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 purpose of these investigations was to determine the effect of halothane on isometric contraction of striated muscle and to measure the associated heat production. This basic information is necessary before studies more directly relating to malignant hyperthermia are undertaken. Sartorius muscles were isolate from Rana pipiens during winter and summer months. It appears from these experiments that there is a prolongation of the relaxation phase of the twitch and tetanus responses with low concentrations of halothane, with a more diffuse effect on the contractile process evident at higher administered concentrations. The results of heat measurements, using a sensitive thermopile-galvanometer system, are compatible with the hypotheses that this effect on relaxation could result from either an interference with calcium reuptake by the sarcoplasmic reticulum or an increased affinity of the troponintropomyosin complex for available calcium.
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PMID:Effect of halothane on isometric twitch and tetanus response and the associated heat production in striated muscle of frogs. 108 24

Skeletal muscle from malignant hyperthermic (MH) pigs incubated at 37 C in 2.3 mM calcium-Krebs-Ringer solution contracts spontaneously when exposed to halothane. In contrast, halothane did not induce contracture in MH muscle incubated in 2.3 mM calcium-Krebs-Ringer solution at 25 C or in calcium-free Krebs-Ringer's solution at 37 C. Halothane did not induce contracture in normal control muscle in 2.3 mM Krebs-Ringer solution at 25 or 37 C. In the presence of halothane, addition of caffeine produced greater contracture in MH muscle than in normal controls. Halothane-caffeine-induced contractures of MH and control muscles at 25 and 37 C were similar. Elucidation that under certain experimental conditions halothane induces contracture in MH muscle, but not in normal muscle 1) may aid in development of a diagnostic test; 2) establishes further evidence for skeletal muscle as the target tissue for anesthetic-induced MH; 3) suggests that halothane may affect systems that regulate sarcoplasmic calcium concentration below contracture threshold in MH muscle. (Key words: Hyperthermia, malignant; Anesthetics, volatile, halothane; Ions, calcium; Muscle, skeletal, malignant hyperthermia.).
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PMID:Porcine malignant hyperthermia: effects of temperature and extracellular calcium concentration on halothane-induced contracture of susceptible skeletal muscle. 111 84

Total calcium content of both human and porcine MHS skeletal muscle is significantly less than normal. This data is consistent with the concept that some organelle (probably the sarcoplasmic reticulum, the mitochondrion or even the sarcolemma) within the MHS muscle stores less than normal amounts of calcium. The large variability between muscle specimens rules out measurement of total calcium content of skeletal muscle as a routine diagnostic test for malignant hyperthermia susceptibility.
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PMID:Total calcium content of skeletal muscle isolated from humans and pigs susceptible to malignant hyperthermia. 114 84

Malignant hyperthermia (MH) is a life threatening complication following anaesthesia with potent inhalational agents and suxamethonium. The signs of MH are caused by increased metabolism and secondary stimulation of the sympathetic nervous system due to uncontrolled, high intracellular concentrations of calcium in skeletal muscle. The hyperthermia is secondary to the increased energy turnover. Calcium release from the sarcoplasmic reticulum is increased due to a low threshold for release and prolonged opening of the calcium channel upon normal stimulation. The gene encoding the calcium channel is localized on chromosome 19 in humans, and a substitution of cysteine for arginine has recently been described in one family with MH.
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PMID:[Malignant hyperthermia]. 131 Mar 56

Malignant hyperthermia (MH) may be life-threatening when genetically predisposed individuals are administered triggering anesthetic agents that are believed to produce intracellular calcium release. To test this theory, the effects of halothane on normal and MH human skeletal muscle calcium-release channels were studied. Single calcium-release channels were incorporated from isolated sarcoplasmic reticulum membrane vesicles into a planar lipid bilayer, and halothane effects on the conductance and gating properties were measured by electrophysiologic techniques. Among the subjects studied, seven were MH-susceptible, and 13 channels were recorded from this group. Five subjects were negative for MH, and 10 channels were recorded from this group. Among the 13 channels recorded from the MH group, 7 were affected by halothane, which increased the probability of the channel to change from the inactive, closed state to an open state. This effect of halothane to increase open-state probability was associated with an overall increase in channel conductance. Thus, halothane affected the activation/inactivation process of the halothane-sensitive calcium-release channel from MH muscle as well as the gating properties of the MH calcium-release channel, as evidenced by the increased conductance. In 6 of the 13 channels recorded from MH muscle, halothane (2.2-17.6 microM) was without effect on these properties of the channel. Halothane (2.2-17.6 microM or 0.0057-0.0456 vol%) also had no measurable effect on the 10 channels from the negatively diagnosed subjects. Results of this study support a defect in the ryanodine-sensitive calcium-release channel from MH human muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Halothane effects on human malignant hyperthermia skeletal muscle single calcium-release channels in planar lipid bilayers. 131 98

The defect in malignant hyperthermia (MH) alters the binding of [3H]ryanodine to the Ca(2+)-release channel by increasing its apparent affinity for the binding site. In sarcoplasmic reticulum (SR) membranes from both normal and mutant pigs the apparent Kd is dependent on a number of parameters. Adenosine 5'-(beta,gamma-methylene)triphosphate, ionic strength, and Ca2+ each increase the apparent affinity of the binding site for [3H]ryanodine. Equilibrium and kinetic evaluation of the binding of [3H]ryanodine to these membranes demonstrates that the MH defect in pigs increases the apparent affinity of the membranes for [3H]ryanodine by increasing the amount of high affinity relative to low affinity binding sites. Both the association and dissociation of [3H]ryanodine with all three types of membranes (normal, heterozygous MH, homozygous MH) are characterized by two or more components, with the relative ratios of these components altered by the MH defect. These findings suggest that the observed Kd is the weighted average of the binding of ryanodine to two or more interconvertible states of the channel. Dilution of [3H]ryanodine bound to normal membranes at high Ca2+ into low Ca2+ solutions enhances the rate of dissociation. This conversion occurs to a much lesser extent with MH membranes, suggesting that the MH defect may alter the rate at which the high affinity form of the protein converts to the low affinity form.
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PMID:[3H]ryanodine as a probe of changes in the functional state of the Ca(2+)-release channel in malignant hyperthermia. 131 19

Absolute linkage between the gene, on chromosome 19, for the calcium release channel (CRC) of the sarcoplasmic reticulum in skeletal muscle and malignant hyperthermia (MH) has been reported by other workers. In the present study of three Swedish Families informative with respect to this linkage relationship, definite recombinants were found in two families. We conclude that mutations in other genes than the CRC gene can cause the clinical picture of MH. Accordingly, MH appears to be genetically heterogeneous.
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PMID:Genetic recombination between malignant hyperthermia and calcium release channel in skeletal muscle. 131 4

Anaesthesia can induce skeletal muscle rigidity, hypermetabolism and high fever in humans genetically predisposed to malignant hyperthermia. If not immediately reversed, such episodes can lead to tissue damage and death. In swine with the corresponding condition, stress can induce death or lead to devalued meat products. Since muscle contraction is controlled by sarcoplasmic Ca2+, the abnormality, as reviewed here by David H. MacLennan, could reside in the skeletal muscle Ca(2+)-release channel gene, RYR1. Several observations support the view that a single RYR1 mutation is causal of malignant hyperthermia in all breeds of pigs and in at least some human families: the substitution of Cys for Arg615 as the sole deduced amino acid sequence change in a comparison of malignant hyperthermia and normal porcine RYR1 cDNAs; the linkage of this mutation to malignant hyperthermia in over 450 pigs in six breeds, including 338 meioses; and the appearance of the corresponding mutation, Cys for Arg614, across a species barrier, in a few human families, where it also cosegregates with malignant hyperthermia. Linkage of malignant hyperthermia to RYR1 is, however, not observed in all human families with malignant hyperthermia. Accordingly, other abnormal genes that may cause the condition are being sought.
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PMID:The genetic basis of malignant hyperthermia. 132 95

The skeletal muscle ryanodine receptor of malignant hyperthermia-susceptible (MHS) pigs contains a mutation at residue 615 that is highly correlated with various abnormalities in the regulation of sarcoplasmic reticulum (SR) Ca2+ channel activity. In isolated SR membranes the Arg615 to Cys615 ryanodine receptor mutation is now shown to be directly responsible for an altered tryptic peptide map, due to the elimination of the Arg615 cleavage site. Furthermore, trypsin treatment released 86-99 kDa ryanodine receptor fragments encompassing residue 615 from the SR membranes. We conclude that the 86-99 kDa domain containing residue 615 is near the cytoplasmic surface of the ryanodine receptor and likely near important Ca2+ channel regulatory sites.
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PMID:Structural and functional correlates of a mutation in the malignant hyperthermia-susceptible pig ryanodine receptor. 133 12

Malignant hyperthermia (MH) is an inherited, potentially lethal condition in which sustained muscle contracture with attendant hypermetabolism and hyperthermia is triggered in humans, heterozygous for the gene defect, by inhalational anaesthetics and skeletal muscle relaxants, and in pigs, homozygous for the defect, by stress. Because muscle contracture could result from a defective Ca2+ release channel, we have focussed our attention on the linkage of MH to defects in the gene (RYR1) encoding the skeletal muscle Ca2+ release channel. We have cloned and sequenced human RYR1 cDNA and found restriction fragment length polymorphisms (RFLPs) in the human gene. We also localized RYR1 to human chromosome 19q13.1. Studies of the cosegregation of MH with these RFLPs established RYR1/MH linkage on human chromosome 19q13.1 (lod score of 4.2; recombinant fraction 0.0). We then sequenced MH and normal porcine RYR1 cDNAs. Mutation of C1843 to T, leading to substitution of Cys for Arg615, was the sole amino acid change noted between MH and normal animals. Linkage of this mutation to MH was established in a study of 338 informative meioses (lod score of 102; recombinant fraction 0.0). We identified the corresponding mutation in 1 of 35 human MH families studied and found cosegregation of the mutation and MH. The combination of a high lod score with crossing of a species barrier supports the causal nature of this mutation. Future studies are aimed at finding the major human MH mutations and establishing assays for their accurate diagnosis.
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PMID:The role of the skeletal muscle ryanodine receptor gene in malignant hyperthermia. 134 Oct 35


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