Treating Diabetes with Exercise – Focus on the Microvasculature

Veldig viktig studie som nevner at det ikke finnes glatt muskulatur i kapillærene, så det er arteriolene som avgjør blodsirkulasjonen i kapillærene. His blodsirkulasjonen i en arteriole blir dårlig stopper sirkulasjonen opp i et område av muskelen som serveres av kapillærene.


The rising incidence of diabetes and the associated metabolic diseases including obesity, cardiovascular disease and hypertension have led to investigation of a number of drugs to treat these diseases. However, lifestyle interventions including diet and exercise remain the first line of defense. The benefits of exercise are typically presented in terms of weight loss, improved body composition and reduced fat mass, but exercise can have many other beneficial effects. Acute effects of exercise include major changes in blood flow through active muscle, an active hyperemia that increases the delivery of oxygen to the working muscle fibers. Longer term exercise training can affect the vasculature, improving endothelial health and possibly basal metabolic rates. Further, insulin sensitivity is improved both acutely after a single bout of exercise and shows chronic effects with exercise training, effectively reducing diabetes risk. Exercise-mediated improvements in endothelial function may also reduce complications associated with both diabetes and other metabolic disease. Thus, while drugs to improve microvascular function in diabetes continue to be investigated, exercise can also provide many similar benefits on endothelial function and should remain the first prescription when treating insulin resistance and diabetes. This review will investigate the effects of exercise on the blood vessel and the potential benefits of exercise on cardiovascular disease and diabetes.

At rest, a low proportion of capillaries are exposed to blood flow at one time, with a rapid increase in the number of perfused capillaries after exercise [31], thus increasing functional capillary density.

Vascular smooth muscle cells are located around the arterioles and some venules, and can constrict to change blood flow patterns, while capillaries do not typically contribute to blood flow changes [30] (Figure 1). Blood flow through capillaries is controlled upstream by small arterioles at rest, and the rapid recruitment of unperfused capillaries by exercise could suggest that nerves are responsible for this action [34]. The sympathetic nervous system is mainly responsible for the vasoconstrictor responses, and as the arterioles and larger vessels are innervated [38] the majority of sympathetic nervous system activity is localized to that area of the vascular tree. Physical exercise can enhance sympathetic nerve activity [39] to maintain arterial pressure, and may be involved in maintaining exercise tolerance, as reviewed by Thomas and Segal [38].

Structural differences between artery, arteriole and capillary. No vascular smooth muscle is located on the capillary; therefore flow through capillaires is modified by pre-capillary arterioles. Cessation of flow through arterioles will prevent flow through a portion of the muscle.

Insulin relies on endothelium-dependent vasodilation to enhance perfusion, thus endothelial dysfunction reduces insulin-mediated increases in muscle perfusion, which can contribute to the metabolic deficit in diabetes. As exercise-mediated changes in perfusion are typically endothelium-independent, exercise is still able to recruit capillaries and thus increase muscle perfusion in obesity and type 2 diabetes, even in the face of endothelial dysfunction. Numerous studies have now shown that while insulin’s vascular effects may be blocked in diabetes, exercise still maintains its ability to increase the distribution of blood flow through muscle [42].

Nitric oxide (NO) is the main vasodilator from the endothelium specifically involved in blood flow and blood distribution, and while reduction in nitric oxide synthesis lowered total blood flow, exercise-mediated capillary recruitment was not affected [46]. In fact, inhibition of NO formation enhances both resting and exercise-mediated muscle oxygen uptake [47]; despite a reduction in total flow, microvascular flow was not affected, suggesting that NO is not involved in the vascular response to exercise.

The distribution of blood through muscle increases the capacity for nutrient exchange. In exercise the primary purpose of functional hyperemiais for oxygen delivery, as the oxygen required by exercising muscle is much higher than resting muscle (reviewed in [37]). Recruitment of capillaries can decrease the velocity of blood flow by increasing the cross-sectional area of the capillary bed and the time available for exchange. Recruitment also increases surface area for exchange and decreases perfusion distances to promote oxygen delivery to tissues with exercise [34] (Figure 2). While in exercise the main metabolite required at the working muscle is oxygen, distribution of other nutrients can also be affected, including glucose, fats, other hormones and cytokines. Muscle metabolism can therefore be altered by perfusion of the tissue [48,49]. While there can be regulated transport of certain larger hormones across the vasculature [50,51], smaller molecules can diffuse across the endothelium easily, possibly making muscle perfusion a more important player in the delivery of glucose and oxygen to the tissue.

Vasodilation affects delivery, and thus metabolism. The rate of transfer across the endothelium is dependent on surface area, permeability of the endothelium, diffusion distance, and concentration difference (Fick’s first law of diffusion). Vasodilation increases surface area in arterioles for exchange, but will also recruit downstream capillaries, which will reduce diffusion distance and increase surface area for exchange. Working muscle increases oxygen utilization, increasing the concentration difference from the blood vessel to the tissue.

Mitochondrial dysfunction has been proposed to be both a cause [72] and a consequence [73] of insulin resistance, and may contribute to endothelial dysfunction [74]. If oxygen delivery is a component of mitochondrial health and biogenesis, it is possible that impaired perfusion may contribute to fiber type switching, where an oxidative fiber, which is typically highly vascularized and contains mitochondria, switches to a glycolytic fiber with less vascularity and mitochondria. As exercise can improve oxidative capacity, increase mitochondria content [75], and also increase muscle perfusion [31,32,34,45,76], the relationship between muscle perfusion, fiber type and mitochondrial function needs to be clarified.

The vascular component of exercise may well be linked to the reduction of diabetic complication such as retinopathy, peripheral neuropathy and nephropathy, as there is a vascular basis to many of these complications. The endothelium has been implicated in diabetic nephropathy [88], and the blood vessels formed in response to reduced perfusion in retinopathy show abnormal structure and function [89].

Systemic inflammation impairs respiratory chemoreflexes and plasticity

Denne studien beskriver hvordan systemisk betennelse påvirker pustefunksjonen og gjør at det blir vanskeligere å endre pustemønser, f.eks. å gjøre pusteøvelser, eller å tilpasse pusten til aktivitetsnivå. Spesielt den kjemiske og motoriske delen av pustefysiologien blir dårligere. Noe som viser seg i laver CO2 sensitivitet (kjemisk) og svakere pustemuskler (Motorisk).

Nevner spesielt at det er mikroglia celler i CNS som påvirkes av betennelse, og som kan oppretthodle betennelse siden de sender ut cytokiner, m.m. Astrosytter kan også bidra mye siden de aktiverer NFkB. Den gode nyheten her er at økt CO2 nedregulerer NFkB. TLR-4 (Toll-like receptor) aktiveres av patogener og problemer i cellene, og aktiverer NFkB, og nedreguleres av økt CO2.


Many lung and central nervous system disorders require robust and appropriate physiological responses to assure adequate breathing. Factors undermining the efficacy of ventilatory control will diminish the ability to compensate for pathology, threatening life itself. Although most of these same disorders are associated with systemic and/or neuroinflammation, and inflammation affects neural function, we are only beginning to understand interactions between inflammation and any aspect of ventilatory control (e.g. sensory receptors, rhythm generation, chemoreflexes, plasticity). Here we review available evidence, and present limited new data suggesting that systemic (or neural) inflammation impairs two key elements of ventilatory control: chemoreflexes and respiratory motor (vs. sensory) plasticity. Achieving an understanding of mechanisms whereby inflammation undermines ventilatory control is fundamental since inflammation may diminish the capacity for natural, compensatory responses during pathological states, and the ability to harness respiratory plasticity as a therapeutic strategy in the treatment of devastating breathing disorders, such as during cervical spinal injury or motor neuron disease.

Most lung and CNS disorders are associated with systemic and/or neural inflammation, including chronic lung diseases (Stockley, 2009), traumatic, ischemic and degenerative neural disorders (Teeling and Perry, 2009) and obstructive sleep apnea.

Systemic inflammation affects sensory receptors that modulate breathing, but can also trigger inflammatory responses in the central nervous system (CNS) through complex mechanisms. The primary CNS cells affected during systemic inflammation are microglia, the resident immune cells of the CNS, and astrocytes (Lehnardt, 2010).

Even when in their “resting state,” microglia are highly active, surveying their environment (Raivich, 2005,Parkhurst and Gan, 2010). When confronted with pathological conditions, such as neuronal injury/degeneration or bacterial/viral/fungal infection, they become “activated,” shifting from a stellate, ramified phenotype to an amoeboid shape (Kreutzberg, 1996). Activated microglia can be phagocytic, or they can release toxic and protective factors, including cytokines, prostaglandins, nitric oxide or neurotrophic factors (e.g. BDNF) (Kreutzberg, 1996Graeber, 2010). Despite the importance of microglia in immune function, they are diffuse in the CNS (~70-90% of CNS cells are glia; microglia are ~5-10% of those cells).

Astrocytes, on the other hand, contribute to the overall inflammatory response since they release cytokines, triggering nuclear factor-kappa B (NFκB) signaling elsewhere in the CNS. Further, they express many TLRs, including TLR-4, capable of eliciting an inflammatory response (Li and Stark, 2002Farina et al., 2007,Johann et al., 2008). Given their relative abundance, astrocytes may play a key role in CNS inflammatory responses.

TLR-4 receptors are cytokine family receptors that activate transcription factors, such as NFκB (Lu et al., 2008). NFκB regulates the expression of many inflammatory genes, including: IL-1β, -6 and -18, TNFα, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) (Ricciardolo et al., 2004Nam, 2006). Endogenous molecules known to activate TLR-4 receptors include (but are not limited to) heat shock proteins (specifically HSP60, Ohashi et al., 2000Lehnardt et al., 2008), fibrinogen, surfactant protein-A, fibronectin extra domain A, heparin sulfate, soluble hyaluronan, β-defensin 2 and HMGB1 (Chen et al., 2007).

The role of inflammation (and specifically microglia) in chronic pain has been studied extensively (reviewed in Woolf and Salter, 2000Trang et al., 2006Mika, 2008Abbadie et al., 2009Baumbauer et al., 2009). A remarkable story has emerged, demonstrating the interplay between neurons, microglia, inflammation and plasticity in this spinal sensory system. In short, inflammation induces both peripheral and central sensitization, leading to allodynia (hypersensitivity to otherwise non-painful stimuli) and hyperalgesia (exaggerated or prolonged responses to a noxious stimulus) (Mika, 2008).

An important aspect of ventilatory control susceptible to inflammatory modulation is the chemoreflex control of breathing. Chemoreflexes are critical for maintaining homeostasis of arterial blood gases viaclassical negative feedback (Mitchell et al., 2009), or acting as “teachers” that induce plasticity in the respiratory control system (Mitchell and Johnson, 2003). Major chemoreflexes include the hypoxic (Powell et al., 1998) and hypercapnic ventilatory responses (Nattie, 2001), arising predominantly from the peripheral arterial and central chemoreceptors (Lahiri and Forster, 2003).

To date, no studies have reported the impact of systemic inflammation on hypercapnic responses. However, increased CO2 suppresses NFκB activation, possibly suppressing inflammatory gene expression (Taylor and Cummins, 2011). In fact, hypercapnia has been used to treat ischemia/reperfusion injury to decrease inflammation and reduce lung tissue damage (Laffey et al., 2000O’Croinin et al., 2005Curley et al., 2010Li et al., 2010).

Further work concerning the influence of systemic inflammation on hypercapnic ventilatory responses is warranted, particularly since impaired CO2 chemoreflexes would allow greater hypercapnia and minimize the ongoing inflammation; in this sense, impaired hypercapnic ventilatory responses during inflammation may (in part) be adaptive.

CO2-beriket vann til fotbad

Å bade i CO2 beriket vann har vært brukt som medisin i alle år. Hellige og mirkauløse kilder har ofter vært vann med et høyt innhold av karbondioksid. Og det har blitt brukt i spa behandling i århundrer, spesielt i Bulgaria. Man finner Co2-rikt vann spesielt ved sovende og inaktive vulkaner.

CO2 er et veldig lite molekyl som diffunderer lett igjennom huden. I CO2-beriket vann kommer derfor CO2 inn i huden og inn til blodkarene i underhuden, hvor alle sansenerver ligger. Den økte CO2 en gjør at blodkarene rundt nervetrådene og i muskelvevet utvides (vasodilasjon) og at oksygene letter hopper av blodcellene slik at det kan bli brukt til energi i celler som vanligvis har lite tilgang på oksygen.

CO2 beriket vann kan vi lage selv på en svært enkel måte: blande Natron, Sitronsyre og vann. Begge disse stoffene fåes kjøpt på vanlig daglivarebutikk. Vannet begynner å bruse, og dette er CO2.

Studier nevner at man bør ha 900-1200 mg CO2 pr liter vann. Ved å måle pH kan vi regne med at vi har det når pH er nede på 5.

Vi kan se CO2 effekten på huden ved at det kommer tett-i-tett med ørsmå bobler. I f.eks. fotbad vil vi se at når vi tar foten opp fra vannet så er den rød, noe som er et tegn på økt blodsirkulasjon i huden.

For alle med nevropatier, diabetes, sår, nevromer, leggspenninger, restless leg syndrom, som lett blir sliten i bena av å gå, så vil dette være verdt et forsøk.

2-3 ganger i uka pleier å være den vanlige oppskriften. Noen studier har brukt det hver dag i mange uker. Spesielt når det gjelder diabetes sår.

Oppskrift: Bland 1 poseNatron med 2 poser Sitronsyre (blandingsforhold ca. 1:1) og hell innholdet i 5L vann. Det bruser veldig pga reaksjonen som lager CO2. Når du setter føttene nedi skal det komme mange små bobler som dekker huden. Etter 5-10 minutter vil huden som er under vann bli rød. Dette er et tegn på økt blodsirkulasjon.

5-15 minutter etter du er ferdig med fotbadet vil du sannsynligvis kjenne det prikker og strømmer ellers i kroppen også. Vanligvis kjennes det først og fremst i armer og bein, som er de stedene vi lettest kjenner økt blodsirkulasjon.

Her er noen studier som bekrefter effektene av CO2 beriket vann.

Beskriver det meste om balneotherapy, som det også heter. Inkludert kontraindikasjoner(hjerteproblemer og hypercapni som følge av lungeskade):

Table 4. Major Indicators for CO2 Balneotherapy

1. Hypertension, especially borderline hypertension

2. Arteriolar occlusion, Stages I and II

3. Functional arteriolar blood flow disorders

4. Microcirculatory disorders

5. Functional disorders of the heart

Beskriver alt om hvordan det øker blodsirkulasjon og oksygenmetning:

Viser at det øker blodsirkulasjonen i huden og oksygenmetningen i muskelvev hos de som lett blir trøtte i beina:

Viser at det øker blodsirkulasjon og produksjonen av blodkar (angiogenese):

Viser at det reparerer sår som ikke vil gro:

Viser at det reparerer muskelskade:

Viser at det reparerer muskelskade og atrofi (muskelsvikt) etter langtids post-operative sengeliggende:

Viser at det reduserer hjertefrekvens gjennom å dempe sympaticus aktivering (ikke ved å øke parasymptaticus aktivering):

Viser at det øker mitokondrier og fjerner syster:

Viser at det øker antioksidant status, reduserer frie radikaler og øker blodsirkulasjon i kapuillærene (mikrosirkulasjon):

Viser at det hjelper til å reparere sår etter operasjon:

Dr. Sircus sin forklaring av CO2 medisin som nevner mange måter å gjøre det på:

Denne artikkelen beskriver mye om historien til CO2-bad.

Mange bilder av diabetes sår (OBS: ikke for sarte sjeler) som blir regenerert i løpet av få uker med 20-30 min fotbad. Disse bruker 900-1000ppm CO2 konsentrasjon. Jeg er usikker på om det er mulig med å blande Sitronsyre og Natron:

Denne artikkelen beskriver de fleste sider ved forskjellig bruk av CO2 behandling. God gjennomgang av hvordan blodsirkluasjonen påvirkes.

The Role of Carbon Dioxide in Free Radical Reactions of the Organism

Nevner flere måter som CO2 virker som en antioksidant, i tillegg som en beskytter av andre antioksidanter. Dette er en teorietisk gjennomgang.

Click to access 51_335.pdf


Carbon dioxide interacts both with reactive nitrogen species and reactive oxygen species. In the presence of superoxide, NO reacts to form peroxynitrite that reacts with CO2 to give nitrosoperoxycarbonate. This compound rearranges to nitrocarbonate which is prone to further reactions. In an aqueous environment, the most probable reaction is hydrolysis producing carbonate and nitrate. Thus the net effect of CO2 is scavenging of peroxynitrite and prevention of nitration and oxidative damage. However, in a nonpolar environment of membranes, nitrocarbonate undergoes other reactions leading to nitration of proteins and oxidative damage. When NO reacts with oxygen in the absence of superoxide, a nitrating species N2O3 is formed. CO2 interacts with N2O3 to produce a nitrosyl compound that, under physiological pH, is hydrolyzed to nitrous and carbonic acid. In this way, CO2 also prevents nitration reactions. CO2 protects superoxide dismutase against oxidative damage induced by hydrogen peroxide. However, in this reaction carbonate radicals are formed which can propagate the oxidative damage. It was found that hypercapnia in vivo protects against the damaging effects of ischemia or hypoxia. Several mechanisms have been suggested to explain the protective role of CO2 in vivo. The most significant appears to be stabilization of the iron-transferrin complex which prevents the involvement of iron ions in the initiation of free radical reactions.

CO2 er en antioksidant

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

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.

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.2521 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,2024 and other metabolic,1221,32 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

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

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.

Intermittent Hypoxia Research in the Former Soviet Union and the Commonwealth of Independent States: History and Review of the Concept and Selected Applications

Svært viktig review om IHT – intermittend hypoxia training – som det har blitt gjort mye forskning på i russland, men først nå begynt å bli interessant i vesten. Nevner hvordan co2 reageer på hypoxi, og nervesystemet og vevet og i mitchondria, inklidert at SOD øker med 70% og at IHT normaliserer NO som lagres i blodkarene. Om at IHT kan brukes i behandling av sykdommer, inkludert strålingskader fra Chernobyl. Metoden er en «rebreathing» frem til O2% er nede på 7% – ca. 5 minutter daglig i 3 dager.

To the present day, intermittent hypoxic training (IHT) has been used extensively for altitude preacclimatization; for the treatment of a variety of clinical disorders, including chronic lung diseases, bronchial asthma, hypertension, diabetes mellitus, Parkinson’s disease, emotional disorders, and radiation toxicity, in prophylaxis of certain occupational diseases; and in sports.

The basic mechanisms underlying the beneficial effects of IHT are mainly in three areas: regulation of respiration, free-radical production, and mitochondrial respiration. It was found that IHT induces increased ventilatory sensitivity to hypoxia, as well as other hypoxia-related physiological changes, such as increased hematopoiesis, alveolar ventilation and lung diffusion capacity, and alterations in the autonomic nervous system.

Skjermbilde 2013-06-23 kl. 11.20.57

Due to IHT, antioxidant defense mechanisms are stimulated, cellular membranes become more stable, Ca2+ elimination from the cytoplasm is increased, and 02 transport in tissues is improved. IHT induces changes within mitochondria, involving NAD-dependent metabolism, that increase the efficiency of oxygen utilization in ATP production. These effects are mediated partly by NO-dependent reactions.

Particularly at issue are the effects in humans of such transient bouts of hypoxia when repeated many times, a practice designated as intermittent hypoxia. Furthermore, when intermittent hypoxia as a specific protocol is employed to accomplish a particular aim, for example, acclimatization to high altitude, we use the term intermittent hypoxic training or IHT.

The interested reader is referred to more extensive recent scientific and historical reviews and investigative reports in Russian and Ukrainian, particularly as related to the potential thera- peutic effects of intermittent hypoxia (Berezovsky et al., 1985; Karash et al., 1988; Meerson et al., 1989; Anokhin et al., 1992; Berezovskii and Levashov, 1992; Donenko, 1992; Ehrenburg, 1992; Fesenko and Lisyana, 1992; Vinnitskaya et al., 1992; Serebrovskaya et al., 1998a,b; Volobuev, 1998; Chizhov and Bludov, 2000; Ragozin et al., 2000). Noted also is the use of IHT in the prophylaxis of professional occupational diseases (Berezovsky et al., 1985; Karash et al., 1988; Serebrovskaia et al., 1996) and in sports (Volkov et al., 1992; Radzievskii, 1997; Kolchinskaya et al., 1998, 1999). Recent reviews from Western Europe and North America are also given (Bavis et al., 2001; Clanton and Klawitter, 2001; Fletcher, 2001; Cozal and Cozal, 2001; Mitchell et al., 2001; Neubauer, 2001; Prabhakar, 2001; Prabhakar et al., 2001; Wilber, 2001).

During successive altitude exposures, compared with the initial exposure, the higher ventilation and blood arterial oxygen saturation, together with the lower blood Pco2, implied that ventilatory sensitivity to hypoxia had been increased.

In the intervening years to the present, intermittent hypoxia has been used extensively in the Soviet Union and the CIS not only for altitude pre acclimatization (Gorbachenkov et al., 1994), but also it has been proposed for treatment of a variety of clinical disorders, including chronic lung diseases and bronchial asthma in children and adults (Meerson et al., 1989; Anokhin et al., 1992; Berezovskii and Levashov, 1992; Donenko, 1992; Ehrenburg and Kordykinskaya, 1992; Fesenko and Lisyana, 1992; Redzhebova and Chizhov, 1992; Vinnitskaya et al., 1992; Lysenko et al., 1998; Serebrovskaya et al., 1998b; Chizhov and Bludov,2000; Ragozin et al.,2000, 2001), hypertension (Meerson et al., 1989; Potievskaya and Chizhov, 1992; Rezapov, 1992), emotional disorders (Gurevich et al., 1941), diabetes mellitus (Kolesnyk et al., 1999; Zakusilo et al., 2001), Parkinson’s disease (Kolesnikova and Serebrovskaya, 1998; Serebrovskaya et al., 1998a), inflammatory processes (Tkatchouk, 1994; Tsvetkova and Tkatchouk, 1999), radiation toxicity (Karash et al., 1988; Sutkovyi et al., 1995; Serebrovskaia et al., 1996; Strelkov, 1997; Strelkov and Chizhov, 1998), and certain occupational diseases (Berezovsky et al., 1985; Karash et al., 1988; Rushkevich and Lepko, 2001).

If so, then in normal humans only a few minutes of daily hypoxic exposure rapidly induces detectable increments in hypoxic ventilatory response, a hallmark of altitude acclimatization.

Hypocapnia occurs with altitude acclimatization and ventilation remains increased for days after the subjects return to sea level. By contrast, in the two above studies, eucapnia was maintained during the hypoxic exposures and neither normoxic venilation nor normoxic PC02 was altered by IHT, suggesting that only the hypoxemia and not changes in PC02 (or pH) were involved.

Changing CO2, either for the carotid body or the brain, did not induce ventilatory acclimatization to hypoxia. The work from Bisgard’s laboratory suggested that ventilatory acclimatization to hypoxia in the goat depends almost exclusively on the carotid body’s response to low oxygen. If similar mechanisms operate in humans, then ventilatory acclimatization to hypoxia, operating via the carotid body and independent of changes in pH or PCO2, can be induced by IHT. What is remarkable is that such brief periods of hypoxia can have such clearly measurable increases in the ventilatory response to hypoxia.

In addition to increasing hypoxic ventilatory sensitivity, CIS investigators have reported that IHT increases tidal volume and alveolar blood flow during exercise, improves matching of ventilation to perfusion, increases lung diffusion capacity, redistributes peripheral blood flow during exercise, decreases heart rate, increases stroke volume, and increases blood erythrocyte counts (Volkov et al., 1992; Kolchinskaya, 1993; Radzievskii 1997; Kolchinskaya et al., 1999; Maluta and Levashov, 2001). These effects have been considered to be beneficial in training athletes (Volkov et al., 1992; Radzievskii, 1997). Such findings await independent confirmation from others.

The spectral analysis suggested that after IHT there was greater parasympathetic preponderance during the hypoxic challenge than in the control group. These novel studies conducted in Ukraine suggested that IHT mimicked the usual acclimatization to high altitude, with its primarily greater parasympathetic activity (Reeves, 1993; Hughson et al., 1994). Such activation of the parasympathetic system by IHT was supported by experiments in rats (Doliba et al., 1993; Kurhalyuk et al., 2001a, b, see below).

Among these effects are that brief hypoxic stimuli of only several minutes per day for only a few days give responses that last many days, even weeks, and also that IHT apparently affects a multitude of normal functions and disease states.

This work, as well as more recent studies (Lukyanova, 1997; Sazontova et al., 1997; Kondrashova et al., 1997; Temnov et al., 1997; Lebkova et al., 1999), indicated that the basic molecular response to any type of hypoxic challenge involves the mitochondrial enzyme complexes (MchEC). There is evidence that energy metabolism under acute hypoxia is affected even before a significant decrease in oxygen consumption becomes measurable and before cytochrome c oxidase (CO) activity is significantly reduced.

In the cascade of hypoxia-induced metabolic alterations, MchEC I is most sensitive to intracellular oxygen shortage. The reversible inhibition of MchEC I leads to both the suppression of reduced equivalent flux through the NAD-dependent site of the respiratory chain and the emergency activation of compensatory metabolic pathways, primarily the succinate oxidase pathway. The switch of energy metabolism to this pathway is the most efficient energy-producing pathway available in response to a lack of O2 (Lukyanova et al., 1982).

Skulachev (1996) proposed a two-stage mechanism that allows mitochondria to regulate O2 concentrations and to protect against oxidative stress: (1) «soft» decoupling of oxidative phosphorylation for «fine-tuning» and (2) decrease of the reduction level of respiratory chain components by opening nonspecific mitochondrial inner membrane pores as a mechanism to cope with massive O2 excess.

However, parallel nonenzymatic processes result in O2 formation. This is especially the case when 02 concentrations reach the capacity of the respiratory chain enzymes. Reduction in O2 concentrations leads to an exponential decrease in radical formation. Skulachev (1995) hypothesizes that mitochondria have a mechanism for «soft» decoupling in stage 4 of the respiratory chain. This mechanism prevents the complete inhibition of respiration, the complete reduction of respiratory carriers, and the accumulation of reactive compounds such as ubisemiquinone (CoQ·-). Such a mechanism will be activated, for example, if the capacity of the respiratory chain is decreased due to a reduced availability of ADP.

In contrast to the constriction of capillaries, which prevents undesirably high O2 concentrations in tissue, «soft» decoupling allows fine-regulation on an intracellular level.

Adaptation to hypoxia by an intermittent hypoxic challenge is associated with the expression of, and a shift toward, enzyme isoforms that can efficiently function in a mitochondrial environment with high concentrations of reduced equivalents as generated during hypoxia. This prevents inactivation of the MchEC and may constitute one of the adaptation mechanisms triggered by intermittent hypoxia.

One of the most significant peculiarities of adaptation to intermittent hypoxia is free-radical processes.

The periods of reoxygenation could lead to oxygen radical formation, which might be analogous to that occurring with normoxic reperfusion of transiently hypoxic or ischemic tissues (Belykh et al., 1992; Meerson et al., 1992a). If periods of hypoxia followed by normoxia led to formation of oxygen radicals, but if the hypoxia were much briefer than the periods of normoxia, and if the exposure sequence were repeated over days, then one might expect that antioxidant defenses could be enhanced much more effectively than in sustained hypoxia.

In a recent study rats were given shorter hypoxic exposures: 15 min five times daily for 14 d (Kurhalyuk and Serebrovskaya, 2001). When they were subsequently challenged by exposure to 7% oxygen, blood catalase and glutathione reductase activity were increased and malon dialdehyde concentration was half that of non-IHT controls. The findings were consistent with the concept that intermittent hypoxia stimulates increased antioxidant defenses.

While there was considerable individual variability in the findings (Table 2), our indexes of oxidant stress before IHT were higher in the Chernobyl workers. We used a program of IHT: isocapnic, progressive, hypoxic rebreathing lasting for 5 to 6 min until inspired air O2 reached 8% to 7%, with three sessions, separated by 5 min, of normoxia, per day for 14 consecutive days. The use of IHT was accompanied by a decrease of spontaneous and hydrogen peroxide-initiated blood chemiluminescene, as well as considerable reduction of MDA content (Table 2). Of interest, more recent study on patients with bronchial asthma, who also were characterized by indexes suggestive of oxidative stress, have shown that similar IHT produced the increase of superoxide dismutase (SOD) activity by nearly 70%. This increase correlated with a decrease in MDA content (r = -0.61, P< 0.05) (Safronova et al., 1999; Serebrovskaya et al., 1999c).

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Thus studies in humans and in tissues have shown that adaptation to intermittent hypoxia induces increased antioxidant defenses, acceleration of electron transport in the respiratory chain, stabilization of cellular membranes, and Ca2+ elimination from the cytoplasm. These data served as the basis for IHT in the treatment of various diseases in which free-radical production might be anticipated, for example, bronchial asthma and post-Chernobyl syndromes.

Recent studies have shown the following principal results: (1) adaptation to intermittent hypobaric hypoxia stimulates NO production in the organism; (2) excessive NO synthesized in the course of adaptation is stored in the vascular wall; (3) adaptation to hypoxia prevents both NO over-production and NO deficiency, resulting in an improvement in blood pressure; and (4) effects of intermittent hypoxia on mitochondrial respiration are mediated mainly by NO-dependent reactions (Manukhina et al., 1999, 2000a,b; Malyshev et al., 2000; Ikkert et al., 2000; Smirin et al., 2000; Kurhalyuk and Serebrovskaya, 2001; Kurhalyuk et al., 2001b; Serebrovskaya et al., 2001).

A somewhat different hypothesis has also been suggested, that the electron transport function of the myocardial respiratory chain in the NAD-cytochrome-b area is limited to a greater extent in animals poorly tolerant to hypoxia than in those that are not. In intolerant animals, even mild hypoxia leads to diminution of the oxidative capacity of the respiratory chain and of ATP production and, as a consequence, to a suppression of the energy-dependent contractile function of the myocardium. In animals more tolerant of hypoxia, this process is less manifest and develops very slowly, which confirms the lesser role of NAD-dependent oxidation of substrates in the metabolism of the myocardium of these animals (Korneev et al., 1990).

Taken together these studies suggest that IHT induces increased ventilatory sensitivity to hypoxia in the absence of Pco2 or pH changes; that it induces other hypoxia-related physiological changes such as increased hematopoiesis and decreased plasma volume and increase in alveolar ventilation and lung diffusion capacity; and that it may be useful in the management of certain disease states. The effects appear to be mediated, at least in part, through release of reactive oxygen species, which then induce an increase of antioxidant defenses. In addition, IHT appears to induce changes within mitochondria, possibly involving NAD-dependent metabolism, that increase the efficiency of oxygen utilization in ATP production.