Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of endogenous nitric oxide (NO) in producing diaphragmatic fatigue was examined in 26 anaesthetized, mechanically ventilated dogs divided into four groups. In Group Ia (n = 5), dogs without fatigue received only Ringer's lactate solution. In Group Ib (n = 5), dogs without fatigue were given i.v. L-arginine analog N omega-nitro-L-arginine methyl ester (L-NAME) 10 mg.kg-1 to inhibit NO synthase (NOS). Groups IIa and IIb (n = 8 of each) received the same doses of i.v. lactate and L-NAME as Groups Ia and Ib effectively. Following administration of the i.v. solution, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20 Hz applied for 30 min. Diaphragmatic contractility was assessed in each group by measuring transdiaphragmatic pressure (Pdi). No difference in Pdi was observed between Groups Ia and Ib. After the fatigue-producing period, in Group IIa, Pdi at low-frequency (20 Hz) stimulation decreased from the pre-fatigued values (P < 0.05), whereas Pdi at high-frequency (100 Hz) stimulation did not change. In Group IIb, given L-NAME before producing fatigue, Pdi at both stimuli did not change. In conclusion, L-NAME inhibits the production of diaphragmatic fatigue. This finding suggests that endogenous NO plays an important role in producing diaphragmatic fatigue.
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PMID:Protection from diaphragmatic fatigue by nitric oxide synthase inhibitor in dogs. 2357 74

Nitric oxide (NO) is essential for optimal myofilament function of the rat diaphragm in vitro during active shortening. Little is known about the role of NO in muscle contraction under hypoxic conditions. Hypoxia might increase the NO synthase (NOS) activity within the rat diaphragm. We hypothesized that NO plays a protective role in isotonic contractile and fatigue properties during hypoxia in vitro. The effects of the NOS inhibitor N(G)-monomethyl-l-arginine (l-NMMA), the NO scavenger hemoglobin, and the NO donor spermine NONOate on shortening velocity, power generation, and isotonic fatigability during hypoxia were evaluated (Po(2) approximately 7 kPa). l-NMMA and hemoglobin slowed the shortening velocity, depressed power generation, and increased isotonic fatigability during hypoxia. The effects of l-NMMA were prevented by coadministration with the NOS substrate l-arginine. Spermine NONOate did not alter isotonic contractile and fatigue properties during hypoxia. These results indicate that endogenous NO is needed for optimal muscle contraction of the rat diaphragm in vitro during hypoxia.
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PMID:Effects of modulation of nitric oxide on rat diaphragm isotonic contractility during hypoxia. 1239 Nov 24

In anaesthetised rats, Fos-immunoreactive and NADPH-diaphorase-positive neurons in the medulla and, for comparison, in the spinal cord were studied after fatiguing stimulation of the hindlimb muscles. Following both direct muscle stimulation and L5 ventral root stimulation, fatigue-related c-fos gene expression was most prominent in the dorsal horn of the ipsilateral L2-L5 segments and within the ipsilateral nucleus tractus solitarius, the caudoventrolateral and rostroventrolateral reticular nuclei, and the intermediate reticular nucleus at levels of -14.3 and -13.8 mm, and contralaterally at -13.2 mm caudal to the bregma. The order of intensity of c-fos expression was as follows: nucleus tractus solitarius>caudoventrolateral and rostroventrolateral reticular nuclei>intermediate reticular nucleus>lateral paragigantocellular nucleus. NADPH-diaphorase reactivity was changed in the following sequence: NTS>intermediate reticular nucleus lateral paragigantocellular nucleus>rostroventrolateral reticular nucleus. Fos-immunoreactive neurons were codistributed with NADPH-diaphorase-reactive cells within the dorsomedial and ventrolateral medulla, and double-staining neurons were found in the nucleus tractus solitarius, intermediate reticular nucleus and lateral paragigantocellular nucleus. The patterns of distribution of c-fos expression and NADPH-diaphorase reactivity show that afferent signals arising from fatiguing muscles may activate spinal and medullary neurons which are involved in nociceptive and cardiovascular reflex pathways. The functional role of nitric oxide (NO) in the generation of cardiovascular and somatosensory responses in the medulla during fatigue of skeletal muscles is discussed.
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PMID:NADPH-diaphorase activity and c-fos expression in medullary neurons after fatiguing stimulation of hindlimb muscles in the rat. 1246 54

Nitric oxide (NO) has an inhibitory action on O2 uptake (VO2) at the level of the mitochondrial respiratory chain. The aim of this study was to evaluate the effects of NO synthase (NOS) inhibition on muscle (VO2) kinetics. Isolated canine gastrocnemius muscles in situ (n = 6) were studied during transitions from rest to 4-min of electrically stimulated contractions corresponding to approximately 60% of the muscle peak . Two conditions were compared: (i) Control (CTRL) and (ii) L-NAME, in which the NOS inhibitor L-NAME (20 mg kg(-1)) was administered. In both conditions the muscle was pump-perfused with constantly elevated blood flow (Q), at a level measured during a preliminary contraction trial with spontaneous self-perfused (Q). A vasodilatory drug was also infused. Arterial and venous O2 concentrations were determined at rest and at 5-7 s intervals during the transition. VO2 was calculated by Fick's principle. Muscle biopsies were obtained at rest and during contractions. Muscle force was measured continuously. Phosphocreatine hydrolysis and the calculated substrate level phosphorylation were slightly (but not significantly) lower in L-NAME than in CTRL. Significantly (P < 0.05) less fatigue was found in L-NAME versus CTRL. The time delay (TD(f)) and the time constant (tau(f)) of the 'fundamental' component of VO2 kinetics were not significantly different between CTRL (TD(f) 7.2 +/- 1.2 s; and tau(f) 10.6 +/- 1.3, +/- s.e.m.) and L-NAME (TD(f) 9.3 +/- 0.6; and tau(f) 10.4 +/- 1.0). Contrary to our hypothesis, NOS inhibition did not accelerate muscle VO2 kinetics. The down-regulation of mitochondrial respiration by NO does not limit the kinetics of adjustment of oxidative metabolism at exercise onset.
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PMID:Effects of nitric oxide synthase inhibition by L-NAME on oxygen uptake kinetics in isolated canine muscle in situ. 1675 29

To assess the role of nitric oxide (NO) in central thermoregulatory mechanisms during exercise, 1.43 micromol (2 microL) of N(omega)-nitro-L-arginine methyl ester (L-NAME, n=6), a NO synthase inhibitor, or 2 microL of 0.15M NaCl (SAL, n=6) was injected into the lateral cerebral ventricle of male Wistar rats immediately before the animals started running (18 m min(-1), 5% inclination). Core (Tb) and skin tail (Ttail) temperatures were measured. Body heating rate (BHR), threshold Tb for tail vasodilation (TTbV), and workload (W) were calculated. During the first 11 min of exercise, there was a greater increase in Tb in the L-NAME group than in the SAL group (BRH=0.17+/-0.02 degrees C min(-1), L-NAME, versus 0.09+/-0.01 degrees C min(-1), SAL, p<0.05). Following the first 11 min until approximately 40 min of exercise, Tb levels remained stable in both groups, but levels remained higher in the L-NAME group than in the SAL group (39.16+/-0.04 degrees C, L-NAME, versus 38.33+/-0.02 degrees C, SAL, p<0.01). However, exercise went on to induce an additional rise in Tb in the SAL group prior to fatigue. These results suggest that the reduced W observed in L-NAME-treated rats (10.8+/-2.0 kg m, L-NAME, versus 25.0+/-2.1 kg m, SAL, p<0.01) was related to the increased BHR in L-NAME-treated animals observed during the first 11 min of exercise (r=0.74, p<0.01) due to the change in TTbV (39.12+/-0.24 degrees C, L-NAME, versus 38.27+/-0.10 degrees C, SAL, p<0.05). Finally, our data suggest that the central nitric oxide pathway modulates mechanisms of heat dissipation during exercise through an inhibitory mechanism.
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PMID:Nitric oxide pathway is an important modulator of heat loss in rats during exercise. 1614 Jan 69

To assess the role of nitric oxide (NO) in the metabolic rate and running performance of rats submitted to exercise on a treadmill, 1.43 micromol (2 microL) of Nomega-nitro-L-arginine methyl ester (L-NAME, n=6), a NO synthase inhibitor, or 2 microL of 0.15M NaCl (SAL, n=6) was injected into the lateral cerebral ventricle of male Wistar rats immediately before the animals started running (18m min(-1), 5% inclination). Oxygen consumption (VO2) was measured at rest, during the exercise until fatigue and thereafter during the 30 min of recovery using the indirect calorimetry system. Mechanical efficiency (ME) was also calculated during the running period. During the first 11 min of exercise, there was a similar increase in VO2 while ME remained the same in both groups. Thereafter, VO2 remained stable in the SAL group but continued to increase and remained higher in the L-NAME group until fatigue. The L-NAME-treated rats also showed a sharper decrease in ME than controls. In addition, there was a significant reduction in workload performance by L-NAME-treated animals compared to SAL-treated animals. This suggests that central blockage of nitric oxide increases metabolic cost during exercise, reduces mechanical efficiency and decreases running performance in rats.
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PMID:Evidence that brain nitric oxide inhibition increases metabolic cost of exercise, reducing running performance in rats. 1627 31

The influence of the central nervous system on metabolic function is of interest in situations deviating from basal states, such as during exercise. Our previous study in rats demonstrated that central nitric oxide (NO) blockade increases metabolic rate, reducing mechanical efficiency during exercise. To assess the role of brain nitric oxide in the plasma glucose, lactate and free fatty acids (FFAs) concentrations of rats submitted to an incremental exercise protocol on a treadmill until fatigue, 1.43 micromol (2 microl) of N(omega)-nitro-l-arginine methyl ester (L-NAME, n=6), a NO synthase inhibitor, or 2 microl of 0.15M NaCl (SAL, n=6) was injected into the lateral cerebral ventricle (icv) of male Wistar rats immediately before exercise (starting at 10 m/min, with increments of 1m/min every 3 min until fatigue, 10% inclination). Blood samples were collected through a chronic jugular catheter at rest and during exercise until fatigue. During exercise, the L-NAME-treated animals had the following metabolic response compared to controls: (1) an increased hyperglycemic response during the first 60% of time to fatigue; (2) higher plasma lactate levels; and (3) a significant transitory increase in plasma free fatty acids during the dynamic phase of exercise that returned to basal levels earlier than controls during the steady state phase of exercise. In addition L-NAME-treated rats fatigued earlier than controls. The data indicate that the inhibition of the brain nitrergic system induced by icv L-NAME treatment disrupted the accuracy of the neural mechanism that regulates plasma glucose and free fatty acids mobilization during exercise in rats.
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PMID:Central nitric oxide inhibition modifies metabolic adjustments induced by exercise in rats. 1708 69

The distribution of c-fos expression as a marker of neuronal activation and NADPH-diaphorase reactivity were examined in the cervical spinal cord, limbic structures and hypothalamus in anaesthetized rats after fatigue induced by intermittent high-rate (100 s(-1)) electrical stimulation of the dorsal neck muscles (mm. trapezius and splenius). In comparison to the control or sham-stimulated animals fatiguing stimulation induced significant increase in ipsilaterally in the C -C4 spinal segments and the contralateral central (Ce), medial (Me) nuclei, paraventricular nucleus of hypothalamus (Pa) and ventrolateral periaqueductal gray (VLPAG). In spinal cord the highest mean number of Fos-immunoreactive (Fos-ir) neurons per section was found in layers 1,4 and 5 (5.8 +/- 0.9, 13.1 +/- 0.9 and 11.1 +/- 0.7, P < 0.05) of the dorsal horn. The order of intensity of c-fos expression in different regions of the brain was as following sequence: Pa > VLPAG > Ce (447.7 +/- 23.5, 196.3 +/- 12.7, 104.6 +/- 12.3, respectively). About 50 % of double-labeled (Fos-ir and NADPH-diaphorase reactive) cells were found in Pa nucleus. Received data show that limbic structures, hypothalamus and VLPAG are involved in activation after neck muscle fatigue and might contribute to nociceptive processing and generation of the autonomic and affective components of the muscle pain.
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PMID:[Investigation of c-fos expression and NADPH-diaphorase activity in the spine cord and brain in the development of the neck muscle weakness in rats]. 1733 17

Parkinson's disease (PD) is a motor disease including disorders of mobility, fine tremor, rigidity and posture caused by a relentless deterioration of dopaminergic cells in the substantia nigra (SN). Disorders of affect and a range of other symptoms including fatigue, cognitive dysfunction and mental confusion, sleep disorder and addictions are also seen as other CNS sites are also affected. Idiopathic and genetic causes together with inflammatory and degenerative disorders of ageing have been postulated as contributing to PD. Autoimmunity affecting certain vasoactive neuropeptides (VNs) has been postulated as contributing to certain fatigue-related conditions in humans and may be consistent with compromise of receptors associated with VNs and including receptors for vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Pro-inflammatory responses are seen in PD patients consistent with apoptotic neurodegeneration. Involvement of the Th1 directed cytokine interferon-gamma has been demonstrated and Th2 directed cytokines such as IL-10 protect against inflammation-mediated degeneration of dopaminergic neurons in the SN. Nitric-oxide dysregulation is also postulated in PD by fostering dopamine depletion via nitric-oxide synthase (iNOS). Both PACAP and VIP have neuroprotective effects in PD models by inhibiting the production of inflammatory mediators. PACAP specifically protects against the neurotoxicity induced by rotenone as well as protecting against oxidative stress-induced apoptosis. These findings suggest that a defect in VN function may act adversely on SN cells and hence contribute to a clinical presentation consistent with PD. The conclusion drawn from these findings is that PD may be an autoimmune disorder of VNs, specifically PACAP and VIP. Possibly unusual or anatomically specific receptors for these VNs may be involved. If proven, this hypothesis would have significant implications for immunological and pharmacological treatment and prevention of PD.
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PMID:Is Parkinson's disease an autoimmune disorder of endogenous vasoactive neuropeptides? 1756 59

Chronic fatigue syndrome (CFS) is a medically unexplained disorder, characterized by profound fatigue, infectious, rheumatological and neuropsychiatric symptoms. There is, however, some evidence that CFS is accompanied by signs of increased oxidative stress and inflammation in the peripheral blood. This paper examines the role of the inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) in the pathophysiology of CFS. Toward this end we examined the production of COX-2 and iNOS by peripheral blood lymphocytes (PBMC) in 18 CFS patients and 18 normal volunteers and examined the relationships between those inflammatory markers and the severity of illness as measured by means of the FibroFatigue scale and the production of the transcription factor nuclear factor kappa beta (NFkappabeta). We found that the production of COX-2 and iNOS was significantly higher in CFS patients than in normal controls. There were significant and positive intercorrelations between COX-2, iNOS and NFkappabeta and between COX-2 and iNOS, on the one hand, and the severity of illness, on the other. The production of COX-2 and iNOS by PBMCs was significantly related to aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, sadness and a subjective experience of infection. The results suggest that a) an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS; b) the inflammatory response in CFS is driven by the transcription factor NFkappabeta; c) symptoms, such as fatigue, pain, cognitive defects and the subjective feeling of infection, indicates the presence of a genuine inflammatory response in CFS patients; and d) CFS patients may be treated with substances that inhibit the production of COX-2 and iNOS.
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PMID:Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome. 1769 78


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