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

To further define the possible involvement of sarcoplasmic reticulum calcium accumulation and release in the skeletal muscle disorder malignant hyperthermia (MH), we have examined various properties of sarcoplasmic reticulum fractions isolated from normal and MH-susceptible pig muscle. A sarcoplasmic reticulum preparation enriched in vesicles derived from the terminal cisternae, was further fractionated on discontinuous sucrose density gradients (Meissner, G. (1984) J. Biol. Chem. 259, 2365-2374). The resultant MH-susceptible and normal sarcoplasmic reticulum fractions, designated F0-F4, did not differ in yield, cholesterol and phospholipid content, or nitrendipine binding capacity. Calcium accumulation (0.27 mumol Ca/mg per min at 22 degrees C), Ca2+-ATPase activity (0.98 mumol Pi/mg per min at 22 degrees C), and calsequestrin content were also similar for MH-susceptible and normal sarcoplasmic reticulum fraction F3. To examine sarcoplasmic reticulum calcium release, fraction F3 vesicles were passively loaded with 45Ca (approx. 40 nmol Ca/mg), and rapidly diluted into a medium of defined Ca2+ concentration. Upon dilution into 1 microM Ca2+, the extent of Ca2+-dependent calcium release measured after 5 s was significantly greater for MH-susceptible than for normal sarcoplasmic reticulum, 65.9 +/- 2.8% vs. 47.7 +/- 3.9% of the loaded calcium, respectively. The C1/2 for Ca2+ stimulation of this calcium release (5 s value) from MH-susceptible sarcoplasmic reticulum also appeared to be shifted towards a higher Ca2+-sensitivity when compared to normal sarcoplasmic reticulum. Dantrolene had no effect on calcium release from fraction F3, however, halothane (0.1-0.5 mM) increased the extent of calcium release (5 s) similarly in both MH-susceptible and normal sarcoplasmic reticulum. Furthermore, Mg2+ was less effective at inhibiting, while ATP and caffeine were more effective in stimulating, this Ca2+-dependent release of calcium from MH-susceptible, when compared to normal sarcoplasmic reticulum. Our results demonstrate that while sarcoplasmic reticulum calcium-accumulation appears unaffected in MH, aspect(s) of the sarcoplasmic reticulum Ca2+-induced calcium release mechanism are altered. Although the role of the Ca2+-induced calcium release mechanism of sarcoplasmic reticulum in situ is not yet clear, our results suggest that an abnormality in the regulation of sarcoplasmic reticulum calcium release may play an important role in the MH syndrome.
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PMID:Enhanced Ca2+-induced calcium release by isolated sarcoplasmic reticulum vesicles from malignant hyperthermia susceptible pig muscle. 287 89

1. Because calcium antagonist drugs increase contracture in both control and malignant hyperpyrexia susceptible (MHS) skeletal muscle, the effect of these drugs on the sarcoplasmic reticulum (SR) was investigated. 2. The calmodulin antagonist drugs inhibited the Ca2+ dependent ATPase activity and the ATP-dependent Ca2+ uptake, and accelerated the efflux of Ca2+ from isolated SR preparations from both control and MHS skeletal muscle. These effects of calmodulin antagonist drugs on SR Ca2+ transport functions were consistent with their in vitro pharmacological effects on control and MHS muscle.
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PMID:The effects of calmodulin antagonist drugs on isolated sarcoplasmic reticulum from malignant hyperpyrexia susceptible swine. 296 33

Sarcolemmal properties implicated in the skeletal muscle disorder, malignant hyperthermia (MH), were examined using sarcolemma-membrane vesicles isolated from normal and MH-susceptible (MHS) porcine skeletal muscle. MHS and normal sarcolemma did not differ in the distribution of the major proteins, cholesterol or phospholipid content, vesicle size and sidedness, (Na+ + K+)-ATPase activity, ouabain binding, or adenylate cyclase activity (total and isoproterenol sensitivity). The regulation of the initial rates of MHS and normal sarcolemmal ATP-dependent calcium transport (calcium uptake after 1 min) by Ca2+ (K1/2 = 0.64-0.81 microM), calmodulin, and cAMP-dependent protein kinase were similar. However, when sarcolemmal calcium content was measured at either 2 or 20 min after the initiation of active calcium transport, a significant difference between MHS and normal sarcolemmal calcium uptake became apparent, with MHS sarcolemma accumulating approximately 25% less calcium than normal sarcolemma. Calcium transport by MHS and normal sarcolemma, at 2 or 20 min, had a similar calmodulin dependence (C1/2 = 150 nM), and was stimulated to a similar extent by cAMP-dependent protein kinase or calmodulin. Halothane inhibited MHS and normal sarcolemmal active calcium uptake in a similar fashion (half-maximal inhibition at 10 mM halothane), while dantrolene (30 microM) and nitrendipine (1 microM) had little effect on either MHS or normal sarcolemmal calcium transport. After 20 min of ATP-supported calcium uptake, 2 mM EGTA plus 10 microM sodium orthovanadate were added to initiate sarcolemmal calcium efflux. Following an initial rapid phase of calcium release, an extended slow phase of calcium efflux (k = 0.012 min-1) was similar for both MHS and normal sarcolemma vesicles. We conclude that although a number of sarcolemmal properties, including passive calcium permeability, are normal in MH, a small but significant defect in MHS sarcolemmal ATP-dependent calcium transport may contribute to the abnormal calcium homeostasis and altered contractile properties of MHS skeletal muscle.
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PMID:Skeletal muscle sarcolemma in malignant hyperthermia: evidence for a defect in calcium regulation. 302 85

The differences observed among rat strains in both basal [Na+]i and the several cation transport systems seem to be due to the different genetic background as clearly shown in F2 populations or after bone marrow transplantation in MHS. The same may be true for humans. In spite of all the caution taken in interpreting the data, because of the great possibility of methodological errors, it is likely that the differences observed in many laboratories are due to uneven genetic or ethnic composition of the samples studied, as shown by Dagher and Canessa. One intriguing observation is that most reports of "low Na-K cotransport" values in hypertensive patients are from Mediterranean countries (Italy, France, and Spain), whereas most reports of "high," or "not low Na-K cotransport," or very high values of countertransport came from populations originating from North Europe (Denmark, USA, South African whites). We are not aware of any study on erythrocyte Na-K cotransport performed in Great Britain (the greatest source of American immigrants). Indeed the difference in cotransport values between North and South European hypertensives might be due to different environmental factors, but if this is so, the difference does not depend on the salt consumption or plasma lipids that are similar in our high and low Na-K cotransport hypertensives (Cusi D et al, submitted). The picture seems relatively less confusing for calcium. The most consistent alterations in different models of hypertension is a decreased Ca-pump in SHR, MHS, and DOCA rats, reduced calcium binding in SHR and MHS, and reduced microsomal ATP dependent calcium uptake in SHR and DOCA rats. [Ca++]i, which is increased in established hypertension in man and rats, is normal in young prehypertensive rats and humans, and returns to normal values after pharmacological treatment of hypertension. This pattern of changes suggests that genetic control of these transport systems is weaker, and probably much influenced by different environmental conditions. However, because of the pivotal role of calcium in vascular smooth muscle cell concentration, its intracellular increase may be the common pathway of the different forms of hypertension. What remains unclear is the relation, if any, between calcium and sodium. Blaustein tried to find a link between them, but his hypotheses have yet to be confirmed.
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PMID:Role of cellular sodium and calcium metabolism in the pathogenesis of essential hypertension. 329 35

It has been speculated that, in malignant hyperthermia-susceptible (MHS) individuals, an abnormality of sympathetic activity is seen during stressful situations, such as exercise. The authors investigated whether muscle metabolism in eight MHS subjects, at rest and during moderate and heavy short-term exercise, is different then that in normals. Leg exchange of energy substrates (glucose, lactate, and glycerol) was quantified by measuring leg blood flow and arterial-venous concentration differences. Muscle biopsies were also performed, and ATP, glycogen, and lactate were analyzed. Catecholamines and oxygen uptake were also measured. The study was performed at rest with subjects in the supine position and during two periods (40% and 80% of the subjects maximal oxygen uptake, respectively) on a bicycle ergometer. The principal finding of the study was that there was no major difference in oxygen uptake or leg exchange of glucose, lactate, and glycerol between MHS-subjects and previously standard normals during different grades of exercise. Furthermore, muscle metabolites and plasma catecholamines did not differ between the groups. This study indicates a normal sympathetic activity and muscle metabolism in MHS subjects during rest, as well as during moderate and severe exercise. The authors' results do not support the opinion that persons with positive in vitro tests for MH should restrict their physical activity.
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PMID:Effects of graded exercise on leg exchange of energy substrates in malignant hyperthermia susceptible subjects. 363 4

A bioassay, using high-performance liquid chromatography (HPLC) analysis of platelet adenosine nucleotides and hypoxanthine, was studied for its potential use as a test for MH susceptibility. A protocol for the assay was developed, based on the method outlined by Solomons and Masson. The HPLC procedure was a rapid, efficient, sensitive, and highly reproducible technique for measuring ATP, ADP, AMP, and hypoxanthine in platelets. Conditions of extraction and storage were critical for preventing degradation of the nucleotides. Extraction of nucleotides at icebath temperature was found necessary. Storage of platelet extract in PCA, even at -20 degrees C, showed loss of ATP and ADP; hence, neutralization with KOH was essential before storage. Contrary to the findings of Solomons et al., the present study demonstrated that neither ATP depletion nor per cent reduction in nucleotide ratios in platelets treated with halothane can be used as a definitive test for the diagnosis of MH susceptibility. The reason for this disagreement is unclear; however, differences in methods and altitude are implicated. It is possible that the platelet is not affected by malignant hyperthermia and thus cannot serve as a test system for the detection of the syndrome.
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PMID:The use of a platelet nucleotide assay as a possible diagnostic test for malignant hyperthermia. 402 92

The biochemical characteristics of skeletal muscle mitochondria of malignant hyperthermia (MH) susceptible Dutch Landrace pigs have been investigated before and during an MH attack, induced in vivo by halothane plus succinylcholine. The muscle homogenates have a decreased capacity to synthesize ATP and creatine phosphate during the MH period. Muscle mitochondria prepared from susceptible pigs in an MH period consume less oxygen than do mitochondria isolated before the attack, or mitochondria from control pigs during the challenge. The oxidative phosphorylation is not uncoupled during the critical period. The production of CO2 indicates that the in vitro measured capacity of the MH muscle mitochondria correctly reflects the in vivo condition during the MH attack. The restricted synthesis may be caused by a factor, finding expression in the mitochondria themselves, and obtained or activated during the MH attack.
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PMID:In vivo induced malignant hyperthermia in pigs. II. Metabolism of skeletal muscle mitochondria. 671 Dec 68

The value of the quantitative electromyogram in the detection of subclinical myopathic signs was tested in a family consisting of 11 members, one of them showing a Malignant Hyperthermia crisis. Furtheron an in vitro contracture test and an ATP-test was performed and the Serum CPK and the isoenzyme in serum and muscle examined. The following conclusions were taken: 1) Although unspecific pattern (in 5 cases more than 12% polyphasic potentials were found, one of them showing a reduction of the mean duration of 30%) the electromyography is a good but not absolutely certain indicator of subclinical myopathic signs in Malignant Hyperthermia. 2) The exclusion of M.H. risk is not possible using a single test. 3) The diagnostic value of not invasive methods, as the electromyography is of special importance. The diagnostic use of many M.H. tests seems necessary.
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PMID:[Electrophysiologic investigations in a family with malignant hyperthermia (author's transl)]. 690 89

Serial ECG's were reviewed in 93 consecutive patients who were proven to be susceptible to malignant hyperthermia by caffeine contracture and ATP depletion tests on skeletal muscle biopsies, but who were without a history of pyrexic crises. There were 46 males and 47 females with a mean age of 33 years. Abnormal ECG's were found in 26 of the patients, with conduction defects in 14, repolarization abnormalities (non-specific ST-T changes) or "Q" waves in nine and increased voltages suggesting left ventricular hypertrophy in three (in the absence of hypertension). An abnormal ECG in a young patient may reflect malignant hyperthermia susceptibility.
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PMID:Electrocardiographic abnormalities associated with malignant hyperthermia susceptibility. 706 30

Ca-releasing action of halothane on fragmented sarcoplasmic reticulum (FSR) from bullfrog and rabbit skeletal muscle was examined to understand the mechanism of Ca release in reference to the etiology of malignant hyperthermia. Halothane has dual action on FSR: the Ca release and the inhibition of Ca uptake. On addition of halothane to loaded FSR, a rapid Ca release was followed by a sluggish Ca leakage which was probably due to a decreased capacity for Ca uptake. The properties of the rapid Ca release by halothane are similar to those of caffeine. It was inhibited by procaine or high concentrations of Mg2+. It was stimulated by a high concentration of ATP. A low temperature was stimulatory for Ca-releasing action on frog FSR while it was inhibitory on rabbit FSR. The result that caffeine shifted the dose response curve for Ca release by halothane to a steeper relation to a range of much lower concentrations suggests that the action of halothane may not be identical with that of caffeine in spite of many similarities.
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PMID:The Ca-releasing action of halothane on fragmented sarcoplasmic reticulum. 714 26


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