Stikkordarkiv: CO2

Fructose Administration Increases Intraoperative Core Temperature by Augmenting Both Metabolic Rate and the Vasoconstriction Threshold

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Mer om hvordan fruktose øker kroppvarme (termogenese). I denne er det snakk om å bruke det intravenøst for å unngå at pasienter blir kalde etter operasjoner. Det øker restitusjonsevnen etter operasjonen.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1473168/

Abstract

Background

We tested the hypothesis that intravenous fructose ameliorates intraoperative hypothermia both by increasing metabolic rate and the vasoconstriction threshold (triggering core temperature)

Methods

40 patients scheduled for open abdominal surgery were divided into two equal groups and randomly assigned to intravenous fructose infusion (0.5 g·kg−1·h−1 for 4 h, starting 3 h before induction of anesthesia and continuing for 4 hours) or an equal volume of saline. Each treatment group was subdivided: esophageal core temperature, thermoregulatory vasoconstriction, and plasma concentrations were determined in half, and oxygen consumption was determined in the remainder. Patients were monitored for 3 h after induction of anesthesia.

Results

Patient characteristics, anesthetic management, and circulatory data were similar in the four groups. Mean final core temperature (3 h after induction of anesthesia) was 35.7±0.4°C (mean ± SD) in the fructose group and 35.1±0.4°C in the saline group (P=0.001). The vasoconstriction threshold was greater in the fructose (36.2±0.3°C) than in the saline group (35.6±0.3°C; P<0.001). Oxygen consumption immediately before anesthesia induction in the fructose group (214±18 ml/min) was significantly greater than in the saline group (181±8 ml/min, P<0.001). Oxygen consumption was 4.0 L greater in the fructose patients during 3 hours of anesthesia; the predicted difference in mean-body temperature based only on the difference in metabolic rates was thus only 0.4°C. Epinephrine, norepinephrine, and angiotensin II concentrations, and plasma renin activity were similar in each treatment group.

Conclusions

Preoperative fructose infusion helped maintain normothermia by augmenting both metabolic heat production and increasing the vasoconstriction threshold.

Fructose is known to provoke the greatest thermogenesis among various carbohydrates.19,20 Fructose also provokes dietary-induced thermogenesis in awake healthy volunteers, and does so far better than glucose.15 We thus tested the hypothesis that intravenous fructose increases metabolic heat production in anesthetized humans. We also tested the hypothesis that fructose, like amino acids, increases the vasoconstriction threshold and thus has a thermoregulatory as well as metabolic contribution to maintaining perioperative normothermia.

CO2 production before infusion showed no significant difference between saline group (147+19 ml min−1) and fructose group (142+16 ml min−1) but increased significantly in the fructose group (201+26 ml min−1) just before induction of anesthesia, compared with the saline group (146+19 ml min−1)(p<0.001). This increased level was maintained for 135 min after induction of anesthesia.

Mitochondrial Uncoupling

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Endelig har jeg begynt å forstå verdien i det de kaller Mitochondrial Uncoupling.

«Uncoupling» innbærer at mitokondriene produserer varme istedet for ATP. I denne prosessen produseres faktisk mer CO2 enn når mitokondriene produserer ATP (energi-molekyl). Overproduksjon av ATP skaper problemer i cellene. Jo mer ATP jo raskere vil cellen bli overstimulert og dø.

Det er «uncoupling» effekten som gir oss livsforlengelse. Jo større evne mitokondriene våre har til å bli «uncoupled», jo lenger vil vi leve.

 

Denne studien er en rapport fra et møte med 50 forskere som jobber med uncoupling. Den beskriver mye av det fysiologiske med 3 uncoupling proteiner, UPC1,UPC2 og UPC3. Det er UPC1 som gir termogenese(varme): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1369193/

Uncoupling proteins: current status and therapeutic prospects

In bioenergetics, ‘uncoupling’ refers to any process through which energy released from the combustion of substrate (food) in the mitochondria is not conserved. The final steps in the oxidation of substrate are the transfer of electrons to oxygen, forming water, by the respiratory chain. The energy released is used by the respiratory chain to pump protons out of the mitochondria, as seen in Fig 1A. In most mitochondria, the majority of these protons re-enter through the ATP synthase, and the energy is used to synthesize ATP. However, if the protons re-enter by any other means, the mitochondria are considered to be uncoupled.

As energy in this process is transferred to heat and not stored as fat in the body, the activity of the uncoupling protein(s) can be viewed as an anti-obesity mechanism—a possibility that has attracted much attention, as both pharmaceutical companies and the general public are looking for easy ‘slimming’ agents.

 

Whether UCP1 needs an ‘activator’ is also a debated issue—however, it is agreed that an activator is necessary in the cell, with most scientists suggesting that fatty acids are good candidates. (Notat: fruktose er også en «aktivator»)

Uncoupling (measured as thermogenesis) is only observed when the cells are adequately stimulated, for example, by norepinephrine (Fig 1B).

However, it was the opinion of several participants at the meeting (in particular, E. Rial, Madrid, Spain, and J. Nedergaard, Stockholm, Sweden) that fatty acids do not participate in the uncoupling process. Instead, the fatty acids function only as anti-inhibitors by relieving the inhibition caused by the purine nucleotides (ATP and ADP) present in the cells—and experimentally by GDP in isolated brown-adipose mitochondria studies (Fig 1B)—prinicpally in accordance with suggestions by Nicholls from the 1970s.

The most discussed hypothesis at the meeting was that UCP2 and UCP3 do indeed function as uncoupling proteins, but only when oxidative stress (superoxide production) can be ameliorated by their activity. This is generally presented as the ‘mild-uncoupling’ hypothesis (Fig 2). It was debated whether this type of ‘not thermogenic but still membrane potential lowering activity’ is bioenergetically possible.

However, the oxidative-stress protection function is supported by the observation that macrophages from UCP2-null mice produce more superoxide, which results in a chronic activation of the NF-κB system with expected inflammatory consequences (S. Collins, Research Triangle Park, NC, USA). In addition, mice without UCP2 are more susceptible than normal mice to chemically induced colon cancer.

Brand suggested that the UCPs—whether or not this includes UCP1 is still open—specifically protect against oxidative damage caused by fatty acids, particularly polyunsaturated fatty acids from membrane phospholipids. These fatty acids can be attacked by mitochondrially-generated superoxide that converts them into 4-hydroxy-2-nonenal (HNE) and then interacts with the UCPs to make them able to conduct protons (or an equivalent). This ‘mild uncoupling’ would decrease the membrane potential and thus diminish the rate of production of superoxide; that is, this would be a self-regulating protective system.

Uncoupling protein 1. In mammals, UCP1 is found only in brown adipose tissue.

Uncoupling protein 2. UCP2 mRNA has been detected in macrophages, lymphocytes, thymocytes, pulmonary cells, enterocytes, adipocytes, pancreatic β-cells and certain neurons and, at a lower level, in liver, muscle and kidney cells. In the brain, UCP2 gene expression is generally low but high levels of UCP2 mRNA have been found in some regions, such as the limbic system and particular subdomains of the hypothalamus (D. Richard, Quebec, Canada).

Uncoupling protein 3. UCP3 expression levels in the skeletal muscle of animals or humans respond to changes in fatty-acid flux (F. Villarroya, Barcelona, Spain; Harper; Dulloo; Schrauwen).

The thyroid hormone tri-iodothyronine has a positive role in the control of UCP3 expression (F. Goglia, Benevento, Italy).

 

Denne studien fra 2002 beskriver de viktigste prisinippene for hva det vil si å ha evnen til å «uncouple» mitokondrienes energiproduksjon:

Living Fast, Dying When? The Link between Aging and Energetics

Her beskrives prosessen med proton-flyt (H+):

During oxidative phosphorylation electrons from reduced substrates are picked up by ubiquinone (Q) on complex 1 of the mitochondrial membrane. As these electrons are passed from complex 1 down the cytochromes the released energy is used to pump protons across the inner mitochondrial membrane creating a protonmotive force. Finally, in complex 4 the electron combines with a proton and oxygen to form water. The hydrogen ions pass back across the membrane via ATP synthase, resulting in the generation of ATP from ADP and inorganic phosphate, although occasionally protons leak back through the membrane without the creation of ATP, either as a membrane leak or via a specialized protein called an uncoupling protein (UCP), which allows the proton to pass uncoupled from the generation of ATP, but resulting in release of the stored energy as heat. Occasionally, however, this process goes wrong and the oxygen reacts with a reduced form of Q, called ubisemiquinone (QH), which results in generation of a superoxide free radical (O2−) (60–63).

Animals can reduce the levels of protonmotive force by increasing the extent of uncoupling in their mitochondria. To continue to generate ATP requires elevated oxygen consumption, although the net production of free-radical species is diminished. The animals uncouple respiration to increase their survival (63). This effect is diametrically opposed to the prevailing notion that increasing uncoupling should lead to an increase in free-radical production because of the elevated oxygen consumption (95). Our data are consistent with a protective effect of uncoupling respiration and, consequently, our current efforts are directed at resolving whether those MF1 mice with high-energy expenditures have more uncoupled mitochondria, or elevated levels of protection and repair processes.

http://m.jn.nutrition.org/content/132/6/1583S.long

 

Denne studiens overskrift (fra 2004) sier alt:

Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer

Mice in the upper quartile of metabolic intensities had greater resting oxygen consumption by 17% and lived 36% longer than mice in the lowest intensity quartile. Mitochondria isolated from the skeletal muscle of mice in the upper quartile had higher proton conductance than mitochondria from mice from the lowest quartile. The higher conductance was caused by higher levels of endogenous activators of proton leak through the adenine nucleotide translocase and uncoupling protein-3. Individuals with high metabolism were therefore more uncoupled, had greater resting and total daily energy expenditures and survived longest – supporting the ‘uncoupling to survive’ hypothesis.

The work we performed on mitochondria extracted from the second and third cohorts of mice, in combination with the first cohort [Fig. 1] where we showed that mice with higher metabolic intensities lived longest, provide greater support for the ‘uncoupling to survive’ hypothesis than for the ‘rate of living-free-radical damage’ hypothesis, at the level of individual phenotypic differences in metabolic intensity. Since we used an outbred strain kept in constant environmental conditions, presumably these phenotypic differences have a genetic component at their origin; this conclusion is supported by the fact that the same association between longevity and metabolic intensity is also observed across inbred strains (Storer et al., 1967).

http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9728.2004.00097.x/full

 

Denne studien fra 1993 nevner at «uncoupled» mitkondria produserer mer CO2:

Characterization of the folate-dependent mitochondrial oxidation of carbon 3 of serine.

In contrast, CO2 production was greatest in uncoupled mitochondria and lowest in respiratory-inhibited mitochondria.

http://www.ncbi.nlm.nih.gov/pubmed/8485144/

An acid-sensing ion channel that detects ischemic pain

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Nevner mange interessante ting om hvordan lav pH som følge av CO2 ikke er det samme som lav pH som følge av f.eks. melkesyre(laktic acid). De sier at melkesyre og ATP må være sammen for å gjøre pH-sensitive nerver aktive. Noe som skjer ved hard trening hvor ATP lekker ut fra muskel cellene. Laktat aktiverer ASICs umiddelbart, mens ATP er «treg» og det skjer i løpet av 30-60 sekunder. Kanskje denne overaskelsen i nervesystemet er utgangspunktet for sentralsensiteringen som skjer ved DOMS?

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2005001100001

Paradox number 2 answered: coincident detection of lactate, ATP and acid

We are left with a seemingly more profound paradox: how can acid be relevant to ischemic pain if no pain is caused by metabolic events such as hypercapnia that can cause the same kind of pH change that occurs during a heart attack? Pan et al. (13) demonstrated the paradox most convincingly. They measured the pH on the surface of the heart when a coronary artery was blocked and found that it dropped from pH 7.4 to 7.0. Then they reperfused the artery and had the animal breathe carbon dioxide until the resulting hypercapnia dropped the pH of the heart to 7.0. The blockade of the artery caused increased firing of sensory axons that innervate the heart, but the hypercapnia did not. How can this observation be reconciled with their other result (see above) that buffering extracellular pH greatly diminishes axon firing during artery occlusion? The simple interpretation is that protons must be necessary to activate the sensory axons, but cannot by themselves be sufficient. In other words, something must act together with protons to activate the axons.

We searched for compounds released during ischemia that might act together with protons to activate ASIC3. We found two: lactate and adenosine 5′-triphosphate (ATP). When the channel is activated by pH 7.0 in the presence of 15 mM lactate, the resulting current is 80% greater than when lactate is absent (Figure 6). These are physiological values. Under resting conditions, extracellular lactate is about 1 mM in skeletal muscle; after extreme ischemic exercise it rises to 15-30 mM (26). The increased current in the presence of lactate makes the channel better at sensing the lactic acidosis that occurs in ischemia than other kinds of acidosis such as the carbonic acidosis when an animal breathes CO2.

Extracellular ATP rises to >10 µM when a muscle contracts without blood flow (27). We find that a transient appearance of such extracellular ATP can greatly increase ASIC3 current even for minutes after the ATP is removed (Figure 7).

Though they both increase ASIC3 current, lactate and ATP have qualitatively different effects. Lactate acts immediately and must be present for the ASIC current to be enhanced. ATP increases the current slowly – a peak is reached between 15 s and 1 min after ATP is applied – and the effect persists for minutes after ATP is removed. Also, lactate acts on every cell that expresses ASIC3 whereas ATP acts on some cells but not others. We find that lactate acts by altering the basic gating of the channel, which, surprisingly, involves binding of calcium in addition to protons (28). In contrast, the ATP binding site must not be the ASIC3 channel itself; there are a variety of purinergic receptors, some of which are ion channels and some of which are G-protein-coupled receptors. We are presently asking if any of these known receptors might mediate ATP modulation of ASIC3.

Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons.

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En studie fra 1991 som beskriver hvordan hyperventillering og lav CO2 (hypokapni) påvirker perifere nervetråder og deres eksitabilitet. Sier at det er et lineært forhold mellom CO2 nedgang og perifere nervetråders eksitabilitet. Altså jo mindre CO2 som er tilstedet i blodet og vevet, jo lettere er det å oppleve smerter og muskelspenninger.

Macefield and Burke 1991. Paraesthesiae and tetany induced by voluntary hyperventilation. Increased excitability of human cutaneous and motor axons.

http://www.ncbi.nlm.nih.gov/pubmed/2004255

To define the nature of the disturbance created in peripheral nerve, the excitability of cutaneous and motor axons was monitored in 6 normal subjects requested to hyperventilate until paraesthesiae developed in the hands, face and trunk. This occurred when alveolar PCO2 (PACO2) had declined on average by 20 mmHg.

As PACO2 declined, the size of the compound sensory and muscle potentials evoked by a constant stimulus progressively increased, indicating an increase in axonal excitability. These changes occurred before paraesthesiae or tetany developed. In each subject there was a statistically significant inverse correlation between PACO2 and axonal excitability.

It is concluded that the paraesthesiae and tetany induced by hyperventilation result solely from changes in the excitability of cutaneous and motor axons in the peripheral nerve, presumably due to an alteration in the electrical properties of the axonal membrane resulting from a reduced plasma [Ca2+].

Respiratory Monitoring: Physiological and Technical Considerations

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Nevner mye viktig om oksygen metning og oximetri. Sier at den normal intracellulære oxygenmetninger er 40 mmHG, som er en SpO2 på 80%.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662504/

A useful caveat is to memorize the significance of 2 saturation readings; 95% and 90%. An SpO2 of 95 reflects a PaO2 of ~80 mm Hg. This is by definition the lower limit of normal oxygenation. The precise oxygen tensions for saturations above 95 are irrelevant; they reflect normal PaO2. An SpO2 of 90 reflects a PaO2 of ~60 mm Hg. By definition, this is hypoxemia, but it is well above the normal intracellular oxygen tension of 40 mm Hg.

More importantly, 90% saturation represents a critical point on the oxygen-hemoglobin dissociation curve (See Figure 1). Further decline leads to a precipitous drop in saturation, thus oxygenation, as hemoglobin loses oxygen rapidly. Saturation that declines to 90% is at the “edge of the cliff” and is a warning to aggressively reestablish adequate ventilation. PaO2 extrapolations no longer require memorization because they are ~30 less than the SpO2 reading. For example, if hemoglobin saturation is 83%, the PaO2 is ~53 mm Hg.

While PaO2 is used to assess oxygenation, PaCO2 is the true measure of ventilation.

Treating Diabetes with Exercise – Focus on the Microvasculature

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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.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000229

Abstract

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

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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.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172820/

Abstract

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, 1996, Graeber, 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, 2002, Farina 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., 2004, Nam, 2006). Endogenous molecules known to activate TLR-4 receptors include (but are not limited to) heat shock proteins (specifically HSP60, Ohashi et al., 2000, Lehnardt 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, 2000, Trang et al., 2006, Mika, 2008, Abbadie et al., 2009, Baumbauer 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., 2000, O’Croinin et al., 2005, Curley et al., 2010, Li 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.

Hypocapnia in patients with chronic neck pain: association with pain, muscle function, and psychologic states.

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Nevner at hypokapni (lav CO2) er assosiert med smerte.

http://www.ncbi.nlm.nih.gov/pubmed/23958733

OBJECTIVE:

The aim of this study was to investigate whether patients with chronic neck pain have changes in their transcutaneous partial pressure of arterial carbon dioxide (PtcCO2) and whether other physical and psychologic parameters are associated.

DESIGN:

In this cross-sectional study, 45 patients with chronic idiopathic neck pain and 45 healthy sex-, age-, height-, and weight-matched controls were voluntarily recruited. The participants’ neck muscle strength, endurance of the deep neck flexors, neck range of movement, forward head posture, psychologic states (anxiety, depression, kinesiophobia, and catastrophizing), disability, and pain were assessed. PtcCO2 was assessed using transcutaneous blood gas monitoring.

RESULTS:

The patients with chronic neck pain presented significantly reduced PtcCO2 (P < 0.01). In the patients, PtcCO2 was significantly correlated with strength of the neck muscles, endurance of the deep neck flexors, kinesiophobia, catastrophizing, and pain intensity (P < 0.05). Pain intensity, endurance of the deep neck flexors, and kinesiophobia remained as significant predictors into the regression model of PtcCO2.

CONCLUSIONS:

Patients with chronic neck pain present with reduced PtcCO2, which can reach the limits of hypocapnia. This disturbance seems to be associated with physical and psychologic manifestations of neck pain. These findings can have a great impact on various clinical aspects, notably, patient assessment, rehabilitation, and drug prescription.

Differential blood flow responses to CO2 in human internal and external carotid and vertebral arteries

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Denne viser hvordan CO2-responsen er litt forskjellige i forskjellige blodkar. Den er sterkere i blodkar inni hjernen enn i blodkar i kraniet, ansiktet og ryggraden. Blodkar i ryggraden har større respons enn blodkar i ansiktet, men mindre respons enn blodkar i hjernen.

http://jp.physoc.org/content/590/14/3277.long

Because of methodological limitations, almost all previous studies have evaluated the response of mean blood flow velocity (Vmean) in the middle cerebral artery (MCA) to changes in CO2 as a measure of CO2 reactivity across the whole brain (Aaslid et al. 1989; Ainslie & Duffin, 2009; Ainslie & Ogoh, 2009).

 

ICA, VA and BA CO2 reactivity was significantly higher during hypercapnia than during hypocapnia (ICA, P < 0.01; VA, P < 0.05; BA, P < 0.05), but ECA and MCA were not significantly different.

The major finding from the present study was that cerebral CO2 reactivity was significantly lower in the VA and its distal artery (BA) than in the ICA and its distal artery (MCA). These findings indicate that vertebro-basilar circulation has lower CO2 reactivity than internal carotid circulation. Our second major finding was that ECA blood flow was unresponsive to hypocapnia and hypercapnia, suggesting that CO2 reactivity of the external carotid circulation is markedly diminished compared to that of the cerebral circulation. These findings suggest that different CO2 reactivity may explain differences in CBF responses to physiological conditions (i.e. dynamic exercise and orthostatic stress) across areas in the brain and/or head.

Hypercapnic cerebral CO2 reactivity in global CBF was greater than the hypocapnic reactivity (Ide et al. 2003) (Table 3). The mechanisms underlying this greater reactivity to hypercapnia compared with hypocapnia may be related to a greater influence of vasodilator mediators on intracranial vascular tone compared with vasoconstrictive mediators (Toda & Okamura, 1998; Ainslie & Duffin, 2009). In humans, Peebles et al.(2008) recently reported that, during hypercapnia, there is a large release of nitric oxide (NO) from the brain, whereas this response was absent during hypocapnia.

The difference in CO2 reactivity between vertebro-basilar territories (VA and BA) and the cerebral cortex (ICA and MCA) may be due to diverse characteristics of vasculature, e.g. regional microvascular density (Sato et al. 1984), basal vascular tone (Ackerman, 1973; Haubrich et al. 2004; Reinhard et al. 2008), autonomic innervation (Edvinsson et al. 1976; Hamel et al. 1988) and regional heterogeneity in ion channels or production of NO (Iadecola & Zhang, 1994; Gotoh et al. 2001).

Interestingly, the response of the ECA to changes in CO2 may be similar to other peripheral arteries. It has long been appreciated that the vasodilatory effect of hypercapnia is much more profound in cerebral than in peripheral vasculature, particularly leg (Lennox & Gibbs, 1932; Ainslie et al. 2005) and brachial arteries (Miyazaki, 1973). These findings suggest that control of CO2 is particularly important in the cerebral circulation. The high resting metabolic requirements of the brain, compared with that of other vasculature, might be one reason why this circulatory arrangement is desirable (Ainslie et al. 2005). Specifically, high CO2 reactivity may be a way for the brain to match metabolism with flow (Ainslie et al. 2005).

Lower CO2reactivity in the vertebro-basilar system may be important for maintaining central respiratory function because Graphic in central chemoreceptors is regulated by Graphic and blood flow to maintain breathing stability.

In summary, our study shows that cerebral CO2 reactivity in the vertebro-basilar circulation is lower than that in the internal carotid circulation, while CO2 reactivity in the external carotid circulation is much lower compared with two other cerebral arteries. These findings indicate a difference in cerebral CO2 reactivity between different circulatory areas in the brain and head, which may explain different CBF responses to physiological stress. Lower CO2 reactivity in the vertebro-basilar system may be beneficial for preserving blood flow to the medulla oblongata to maintain vital systemic functions, while higher CO2 reactivity in the internal carotid system may imply a larger tolerance for varied blood flow in the cerebral cortex.