An acid-sensing ion channel that detects ischemic pain

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.

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.

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, 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.

Is recovery driven by central or peripheral factors? A role for the brain in recovery following intermittent-sprint exercise

Nevner svært mye spennende om stølhet (DOMS). Spesielt om hvor mye central sensitering har å si, og mye om hydrering (vann). Samt alt om betennelser og andre faktorer knyttet til DOMS. Sier bl.a. at glucogenlagre normaliseres etter 24 timer uavhengig av hva man spiser, men glykogen omsetningen i kroppen er begrenset i 2-3 dager etter. Nevner også at det er alle de perifere faktorene, sammen med de sentrale, som tilsammen skaper DOMS tilstanden.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909945/

Abstract

Prolonged intermittent-sprint exercise (i.e., team sports) induce disturbances in skeletal muscle structure and function that are associated with reduced contractile function, a cascade of inflammatory responses, perceptual soreness, and a delayed return to optimal physical performance. In this context, recovery from exercise-induced fatigue is traditionally treated from a peripheral viewpoint, with the regeneration of muscle physiology and other peripheral factors the target of recovery strategies. The direction of this research narrative on post-exercise recovery differs to the increasing emphasis on the complex interaction between both central and peripheral factors regulating exercise intensity during exercise performance. Given the role of the central nervous system (CNS) in motor-unit recruitment during exercise, it too may have an integral role in post-exercise recovery. Indeed, this hypothesis is indirectly supported by an apparent disconnect in time-course changes in physiological and biochemical markers resultant from exercise and the ensuing recovery of exercise performance. Equally, improvements in perceptual recovery, even withstanding the physiological state of recovery, may interact with both feed-forward/feed-back mechanisms to influence subsequent efforts. Considering the research interest afforded to recovery methodologies designed to hasten the return of homeostasis within the muscle, the limited focus on contributors to post-exercise recovery from CNS origins is somewhat surprising. Based on this context, the current review aims to outline the potential contributions of the brain to performance recovery after strenuous exercise.

recovery strategies might be broadly differentiated as being either physiological (e.g., cryotherapy, hydrotherapy, massage, compression, sleep), pharmacological (e.g., non-steroidal anti-inflammatory medications) or nutritional (e.g., dietary supplements), all mean to limit continued post-exercise disturbances and inflammatory events within the exercised muscle cells. This peripheral focus emphasizes the importance of an accelerated return of structural integrity and functional capacity from below the neuromuscular junction.

Conceptually, if the brain is held as central to the process of performance declines (i.e., fatigue), it stands to reason that it would also have some role in post-exercise recovery (De Pauw et al., 2013).

Classically defined as an exercise-induced reduction in force generating capacity of the muscle, fatigue may be attributed to peripheral contractile failure, sub-optimal motor cortical output (supraspinal fatigue) and/or altered afferent inputs (spinal fatigue) innervating the active musculature (Gandevia, 2001).

Alternatively, concepts of residual fatigue remain predominately within the domain of peripherally driven mechanisms, such as blood flow, muscle glycogen repletion and clearance of metabolic wastes (Bangsbo et al., 2006).

The physical and biochemical changes observed during intermittent-sprint exercise have traditionally been interpreted in terms of metabolic capacity (Glaister, 2005). Indeed, lowered phosphocreatine concentrations (Dawson et al., 1997), reduced glycolytic regeneration of ATP (Gaitanos et al., 1993) and increasing H+ accumulation (Bishop et al., 2003) have all been associated with declining intermittent-sprint performance.

While reductions in muscle excitability after intermittent-sprint exercise have also been observed (Bishop, 2012), metabolic perturbations are rapidly recovered within minutes (Glaister, 2005).

The ultimate indicator of post-exercise recovery is the ability of the muscle to produce force i.e., performance outcomes.

Reductions in skeletal muscle function after intermittent-sprint exercise are often proposed to be caused by a range of peripherally-induced factors, including: intra-muscular glycogen depletion; increased muscle and blood metabolites concentrations; altered Ca++ or Na+-K+ pump function; increased skeletal muscle damage; excessive increases in endogenous muscle and core temperatures; and the reduction in circulatory function via reduced blood volume and hypohydration (Duffield and Coutts, 2011; Bishop, 2012; Nédélec et al., 2012).

Conversely, Krustrup et al. (2006) reported declines in intramuscular glycogen of 42 ± 6% in soccer players, with depleted or almost depleted glycogen stores in ~55% of type I fibers and ~25–45% of type II fibers reasoned to explain acute declines in sprint speed post-match. Importantly, muscle glycogen resynthesis after team sport activity is slow and may remain attenuated for 2–3 days (Nédélec et al., 2012). Such findings highlight the importance of nutrition in post-exercise recovery (Burke et al., 2006); yet it is noteworthy that muscle glycogen stores remain impaired 24 h after a soccer match, irrespective of carbohydrate intake and should be recognized as a factor in sustained post-match suppression of force (Bangsbo et al., 2006; Krustrup et al., 2011).

Mechanical disruptions to the muscle fiber are task dependant, though likely relate to the volume of acceleration, deceleration, directional change and inter-player contact completed (i.e., tackling or collisions) (McLellan et al., 2011; Duffield et al., 2012). Importantly, EIMD manifests in reduced voluntary force production that has been associated with the elevated expression of intracellular proteins (e.g., creatine kinase and C-reactive protein), swelling, restricted range of motion and muscle soreness (Cheung et al., 2003). Whilst it is generally accepted that lowering blood-based muscle damage profiles may hasten athletic recovery, mechanisms explaining the return of skeletal muscle function are somewhat ambiguous (Howatson and Van Someren, 2008).

Interestingly, markers of EIMD are also not closely associated with muscle soreness (Nosaka et al., 2002; Prasartwuth et al., 2005), though perceptual recovery is reportedly related with the recovery of maximal sprint speed (Cook and Beaven, 2013). While this raises questions in terms of the physiological underpinnings of muscle soreness, weaker relationships between EIMD and neuromuscular performance may suggest the potential for other drivers of recovery outside of peripheral (muscle damage or metabolic) factors alone.

Finally, while the relationship between hydration status and intermittent-sprint performance remains contentious (Edwards and Noakes, 2009), fluid deficits of 2–4% are common following team-sport exercise (Duffield and Coutts, 2011). Mild hypohydration reportedly demonstrates limited effects on anaerobic power and vertical jump performance (Hoffman et al., 1995; Cheuvront et al., 2006); however, some caution is required in interpreting these data as these testing protocols reflect only select components of team sport performance.

Nevertheless, the role of hydration in recovery should not be overlooked as changes in extracellular osmolarity are suggested to influence glucose and leucine kinetics (Keller et al., 2003). Further, the negative psychological associations (conscious or otherwise) derived from a greater perceptual effort incurred in a hypohydrated state may impact mental fatigue (Devlin et al., 2001; Mohr et al., 2010).

Rather, that the integrative regulation of whole body disturbances based on these peripheral factors, alongside central regulation may be relevant.

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.

http://www.biomed.cas.cz/physiolres/pdf/51/51_335.pdf

Summary

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

CO2 sin relasjon til pH

Tabell som viser sammenhengen mellom CO2 og pH. CO2 mellom 35-45 er normalt, over eller under dette kaller man det alkalose eller acidose. Med Metabolsk Pust (RecoveryBreathing.com) ønsker vi å få CO2 opp mot 40-50 mmHg. Legg merke til at også HCO3- økes når CO2 økes i blod. Bikarbonat kalles det og er det stoffet som er i Natron.

http://www.ucdenver.edu/academics/colleges/medicalschool/departments/medicine/intmed/imrp/CURRICULUM/Documents/Oxygenation%20and%20oxygen%20therapy.pdf

TABLE IV

PaCO2 (mm Hg)

pH

HCO3-

15

7.61-7.74

15.3-20.5

20

7.55-7.66

17.7-22.8

30

7.45-7.53

21.0-25.6

40

7.38-7.45

22.8-26.8

50

7.31-7.36

24.1-27.5

60

7.24-7.29

25.1-27.9

70

7.19-7.23

25.7-28.5

80

7.14-7.18

26.2-28.9

90

7.13-7.09

Tabell som viser hvordan O2 og CO2 synker når man kommer opp i høyden.

TABLE V. Gas Pressures at Various Altitudes*

LOCATION

ALT.

PB

FIO2

PIO2

PaCo2

PAO2

PaO2

Sea Level

0

760

.21

150

40

102

95

Cleveland

500

747

.21

147

40

99

92

Denver

5280

640

.21

125

34

84

77

*Pikes’s Peak

14114

450

.21

85

30

62

55

*Mt. Everest

29028

253

.21

43

7.5

35

28

*All pressures in mm Hg; Pike’s Peak and Mt. Everest data from summits