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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blocking of myoneural transmission resulting from indirect low-frequency stimulation (fatigue) was not followed by amplitude changes in miniature end-plate potentials and acetylcholine-potentials. A conclusion was drawn that in performed experiments the acetylcholine sensitivity of the postsynaptic membrane was not changed and the decrease of endplate potentials amplitude during fatigue was due to the lowering of EPPs quantum content. A reduction in the quantum content of EPP results from negative antidromic influence of the muscle on the motor nerve endings caused by chemical agents formed in muscle during its contractile appartus activity.
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PMID:[Postsynaptic membrane sensitivity to acetylcholine during blockade of excitatory transmission from nerve to skeletal muscle during long-term low-frequency transmission]. 17 16

beta-Blocking drugs are widely used throughout the world and serious adverse reactions are relatively uncommon. Most of those which do occur are pharmacologically predictable and may be avoided by ensuring that patients who are to be given beta-blockers do not have a predisposition to the development of bronchospasm, cardiac failure or peripheral ischaemia. In some situations, the use of a beta 1-selective blocking drug may reduce the risk of a severe adverse reaction, but there is little evidence that other ancillary properties such as partial agonist activity are of relevance in this context. Long term experience with many of the beta-blockers in current use suggests that unpredictable major adverse reactions such as the practolol oculomucocutaneous syndrome are unlikely to be repeated, although some of these drugs may be associated with immunological disturbances and some have been implicated in the development of retroperitoneal fibrosis. beta-Blocking drugs appear to be associated with a number of subjective side effects including muscle fatigue, peripheral coldness and some neurological symptoms. These side effects are highly subjective and are therefore difficult to quantify and it is not known whether they are of major importance in terms of their effect upon patients' overall well-being. It cannot be assumed that simply because such side effects can be elicited that they do, in fact, matter. However, because beta-blockers are often prescribed for patients who have no symptoms and for whom the benefits of therapy are generally small, such side effects would be of considerable importance if they had an overall effect upon quality of life. There are theoretical reasons to suppose that the incidence and severity of such side effects may be related to the ancillary properties of the individual drugs, but there is little evidence that parameters such as beta 1-selectivity, or partial agonist activity are clinically important determinants of the severity of these side effects. Lipophilicity, however, may be associated with an increased incidence of neurological symptoms. beta-Blocking drugs may cause a variety of metabolic disturbances including an increase in serum VLDL-cholesterol concentrations. However, long term studies have not shown that such disturbances are associated with an increased risk of cardiovascular disease, indicating that such metabolic changes may not be of major importance in practice. beta-Blocking drugs may be involved in a number of interactions with other drugs, but few of these have been shown to be of clinical significance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adverse reactions and interactions with beta-adrenoceptor blocking drugs. 287 46

Calcium-mediated phosphorylase kinase activation has been studied in the rat flexor digitorum brevis, a fast-twitch oxidative-glycolytic skeletal muscle that exhibits a robust inward Ca2+ current [Can J. Physiol. Pharmacol. 63:958-965, 1985]. This system provided an opportunity to compare the regulation of contraction and activation of phosphorylase by extracellular and intracellular sources of Ca2+. In muscles repetitively stimulated at 21 degrees, there appeared to be a close correlation between the control of contraction and phosphorylase activation. Blocking extracellular Ca2+ entry promoted an inactivation of phosphorylase and diminished the elevation of resting tension, which in untreated muscles ensues with the onset of fatigue. The response of muscles stimulated at 37 degrees was in distinct contrast. Phosphorylase, following initial rapid activation, was then briskly inactivated despite the continuation of a near-maximal contractile response. An elevation in resting tension during stimulation was observed at 37 degrees but was a transitory response in comparison to what was seen at 21 degrees. Blocking the entry of external Ca2+ inhibited this response. Sarcolemmal Ca2+ channel blockers had no effect on the observed phosphorylase response at 37 degrees, but phosphorylase was already nearly fully inactivated before their effects were manifested on contraction. Thus, at this temperature there is a clear dissociation between Ca2+-mediated regulation of contraction and the production of metabolic energy by enhanced glycogenolysis. This appears to occur because, although Ca2+ induces phosphorylase activation, a subsequent, but rapid non-Ca2+-mediated event promotes inactivation, even while Ca2+-mediated contraction is being sustained.
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PMID:Calcium-dependent regulation of phosphorylase activation in a fast-twitch oxidative-glycolytic skeletal muscle. 334 81

The ratings of perceived exertion (RPE) scale has received widespread acceptance for gaining a subjective estimate of work intensity and as a means of monitoring and regulating exercise intensity across a variety of populations. The original premise for the use of the scale was its high correlation with heart rate (HR). Although individual correlations between HR and RPE in individuals on beta-blocker therapy are probably as high as in untreated individuals, there is evidence to suggest that the RPE response is mediated at a given work rate, particularly at higher absolute work rates. The variation in the RPE response appears to be mediated by the type of beta-blocker therapy administered. In the interests of safety it is necessary for the exercise specialist to develop at least a basic understanding of the mechanism and effects of beta-blocker therapy as they relate to exercise prescription. beta-Blocking drugs cause a decrease in HR and cardiac output at rest and during exercise, a decrease in myocardial contractility and a decrease in coronary and muscle blood flow. These effects can initiate premature fatigue and apprehension in the exercising patient. In the light of these responses, the RPE scale provides important information and may be used to increase the accuracy of monitoring and the prescription of exercise intensity in the cardiac population. While results regarding the use and accuracy of the scale during beta-blocker treatment are equivocal, this appears to be due mainly to variations in dosage of the drug, the mode, intensity and duration of exercise and the health status of the individuals used. Overall, the RPE scale appears to be an appropriate monitoring tool, particularly when it is used after a learning period. It is concluded that nonselective beta-blockade therapy increases RPE, particularly localised RPE. This could be attributed to a decreased blood flow and oxygen delivery to the muscle and altered glycolytic metabolism, which increases local muscle fatigue. There is no evidence to suggest a decrease in the total level of oxygen consumption at given work rates. However, as beta-blocker therapy reduces the maximal oxygen consumption (VO2max) attainable, this serves to increase the exercise intensity at all work rates. Thus, for a given absolute work rate, the RPE response is higher. However, when the work rate is expressed as a proportion of the VO2max attainable during beta-blockade, the differences in RPE are minimised or disappear. Although the evidence is not conclusive, it appears that cardioselective beta-blocker therapy does not have such profound effects on the RPE response, compared with nonselective beta-blocker therapy, when this is expressed as a proportion of VO2max. However, localised RPE tends to be higher for nonselective beta-blocker therapy. Thus, the evidence indicates that RPE can be used to estimate exercise intensity, provided the specific effects of the type of beta-blocker therapy on local and central fatigue (and local and central RPE) are taken into account. Studies which have examined the effects of an endurance training programme during beta-blocker therapy have shown that RPE are decreased at given work rates after training. This has been observed for cardioselective and nonselective beta-blocker therapy, and local and central RPE. There is also some evidence to suggest that the RPE can be used as the controlling variable to regulate the exercise response. Patients on cardioselective beta-blocker therapy produce similar exercise intensities to other cardiac patients who are not receiving beta-blocker treatment.
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PMID:The use of ratings of perceived exertion for exercise prescription in patients receiving beta-blocker therapy. 877 8

We studied the effect of abolishing cutaneous sensation (by infiltrating local anaesthetic around the median nerve at the wrist) on the ability of 10 healthy volunteers (a) to maintain a submaximal isometric pinch-grip force for 30 s without visual feedback, and (b) to perform a fine finger-manipulation 'handwriting' task. Blocking cutaneous sensation had no effect on ability to maintain pinch force, suggesting that muscle afferents have the major role in force-control feedback. However, a near-linear fall in force, present with or without block (mean slope=-1.3+/-0.2% s(-1)), which cannot be attributed to motor fatigue, reveals a shortcoming of the afferent feedback system. Blocking cutaneous sensation did impair ability to perform the more demanding writing task, as judged by an 18+/-6% increase in the length of the path between target points, a 22+/-9% increase in the duration of the movement and a 63+/-24% in 'normalised averaged rectified jerk', an averaged time-derivative of acceleration (all significantly nonzero, P < 0.04). These experiments demonstrate the relative importance of muscular and cutaneous afferent feedback on two aspects of hand performance, and provide a way to quantify the deficit resulting from the lack of cutaneous sensation.
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PMID:The role of cutaneous sensation in the motor function of the hand. 1518 46

Terminal sterilization of bone allografts by gamma radiation is often essential prior to their clinical use to minimize the risk of infection and disease transmission. While gamma radiation has efficacy superior to other sterilization methods it also impairs the material properties of bone allografts, which may result in premature clinical failure of the allograft. The mechanisms by which gamma radiation sterilization damages bone tissue are not well known although there is evidence that the damage is induced via free radical attack on the collagen. In the light of the existing literature, it was hypothesized that gamma radiation induced biochemical damage to bone's collagen that can be reduced by scavenging for the free radicals generated during the ionizing radiation. It was also hypothesized that this lessening of the extent of biochemical degradation of collagen will be accompanied by alleviation in the extent of biomechanical impairment secondary to gamma radiation sterilization. Standardized tensile test specimens machined from human femoral cortical bone and specimens were assigned to four treatment groups: control, scavenger treated-control, irradiated and scavenger treated-irradiated. Thiourea was selected as the free radical scavenger and it was applied in aqueous form at the concentration of 1.5 M. Monotonic and cyclic mechanical tests were conducted to evaluate the mechanical performance of the treatment groups and the biochemical integrity of collagen molecules were assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The native mechanical properties of bone tissue did not change by thiourea treatment only. The effect of thiourea treatment on mechanical properties of irradiated specimens were such that the post-yield energy, the fracture energy and the fatigue life of thiourea treated-irradiated treatment group were 1.9-fold, 3.3-fold and 4.7-fold greater than those of the irradiated treatment group, respectively. However, the mechanical function of thiourea treated and irradiated specimens was not to the level of unirradiated controls. The damage occurred through the cleavage of the collagen backbone as revealed by SDS PAGE analysis. Irradiated specimens did not exhibit a noteworthy amount of intact alpha-chains whereas those irradiated in the presence of thiourea demonstrated intact alpha-chains. Results demonstrated that free radical damage is an important pathway of damage, caused by cleaving the collagen backbone. Blocking the activity of free radicals using the scavenger thiourea reduces the extent of damage to collagen, helping to maintain the mechanical strength of sterilized tissue. Therefore, free radical scavenger thiourea has the potential to improve the functional life-time of the allograft component following transplantation.
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PMID:Free radical scavenging alleviates the biomechanical impairment of gamma radiation sterilized bone tissue. 1602 98

K(+) channels play important roles in skeletal muscle contraction by regulating action potential duration. Blocking these channels, for example with 3,4-diaminopyridine (DAP), augments muscle force considerably, and these force increases are maintained well during fatigue-inducing contractions. The present study tested the hypothesis that K(+) channel blockade also improves force of previously fatigued muscle. Rat diaphragm underwent fatigue-inducing stimulation in vitro with four different stimulation protocols consisting of 20 Hz vs. 50 Hz trains and 1 min vs. 4 min stimulation durations. DAP administered at the onset of the recovery period produced significant force increases irrespective of the amount of antecedent force loss. These force gains considerably exceeded those resulting from normal force recovery in untreated muscle. Furthermore contraction time was prolonged by DAP in all cases, and half-relaxation time was prolonged by DAP in most cases. Several differences were found compared with previous studies of DAP in fresh muscle, including smaller magnitude and slower time course of force increases. Intracellular electrophysiological recordings found smaller effects of DAP on action potential overshoot and time-depolarization integral in previously stimulated compared with fresh muscle. These data indicate that K(+) channel blockade does indeed increase force of fatigued diaphragm, but to an attenuated extent relative to its effects on non-fatigued muscle, which can be explained on the basis of electrophysiological findings. Nonetheless DAP-induced force increases were usually sufficient to restore force to values present prior to the onset of fatigue-inducing stimulation.
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PMID:Inotropic effects of the K+ channel blocker 3,4-diaminopyridine on fatigued diaphragm muscle. 1788 Dec 99

Mechanical overloading is a major causative factor of tendinopathy; however, its underlying mechanisms are unclear. We hypothesized mechanical overloading would damage tendons and alter genes associated with tendinopathy in a load-dependent manner. To test this hypothesis, we fatigue loaded rat patellar tendons in vivo and measured expression of the matrix-degrading enzyme MMP-13 and the inflammatory cytokine IL-1beta. We also examined these responses in cultured tenocytes exposed to intermittent hydrostatic pressure in vitro. Additionally, we hypothesized load-induced changes in tenocyte MMP-13 expression would be dependent on expression of IL-1beta. In vivo fatigue loading at 1.7% strain caused overt microstructural damage and upregulated expression of MMP-13 and IL-1beta, while 0.6% strain produced only minor changes in matrix microstructure and downregulated expression of both MMP-13 and IL-1beta. Loading of cultured tenocytes at 2.5 and 7.5 MPa produced comparable changes in expression to those of in vivo tendon loading. Blocking IL-1beta expression with siRNA suppressed load-induced both MMP-13 mRNA expression and activity. The data suggest fatigue loading alters expression of MMP-13 and IL-1beta in tendons in vivo and tenocytes in vitro in a load-dependent manner. The data also suggest MMP-13 is regulated by both IL-1beta-dependent and IL-1beta-independent pathways.
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PMID:Coordinate regulation of IL-1beta and MMP-13 in rat tendons following subrupture fatigue damage. 1847 May 77

Blocking K(+) channels with aminopyridines enhances muscle contractile performance in vitro, but the improvements are relatively short-lasting during fatigue-inducing stimulation. We hypothesized that in vivo inotropic actions persist over long periods of fatigue-inducing stimulation. The effects of 3,4-diaminopyridine (DAP) were evaluated for rat extensor digitorum longus (EDL) muscle. DAP increased twitch force by 105%. There was a significant leftward shift in the force-frequency relationship, with force values being increased at frequencies up to and including 20 HZ. During repetitive fatigue-inducing 20-HZ stimulation, DAP-induced force increases were large and persisted significantly for at least 30 minutes. Thus, DAP substantially improves contractile performance of EDL muscle in vivo for much longer periods during fatigue-inducing contractions than in vitro. These data provide support for a potential role for aminopyridines as inotropic agents in applications such as functional electrical stimulation, in which low to medium stimulation frequencies are typically utilized.
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PMID:Long-lasting in vivo inotropic effects of the K(+) channel blocker 3,4-diaminopyridine during fatigue-inducing stimulation. 1901 49

Recent advances in neurobiology have aided our understanding of attention-deficit hyperactivity disorder (ADHD). The higher-order association cortices in the temporal and parietal lobes and prefrontal cortex (PFC) interconnect to mediate aspects of attention. The parietal association cortices are important for orienting attentional resources in time/space, while the temporal association cortices analyse visual features critical for identifying objects/places. These posterior cortices are engaged by the salience of a stimulus (its physical characteristics such as movement and colour). Conversely, the PFC is critical for regulating attention based on relevance (i.e. its meaning). The PFC is important for screening distractions, sustaining attention and shifting/dividing attention in a task-appropriate manner. The PFC is critical for regulating behaviour/emotion, especially for inhibiting inappropriate emotions, impulses and habits. The PFC is needed for allocating/planning to achieve goals and organizing behaviour/thought. These regulatory abilities are often referred to as executive functions. In humans, the right hemisphere of the PFC is important for regulating distractions, inappropriate behaviour and emotional responses. Imaging studies of patients with ADHD indicate that these regions are underactive with weakened connections to other parts of the brain. The PFC regulates attention and behaviour through networks of interconnected pyramidal cells. These networks excite each other to store goals/rules to guide actions and are highly dependent on their neurochemical environment, as small changes in the catecholamines noradrenaline (NA) or dopamine (DA) can have marked effects on PFC function. NA and DA are released in the PFC according to our arousal state; too little (during fatigue or boredom) or too much (during stress) impairs PFC function. Optimal amounts are released when we are alert/interested. The beneficial effects of NA occur at postsynaptic alpha(2A)-receptors on the dendritic spines of PFC pyramidal cells. Stimulation of these receptors initiates a series of chemical events inside the cell. These chemical signals lead to the closing of special ion channels, thus strengthening the connectivity of network inputs to the cell. Conversely, the beneficial effects of moderate amounts of DA occur at D(1) receptors, which act by weakening irrelevant inputs to the cells on another set of spines. Genetic linkage studies of ADHD suggest that these catecholamine pathways may be altered in some families with ADHD, e.g. alterations in the enzyme that synthesizes NA (DA beta-hydroxylase) are associated with weakened PFC abilities. Pharmacological studies in animals indicate catecholamine actions in the PFC are highly relevant to ADHD. Blocking NA alpha(2A)-receptors in the PFC with yohimbine produces a profile similar to ADHD: locomotor hyperactivity, impulsivity and poor working memory. Conversely, drugs that enhance alpha(2)-receptor stimulation improve PFC function. Guanfacine directly stimulates postsynaptic alpha(2A)-receptors in the PFC and improves functioning, while methylphenidate and atomoxetine increase endogenous NA and DA levels and indirectly improve PFC function via alpha(2A)- and D(1) receptor actions. Methylphenidate and atomoxetine have more potent actions in the PFC than in subcortical structures, which may explain why proper administration of stimulant medications does not lead to abuse. Further understanding of the neurobiology of attention and impulse control will allow us to better tailor treatments for specific patient needs.
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PMID:Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. 1962 76


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