Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dantrolene sodium or dantrolene1 is 1([5-(nitrophenyl)furfurylidend] amino) hydantoin sodium hydrate. It is indicated for use in chronic disorders characterised by skeletal muscle spasticity, such as spinal cord injury, stroke, cerebral palsy and multiple sclerosis. Dantrolene is believed to act directly on the contractile mechanism of skeletal muscle to decrease the force of contraction in the absence of any demonstrated effects on neural pathways, on the neuromuscular junction, or on the excitable properties of the muscle fibre membranes. Controlled trials have demonstrated that dantrolene is superior to placebo in adults or children with spasticity from various causes, as evidenced by clinical assessments of disability and daily activities, and by muscle and reflex responses to mechanical and electrical stimulation. It is somewhat less effective in patients with multiple sclerosis than in those with spasticity from other causes. There has been a general clinical impression in controlled trials that dantrolene caused less sedation than would have been expected from therapeutically comparable doses of diazepam. In 2 controlled trials, there was no significant difference between dantrolene and diazepam in terms of reductions in spasticity, clonus, and hyperreflexia, but side-effects such as drowsiness and inco-ordination occurred significantly more frequently on diazepam. Long-term studies have indicated continuing benefit for patients taking dantrolene, though the incidence of side-effects has often been high and there has been a suggestion of exacerbation of seizures in children with cerebral palsy. Dantrolene may be of value in the medical treatment of spasm of the external urethral sphincter due to neurological and non-neurological disease, and animal studies suggest a potential use in the management of malignant hyperpyrexia. Chemical evidence of liver dysfunction may occur in 0.7 to 1% of patients on long-term treatment with dantrolene, with symptomatic hepatitis in 0.35 to 0.5% and fatal hepatitis in 0.1 to 0.2%. The drug commonly causes transient drowsiness, dizziness, weakness, general malaise, fatigue and diarrhoea at the start of therapy. Muscle weakness may be the principal limiting side-effect in ambulant patients, particularly in those with multiple sclerosis, and therapy could be hazardous in patients with pre-existing bulbar or respiratory weakness. The dosage of dantrolene has been fixed in most controlled trials, though long-term studies have indicated the need for individualisation of dosage. The initial dose is usually 25mg once daily, increasing to 25mg two, three or four times daily, and then by increments of 25mg up to as high as 100mg two, three or four times daily. The lowest dose compatible with optimal response is recommended.
 ...
PMID:Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity. 31 89

We have examined the influence of electrical stimulation on caffeine-induced tension generation during contracture testing used to diagnose malignant hyperthermia. The cumulative contracture response to caffeine was compared in pairs of morphologically comparable muscle bundles obtained from the same patient. Only one of the two bundles was stimulated electrically during the test. Statistically significant differences in tension were found at caffeine concentrations greater than or equal to 4 mmol litre-1, the tension developed being invariably larger in the unstimulated fascicles. These results suggest that electrical stimulation results in suppression of the dose-dependent, caffeine-induced contracture. This effect could be a result of the potentiation of twitch tension by caffeine, muscle fatigue, or both. Overall, the observed differences did not alter the in vitro diagnosis of malignant hyperthermia.
 ...
PMID:In vitro diagnosis of malignant hyperthermia: influence of electrical stimulation on the contracture response to caffeine. 163 10

The development of muscle fatigue due to exhaustive exercise is associated with impaired sarcoplasmic reticulum (SR) Ca-transport activity. This study tested the hypothesis that SR failure is a consistent feature of cardiac and skeletal muscle fatigue owing to relative functional overload regardless of the method of induction: excessive stimulation, diminished performance capacity, or excessive excitation-contraction coupling. The Ca-transport activity was determined using three unique models of muscle fatigue: chronic and rapid ventricular pacing in dogs; metabolic inhibition caused by global cardiac ischemia in swine; and the hypermetabolic syndrome of porcine malignant hyperthermia (MH). Both pacing- and ischemia-induced fatigue resulted in reduction of SR Ca-transport ATPase activity: from 275 +/- 58 to 159 +/- 57 nmol.min-1.mg-1 (mU/mg) and from 577 +/- 82 to 177 +/- 133 mU/mg, respectively. Both pacing-induced fatigue and halothane-induced MH resulted in reduction of Ca-sequestration activity of muscle homogenates from 5.95 +/- 2.4 to 3.11 +/- 0.67 nM/s at 300 nM Ca and 38.7 +/- 10.5 to 16.3 +/- 8.0 nM/s at 1500 nM Ca, respectively (all p less than 0.01). The isolated SR Ca-ATPase activity correlated with Ca-sequestration activity of myocardial homogenates (r = 0.76; p less than 0.005). Different models were used to study the relationship of Ca-transport activity with relaxation function, degree of acidosis, and ionized Ca concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cardiac and muscle fatigue due to relative functional overload induced by excessive stimulation, hypersensitive excitation-contraction coupling, or diminished performance capacity correlates with sarcoplasmic reticulum failure. 205 42

Calcium signalling in cells is dependent on a communication between channels/ transporters in two membrane structures: the cell membrane and the membranes of endo- and sarcoplasmic reticula (ER/SR). In general, cytosolic Ca2+ can be raised by influx of calcium over the cell membrane through three types of channels: voltage-, receptor-, and store-operated channels (VOCs, ROCs and SOCs). This small Ca2+ influx is most often amplified by a Ca2+ release from the ER/SR through two types of channels: the IP3-receptor and the ryanodine receptor (RyR), which are huge proteins identified and cloned in recent years. We focus on the 'synaptic' connection between VOCs (L-type calcium channels) and RyRs of the SR in heart and skeletal muscle. Depolarization of the cell membrane (an action potential) opens the VOC and moves it in the membrane. One VOC triggers opening of a certain number of underlying RyRs that together release a quantum of calcium from the SR, a calcium spark. The communication between the VOC and RyRs is probably achieved primarily by a mechanical link in skeletal muscle (voltage-controlled calcium release), and by the small inward calcium flux through the VOC in the heart (calcium-induced calcium release, CICR). Conditions as different as heart failure, myasthenia gravis, malignant hyperthermia, and skeletal muscle fatigue, may be examples of deteriorated control or function of the RyR.
 ...
PMID:Intracellular calcium signalling in striated muscle cells. 939 86

Although the defects in cellular Ca(2+) homeostasis associated with malignant hyperthermia (MH) have been extensively studied, the functional consequences of the MH mutation are not clear. We used continuous and intermittent high-frequency stimulation to determine whether this mutation might alter the fatigue resistance of muscle from MH susceptible (MHS) pigs. Force decline with 10 s continuous stimulation (150 Hz) was significantly less in MHS muscle (58.4 +/- 1.0%) than in normal muscle (50.5 +/- 3.0%). With intermittent stimulation, there was no significant difference in tension decline between muscle types. Post-stimulation twitch and tetanus responses were similar in MHS and normal muscles except: 1) twitch potentiation was significantly greater in normal muscle after continuous stimulation, and 2) recovery of tetanic tension was slowed in MHS muscle. Although the MH defect does not cause major functional abnormalities, subtle differences in MHS muscle response to fatiguing stimulation are apparent. Therefore, it is unlikely the work capacity of MH patients would be limited by any MH associated defect within the muscle.
 ...
PMID:Malignant hyperthermia: fatigue characteristics of skeletal muscle. 1063 15

Mammalian skeletal muscle shows an enormous variability in its functional features such as rate of force production, resistance to fatigue, and energy metabolism, with a wide spectrum from slow aerobic to fast anaerobic physiology. In addition, skeletal muscle exhibits high plasticity that is based on the potential of the muscle fibers to undergo changes of their cytoarchitecture and composition of specific muscle protein isoforms. Adaptive changes of the muscle fibers occur in response to a variety of stimuli such as, e.g., growth and differentition factors, hormones, nerve signals, or exercise. Additionally, the muscle fibers are arranged in compartments that often function as largely independent muscular subunits. All muscle fibers use Ca(2+) as their main regulatory and signaling molecule. Therefore, contractile properties of muscle fibers are dependent on the variable expression of proteins involved in Ca(2+) signaling and handling. Molecular diversity of the main proteins in the Ca(2+) signaling apparatus (the calcium cycle) largely determines the contraction and relaxation properties of a muscle fiber. The Ca(2+) signaling apparatus includes 1) the ryanodine receptor that is the sarcoplasmic reticulum Ca(2+) release channel, 2) the troponin protein complex that mediates the Ca(2+) effect to the myofibrillar structures leading to contraction, 3) the Ca(2+) pump responsible for Ca(2+) reuptake into the sarcoplasmic reticulum, and 4) calsequestrin, the Ca(2+) storage protein in the sarcoplasmic reticulum. In addition, a multitude of Ca(2+)-binding proteins is present in muscle tissue including parvalbumin, calmodulin, S100 proteins, annexins, sorcin, myosin light chains, beta-actinin, calcineurin, and calpain. These Ca(2+)-binding proteins may either exert an important role in Ca(2+)-triggered muscle contraction under certain conditions or modulate other muscle activities such as protein metabolism, differentiation, and growth. Recently, several Ca(2+) signaling and handling molecules have been shown to be altered in muscle diseases. Functional alterations of Ca(2+) handling seem to be responsible for the pathophysiological conditions seen in dystrophinopathies, Brody's disease, and malignant hyperthermia. These also underline the importance of the affected molecules for correct muscle performance.
 ...
PMID:Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. 1089 34

In this review, potential roles for the endogenous sphingolipid, sphingosine, and its derivatives are described for muscle cells. Sphingosine modulates the function of important calcium channels in muscle, including the ryanodine receptor (RyR) calcium release channel of the sarcoplasmic reticulum (SR). Sphingosine blocks calcium release through the SR ryanodine receptor and reduces the activity of single skeletal muscle RyR channels reconstituted into planar lipid bilayers. Sphingosine-blocked calcium release is coincident with the inhibitory effects of sphingosine on [3H]ryanodine binding to the RyR. The sphingomyelin signal transduction pathway has also been identified in both skeletal and cardiac muscle. A neutral form of sphingomyelinase (nSMase) enzyme has been localized to the junctional transverse tubule membrane. The high turnover of the SMase is responsible for the production of ceramide and sphingosine. HPLC analyses indicate that significant resting levels of sphingosine are present in muscle tissue. A model of excitation-contraction coupling is presented suggesting a potential role for this endogenous sphingolipid in normal muscle function. Putative roles for sphingolipid mediators in skeletal muscle dysfunction are also discussed. We hypothesize that sphingosine plays important roles in malignant hyperthermia and during the development of muscle fatigue.
 ...
PMID:The role of sphingolipids in the control of skeletal muscle function: a review. 1093 63

Phosphorus magnetic resonance spectroscopy (P-MRS) has now been used in the investigation of muscle energy metabolism in health and disease for over 15 years. The present review describes the basics of the metabolic observations made by P-MRS including the assumptions and problems associated with the use of this technique. Extramuscular factors, which may affect the P-MRS results, are detailed. The important P-MRS observations in patients with mitochondrial myopathies, including the monitoring of experimental therapies, are emphasized. The findings in other metabolic myopathies (those associated with glycolytic defects or endocrine disturbances) and in the destructive myopathies (the dystrophies and the inflammatory myopathies) are also described. Observations made in normal and abnormal fatigue, fibromyalgia, and malignant hyperthermia are considered. Finally, a summary of the possible diagnostic use of P-MRS in exercise intolerance is provided.
 ...
PMID:Insights into muscle diseases gained by phosphorus magnetic resonance spectroscopy. 1095 34

Fluoroquinolones cause myalgia, but this complication is not clearly documented. We describe a patient who developed myalgia and rhabdomyolysis during fluoroquinolone treatment. The patient was a 33-year-old man treated with norfloxacin for common cystitis. He complained of general muscular fatigue, tendon disorders, and articular pain during treatment. When the antimicrobial agent was stopped, symptoms decreased, with persistence of slight myalgia for 10 days. Rhabdomyolysis was detected. Six months later, investigation by 31P magnetic resonance spectroscopy revealed an oxidative disorder and an abnormal abundance of phosphomonoesters. In vitro contracture tests led to a diagnosis of malignant hyperthermia susceptibility. Our case shows that for any subject presenting myalgia with rhabdomyolysis triggered by fluoroquinolone treatment, the presence of a latent myopathy should be investigated.
 ...
PMID:Malignant hyperthermia susceptibility revealed by myalgia and rhabdomyolysis during fluoroquinolone treatment. 1140 39

Important aspects of the excitation-contraction (EC) coupling process in skeletal muscle have been revealed using mechanically-skinned fibers in which the transverse-tubular system can be depolarized by ion substitution or electrical stimulation, activating the voltage-sensors which in turn open the Ca2+ release channels in the adjacent sarcoplasmic reticulum (SR). Twitch and tetanic force responses elicited in skinned fibers closely resemble those in intact fibers, showing that the coupling mechanism is entirely functional. It was found that ATP has to be bound to the Ca2+ release channels for them to be activated by the voltage-sensors and that the coupling mechanism likely involves the voltage-sensors removing the inhibitory effects of cytoplasmic Mg2+ on the release channels; such findings are relevant to the basis of muscle fatigue and to certain diseases such as malignant hyperthermia (MH). EC coupling is evidently not mediated by upmodulation of Ca2+-induced Ca2+ release (CICR) or by an oxidation or phosphorylation reaction. The Ca2+ load in the SR of skinned fibers can be set at the endogenous level or otherwise. The normal coupling mechanism functions well in mammalian fast-twitch fibers even when the SR is only partially loaded, whereas CICR is highly dependent on SR luminal Ca2+ and caffeine is poorly effective at inducing release at the endogenous SR Ca2+ load level.
 ...
PMID:Voltage-sensor control of Ca2+ release in skeletal muscle: insights from skinned fibers. 1189 57


1 2 Next >>