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.

Klikk for å få tilgang til 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.

Two routes to functional adaptation: Tibetan and Andean high-altitude natives

Om hvordan pusten endres når man bor i høyland. Nevner mye om oksygentilgjengelighet, oksygenkaskade, hypoxi, kapillærer, mitokondrier, m.m., og om hvorfor vi har lite oksygen i mitokondriene. Studier undersøker spesifikt om at tibetanere har endrede gener siden de med gener som er tilpasset lave oksygennivåer har mindre fysiologisk stress og dermed større sjangse for barn som overlever, og hvilke forkjeller i hypoxi-tilpasning som har sjedd i de to befolkningene.

Ny, som må gjennomgåes:

These reveal generally more genetic variance in the Tibetan population and more potential for natural selection. There is evidence that natural selection is ongoing in the Tibetan population, where women estimated to have genotypes for high oxygen saturation of hemoglobin (and less physiological stress) have higher offspring survival.

At 4,000-m elevation, every breath of air contains only ≈60% of the oxygen molecules in the same breath at sea level. This is a constant feature of the ambient environment to which every person at a given altitude is inexorably exposed. Less oxygen in inspired air results in less oxygen to diffuse into the bloodstream to be carried to the cells for oxygen-requiring energy-producing metabolism in the mitochondria.

Humans do not store oxygen, because it reacts so rapidly and destructively with other molecules. Therefore, oxygen must be supplied, without interruption, to the mitochondria and to the ≥1,000 oxygen-requiring enzymatic reactions in various cells and tissues (4).

Fig. 1. Ambient oxygen levels, measured by the partial pressure of oxygen (solid line) or as a percent of sea-level values (dashed line), decrease with increasing altitude, a situation called high-altitude or hypobaric hypoxia. The atmosphere contains ≈21% oxygen at all altitudes.

The oxygen level is near zero in human mitochondria at all altitudes (5). This condition is described as “primitive,” because it has changed little for the past 2.5 billion years despite wide swings in the amount of atmospheric oxygen (at times it has been 10,000-fold lower; refs. 6 and 7) and “protective” in the sense that it circumvents potentially damaging reactions of oxygen with other molecules (8).

Fig. 2. The oxygen transport cascade at sea level (solid line) and at the high altitude of 4,540 m (dashed line) illustrates the oxygen levels at the major stages of oxygen delivery and suggests potential points of functional adaptation (data from ref. 60).

Potential and Actual Points of Adaptation to Hypoxia

Energy Production.

Lowlanders traveling to high altitude display homeostatic responses to the acute severe hypoxia. The responses are energetically costly, as indicated by an increase in basal metabolic rate (BMR; the minimum amount of energy needed to maintain life with processes such as regulating body temperature, heart rate, and breathing). BMR is increased by ≈17–27% for the first few weeks upon exposure to high altitude and gradually returns toward sea-level baseline (9). In other words, for acutely exposed lowlanders, the fundamental physiological processes required to sustain life at high altitude require more oxygen despite lower oxygen availability.

In contrast to acutely exposed lowlanders and despite the equally low level of oxygen pressure in the air and lungs, both Andean and Tibetan highlanders display the standard low-altitude range of oxygen delivery from minimal to maximal. Both populations have the normal basal metabolic rate expected for their age, sex, and body weight (1416), implying that their functional adaptations do not entail increased basal oxygen requirements. Furthermore, Andean and Tibetan highlanders have maximal oxygen uptake expected for their level of physical training (12, 13, 17).


One potential point of adaptation in oxygen delivery is ventilation, which, if raised, could move a larger overall volume of air and achieve a higher level of oxygen in the alveolar air (Fig. 2) and diffusion of more oxygen. An immediate increase in ventilation is perhaps the most important response of lowlanders acutely exposed to high altitude, although it is not sustained indefinitely and is not found among members of low-altitude populations born and raised at high altitude, such as Europeans or Chinese (3, 18).

For example, a comparative analysis summarizing the results of 28 samples of Tibetan and Andean high-altitude natives at an average altitude of ≈3,900 m reported an estimated resting ventilation of 15.0 liters/min among the Tibetan samples as compared with 10.5 liters/min among the Andean samples (19).

Fig. 3 illustrates the higher resting ventilation of Tibetans as compared with Andean highlanders evaluated using the same protocol at ≈4,000 m. The mean resting ventilation for Tibetans was >1 SD higher than the mean of the Andean highlanders (20).

Oxygen in the Bloodstream.

The higher ventilation levels among Tibetans that move more oxygen through the lungs, along with the higher HVRs that respond more vigorously to fluctuations in oxygen levels, might be expected to result in more oxygen in the bloodstream. However, the level of oxygen in the arterial blood (Fig. 2) of a sample of Tibetans at ≈3,700 m was lower than that of a sample of Andean high-altitude natives at the same altitude (54 as compared with 57 mmHg; 1 mmHg = 133 Pa) (24, 25). In addition, hemoglobin, the oxygen-carrying molecule in blood, is less saturated with oxygen among Tibetans than among their Andean counterparts (26, 27). Fig. 3 illustrates the lower percent of oxygen saturation of hemoglobin in a sample of Tibetans at ≈4,000 m. The increased breathing of Tibetans does not deliver more oxygen to the hemoglobin in the arteries.

Fig. 3 illustrates the markedly lower hemoglobin concentrations in a sample of Tibetan men and women as compared with their Andean counterparts at ≈4,000 m. [The average hemoglobin concentrations were 15.6 and 19.2 g/dl for Tibetan and Andean men, respectively, and 14.2 and 17.8 g/dl for women (28).] Hemoglobin concentration is influenced by many factors, including erythropoietin, a protein that causes differentiation of the precursors that will become hemoglobin-containing red blood cells. Tibetans have slightly lower erythropoietin concentrations than Andean highlanders at the same altitude (25). When matched for volume of red blood cells, a procedure that would effectively compare the highest Tibetan and the lowest Andean values, Andean highlanders have much higher erythropoietin levels, which implies that some sensor is responding as if the stress were more severe, even though the samples were collected at the same altitude of ≈3,700 m.

Andean highlanders have overcompensated for ambient hypoxia according to this measure, whereas Tibetan highlanders have undercompensated. Indeed, Tibetans are profoundly hypoxic and must be engaging other mechanisms or adapting at different points in the oxygen transport cascade to sustain normal aerobic metabolism.

Fig. 4. The calculated arterial oxygen content of Tibetan men and women is profoundly lower than their Andean counterparts measured at ≈4,000 m (data from ref. 62), whereas the exhaled NO concentration is markedly higher (recalculated from data reported in ref. 34).

Blood Flow and Oxygen Diffusion.

Other potential points of functional adaptation include the rate of flow of oxygen-carrying blood to tissues and the rate of oxygen diffusion from the bloodstream into cells.

Because blood flow is a function of the diameter of blood vessels, dilating factors could, in principle, improve the rate of oxygen delivery. Sea-level populations respond to high-altitude hypoxia by narrowing the blood vessels in their lungs, the first point of contact with the circulation. Known as hypoxic pulmonary vasoconstriction, that reflex evolved at sea level to direct blood away from temporarily poorly oxygenated toward better oxygenated parts of the lung. High-altitude hypoxia causes poor oxygenation of the entire lung and general constriction of blood vessels to the degree that it raises pulmonary blood pressure, often to hypertensive levels (3, 29).

In contrast, most Tibetans do not have hypoxic pulmonary vasoconstriction or pulmonary hypertension. This is indicated by essentially normal pulmonary blood flow, as measured by normal or only minimally elevated pulmonary artery pressure (29, 30).

a mean pulmonary artery pressure of 31 mmHg for the Tibetan 28% lower than the mean of 43 mmHg for the Andean (35 mmHg is often considered the upper end of the normal sea-level range) (30, 31). Andean highlanders are consistently reported to have pulmonary hypertension (29). Thus, pulmonary blood flow is another element of oxygen delivery for which Tibetans differ from Andean highlanders in the direction of greater departure from the ancestral response to acute hypoxia.

A probable reason for the normal pulmonary artery pressure among Tibetans is high levels of the vasodilator nitric oxide (NO) gas synthesized in the lining of the blood vessels. Low-altitude populations acutely exposed to high-altitude down-regulate NO synthesis, a response thought to contribute to hypoxic pulmonary vasoconstriction (32, 33). In contrast, NO is substantially elevated in the lungs of Tibetan as compared with Andean highlanders and lowlanders at sea level (Fig. 4) (34). Among Tibetans, higher exhaled NO is associated with higher blood flow through the lungs (30).

Several other lines of evidence highlight the importance of high blood flow for Tibetans. These include greater increase in blood flow after temporary occlusion (35) and higher blood flow to the brain during exercise (36) as compared with lowlanders.

Generally, Tibetans appear to have relatively high blood flow that may contribute significantly to offsetting their low arterial oxygen content.

A denser capillary network could potentially improve perfusion and oxygen delivery, because each capillary would supply a smaller area of tissue, and oxygen would diffuse a shorter distance. Tibetans (the study sample were Sherpas, an ethnic group that emigrated from Tibet to Nepal ≈500 years ago) who are born and raised at high altitude have higher capillary density in muscles as compared with Andean high-altitude natives, Tibetans born and raised at low altitude, or lowlanders (Fig. 5) (40).

Fig. 5. High-altitude native Tibetans have higher capillary density than their Andean counterparts or populations at low altitude; Tibetan and Andean highlanders both have lower mitochondrial volume than low-altitude populations (data from refs. 40, 44, 63, and64).

The last potential point of adaptation is at the level of the mitochondrion itself. Acutely exposed lowlanders lose mitochondria in leg muscles during the first 3 weeks at altitude. Similarly, both Tibetan (Sherpas) and Andean high-altitude natives have a lower mitochondrial volume in leg muscle tissue than sea-level natives at sea level (Fig. 5) (40).

Among Tibetans, a smaller mitochondrial volume somehow supports a relatively larger oxygen consumption, perhaps by higher metabolic efficiency (12, 43, 44).

Another candidate gene is the transcription factor hypoxia-inducible factor 1 (HIF1) often called the “master regulator” of oxygen homeostasis, because it induces >70 genes that respond to hypoxia (5658). An investigation of polymorphisms in the HIF1A gene of Tibetans (Sherpas) found a dinucleotide repeat in 20 Tibetans that was not found in 30 Japanese lowlander controls (59).

Differences in the control of breathing between Himalayan and sea-level residents

Om hvordan langvarig høydeopphold utvisker sensitiviteten til CO2.

Highlanders had lower mean ± S.E.M.ventilatory sensitivities to CO2 than lowlanders at both isoxic tensions (hyperoxic: 2.3 ± 0.3 vs. 4.2 ± 0.3 l min−1 mmHg−1, P = 0.021; hypoxic: 2.8 ± 0.3 vs. 7.1 ± 0.6 l min−1mmHg−1, P < 0.001), and the usual increase in ventilatory sensitivity to CO2 induced by hypoxia in lowlanders was absent in highlanders (P = 0.361).

Furthermore, the ventilatory recruitment threshold (VRT) CO2 tensions in highlanders were lower than in lowlanders (hyperoxic: 33.8 ± 0.9 vs. 48.9 ± 0.7 mmHg, P < 0.001; hypoxic: 31.2 ± 1.1 vs. 44.7 ± 0.7 mmHg, P < 0.001).

We conclude that control of breathing in Himalayan highlanders is distinctly different from that of sea-level lowlanders. Specifically, Himalayan highlanders have decreased central and absent peripheral sensitivities to CO2. Their response to hypoxia was heterogeneous, with the majority decreasing their VRT indicating either a CO2-independent increase in activity of peripheral chemoreceptor or hypoxia-induced increase in [H+] at the central chemoreceptor.

Control of breathing in humans can be broadly divided into chemoreflex and non-chemoreflex drives to breathe (Fig. 1) (Lloyd & Cunningham, 1963). Non-chemoreflex breathing stimuli include a wakefulness drive (Longobardo et al. 2002), voluntary (cortical) drive (Shea, 1996) and hormonal factors (Jensen et al. 2008), as well as neural and humoral mediating factors that are especially important in the control of breathing during exercise (Bell, 2006; Dempsey, 2006; Haouzi, 2006). The chemoreflex drive to breathe can be further divided into central and peripheral chemoreceptor drives. Both central and peripheral chemoreceptors respond to changes in the hydrogen ion concentration ([H+]) in their immediate environments (Torrance, 1996; Nattie & Li, 2009).

In contrast to the central chemoreceptors, peripheral chemoreceptors are also sensitive to changes in arterial Graphic (Graphic) via a hypoxia-mediated increase in their sensitivity to [H+] (Cunningham, 1987; Torrance, 1996; Kumar & Bin-Jaliah, 2007), and hyperoxia (Graphic ≥ 150 mmHg) effectively silences this response (Lloyd & Cunningham, 1963; Mohan & Duffin, 1997).

Central and peripheral chemoreceptor neural drives are integrated in the medulla to provide the total chemoreflex neural drive (Fink, 1961; Shea, 1996; Mohan & Duffin, 1997; Orem et al. 2002) that, in combination with non-chemoreflex drives, provides ventilatory drive to respiratory muscles.

Figure 3. Hypercapnic ventilatory response The graph displays two isoxic responses: hyperoxic (Graphic = 150 mmHg) representing central chemoreflex response, and hypoxic (Graphic = 50 mmHg) representing the addition of central and peripheral chemoreflexes responses. The slope of each isoxic response represents sensitivity of the chemoreflex to CO2. The inflection point at which ventilation starts to increase in response to increasing Graphic is the ventilatory recruitment threshold (VRT), where the chemoreflex neural drive to breathe exceeds a drive threshold and starts to produce an increase in pulmonary ventilation. Ventilation below VRT represents non-chemoreflex drives to breathe and is known as the basal ventilation. The differences in ventilation between isoxic rebreathing lines at any given isocapnic Graphic can be used to calculate the hypoxic ventilatory response (indicated by vertical arrows). Note that the choice of isocapnic Graphic affects the magnitude of the measured HVR even within the same subject (Duffin, 2007), with higher HVRs measured at higher isocapnic Graphicvalues in the illustrated example. Note also that the magnitude of HVR provides little information about the characteristics of the control of breathing model, as HVR magnitude is dependent on the combination of central and peripheral chemoreflex responses.

There was no difference in the non-chemoreflex drives to breathe between highlanders and lowlanders, as indicated by similar basal (below VRT) ventilations in the two populations (Table 2).

The highlanders had decreased VRTs compared to lowlanders during both hypoxic and hyperoxic rebreathing tests. The leftward shift of the VRTs in highlanders suggests that a lower Graphic was required to exceed the VRT in highlanders compared to lowlanders. Since both central and peripheral chemoreceptors are actually [H+] sensors, interpretation of this result should consider the acid–base status in both populations. According to the Henderson–Hasselbach equation (Nunn, 1993), the relationship between [H+] and Graphiccan be described as follows:Formulawhere [HCO3] is the bicarbonate ion concentration. In a hypothetical sea-level resident at sea-level, [H+] is approximately 40 nM l−1, Graphic is 40 mmHg and [HCO3] is 24 mM l−1. At altitude, hypoxia-induced hyperventilation results in a reduction of Graphic that leads to a reduction in [H+] and respiratory alkalosis according to the above equation. Highlanders compensate for respiratory alkalosis by presumably reducing their [HCO3] through increased renal excretion, thereby restoring the Graphic/[HCO3] ratio to sea-level values and normalizing [H+].

For example, if hypoxia-induced hyperventilation reduced CO2 from 40 to 30 mmHg, and HCO3− fell from 24 to 18 mM l−1, then the overall ratio of CO2/HCO3− would be maintained at 5/3 as in sea-level lowlanders, but normal [H+] of 40 nM l−1 would be achieved at a lower Graphic of 30 mmHg rather than 40 mmHg, as at sea-level. Considering that the highlanders in our study have an adapted acid–base status (Santolaya 1989), the observed difference in VRTs can be explained by the altered [H+]–Graphic relationship in highlanders compared to lowlanders, with the assumption that the chemoreceptor thresholds [H+] are similar (Duffin, 2005).

The sensitivity of the central chemoreceptor to CO2, as indicated by the ventilatory sensitivity during hyperoxic rebreathing, was lower in highlanders compared to lowlanders (2.5 ± 0.4 vs. 4.2 ± 0.3 l min−1 mmHg−1, P = 0.011). Hyperoxia effectively silences the peripheral chemoreceptor (Lloyd & Cunningham, 1963; Mohan & Duffin, 1997), and therefore the ventilatory sensitivity measured during hyperoxic rebreathing can be taken as a measure of central chemoreceptor sensitivity (Duffin, 2007).

Since the ventilatory response to hypercapnia decreases with age (Nishimura et al. 1991; Jones et al. 1993; Poulin et al.1993; McGurk et al. 1995) and increases with weight (Marcus et al. 1994), the observed lower central CO2 chemosensivity in our highlander subjects may be the result of their older age and smaller body size.

Ventilatory response to hypoxia in highlanders was markedly different from that in lowlanders. Unlike lowlanders, who responded to hypoxia by increasing the sensitivity of their ventilatory response to CO2 (Mohan & Duffin, 1997), the highlanders seemed to decrease their VRT in response to hypoxia with no change in the sensitivity to CO2.

The ventilatory response to hypoxia in sea-level residents is mediated by peripheral chemoreceptors via an increase in the peripheral chemoreceptor sensitivity to [H+] (Cunningham, 1987; Torrance, 1996; Kumar & Bin-Jaliah, 2007). A lack of increase in ventilatory sensitivity to CO2 with induction of hypoxia in highlanders suggests that their peripheral chemoreceptors are relatively insensitive to CO2.

Other possible mechanisms of CO2-independent peripheral responses to hypoxia may include a hypoxia-induced increase in the carotid body tonic drive to breathe, changes in systemic hormonal mediators, an altered cerebral spinal fluid-buffering capacity at the central chemoreceptor or an alteration in cerebral vascular reactivity leading to a higher [H+] at central chemoreceptor.

Specifically, we showed that Himalayan highlanders have decreased central and absent peripheral chemoreceptor sensitivity to CO2, and that they are sensitive to hypoxia, albeit via a different mechanism than that observed in lowlanders at sea-level. A blunted central and an absent peripheral ventilatory sensitivity to CO2 in Himalayan highlanders may stabilize their ventilatory controller by reducing the overall gain in the feedback part of the controller circuit, thereby reducing altitude-related breathing instability (Ainslie & Duffin, 2009)

The non-chemoreflex drives to breathe were similar between Himalayan highlanders and sea-level lowlanders.

The role of nitric oxide in skin blood flow increases due to vibration in healthy adults and adults with type 2 diabetes

Vibrasjon på underamren øker blodsirkulasjon pga økt NO utskillelse fra blodkarveggene.

those with diabetes had significantly lower (223%; P = 0.003) skin blood flows compared to the healthy older adults (461%). The rate of NO production, expressed as microM NO . flux, also increased significantly in both groups after vibration (healthy group, 374%; diabetes group, 236%) and remained significantly elevated (healthy group, 258%; diabetes group, 177%) for at least 5 min