Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026837 (muscle rigidity)
 1,077 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on studies in swine, the malignant hyperthermia syndrome has been postulated to result from an enhanced sensitivity (low threshold) of the Ca2(+)-induced Ca2(+)-release process. However, fatty acid production is elevated in homogenates of skeletal muscle from pigs and humans susceptible to malignant hyperthermia. In the present study, we demonstrate that the threshold of Ca2(+)-induced Ca2+ release is normal in susceptible humans and in susceptible swine depleted of triglycerides. Exogenously added unsaturated fatty acids decreased the threshold of Ca2(+)-induced Ca2+ release to a much greater extent in porcine and equine muscle than in human muscle. When triglyceride and free fatty acid values were reduced to about 40 and 60%, respectively, of control values, malignant hyperthermia-susceptible swine did not exhibit muscle rigidity when challenged in vivo with halothane and succinylcholine and the threshold of the Ca2(+)-induced Ca2(+)-release process in heavy sarcoplasmic reticulum fractions was normal. Despite the reduced triglyceride and fatty acid levels, these swine had a positive in vitro contracture test for malignant hyperthermia. A low Ca2(+)-induced Ca2(+)-release threshold is not essential for malignant hyperthermia susceptibility, but appears to be the result of excessive free fatty acids produced during organelle isolation.
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PMID:Fatty acids modulate calcium-induced calcium release from skeletal muscle heavy sarcoplasmic reticulum fractions: implications for malignant hyperthermia. 212 24

Thyroid crisis on induction of anaesthesia was treated with dantrolene, because of a mistaken diagnosis of malignant hyperthermia. There was immediate improvement after dantrolene with reduction in muscle rigidity, mental confusion and pyrexia. High circulating T4 has an effect on calcium flux across the sarcoplasmic reticulum and dantrolene may inhibit this pathological mechanism. We suggest the same dosage regimen as is used in the treatment of malignant hyperthermia.
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PMID:Acute thyroid crisis on induction of anaesthesia. 292 4

A study was carried out to investigate the effects of ionic strength and monovalent cations on isometric, Ca2+-activated force and rigor responses in mechanically skinned muscle fibres. Three types of skeletal muscle fibres were used: rat fast- and slow-twitch fibres and toad twitch fibres. The contractile apparatus of rat slow-twitch fibres was affected differently from that of rat fast-twitch and amphibian twitch fibres when changing the ionic strength (expressed either in terms of ionic equivalents as I or formally as gamma/2) and [K+]. Thus, the apparent sensitivity to Ca2+ decreased substantially more in slow-twitch fibres (by a factor of 20) than in the other fibre types (by a factor of 12) when I and [K+] were increased from 94 to 354 mM and from 56 to 316 mM respectively. Maximum Ca2+-activated force, however, declined only by a factor of 2.2 in slow-twitch fibres compared with 4.2 in the other fibre types, when I was increased from 154 to 354 mM. In slow-twitch fibres the force oscillations of myofibrillar origin were found to increase substantially in amplitude, duration and frequency at low values of I and almost disappeared at high ionic strength. At low values of I, it was also discovered that ca. 50% of the fast-twitch fibres responded with myofibrillar force oscillations when submaximally activated. The characteristics of these oscillations were different from those of slow-twitch fibres. Rigor force levels were found to decline markedly with increasing iota and [K+] in all fibre types. Unexpectedly, once rigor force was established in a certain ionic environment, the level of force was stable regardless of further changes in ionic strength and monovalent cation concentration. These results indicate that the rigor cross-bridges can be formed in different stable positions and that the probability of attachment in certain positions (rather than the total number of cross-bridges that can be formed) is influenced by the ionic conditions. Further experimental evidence provided in this study shows that the increase in [K+] is mainly responsible for the decrease of the Ca2+-sensitivity of the contractile apparatus and that ionic strength (expressed as I rather than gamma/2) influences markedly the maximal Ca2+-activated force, the maximum steepness of the pCa-force relations and the oscillatory processes of myofibrillar origin.
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PMID:Potassium and ionic strength effects on the isometric force of skinned twitch muscle fibres of the rat and toad. 308 99

1. A technique was developed to generate 2-8 degrees C step temperature perturbations (T-jumps) in single muscle fibres to study the thermodynamics of muscle contraction. A solid-state pulsed holmium laser emitting at 2.065 microns heated the fibre and surrounding solution in approximately 150 mus. The signal from a 100 microns thermocouple fed back to a heating wire maintained the elevated temperature after the laser pulse. 2. Tension of glycerol-extracted muscle fibres from rabbit psoas muscle did not change significantly following T-jumps when the fibre was relaxed. 3. In rigor, tension decreased abruptly on heating indicating normal (not rubber-like) thermoelasticity. The thermoelastic coefficient (negative ratio of relative length change to relative temperature change) of the fibre was estimated to be -0.021 at sarcomere lengths of 2.5-2.8 microns. Rigor tension was constant after the temperature step and returned to the original value on recooling. 4. In maximal Ca2+ activation, tension transients initiated by T-jumps had several phases. An immediate tension decrease suggests that thermoelasticity during contraction is similar to that in rigor. Active tension then recovered to the value before the T-jump with an apparent rate constant of approximately 400 s-1 (at 10-20 degrees C). This rate constant did not have an appreciable dependence on the final temperature. Finally, tension increased exponentially to a new higher level with a rate constant of approximately 20 s-1 at 20 degrees C. This rate constant increased with temperature with a Q10 of 1.4. 5. At submaximal Ca2+ activation the tension rise was followed by a decay to below the value before the T-jump. This decline was expected from the temperature dependence of steady pCa-tension curves. The final tension decline occurred on the 1-5 s time scale. 6. The value and amplitude dependence of the rate constant for the quick recovery following T-jumps were similar to those of the quick recovery following length steps during active contractions. The enthalpy change associated with the quick tension recovery following temperature-step perturbations was estimated to be positive suggesting that the recovery process is an endothermic reaction. Slower reaction steps on the 10-30 ms timescale, as well as reactions corresponding to the quick recovery, may contribute to the cross-bridge power stroke.
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PMID:Transient tension changes initiated by laser temperature jumps in rabbit psoas muscle fibres. 344 91

Dantrolene sodium acts primarily by affecting calcium flux across the sarcoplasmic reticulum of skeletal muscle. Recently, dantrolene has been used very successfully in the treatment of several rare hypercatabolic syndromes which have previously been associated with high mortality rates. In malignant hyperthermia, where early diagnosis and treatment usually with intravenous dantrolene in association with other supportive measures (and often subsequent dantrolene therapy) is performed, recovery is seen in virtually 100% of patients. There is a rapid resolution of hyperthermia, dysrhythmias, muscle rigidity, tachycardia, hypercapnia, mottled or cyanotic skin, and metabolic acidosis, and a slower normalisation of myoglobinuria and elevated serum creatine phosphokinase levels. In patients with family history or previous episodes of malignant hyperthermia, prophylactic treatment with dantrolene prior to anaesthesia prevents the syndrome occurring in most cases. Where malignant hyperthermia has developed patients have been successfully treated with further dantrolene therapy. Dantrolene has also been used successfully in the treatment of a few cases of heat stroke and the neuroleptic malignant syndrome--both of which have many similarities to malignant hyperthermia. Dantrolene is well established in the treatment of patients with muscle spasticity where it generally improves at least some of the components of spasticity (i.e. hyper/hypotonia, clonus, muscle cramps and spasms, resistance to stretch and flexor reflexes, articular movement, neurological and motor functions and urinary control). However, in some patients, particularly those with multiple sclerosis, dantrolene may not be effective, and in many cases muscular strength may diminish. Long term dantrolene therapy has been associated with hepatic toxicity and may cause problems in patients treated for disorders of muscle spasticity. Thus, dantrolene offers a unique advance in the therapy available for the treatment of hypercatabolic disorders and is also useful in the treatment of muscle spasticity of various aetiology.
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PMID:Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. 352 59

Anesthetic-induced malignant hyperthermia in pigs and humans is characterized by muscle rigidity and rapid, often fatal, increases in body temperature. A defect in Ca2+ homeostasis has been suspected as underlying the disease, based on the preventive effect of dantrolene sodium, an agent thought to reduce Ca2+ levels in the cytoplasm. We describe here direct measurements of cytoplasmic ionized Ca2+ levels in lymphocytes from seven normal and 12 malignant hyperthermia-susceptible pigs, using the fluorescent indicator quin2. No differences in the concentration of cytoplasmic ionized Ca2+ were found in cells from malignant hyperthermia-susceptible pigs (160 +/- 10 nM) relative to the controls (150 +/- 10 nM). However, addition of halothane in vitro caused a significant increase (to 270 +/- 30 nM) in lymphocytes from malignant hyperthermia-susceptible pigs, but not from normal pigs (180 +/- 10 nM). The halothane-mediated increase in cytoplasmic ionized Ca2+ required extracellular Ca2+. It is suggested that general anesthetics such as halothane increase the permeability of the cell surface to Ca2+, and that this increase may, on its own or indirectly, increase the cytoplasmic level of ionized Ca2+ during a malignant hyperthermia crisis. The detection of a halothane-dependent increase in cytoplasmic ionized Ca2+ selectively in malignant hyperthermia-susceptible pigs could be the basis for a noninvasive test for malignant hyperthermia.
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PMID:Selective increase in cytoplasmic calcium by anesthetic in lymphocytes from malignant hyperthermia-susceptible pigs. 357 44

Rigor complexes between actin and myosin have been shown to cause increased binding of Ca2+ to troponin C. A similar effect of force-generating crossbridges has been suggested as an explanation for the coupling between load and activation which has been observed in skeletal and cardiac muscle. The goal of this study was to test the hypothesis that Ca2+-troponin affinity during crossbridge cycling is load-dependent. Ca2+-binding to detergent-extracted rabbit psoas fibres was measured during ATP-induced force generation and in the relaxed state. To compare Ca2+ binding in the latter two states it was necessary to establish conditions in which ATP-induced force could be regulated independently of free Ca2+ concentration. Such conditions were obtained by the use of either the ATPase inhibitor sodium vanadate or the substitution of MgITP for MgATP as an energy source. This study showed that in the presence of MgATP (or MgITP) the amount of Ca2+ bound to the myofilaments at a given free Ca2+ concentration was independent of the force generated. Thus force per se is not a determinant of Ca2+-troponin affinity.
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PMID:The binding of calcium to detergent-extracted rabbit psoas muscle fibres during relaxation and force generation. 385 10

Mechanical and biochemical descriptions of the muscle cross-bridge cycle have been correlated. Skinned muscle fibres of rabbit psoas muscle in rigor were incubated in solutions containing approximately equal to 30 microM-Ca2+ ions and P3-1-(2-nitro)phenylethyladenosine-5'-triphosphate, 'caged ATP', an inert photolabile precursor of ATP. ATP was liberated from caged ATP within the fibres by pulses of 347 nm radiation from a frequency-doubled ruby laser. The mechanical responses of muscle fibres to the rapid increase of ATP concentration were monitored. Tension dropped briefly and then rose above the rigor value to the level characteristic of a steady active contraction. Liberation of ATP decreased in-phase stiffness (measured at 500 Hz) from the rigor level to a maintained value intermediate between rigor and relaxed values. Out-of-phase stiffness increased to a maintained level indicating a phase lead of tension with respect to imposed length oscillations. Rigor tension was varied prior to photolysis by slight alterations of fibre length. Tension traces starting at different rigor tensions converged to a common tension level at the same rate, whether or not Ca2+ was included in the medium. These data suggest that the rate of cross-bridge detachment by ATP from the rigor state is not influenced by Ca2+. Analysis of the tension records, in terms of sequential detachment and reattachment reactions, provided a measure of cross-bridge reattachment rate and an alternate measure of the detachment rate. Detachment from the rigor state was approximately proportional to the ATP concentration, with a second-order rate constant of at least 5 X 10(5) M-1 S-1. Reattachment with force generation had no detectable dependence on the concentration of ATP liberated by photolysis. A simple kinetic model of the cross-bridge cycle in terms of chemically defined intermediates was compatible with most of the experimental data. The ATP dependence of cross-bridge detachment, the kinetics of maintained cross-bridge reattachment in the presence of Ca2+, and transient reattachment and final relaxation in the absence of Ca2+ were explained. In this model, reversibility of cross-bridge attachment and the steps leading to force production allow the relatively high observed detachment rate to be accommodated with other data relating to active contraction. These data include the steady ATPase rate of active muscle fibres and the fewer attached cross-bridges in active contractions compared to rigor.
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PMID:Initiation of active contraction by photogeneration of adenosine-5'-triphosphate in rabbit psoas muscle fibres. 648 46

The incidence, etiology, clinical manifestations, and management of malignant hyperthermia (MH) are reviewed. The syndrome of MH is recognized as one of the causes of anesthesia-related deaths. It is considered pharmacogenetic because both an abnormal gene and precipitating environmental factors are necessary to produce an acute reaction. Metabolic defects, involving a derangement of calcium dynamics, appear to be the common characteristic of susceptible individuals. Calcium release and uptake from the sarcoplasmic reticulum is altered when an individual with MH is exposed to certain anesthetic agents or triggering physical and emotional stresses. Muscle rigidity, tachycardia, tachypnea, and high fever can lead to other complications and death. Management of an acute reaction of MH includes cooling methods to lower body temperature, hyperventilation, sodium bicarbonate control of acidosis, maintenance of fluid and electrolyte balance, and the administration of dantrolene sodium. A thorough family history, baseline CPKs, caffeine-halothane contracture tests, and ultramicroscopic examination of muscle biopsy specimens are recommended as screening techniques. The early administration of dantrolene sodium in acute reaction of MH has been shown to rapidly alleviate the symptoms and ensuing severe complications. Individuals with a strong family history of MH or previous episodes may be treated with oral dantrolene sodium before surgery to effectively prevent a crisis, and after surgery to prevent recurrence.
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PMID:Malignant hyperthermia: current perspectives. 728 92

Oxygen-derived free radicals (FRs) and other reactive oxygen species (ROS) have been implicated in the deleterious aspects of myocardial infarction, neutrophil infiltration and post-ischaemic reperfusion. We studied their actions on the main intracellular organelles of Ca-compartmentation and force production (the sarcoplasmic reticulum (SR) and myofilaments) in rat heart preparations by using two forms of chemical 'skinning'. We recorded Ca(2+)-activated isometric tension or, in saponin-treated trabeculae where SR function is maintained, either tension alone or tension and [Ca2+] transients evoked by caffeine. A single, brief application of xanthine/xanthine oxidase (generating superoxide; O2-) rapidly and irreversibly inhibits Ca(2+)-activated force with a dose- and time-dependent action. The kinetics of residual force production are slowed. Rigor induction (by ATP withdrawal) before and during exposure to .O2- prevents this action, suggesting the .O2(-)-sensitive site is occluded in rigor. Myofilament Ca-sensitivity and SR function were unaffected by .O2- or physiologically relevant [H2O2] (< 10 microM). Briefly applying 10-50 microM hypochlorous acid (HOCl) increased Ca-sensitivity and resting tension, but reduced Ca-activated force, in a manner consistent with 'rigor-like' crossbridges being involved. HOCl also provoked spontaneous Ca-release but reduced net SR Ca-uptake. Electron microscopy reveals that the myofilament lattice suffers a characteristic disruption by HOCl but not by .O2-. We conclude that FRs and ROS associated with myocyte dysfunction, reperfusion and inflammation could contribute to post-ischaemic myocardial dysfunction.
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PMID:Intracellular effects of free radicals and reactive oxygen species in cardiac muscle. 747 29


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