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)

The binding properties of [3H]ryanodine, a specific ligand of the receptor complex that forms the Ca2+ release channel of sarcoplasmic reticulum, were studied in normal (N) and malignant hyperthermia-susceptible (MH) human skeletal muscle. Integrity of the solubilized ryanodine receptor was demonstrated by single-channel recordings in planar bilayers and by the changes produced by activators and inhibitors of the Ca2+ release channel on the binding properties of [3H]ryanodine. N and MH receptors were capable of binding [3H]ryanodine in a Ca(2+)-dependent manner. Scatchard analysis showed that a single binding site for [3H]ryanodine was present in either N or MH muscle. Binding affinity was approximately the same in N and MH (Kd approximately 7 nM), when the Ca2+ concentration was greater than 30 microM. At 0.3 microM Ca2+, MH receptors displayed a higher affinity for [3H]ryanodine (Kd = 4.1 +/- 1.0 nM) than N receptors (Kd = 7.1 +/- 0.8 nM). The presence of a single Kd for [3H]ryanodine in MH muscle, distinct from that of N muscle, indicated that MH muscle does not have detectable levels of N receptors. Ca2+ dependence of [3H]ryanodine binding further suggested that MH receptors had a higher affinity for Ca2+ (Kd[Ca2+] = 120 +/- 50 nM) than N receptors (Kd[Ca2+] = 250 +/- 80 nM). Caffeine increased [3H]ryanodine binding at submicromolar [Ca2+], and the effect was larger in MH. Apparent affinity constants for caffeine were 13 +/- 1.8 mM in N and 6 +/- 0.8 mM in MH receptors. Evidently, the ryanodine receptor of MH-susceptible human skeletal muscle has an unusually high sensitivity to Ca2+ which is augmented by caffeine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered binding site for Ca2+ in the ryanodine receptor of human malignant hyperthermia. 187 69

A patient for fixation of ankle arthrodesis diagnosed as having malignant hyperthermia trait preoperatively is reported. A 17 year old man was anesthetized with enflurane for orthopedic surgery of the knee joint. At that time malignant hyperthermia developed. He was critically ill, but resuscitated and recovered from acute renal failure on 7th day after operation. Ca2+ release test was performed. Ca2+ releasing speed was prominently accelerated in this patient. We could identify him as having malignant hyperthermia trait. Epidural anesthesia with procaine chloride was given cautiously. No drug which may induce malignant hyperthermia was used. Nevertheless, malignant hyperthermia occurred. This disease has various forms of presentation. The mechanism is equivocal, and in some cases, it is difficult to judge it immediately. This patient was managed without complication. We consider that tourniquet and stress provoked signs of malignant hyperthermia in this patient.
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PMID:[The anesthetic management of a patient with the malignant hyperthermia trait diagnosed preoperatively]. 187 46

There is thought to be a genetic defect within the calcium release channel of the sarcoplasmic reticulum in malignant hyperthermia (MH). This primary alteration is hypothesized to influence the function and/or structure of various muscle membrane systems; e.g., to have a direct effect on the composition of the lipid matrix. Therefore, in striated muscle samples, we determined the quantity and fatty acid composition of the various types of membrane phospholipids. German Landrace pigs were classified as normal or susceptible to MH. Total lipid content from longissimus dorsi, semi-membranosus muscle, and heart left ventricular (HLV) samples were extracted with chloroform/methanol and subsequently separated by high performance liquid chromatography. The single phospholipid fractions were collected and, following derivatization, the quantities of individual fatty acids were determined using a capillary gas chromatographic method. In general, samples from the susceptible pigs contained lower absolute amounts of individual phospholipids. The most notable differences occurred in the HLV, where phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and sphingomyelin were all significantly less (P less than or equal to 0.05). The muscle from the susceptible animals also contained decreased amounts of the polyunsaturated phospholipid-bound fatty acids (P less than or equal to 0.05). These differences in phospholipid and fatty acid concentrations of membranes isolated from swine susceptible to MH may relate to their apparently increased sensitivities to halothane (e.g., fluidizing effects) or elevated temperature.
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PMID:Malignant hyperthermia: an altered phospholipid and fatty acid composition in muscle membranes. 188 38

The aim of the present study was to investigate whether the three different caffeine preparations--caffeine citrate, caffeine benzoate and the free base--used for in vitro diagnosis of malignant hyperthermia susceptibility--produced the same amount of contracture in rat diaphragm. At equimolar caffeine concentrations, the pure base generated more tension in the rat diaphragm muscle than caffeine benzoate or caffeine citrate. The citrate lowers the pH and the free Ca2+ concentration of the test bath and thus suppresses the caffeine contracture. The benzoate is believed to inhibit the caffeine contracture by its carbonyl group in a way similar to the effect of benzocaine.
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PMID:The caffeine contracture test for malignant hyperthermia: caffeine citrate, caffeine benzoate or caffeine free base? 189 51

Malignant hyperthermia (MH) is a rare but serious complication of general anesthesia that potentially carries a high mortality and morbidity. It is associated with excessive release of calcium into skeletal muscle following exposure to certain drugs, including the volatile general anesthetics. Since these are recognized membrane fluidizing agents it has been speculated that this condition might represent a generalized defect in membrane physical properties either at rest or inducible by fluidizing agents. If this hypothesis were found to be correct, malignant hyperthermia might conveniently be detected by examining membrane physical properties of easily accessible cells rather than the cumbersome method of muscle biopsy currently employed. To test this hypothesis we identified patients proven to be susceptible to MH by muscle biopsy and a cohort of patients not susceptible to MH as defined by negative muscle biopsy testing. Erythrocytes were isolated from both groups and membrane physical properties examined using conventional, widely available, steady-state fluorescence polarization techniques. Erythrocyte membranes were evaluated with multiple probes both in the basal condition and following fluidization with either increasing temperature or two concentrations of a fluidizing alcohol. We report, contrary to previous publications, that no discernable differences were detectable between MH-positive or negative patients. Thus, we find no evidence for a generalized membrane defect in MH and conclude that the determination of erythrocyte membrane physical properties, by these techniques, are of no use in the preoperative screening for this disorder.
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PMID:Erythrocyte membrane fluidity in malignant hyperthermia. 193 56

Malignant hyperthermia is caused by an abnormal increase in Ca2+ levels in skeletal muscle in response to anesthetics, including halothane. Since fatty acid production is elevated in skeletal muscle from individuals with malignant hyperthermia, the effects of fatty acids on the threshold of halothane-induced Ca2+ release were examined. In the absence of fatty acids halothane caused Ca2+ release from porcine and human heavy sarcoplasmic reticulum fractions, but only at concentrations above the clinically relevant range. Oleic acid (20 microM), an unsaturated fatty acid, reduced the threshold at which halothane induced Ca2+ release to concentrations used for anesthesia. Stearic acid, a saturated fatty acid had considerably less effect on the threshold of halothane action. The greater sensitivity of malignant hyperthermia muscle to halothane can be explained by elevated fatty acid production.
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PMID:Fatty acids markedly lower the threshold for halothane-induced calcium release from the terminal cisternae in human and porcine normal and malignant hyperthermia susceptible skeletal muscle. 194 69

Malignant hyperthermia (MH) is a potentially lethal condition in which sustained muscle contracture, with attendant hypercatabolic reactions and elevation in body temperature, are triggered by commonly used inhalational anaesthetics and skeletal muscle relaxants. In humans, the trait is usually inherited in an autosomal dominant fashion, but in halothane-sensitive pigs with a similar phenotype, inheritance of the disease is autosomal recessive or co-dominant. A simple and accurate non-invasive test for the gene is not available and predisposition to the disease is currently determined through a halothane- and/or caffeine-induced contracture test on a skeletal muscle biopsy. Because Ca2+ is the chief regulator of muscle contraction and metabolism, the primary defect in MH is believed to lie in Ca2+ regulation. Indeed, several studies indicate a defect in the Ca2+ release channel of the sarcoplasmic reticulum, making it a prime candidate for the altered gene product in predisposed individuals. We have recently cloned complementary DNA and genomic DNA encoding the human ryanodine receptor (the Ca2(+)-release channel of the sarcoplasmic reticulum) and mapped the ryanodine receptor gene (RYR) to region q13.1 of human chromosome 19 (ref. 14), in close proximity to genetic markers that have been shown to map near the MH susceptibility locus in humans and the halothane-sensitive gene in pigs. As a more definitive test of whether the RYR gene is a candidate gene for the human MH phenotype, we have carried out a linkage study with MH families to determine whether the MH phenotype segregates with chromosome 19q markers, including markers in the RYR gene. Co-segregation of MH with RYR markers, resulting in a lod score of 4.20 at a linkage distance of zero centimorgans, indicates that MH is likely to be caused by mutations in the RYR gene.
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PMID:Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. 196 23

1. Neuroleptic drugs (antipsychotics) produce numerous side effects which include serious extrapyramidal symptoms consisting of akathisia, dystonia, neuroleptic malignant syndrome, parkinsonian reactions such as postural abnormality, tremor, akinesia or bradykinesia, rigidity, and tardive dyskinesia. 2. Among the complications of neuroleptic chemotherapy, the most serious and potentially fatal complication is malignant syndrome, which is characterized by extreme hyperthermia, "lead pipe" skeletal muscle rigidity causing dyspnea, dysphagia, and rhabdomyolysis, autonomic instability, fluctuating consciousness, leukocytosis, and elevated creatine phosphokinase. 3. Neuroleptic malignant syndrome should be differentiated from malignant hyperthermia, lethal catatonia, and other pathological states producing some of these same symptoms. 4. In addition to neuroleptics, malignant syndrome has been caused by thymoleptics (antidepressants), metoclopramide (antiemetic), metoclopramide combined with cimetidine, tetrabenazine, overdosage of benzodiazepine, phenelzine, dothiepin and alcohol, and amphetamine. 5. Factors leading to and/or facilitating the emergence of neuroleptic malignant syndromes are reportedly organic brain syndrome, dehydration, exhaustion, external heat load, excessive sympathetic discharge, use of long acting neuroleptics, high doses of neuroleptics, rapid dose titration with neuroleptics, abrupt discontinuation of antiparkinsonism agents, and concurrent lithium therapy. 6. Although, the pathogenesis of neuroleptic malignant syndrome is not understood completely, a blockade of dopaminergic receptors in the hypothalamus, spinal cord and striatum, an alteration of dopaminergic-serotonergic transmission in the body, an enhanced synthesis and action of prostaglandin E1 and E2, and a modification of calcium-mediated signal transduction in the body have been suggested. 7. The treatment of malignant syndrome includes immediate withdrawal of neuroleptic drugs, i.v. infusion of dantrolene, and oral administration of bromocriptine; or alternatively i.v. infusion of dantrolene and the combination of levodopa-carbidopa. 8. Other measures to enhance the therapeutic effectiveness of the aforementioned regimens are to include the use of anticholinergic drugs such as benztropine to enhance the effectiveness of bromocriptine, of lorazepam if catatonic symptoms persist, or of electroconvulsive therapy (ECT) if psychotic symptoms persist. 9. These treatments, however, must be "active" rather than "passive", in order to avert fatalities and/or unfortunate sequelae from this iatrogenic and incompletely understood disease.
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PMID:Pathogenesis and treatment of neuroleptic malignant syndrome. 197 19

Halothane, in a dose-dependent manner, induced the release of intracellular Ca2+ in hepatocytes prepared from swine. The magnitude of the release induced by halothane was greater for hepatocytes prepared from animals susceptible to malignant hyperthermia (MH) than for those from normal swine. Two different methods were used to ascertain the release of Ca2+ induced by halothane: 1) the release of 45Ca2+ from nonmitochondrial stores of saponin-permeabilized hepatocytes was measured; and 2) changes in luminescence from intact hepatocytes loaded with the Ca2(+)-sensitive photoprotein aequorin were recorded. It was also observed that, although 1,4,5-inositol trisphosphate (IP3), guanosine-5-triphosphate, and arachidonic acid all induced a significant release of 45Ca2+ from permeabilized swine hepatocytes, only the quantities of 45Ca2+ released by IP3 were significantly greater for the hepatocytes prepared from the animals susceptible to MH. These data indicate an abnormal Ca2+ homeostasis in hepatocytes isolated from swine susceptible to MH, which supports the hypothesis that membrane systems from multiple organs may be affected in this genetic disorder.
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PMID:Enhanced mobilization of intracellular Ca2+ induced by halothane in hepatocytes isolated from swine susceptible to malignant hyperthermia. 200 Oct 32

Platelets from normal and malignant hyperthermia (MH)-susceptible pigs were evaluated for differences in 45calcium uptake in the absence or presence of caffeine (2-16 mM), halothane (0.05-0.5%), or halothane and caffeine together. There were no statistically significant differences in basal or halothane-inhibited calcium uptake by platelets from either source. There was a small statistically significant difference in calcium uptake between platelets from normal and MH-susceptible pigs in the presence of 16 mM caffeine and 0.5% halothane. Calcium uptake by platelets from one pedigree of MH-susceptible pigs were stimulated in a concentration-dependent manner by caffeine. These data suggest that exposure of platelets to caffeine may have potential for identifying MH-susceptibility.
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PMID:Calcium handling by platelets from normal and malignant hyperthermia-susceptible pigs. 201 Oct 50


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