increas- ing respectively Hct and Hb and serum EPO concentrations [2,23].

First, the splenic contraction develops quickly after three or four apneas separated by two minutes of recovery and is associ- ated with a transient increase in Hb concentration. The amplitude of the spleen volume reduction after repeated apneas, with or without face immersion, varies widely (20–46%) depending on the rate of change in oxygenation [3,19,22,25–27]. The rapidity of the splenic contraction after simulated apneas strongly suggested a centrally-mediated feed-forward mechanism rather than the influ- ence of slower peripheral triggers [19]. These spleen and Hb re- sponses may be trainable.

Second, DeBruijns et al. [2] recently observed that repeated apneas increased EPO concentration by 24%, with the peak value reached 3 h after the last apnea and a return to baseline 2 h later.

The rapid reduction in tissue oxygen levels that oc- curs during apneas has been suggested to stimulate enhanced EPO production [25]. The decreased kidney blood flow induced by apneic vasoconstriction would result in local ischemic hypoxia, stimulating kidney EPO production. Similarly, obstructive sleep ap- nea increases the levels of EPO (􏰀1.6) and Hb (+18%) [24].

The lower SaO2 decrease found in trained divers after repeated apneas may account for the reduced oxygen delivery because of the diving response (bradycardia and vasocon- striction) and/or an increase in oxygen content [1].

Long term-effects

Another important consideration is the persistence of the per- formance gains. Most of the altitude exposure studies reported short-term effects (i.e., weeks). Repeated apneas increase Hct but this increase disappears within 10min after the last apnea [22,26].

The effects of repeated apneas on spleen and endogenous EPO may also constitute an alternative to using rhEPO or its analogues. In addition, comparison of resting Hb mass in elite BHDs and untrained subjects showed a 5% higher Hb mass in the BHDs, and the BHDs also showed a larger relative increase in Hb after three apneas (2.7%). The long-term effect of apnea training on Hb mass might be implicated in elite divers’ performances. Re- cently, it has been found that after a 3-month apnea training pro- gram, the forced expiratory volume in 1 s was higher (4.85 ± 0.78 vs. 4.94 ± 0.81 L, p < 0.05), with concomitant increases in the max- imal oxygen uptake, arterial oxygen saturation, and respiratory compensation point values during an incremental test [30].

In addition to increasing EPO and provoking splenic contraction, apnea training has been hypothesized to modify muscle glycolytic metabolism. An improvement in muscle buffer capacity [6,7,32] would reduce blood acidosis and post-apnea oxidative stress [6]. Delayed acidosis would also be advantageous for exercise perfor- mance. Finally, trained BHDs exhibit high lung volumes [15]. Ap- nea training might be interesting to improve respiratory muscle performance [15], thereby delaying the respiratory muscle fatigue during prolonged and maximal exercise.

Greater cerebral blood flow (CBF) increase was described during long apnea in elite BHDs than in controls and interpreted as a protection of the brain against the alteration of blood gas [33]. The CBF increase observed in BHDs could be the re- sult of an increased capillary density in the brain as has been de- scribed after a prolonged hypobaric hypoxia exposure [35]. These results suggest that apnea training per se provides hypoxic precon- ditioning, increasing hypoxemia and ischemia tolerance [33].

The physiological responses to apnea training exhibited by elite breath-hold divers may contribute to improving sports perfor- mance. These adaptations may be an effective alternative to hypo- baric or normobaric hypoxia to increase performance. Further experimental research of the apnea training effects on aerobic and/or anaerobic performance are needed to confirm this theory.

Diaphragmatic Breathing Reduces Exercise-Induced Oxidative Stress

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Om hvordan diafragmisk pust (med magen) øker antioksidantbeskyttelsen og restitusjonen ved å senke kortison og øke melatonin. Gjort på et 24t sykkerlritt hvor de som gjorde 1t pusteing før de sovnet fikk raskere restitusjon. Nevner direkte sammenheng mellom kortisol og melatonin. Og påstår at pusten bør implementeres i ethvert treningsregime som restitusjon.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139518/

Analysis of oxidative stress levels in people who meditate indicated that meditation correlates with lower oxidative stress levels, lower cortisol levels and higher melatonin levels. It is known that cortisol inhibits enzymes responsible for the antioxidant activity of cells and that melatonin is a strong antioxidant

Results demonstrate that relaxation induced by diaphragmatic breathing increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol and the increase in melatonin. The consequence is a lower level of oxidative stress, which suggests that an appropriate diaphragmatic breathing could protect athletes from long-term adverse effects of free radicals.

Stress is defined as a physiological reaction to undesired emotional or physical situations. Initially, stress induces an acute response (fight or flight) that is mediated by catecholamines. When stress becomes chronic and lasts for a long time, the stressed organism reacts with physiological alterations to adapt to the unfavorable conditions. This ACTH-mediated reaction affects the immune and neuroendocrine systems, and it is responsible for several diseases [1]. Numerous data support the hypothesis that the pathophysiology of chronic stress can be due, at least partially, to an increase in oxidative stress [2–4], which may also contributes to heart disease [5,6], rheumatoid arthritis [7,8], hypertension [9,10], Alzheimer’s disease [11,12], Parkinson’s disease [13], atherosclerosis [14] and, finally, aging [15].

High levels of glucocorticoids are known to decrease blood reduced glutathione (GSH) and erythrocyte superoxide dismutase (SOD) activity in rats [20]. Other enzymes are also involved, and NADPH oxidase, xanthine oxidase and uncoupled endothelial nitric oxide synthase are important sources of reactive oxygen species (ROS) in glucocorticoid-induced oxidative stress (see [9] for a review on this argument).

Hormonal reactions to stressors, in particular plasma cortisol levels, are lower in people who meditate than in people who do not [31–36], suggesting that it is possible to modulate the neuroendocrine system through neurological pathways. Analysis of oxidative stress levels in people who meditate indicated that transcendental meditation, Zen meditation and Yoga correlate with lower oxidative stress levels [37–43].

Melatonin could also be involved in the reduction of oxidative stress because increased levels of this hormone have been reported after meditation [44–46]. This neurohormone is considered a strong antioxidant and is used as a treatment for aging. Melatonin in fact, increases several intracellular enzymatic antioxidant enzymes, such as SOD and glutathione peroxidase (GSH-Px) [47,48], and induces the activity of γ-glutamylcysteine synthetase, thereby stimulating the production of the intracellular antioxidant GSH (49]. A number of studies have shown that melatonin is significantly better than the classic antioxidants in resisting free-radical-based molecular destruction. In these in vivostudies, melatonin was more effective than vitamin E, β-carotene [50–52] and vitamin C [53–55].

Although it has been established that a continuous and moderate physical activity reduces stress, intense and prolonged exercise is deleterious and needs a proper recovery procedure.

Plasma cortisol levels increase in response to intense and prolonged exercise [60,61]. Ponjee et al. [62] demonstrated that cortisol increased significantly in male athletes after they ran a marathon. In another study, plasma ACTH and cortisol were found elevated in highly trained runners and in sedentary subjects after intense treadmill exercise [63].

Most, if not all, meditation procedures involve diaphragmatic breathing (DB), which is the act of breathing deeply into the lungs by flexing the diaphragm rather than the rib cage. DB is relaxing and therapeutic, reduces stress and is a fundamental procedure of Pranayama Yoga, Zen, transcendental meditation and other meditation practices.

Athletes were monitored during a training session for a 24-h long contest. This type of race lasts for 24h, generally starting at 10:00am and ending at 10:00am the following day. Bikers ride as many kilometers as possible on a specific circuit trail in the 24-h period. Athletes are allowed to stop, to sleep, to rest and to eat as much food as they want to eat.

Subjects of the studied group were previously trained to relax by performing DB and concentrating on their breath. These athletes spent 1h (6:30–7:30pm) relaxing performing DB in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. The only activity allowed was reading magazines. Lighting levels were monitored throughout the experiment and did not exceed 15 lux, a level well below that known to influence melatonin secretion [73,74].

As expected, the exercise induced a strong oxidative stress in athletes (Figure 1).

BAP (Biological Antioxidant Potential) levels were determined at different times, before and after exercise. Athletes were divided in two equivalent groups of eight subjects. Subjects of the studied group spent 1h relaxing performing DB and concentrating on their breath in a quiet place. The other eight subjects, representing the control group, spent the same time sitting in an equivalent quite place. Since this test must be performed several hours after food ingestion, BAP levels were determined pre-exercise at 8:00am before breakfast, at 2:00am, and at 8:00am 24h post-exercise. Values shown are mean ± SD. *P < .05 DB versus control group. **P < .01 DB versus control group.

This study demonstrates that DB reduces the oxidative stress induced by exhaustive exercise. To our knowledge, this is the first study which explores the effect of DB on the stress caused by exhaustive physical activity.

The rationale is as follows (Figure 5)

  1. intense exercise increases cortisol production;
  2. a high plasmatic level of cortisol decreases body antioxidant defenses;
  3. a high plasmatic level of cortisol correlates with a high level of oxidative stress;
  4. DB reduces the production of cortisol;
  5. DB increases melatonin levels;
  6. melatonin is a strong antioxidant;
  7. DB increases the BAP and
  8. DB reduces oxidative stress.

If these results are confirmed in other intense physical activity programs, relaxation could be considered an effective practice to significantly contrast the free radical-mediated oxidative damage induced by intense exercise. Therefore, similar to the way that antioxidant supplementation has been integrated into athletic training programs, DB or other meditation techniques should be integrated into many sports as a method to improve performance and to accelerate recovery.

Hyperventilation, in fact, induces hyperoxia which is known to be related with oxidative stress [81,82]. The hyperventilation syndrome affects 15% of the population and occurs when breathing rates elevate to 21–23 bpm as a result of constricted non-DB. DB can treat hyperoxia and its consequences acting by two synergic ways: restoring the normal breath rhythm and reducing oxidative stress mainly through the increase in melatonin production which is known for its ability to reduce oxidative stress induced by exposure to hyperbaric hyperoxia [83].

Moreover, Orme-Johnson observed greatly reduced pathology levels in regular meditation practitioners [84,85]. A 5 years statistic of approximately 2000 regular participants demonstrated that Transcendental Meditation reduced benign and malignant tumors, heart disease, infectious diseases, mental disorders and diseases of the nervous system. Mourya et al. evidenced that slow-breathing exercises may influence autonomic functions reducing blood pressure in patients with essential hypertension [86]. Finally, there are also evidences that procedures which involve the control of the breathing can positively affect type 2 Diabetes [87], depression, pain [88], high glucose level and high cholesterol [89].

The role of melatonin must also be emphasized. Beyond its antioxidant properties, melatonin is involved in the regulation of the circadian sleep-wake rhythm and in the modulation of hormones and the immune system. Due to its wide medical implications, the increase in melatonin levels induced by DB suggests that this breath procedure deserves to be included in public health improvement programs.

DB increased the levels of melatonin in athletes, and this correlates with lower oxidative stress (ROMs), with lower cortisol levels and with the higher antioxidant status (BAP) in these athletes.

Tooley et al. [46] speculated that meditation-reduced hepatic blood flow [91] could raise the plasma levels of melatonin. Alternatively, since meditation increases plasma levels of noradrenaline [92] and urine levels of the metabolite 5HIAA [93], a possible direct action on the pineal gland could be hypothesized, as melatonin is synthesized in the pineal by serotonin under a noradrenaline stimulus [94]. More likely, we suspect that the increase in melatonin levels determined in our experiment can be mainly attributed to the reduced cortisol levels. Actually, a relationship between cortisol and melatonin rhythms has been observed [95], indicating that melatonin onset typically occurs during low cortisol secretion.

Overall, these data demonstrate that relaxation induced by DB increases the antioxidant defense status in athletes after exhaustive exercise. These effects correlate with the concomitant decrease in cortisol, which is known to negatively affect antioxidant defenses, and the increase in melatonin, a strong antioxidant. The consequence is a lower level of oxidative stress, which suggests that an appropriate recovery could protect athletes from long-term adverse effects of free radicals.