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Neuromuscular strain as a contributor to cognitive and other symptoms in chronic fatigue syndrome: hypothesis and conceptual model

Viktig studie om nervesystemet og bindevevets «adhesions» som bidragsyter til smerte.

http://www.frontiersin.org/Integrative_Physiology/10.3389/fphys.2013.00115/full

«Work by Brieg, Sunderland, and others has emphasized the ability of the nervous system to undergo accommodative changes in length in response to the range of limb and trunk movements carried out during daily activity. If that ability to elongate is impaired—due to movement restrictions in tissues adjacent to nerves, or due to swelling or adhesions within the nerve itself—the result is an increase in mechanical tension within the nerve. »

«This adverse neural tension, also termed neurodynamic dysfunction, is thought to contribute to pain and other symptoms through a variety of mechanisms. These include mechanical sensitization and altered nociceptive signaling, altered proprioception, adverse patterns of muscle recruitment and force of muscle contraction, reduced intra-neural blood flow, and release of inflammatory neuropeptides. »

«In our clinical work, we have found that neuromuscular restrictions are common in CFS, and that many symptoms of CFS can be reproduced by selectively adding neuromuscular strain during the examination.»

«As defined by Yunus, central sensitivity is “clinically and physiologically characterized by hyperalgesia (excessive sensitivity to a normally painful stimulus, e.g., pressure), allodynia (painful sensation to a normally non-painful stimulus, e.g., touch and massage), expansion of the receptive field (pain beyond the area of peripheral nerve supply), prolonged electrophysiological discharge, and an after-stimulus unpleasant quality of pain (e.g., burning, throbbing, numbness)” (Yunus, 2008).»

«These symptoms might be mediated by amplified central sensitivity, but peripheral factors, which have been described in FM and irritable bowel syndrome (IBS), may also play a role (e.g., Price et al., 2009; Staud et al., 2009). »

«Staud has shown that local anesthetic injection into trapezius muscle tender points results in lower levels of thermal hyperalgesia in the forearm, consistent with peripheral nociceptive input as a contributor to central sensitization (Staud et al., 2009).»

«The interaction of nerve mechanics and function has been termed neurodynamics. As an example of the principles of neurodynamics, the median nerve elongates approximately 20% as the upper extremity moves from a position of full wrist and elbow flexion to one of full wrist and elbow extension (Butler, 1991). »

» If that ability to elongate is impaired—due to movement restrictions in tissues adjacent to the median nerve and its branches, or due to swelling or adhesions within the median nerve itself—the result is an increase in mechanical tension within the nerve. This adverse neural tension, also termed neurodynamic dysfunction, is thought to contribute to pain and other symptoms through mechanical sensitization and altered nociceptive signaling, altered proprioception, adverse patterns of muscle recruitment and force of muscle contraction, reduced intra-neural blood flow, and release of inflammatory neuropeptides (Lindquist et al., 1973; Kornberg and McCarthy, 1992;Shacklock, 1995; Slater and Wright, 1995; Balster and Jull, 1997; Van der Heide et al., 2001; Kobayashi et al., 2003; Orlin et al., 2005).»

«It is now well-established that manual stretch of nerves is capable of evoking increased sweating and alterations of blood flow in peripheral tissues, providing evidence of electrophysiologic activity in sympathetic nerve fibers (Lindquist et al., 1973; Kornberg and McCarthy, 1992; Slater and Wright, 1995; Orlin et al., 2005). Conversely, treatment of areas of adverse neural tension (for example in carpal tunnel syndrome, cervico-brachial pain, and osteoarthritis) leads to improved functional outcomes (Rozmaryn et al., 1998; Deyle et al., 2000; Tal-Akabi and Rushton, 2000;Akalin et al., 2002; Allison et al., 2002).»

«The most notable examples of these provocation maneuvers are ankle dorsiflexion, the passive straight leg raise test, the upper limb tension (or neurodynamic) tests, and the seated slump test (Butler, 1991,2000). Test-retest reliability is good for straight leg raise, slump testing, and upper limb neurodynamic testing. (Coppieters et al., 2001;Herrington et al., 2008

«Because it is not possible to differentiate completely between adverse neural tension and strain in muscles, fascia, and other soft tissues, we will use the more general term “neuromuscular strain” in this paper. »

«As shown on the left in Figure 1, neuromuscular strains and movement restrictions can develop as a result injuries and activities of daily life (for example, due to soft tissue and peri-neural adhesions around scars, contusions and fractures that reduce range of motion, anatomic abnormalities like scoliosis and kyphosis, overuse injuries, and others).»

«If the neuromuscular strains were not treated, and if the individual adapted to the increased symptom burden with decreased activity, then neural, soft tissue and muscular restrictions would be expected to worsen, leading to greater impairment and greater central sensitization. »

«In our clinical work, we have found that neuromuscular restrictions are common in CFS.»
«We have also noted that many symptoms of CFS can be reproduced by selectively adding neuromuscular strain during the examination (Rowe et al., 2013a,b). »

«Despite the elevation of the leg, which might have been expected to improve venous return to the heart and thereby improve blood flow to the brain, lightheadedness increased, as did visual blurring. Both individuals remained more fatigued than usual for 12–24 h. Thus, supine neuromuscular strain provoked increased fatigue and cognitive disturbance, the two symptoms not adequately explained by the central sensitivity hypothesis thus far.»

«We have observed that open treatment of these movement restrictions using manual therapy is associated with clinical improvement (Rowe et al., 2013a,b).»

«The hypothesis can be tested by evaluating the whether the response to a given neuromuscular strain differs between CFS subjects and controls with regard to immediate and delayed (24-h) symptoms, and with regard to measures of central sensitivity, such as changes in heart rate variability, or changes in pain sensitivity as measured by pressure-pain thresholds. «

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Recognition of central sensitization in patients with musculoskeletal pain: Application of pain neurophysiology in manual therapy practice

Nevner det aller meste om sentral sensitering og hvordan de gjenkjennes i klinisk praksis.

http://www.thblack.com/links/RSD/ManTher2010_15_135_CSinMusculoskelPain-PainNeurophys.pdf

«Even with acute pain the nervous system undergoes some changes. When tissue is damaged and pain persists for a few days with adaptation of unimodal nociceptors, the responsiveness of polymodal nociceptive endings is enhanced by substances released from various sources (i.e. serotonin released by platelets) (Purves et al., 1997). This process is called primary hyperalgesia or peripheral sensitization of nociceptors, and represents a protective action by the human body in order to prevent further use of damaged structures and consequent further damage of the traumatized and surrounding tissues.»

«Secondary hyperalgesia refers to increased responsiveness of dorsal horn neurons localized in the spinal segments of the primary source of nociception.»

«Central sensitization is defined as an augmentation of responsiveness of central neurons to input from unimodal and polymodal receptors (Meyer et al., 1995). Central sensitization encompasses altered sensory processing in the brain (Staud et al., 2007), malfunctioning of descending anti-nociceptive mechanisms (Meeus et al., 2008), increased activity of pain facilitatory path- ways, temporal summation of second pain or wind-up (Meeus and Nijs, 2007; Staud et al., 2007), and long-term potentiation of neuronal synapses in the anterior cingulate cortex (Zhuo, 2007).»

«The presence of central sensitization in patients with musculoskeletal pain implies an increased complexity of the clinical picture (i.e. an increase in unrelated symptoms and hence a more difficult clinical reasoning process) (Nijs et al., 2009), as well as decreased odds for a favorable rehabilitation outcome (Jull et al., 2007).»

«Central sensitivity syndromes is a term first used by Yunus in 2000 to describe a group of overlapping conditions bound by a common pathophysiological mechanism of central sensitization (Yunus, 2007a).»

«Another example is chronic non-specific low back pain. Some studies provided evidence in support of the presence of central sensitization in patients with non-specific chronic low back pain (Giesecke et al., 2004; Schmidt-Wilcke et al., 2006), while others refute such an association (Hoffman et al., 2005; Julien et al., 2005). It is concluded that central sensitization is present in some cases of chronic non-specific low back pain, possibly representing one of the subgroups of this frequent musculoskeletal disorder (Wand and O’Connell, 2008).»

«The myofascial variety within the heterogeneous group of temporomandibular disorders is also characterized by central sensitization (Yunus, 2007a). Likewise, regional chronic pain conditions that present with tender and/or trigger points in the absence of structural pathology (frequently referred to as myofascial pain syndrome) should alert the manual therapist to the possibility that central sensitization is determining the clinical picture (Yunus, 2007a). However, to our knowledge available evidence in support of central sensitization in patients with myofascial pain syndrome is limited to chronic whiplash associated disorders, temporoman- dibular disorders and chronic non-specific low back pain.»

«Furthermore, various subgroups of headache, chronic tension-type headache (Langemark et al., 1993; Pielsticker et al., 2005) and migraine (Burnstein et al., 2000; Weissman-Fogel et al., 2003) can be viewed as central sensitivity syndromes. Finally, rheumatoid arthritis and osteoarthritis are examples of local musculoskeletal disorders possibly causing continuous activation of polymodal nociceptors that initiate or sustain central sensitization (Yunus, 2007a).»

table1

«Central sensitization entails much more than generalized hypersensitivity to pain: it is characterized by an increased responsiveness to a variety of stimuli including mechanical pressure (Desmeules et al., 2004), chemical substances (Morris et al., 1997), cold temperature (Kasch et al., 2005), heat temperature (Meeus et al., 2008), electrical stimuli (Banic et al., 2004; Desmeules et al., 2004), stress, emotions, and mental load. The clinical picture is suggestive of a general intolerance to all kinds of physical and emotional stressors and hence a large decreased load tolerance of the human body in general.»

table2

«An ongoing source of peripheral nociception is required before the process of peripheral sensitization can establish central sensitization (Nijs and Van Houdenhove, 2009). Tissue injury healing and focal pain recovery should occur as soon as possible to prevent development of central sensitization (Vierck, 2006).»

«One of the main characteristics of central sensitization in patients with musculoskeletal pain is a generalized rather than a localized decrease in their pressure pain threshold. Here, ‘generalized’ implies more than a segmental spreading of the symptom area, in that it means that the increased sensitivity is localized at sites segmentally unrelated to the primary source of nociception (e.g. the lower limbs in case of a whiplash trauma).»

«Lower pressure pain thresholds at symptomatic areas most often represent primary hyperalgesia due to sensitized polymodal noci- ceptors within injured musculoskeletal structures. By measuring pressure pain thresholds outside the area of primary nociception, widespread hyperalgesia or secondary hyperalgesia can be detec- ted.»

«In cases of secondary hyperalgesia, a reduced pressure pain threshold in the various tissues innervated by the same segment (or two neighboring segments) can be detected.»

«Findings of numerous areas of hyperalgesia at sites outside and remote from the symp- tomatic site, together with a non-segmental general decrease in pressure pain threshold, may imply a generalized hyperexcitability of central nociceptive pathways (Sterling et al., 2004).»

«Pressure algometry provides a reliable and valid measure of the pressure pain threshold (Vanderweeen et al., 1996; Farasyn and Meeusen, 2003). In the absence of a pressure algometer, manual palpation can be used. Even when a manual therapist is not sus- pecting central sensitization, the finding of generalized hypersen- sitivity to manual palpation during routine clinical examination should alert the clinician.»

«Like every other tissue in the human body, peripheral nerves and nervous tissues (including connective tissue) themselves can become hypersensitive to mechanical stimuli such as tension and pressure.»

«Besides the passive tests listed above (Table 3), altered sensory processing can be demonstrated during exercise. Pain thresholds increase during physical activity in healthy individuals and can stay augmented for up to 30 min post-exercise. This is the result of endogenous opioid release (Koltyn and Arbogast, 1998) and related activation of several (supra)spinal anti-nociceptive mechanisms such as the adrenergic and serotonergic pathways (Millan, 2002).»

 

«Stress (particularly when chronic) may well trigger lower pain thresholds. This was demonstrated by Suarez-Roca et al. (2008) who reported reduced GABA neurotransmission and consequent hyperalgesia in rats after repeated forced swimming stress.»

«A constant or decreased pain threshold during and following exercise suggests malfunc- tioning of these anti-nociceptive mechanisms (Whiteside et al., 2004) and hence central sensitization. An abnormal pain threshold response to exercise should be regarded as one of the many possible signs of central sensitization.»

table4

 

 

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PROLONGED ALTERATION OF VASOCONSTRICTOR AND VASODILATOR RESPONSES IN RAT KNEE JOINTS BY ADJUVANT MONOARTHRITIS

Viktig bekreftelse på at blodsirkulasjon hemmes i betente ledd og at dette er noe av utgangspunktet for slitasjeskader siden vevet og skjelettet ikke får de næringsstoffene de trenger. Viktig studie å se på men vanskelig å copy-paste sitater…

Klikk for å få tilgang til 349.full.pdf

«These vasoactive responses were completely abolished in the chronically inflamed knee joint, the abolition persisting throughout the investigation. »

«Since articular cartilage is critically dependent on synovial fluid formation for its nutrition, loss of neurovascular control of the synovial microcirculation could contribute to the degenerative changes that commonly accompany chronic inflammatory joint diseases.»

«The role of synovial nerves in the development of various forms of acute inflammation has previously been reported (Lam & Ferel,1991)and it is thought that their efects may be mediated by local release of SP, which is known to be pro-inflammatory in this region.»

«These experiments showed that electrical stimulation of nerves supplying the rat knee joint caused a frequency-dependent constriction of articular bloodvesels, and that topical aplication of SP to the exposed joint surface produced a potent vasodilatation, although this particular effect was found to be transient.»

Viser at nervesignaler gjør at blodkar trekker seg sammen i leddet. Kan henvise til at et overstimulert nervesystem (sympaticus dominans) trekker blodkar sammen.

«A highly significant frequency-dependent decrease in joint bloodflow occurred in normal rats when electrical stimulation of the saphenous nerve was performed (P < 0 001, repeated measures one-way ANOVA; n = 10). The greatest vasoconstriction resulted when 30 Hz stimulation was applied to the nerve: this elicited a 37.3+7.3% fall in perfusion.»

Nevner at Substans P gir vasodilasjon (37%) umiddelbart, men at det over tid gir en vasokonstriksjon (40%).
«Substance P, when applied topically to the exposed surface of normal knee joints, produced a significant dose-dependent augmentation of joint bloodflow (P<0.001;n= 10), culminating in a peak rise of 45*1+8*6% with the10-9 mol dose.»
«At week 1, SP had no significant effect on synovial blood flow (P= 0.511;n= 10),but at week 3 vasoconstriction was recorded (P< 0*001;n= 9); at both these times the results were significantly different from those of normal rats (P < 0.001). A fall of articular perfusion of about 40% occurred at week 3 when 10-8 and10-t2 mol of SP was administered to the joint, but the intermediate doses produced less efect. »

Nevner at blodsirkulasjonen er dårlig i over 3 uker etterpå, selv om betennelsen er borte.
«Since articular cartilage is dependent on the synovial perfusion (McKibbin& Maroudas, 1979), this initial reduction in joint blood flow could cause the integrity of the joint to deteriorate and lead to degenerative changes. It has previously been shown that adjuvant- induced inflammation in the rat knee joint abolishes sympathetic vasoconstriction and the neuropeptidergic vasodilator response to SP at 1week post-treatment (McDougall et al. 1994).The investigation outlined here has shown that these alterations are not transitory, and are stil present 3 weeks after injection of adjuvant, even though the inflammatory process appears to be abating by then.»

Nevner at det blir vasokonstriksjon når det er betennelse samtidig.
«Chronically inflamed joints did not show vasodilatation in response to SP at any stage; indeed there was some evidence of vaso- constriction. This finding suggests that the SP receptors are either radically transformed or possibly inactivated by the inflammatory process.»

«Comparing this finding with that of the present study, it would appear that the integrity of sympathetic transmission and SP receptor activation in rat knee joints declines as inflammation becomes more chronic. Loss of these neurovascular controls could contribute to the degenerative changes that commonly accompany chronic inflammatory joint diseases.»

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Inflammation Induces Ectopic Mechanical Sensitivity in Axons of Nociceptors Innervating Deep Tissues

Viktig studie som nevner hvordan betennelser i nervene gir lavere terskel for nociceptiv avfyring, altså smerte selv ved lette trykk, og kan gi spontane avfyringer, altså smerte uten noen fysiologisk årsak.

http://jn.physiology.org/content/90/3/1949.full

«Here we show that inflammation led to mechanical sensitivity of the axons of a subset of mechanically sensitive primary sensory neurons. Dorsal root recordings were made from 194 mechanically sensitive neurons that innervated deep and cutaneous structures and had C, Aδ, and Aαβ conduction velocities. »

«However, the axons of neurons innervating deep structures and having C- or Aδ-conduction velocities became mechanically sensitive during the neuritis, and also exhibited an increased incidence of spontaneous discharge. »

«However, the axons of neurons innervating deep structures and having C- or Aδ-conduction velocities became mechanically sensitive during the neuritis, and also exhibited an increased incidence of spontaneous discharge. »

«Primary sensory neurons are considered to “sense” only at their endings, within the structure they innervate. Sensory quality and localization are normally initiated by the activation of modality-specific sensory transducers in the tissue being stimulated, resulting in action potentials that are carried by axons, bundled in nerves, to the CNS. However, in many human patients, movements of intact, apparently uninjured nerves far from the innervated tissue can elicit radiating pain (e.g., “sciatica”). Such movement-induced radiating pain could be explained by the induction of ectopic sensory function along the axon.»

Svært viktig sitat som nevner at dette ikke gjelder i huden, men i dypere nivåer av kroppen.
«Using extracellular recording techniques in a model of neuritis, we now report that inflammation of intact axons leads to axonal mechanical sensitivity. We found that this phenomenon was limited to slowly conducting axons innervating noncutaneous structures.»
«Deep RFs were identified through the skin and proved by moving the overlying skin and repeating the effective stimulus to the same underlying spot, through a different portion of skin. »

«Action potentials in the absence of evident or applied stimuli are termed ongoing activity(OA). Ongoing activity was recorded for 2 min after the RF was located, and after mechanical stimulation of the nerve. During CFA neuritis, more deep neurons with C- and Aδ-axons had OA (19/111) than did cutaneous neurons with C- and Aδ-axons recorded during the same experiments [2/43; P < 0.05 (chi-square)], or than did deep neurons with C- and Aδ-axons recorded during the control experiment [1/27; P = 0.05 (Fisher’s exact)]. »

Betennelser i nervene gir hypeaemi, økt blodgjennomgstrømning. Dette er nok bare i akuttfasen.
«At 7 days postoperatively, the affected section of the nerve was characterized by encasement with granulation tissue and hyperemia of the intrinsic vasculature. Histology of the lesion demonstrated epineurial edema, increased lymphocytes, and a massive infiltration of macrophages within the epineurium and the granuloma (Fig. 4, B, D, and F). »

«These data demonstrate that neurons innervating deep structures and having properties of nociceptors (i.e., slow conduction velocities and high mechanical activation thresholds) developed axonal mechanical sensitivity during neuritis. »

«We employed noxious stimuli in the search for receptive fields, and thus especially for deep neurons, the tissues containing the terminals were often swollen, and therefore inflamed, before identification. Such inflammation is likely to reveal the latent receptive fields of otherwise silent nociceptors (Kress et al. 1992), making specific identification of such neurons improbable. Inflammation is also known to induce ongoing activity. Although we observed a statistically significant, increased incidence of ongoing activity in deep neurons during neuritis, these data must also be considered carefully because of the methodology used to identify the receptive fields. With these data, we cannot rule out that the axons of silent nociceptors from either deep or cutaneous tissues become mechanically sensitive during neuritis.»

«The development of axonal mechanical sensitivity was induced by local inflammation, which was characterized by the recruitment of epineurial macrophages and lymphocytes. This cellular infiltrate may play a key role in the axonal mechanical sensitivity. These cells lead to increased levels of tumor necrosis factor alpha, which increases sodium conductance in mammalian cell membranes (Hribar et al. 1999) and induces spontaneous activity in nociceptors when applied to axons (Leem and Bove 2002; Sorkin et al. 1997). »

«Second, the membrane potential in sensory neurons oscillates, dependent on Na+ channels, and normally approaches but does not reach the triggering threshold of the neuron (Amir et al. 1999). These oscillations become greater as the membrane is depolarized (Amir et al. 1999). Such oscillations would be potentiated by increased sodium conductance or sodium current, and could lead to spontaneous activity. Importantly, these oscillations are more pronounced in neurons innervating noncutaneous structures (Liu et al. 2002), which may be the basis for our observations that only the axons of noncutaneous neurons became mechanically sensitive.»

«Moreover, cutaneous allodynia seems dependent on at least transient activation of slowly conducting axons (Vatine et al. 1998). These findings, and ours, suggest that the observed sensitivity change was related to changes in the sensitivity of higher-order neurons that receive convergent information from the noncutaneous peripheral neurons that were sensitized by the neuritis. Alternatively, the cutaneous sensitivity may have been secondary to changes in ongoing activity of silent nociceptors (not specifically recorded from, as discussed above), or transient changes in neurons with faster conducting axons, which were not tested before or at the peak of heightened cutaneous sensitivity.»

«The appearance of axonal mechanical sensitivity during neuritis is consistent with reports of typically deep pain radiation provoked by mechanical stimulation of inflamed human dorsal roots (Kuslich et al. 1991; Smyth and Wright 1958; G. M. Bove and Z. H. Bajwa, unpublished observations), and radiating deep pain in the apparent absence of nerve injury (Verdugo and Ochoa 1993). »

Nevner at betente nerver er viktig forståelse for å forklare symptomene som kommer med sykdommer som har betennelser som utgangspunkt.
«Neuritis has long been recognized as a common malady of the peripheral nervous system (Gowers 1886), and can occur as a result of direct nerve injury or by extension from other diseases with inflammatory components, such as diabetes and endometriosis (Dyck et al. 2000; Zager et al. 1998). »

«Neuritis may be a common denominator in these otherwise seemingly unrelated disorders. The development of axonal mechanical sensitivity seems necessary to explain some clinical features of patients with radiating pain worsened by movements (e.g., “sciatica”), suffered by more than one-half of the population at some point in their lives (Frymoyer et al. 1983; Hult 1954).»

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The underlying mechanisms for development of hypertension in the metabolic syndrome

Studie som nevner «alt» om insulinresistens og hva det gjør i kroppen: magefett, symatisk overstimulering, oksidativt stress og blodkardysfunksjon, renin-angiotensin, betennelser og søvnapne.

http://www.nutritionj.com/content/7/1/10

«Visceral obesity, insulin resistance, oxidative stress, endothelial dysfunction, activated renin-angiotensin system, increased inflammatory mediators, and obstructive sleep apnea have been proposed to be possible factors to develop hypertension in the metabolic syndrome. These factors may induce sympathetic overactivity, vasoconstriction, increased intravascular fluid, and decreased vasodilatation, leading to development of hypertension in the metabolic syndrome.»

«As shown in Figure 1, accumulated visceral adipose tissue produce and secrete a number of adipocytokines, such as leptin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), angiotensinogen, and non-esterified fatty acids (NEFA), which induce development of hypertension [11]. «

«Insulin resistance is the main pathophysiologic feature of the metabolic syndrome. Several mechanisms connect insulin resistance with hypertension in the metabolic syndrome. An anti-natriuretic effect of insulin has been established by accumulating data indicating that insulin stimulates renal sodium re-absorption [1214]. This anti-natriuretic effect is preserved, and may be increased in individuals with insulin resistance, and this effect may play an important role for development of hypertension in the metabolic syndrome [15].»

«NEFA has been reported to raise blood pressure, heart rate, and α1-adrenoceptor vasoreactivity, while reducing baroreflex sensitivity, endothelium-dependent vasodilatation, and vascular compliance[28]. Insulin resistance increases plasma leptin levels, and leptin has been reported to elevate sympathetic nervous activity, suggesting that leptin-dependent sympathetic nervous activation may contribute to an obesity-associated hypertension [29]. Accumulating data suggest that metabolic syndrome is associated with markers of adrenergic overdrive [30].»

«In rats with the metabolic syndrome, induced by chronic consumption of a high fat, high refined sugar [31], hypertension is associated with oxidative stress [32], avid nitric oxide (NO) inactivation, and down-regulation of NO synthase (NOS) isoforms and endothelial NOS activator[32], suggesting that oxidative stress and endothelial dysfunction may be strongly associated with development of hypertension in the metabolic syndrome. Further, recent evidences suggest that oxidative stress, which is elevated in the metabolic syndrome [33], is associated with sodium retention and salt sensitivity [34].»

«The renin-angiotensin system (RAS) plays a crucial role in blood pressure regulation, by affecting renal function and by modulating vascular tone. The activity of the RAS appears to be regulated by food intake, and overfeeding of rodents has been reported to lead to increased formation of angiotensin II in adipocytes [38]. «

«Recent cohort studies have demonstrated that high-sensitivity C-reactive protein (hsCRP) independently presents additive prognostic values at all levels of metabolic syndrome [45]. Ridker PM, et al. suggest a consideration of adding hsCRP as a clinical criterion for metabolic syndrome[45]. Abnormalities in inflammatory mediators have been also reported to be implicated with development of hypertension.»

«TNF-α is involved in the pathophysiology of hypertension in the metabolic syndrome. TNF-α stimulates the production of endothelin-1 and angiotensinogen [48,49].»

«IL-6 stimulates the central nervous system and sympathetic nervous system, which may result in hypertension [54,55]. The administration of IL-6 leads to elevation in heart rate and serum norepinephrine levels in women [56]. Further, IL-6 induces an increase in plasma angiotensinogen and angiotensin II [57], leading to development of hypertension.»

«Patients with OSA are often considered to be obese, however, Kono M et al. reported that OSA was associated with hypertension, dyslipidemia, and hyperglycemia, independent of visceral obesity [59]. «

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Vascular insulin abnormalities, hypertension, and accelerated atherosclerosis

Studie som bekrefter at insulin resistens (ikke høyt insulinnivå alene) gjør at blodkar trekker seg sammen og hemmer blodsirkulasjon. Pluss at de mister sin sensitivitet for sammentreking og utvidelse, de blir med andre ord stive.

http://www.ncbi.nlm.nih.gov/pubmed/8503434

«However, recent data from our laboratory suggest that cellular insulin resistance rather than hyperinsulinemia per se may lead to hypertension. The basic tenet proposed in this article is that a deficiency of insulin at the cellular level represents a common mechanism that is involved in the development of hypertension in both type I and type II diabetes mellitus»

«For example, recently reported studies from our laboratory demonstrate that insulin attenuates the vascular contractile response to phenylephrine, serotonin, and potassium chloride. Thus, it appears that insulin normally modulates (attenuates) vascular smooth muscle contractile responses to vasoactive factors, and insulin resistance should accordingly be associated with enhanced vascular reactivity.»

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Carbon dioxide influence on nitric oxide production in endothelial cells and astrocytes: Cellular mechanisms

Viktig studie som nevner hvordan CO2 forholder seg til NO og vasodilasjon. Nevner mekanismene bak eNOS og nNOS og hva som faktisk skjer i cellene. Denne studien er på celler, men beskriver mye av det som skjer in vivo og refererer til andre viktige studier.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073030/

«Cerebral vessels may regulate cerebral blood flow by responding to changes in carbon dioxide (CO2) through nitric oxide (NO) production. »

«NO levels in endothelial cells increased during hypercapnia by 36% in 8 hours and remained 25% above baseline. NO increase in astrocytes was 30% after 1 hour but returned to baseline at 8 hours. NLA blocked NO increase in endothelial cells under hypercapnia.»

«This study suggests that cerebral endothelial cells and astrocytes release NO under normocapnic conditions and NO production is increased during hypercapnia and decreased during hypocapnia independent of pH. Further, this demonstrates that endothelial cells may play a pivotal role in chemoregulation by modulating NOS activity.»

«Modulation of cerebral vascular tone in response to changes in the arterial partial pressure of carbon dioxide (pCO2) is defined as chemoregulation. In humans hypocapnia produces vasoconstriction resulting in decreased cerebral blood flow (CBF), whereas hypercapnia produces vasodilation and increased CBF (Lavi et al., 2003). »

«Using nitric oxide synthase (NOS) inhibitors, several in vivo studies have suggested that vasodilation in response to increased pCO2may be mediated by NO (Lavi et al., 2006). »

«Under hypercapnic conditions (pCO2 56.3±8.7 mmHg), NO concentration increased from baseline levels to a mean of 10±0.6×10-10M during the first 4 hours (Figure 1A). NO concentration peaked at 36% (10.2±0.5×10-10M) above baseline at 8 hours and stabilized 25% (9.4±0.5×10-10M) above baseline until completion of the experiment.»

«By plotting NO changes as a function of pCO2, we could disregard time as a variable in NO production (Figure 3) to establish that changes in NO levels correlate with changes in pCO2 (R=0.99).»

CO2 og NO

«Under hypercapnic conditions (pCO2 56.3±8.7 mmHg), human fetal astrocytes increased NO production by 30% over baseline values to a mean level of 2.5±1.2×10-10M in the first hour of hypercapnia (Figure 2). NO production then gradually decreased to control levels after 8 hours and remained at control levels for the remainder of the experiments.»

CO2 og NO i astrocytt

«The pH values were kept stable within a neutral gap under normocapnic (7.39±0.01), hypercapnic (7.36±0.02) and hypocapnic (7.40±0.01) conditions.»

» Stimulation of NOS in the endothelial cells is consistent with the NO-dependent vasodilation and increased CBF that occur in vivo during hypercapnia, as has been shown in rats (Iadecola, 1992) and in primates (Thompson et al., 1996). Decreased NO production by endothelial cells also correlates with the in vivo vasoconstrictive response to hypocapnia shown previously (Lavi et al., 2003;Thompson et al., 1996).»

«Thus, it is unlikely that eNOS is responsible for the early or fast phase response during chemoregulation in vivo. There are several explanations for this phenomenon. First, nitrite (NO2), being a storage pool of NO, can be reduced to NO under acidic and hypoxic conditions in vivo (Cosby et al., 2003). Under these conditions nitrite releases NO in the presence of deoxygenated hemoglobin in blood (Cosby et al., 2003;Nagababu et al., 2003) or neuroglobin (Burmester et al., 2000) in neurons acting as a nitrite reductase (Petersen et al., 2008). »

«The chemoregulatory response to CO2 changes in vivo is rapid, occurring on the order of milliseconds; our results did not demonstrate this component of the chemoregulatory response.»

«Cerebrovascular reactivity in response to CO2 is impaired in diabetic or hypertensive patients with endothelial dysfunction (Lavi et al., 2006), suggesting an important role for endothelial cells in modulating CBF response to CO2. »

«It has been reported that the ATP-sensitive K+ channels play a pivotal role in microvessel vasodilation of the cerebral cortex in response to decreased pH corresponding to mild hypercapnia and that a NOS inhibitor could not alter this vasodilation (Nakahata et al., 2003).»

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The role of systemic inflammation in age-related muscle weakness and wasting

Om at kronisk betennelse svekker muskler, spesielt i alderdom. Det er mengden av TNF-a og varigheten som avgjør om det virker muskelsvekkende eller ikke. Store mengder over lang tid tærer på muskelen ved at cellene går inn i apoptose (celledød).

http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0838.2009.01018.x/abstract

«Thus, the negative effect of systemic inflammation on muscle strength at old age may only become apparent when it exceeds a certain threshold and persists for a prolonged period.»

«Satellite cell function may be affected by circulating factors, as muscle regeneration in old mice sharing the circulation of young mice is not impaired. Chronic low-grade systemic inflammation in old organisms may be that environmental factor.»

«TNFα destabilizes MyoD, a muscle-specific transcription factor involved in satellite cell proliferation and differentiation, and induces apoptosis of satellite cells, particularly at old age. »

«Yet, the increase in TNFα during the normal inflammatory response helps, rather than impairs, the repair process. This apparent contradiction may be resolved by the fact that the effects of TNFα are concentration and time dependent.»

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The role of corticosteroids in the regulation of vascular tone

Viser til mekanismene for hvordan kortisol (og stress) hemmer blodsirkulasjon og over tid kan gi høyt blodtrykk og mange medfølgende sykdommer. Kortisols effekt på blodkar sammentrekning er først og fremst ved å øke reaksjonen og blodkarcellenes sensitivitet til adrenalin. Men også øke nyrenes tilbakeholdelse av salt.

http://cardiovascres.oxfordjournals.org/content/41/1/55.full

«In addition, corticosteroids in lesser amounts are essential for the maintenance of peripheral vascular resistance in healthy persons. This review details the proposed mechanisms by which corticosteroids maintain and, in excess, enhance vascular tone.»

«Disease states resulting from excesses of circulating (adreno)corticosteroids include primary hyperaldosteronism, renal artery stenosis, ACTH-secreting tumors, and administration of glucocorticoids for treatment of other diseases. Hypertension is commonly associated with these diseases. »

«Potent vasoconstrictor hormones that have been investigated include α-adrenergic agonists (norepinephrine), angiotensin II, arginine vasopressin, endothelin and thromboxanes.»

«Results from other studies have suggested that corticosteroids act directly on blood vessels in potentiating norepinephrine vasoconstrictor actions. »

«Corticosteroids enhance contractile responses to norepinephrine in humans. For example, Kurland and Freedberg [20]administered increasing doses of norepinephrine intravenously to three patients before and 24 h after initiation of glucocorticoid therapy and observed much greater pressor responses in the presence of corticosteroid than in the absence of corticosteroid. »

«For the most part, glucocorticoids and mineralocorticoids have been reported to enhance the vasoconstrictor actions of angiotensin II.»

Viser til at forskjellige steder i kroppen har forskjellig sensitivitet for kortisol:
«It is possible that differences in responses to corticosteroids in vascular beds in different parts of the body may explain the above-mentioned discrepancies. »

«From the above review, one can see that corticosteroids foster hypertension not only by enhancing renal sodium reabsorption but also by augmenting vascular tone. «

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Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease

Nevner at lavgrads betennelse er utgangspunktet for arterosklerose. Og at det hemmer endotelfunksjonen, altså blodkar cellenes evne til å trekke seg sammen og utvide seg.

http://www.clinsci.org/cs/098/0531/cs0980531.htm

«Low-grade chronic inflammation, characterized by elevated plasma concentrations of C-reactive protein (CRP), is associated with an increased risk of atherosclerotic cardiovascular disease.»

«These data demonstrate for the first time a relationship between low-grade chronic inflammation and basal endothelial NO synthesis (measured using an invasive method), and support the notion that endothelial dysfunction is a critical intermediate phenotype in the relationship between inflammation and cardiovascular disease.»

«Inflammation may increase cardiovascular risk via effects on known cardiovascular risk factors (e.g. lipid profiles), by altering other putative risk markers (e.g. fibrinogen, plasminogen activator inhibitor-1), or by impairing carbohydrate metabolism [2]. «

«In this clinical study we provide, to the best of our knowledge, the first direct evidence for an association between endothelial dysfunction and low-grade chronic inflammation. »

Viser til at blodkar får vansker med å slappe av når det er betennelsesfaktorer tilstedet:
«Our data also complement previous experiments by Bhagat et al. [6,7], who noted that infusion of endotoxin or pro-inflammatory cytokines [interleukin-1, tumour necrosis factor-a (TNF-a)] into superficial hand veins of healthy volunteers (provoking a local acute inflammatory response) caused a selective impairment of endothelium-dependent relaxation. «

«Correlation does not imply causality, but the relationship we have suggested between inflammation and endothelial dysfunction is biologically plausible. Low-grade chronic vascular inflammation may promote biochemical (e.g. peroxidative) and cellular changes in the vessel wall.»

Viser at NO produksjonen synker ved betennelse og gjør at blodet lettere levrer seg, som videre øker sjansen for sammentrekning, trombose og full avstengning av blodkar.
«A decrease in basal NO production secondary to low-grade chronic inflammation would favour increased expression of cell-surface adhesion molecules for leucocytes and platelets, promote interaction between these cells and the vascular endothelium, and induce procoagulant activity. Such effects, in turn, might increase the likelihood of vasospasm, thrombosis and vessel occlusion [1]. Thus endothelial dysfunction may be a critical factor in the relationship between low-grade chronic inflammation and cardiovascular disease.»