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)

Human endothelial cell monolayers prepared from umbilical veins have been incubated with aspirin (1--2 mM) dissolved in Hepes modified solution and in platelet-rich plasma. They have also been incubated with plasma prepared from subjects before and after intake of aspirin giving a mean plasma concentration of 0.5 mM. The effects of the endothelial cells on ADP and collagen-induced platelet aggregation and malondialdehyde production in platelet-rich plasma have been tested. The endothelial cells had a spontaneous inhibitory effect on all three parameters. This effect was abolished when the cells were incubated with aspirin dissolved in MHS for 20 min and the increase in effect observed when platelet-rich plasma was incubated with endothelial cells for a period of 30 min was similarly inhibited when aspirin was dissolved in plasma or when plasma prepared from subjects who had taken aspirin were used. Aspirin had no inhibitory effect on prostacyclin (PGI2) with regard to the effect of PGI2 on platelets. On the contrary, the two compounds had an additive inhibitory effect on platelet aggregation induced by ADP and collagen. These findings should be considered with regard to the use of aspirin as an antithrombotic agent.
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PMID:The inhibitory effect of aspirin on human endothelial cells. 36 62

Effort rhabdomyolysis is a syndrome which takes the form of a pathology with different etiopathogenetic stages. General anesthesia may trigger off acute muscular cytolysis which is probably influenced by the inflammatory surgical pathology itself. The observation of two cases of post-anesthetic rhabdomyolysis following muscular stress suggest that the exhaustion of muscle energy reserves and the consequent alteration of the ATP/ADP ratio may act as a trigger mechanism for this syndrome. Its close relationship with malignant hyperthermia makes a precise anamnesis vitally important, especially in relation to recent intense physical effort in patients undergoing emergency surgery for acute pathologies.
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PMID:[Post-anesthesia rhabdomyolysis syndrome following muscular stress. 2 case reports]. 129 23

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 effects of halothane on adenylate kinase activity in porcine muscle have been examined. No abnormality in malignant hyperpyrexia susceptible muscle was found. At clinical concentrations of halothane only slight inhibition of adenylate kinase activity was observed. The inhibition increased with increasing concentrations of halothane and with decreasing concentrations of the substrates AMP or ADP. The inhibition was similar in both malignant hyperpyrexia susceptible and control muscle. It seems unlikely that adenylate kinase is involved directly in triggering malignant hyperpyrexia.
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PMID:Effect of halothane on adenylate kinase in porcine malignant hyperpyrexia. 628 70

Platelet responses to halothane in normal individuals and in patients susceptible to malignant hyperthermia were evaluated. Platelets in platelet-rich plasma from both normal controls and patients underwent aggregation in response to halothane. There was no significant difference in the degree of aggregation between normal subjects and patients. Aggregation by halothane was associated with a change in platelet shape, centralization of platelet granules, and phosphorylation of platelet actin binding protein, myosin light chain, and a 40 000-dalton protein. Aggregation induced by halothane could be inhibited by EGTA, PGE1, adenosine and verapamil, but not by aspirin. Aggregation induced by halothane could be potentiated by small doses of adrenaline or ADP and in some individuals by caffeine. However, previous exposure of platelets to halothane made them subsequently less aggregable to ADP. The results of these studies do not support a use of halothane-induced aggregation of platelets to detect an abnormality in individuals susceptible to malignant hyperthermia, but do provide new evidence of the effects of halothane on cellular function.
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PMID:Halothane stimulates the aggregation of platelets of both normal individuals and those susceptible to malignant hyperthermia. 665 14

Since the cellular defect of malignant hyperthermia (MH) may occur in tissues other than muscle and since platelets share certain contractile characteristics with muscle cells, testing platelets has been suggested as a way to diagnose susceptibility to MH. In analogy to the in vitro depletion of muscle adenosine triphosphate (ATP), the authors compared platelet basal nucleotide levels and halothane-induced depletion of ATP from 10 MH-susceptible patients and from 12 unrelated nonsusceptible controls. A rapid and simple isocratic high-pressure liquid chromatography technique was used to analyze acid-extracted platelet nucleotides. Halothane added to platelet-rich plasma at 37 degrees C significantly decreased ATP in platelets in a dose-dependent as well as a time-dependent manner. In contrast, adenosine diphosphate (ADP) and adenosine monophosphate (AMP) were not changed significantly. Other volatile anesthetic agents also depleted ATP in platelets. Although ATP in platelets exposed to halothane was depleted significantly, there was no difference between platelets from MH-susceptible patients and nonsusceptible controls. Therefore, halothane-induced ATP depletion in platelets is not a reliable test for diagnosing MH susceptibility.
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PMID:Halothane-induced ATP depletion in platelets from patients susceptible to malignant hyperthermia and from controls. 683 75

The interaction of Ca2+ with mitochondria isolated from longissismus dorsi, a predominantly white skeletal muscle, of normal and malignant hyperthermia pigs was investigated using tightly-coupled preparations. Arrhenius plots of mitochondrial Ca2+ -stimulated respiration for succinate oxidation of malignant hyperthermia pigs showed a transition temperature (Tt) of 26.31 +/- 0.80 degrees C (n = 5), which was decreased by spermine to 15.41 +/- 0.69 degrees C (n = 3), a value very similar to that for normal pigs. No difference in either the Tt or in the activation energy (Ea) was observed between the two types of pigs when ADP was used instead of Ca2+. Mitochondria of malignant hyperthermia pigs were uncoupled at 40 degrees C by exogenous Ca2+ at 1221 +/- 301 (n = 9) nmol Ca2+ per mg proteinn during succinate oxidation and the uncoupled mitochondria showed large amplitude swelling. Both the Ca2+ -induced uncoupling and swelling were prevented by bovine serum albumin and by the phospholipase inhibitors, spermine and tetracaine. In contrast, mitochondria of normal pigs were still tightly coupled even after a total addition of 2313 +/- 287 (n = 5) nmol Ca2+ per mg protein and retained the original condensed configuration in the presence or absence of spermine and tetracaine. Mitochondria of malignant hyperthermia pigs contained significantly (P less than 0.001) higher quantities of endogenous Ca2+ and showed a significantly (P less than 0.001) faster FCCP-induced endogenous Ca2+ efflux rate than normal when monitored spectroscopically with murexide. No significant difference was observed in either the rate of exogenous Ca2+ uptake or in the extent of Ca2+ accumulated in the aerobic steady state during succinate oxidation between the two types of pigs. The rate of mitochondrial Ca2+ efflux of malignant hyperthermia pigs during anaerobiosis was about twice that of normal. Experimental evidence suggests that mitochondria from musculi longissimus dorsi of malignant hyperthermia pigs contained a Ca2+ -stimulated phospholipase A2 (EC 3.1.1.4, phosphatide 2-acylhydrolase), and that this enzyme if present in mitochondria of normal pigs is either latent or in very low concentration. The significance of the Ca2+ -stimulated phospholipase A2 and its association with the enhanced rate of glycolysis in porcine malignant hyperthermia syndrome and in the post-mortem formation of the pale, soft and exudative conditions observed in white skeletal muscles of malignant hyperthermia pigs is discussed.
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PMID:Mitochondrial calcium transport and calcium-activated phospholipase in porcine malignant hyperthermia. 747 May

The missing link in our understanding of excitation-contraction coupling (ECC) in skeletal muscle is the mechanism by which Ca2+ increases in the cytosol to trigger contraction. We discuss here a general background of intracellular Ca2+ handling, some characteristics of the major proteins involved in Ca2+ flow during ECC, and mechanisms currently believed to explain the increase in Ca2+ upon stimulation of muscle cells. These mechanisms include the calcium-induced calcium release, the direct coupled mechanism in which a plasma membrane and sarcoplasmic reticulum membrane protein interact, and mechanisms involving Ca2+ secretagogues that are known to elicit increases in calcium in other cells, inositol trisphosphate, and cyclic ADP ribose. We also consider possible roles for proteins associated with the principal calcium release channel of the sarcoplasmic reticulum, the ryanodine receptor. Finally, we discuss malignant hyperthermia, a disease associated directly with aberrant control of muscle cell calcium release.
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PMID:Control of calcium in skeletal muscle excitation-contraction coupling: implications for malignant hyperthermia. 978 3

Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Cyclic adenosine diphosphate-ribose (cADPR) is an endogenous metabolite of beta-NAD+ that induces Ca2+ release from intracellular stores in many tissues. Microinjection of cADPR (0.5 or 1 microM) increased the intracellular resting Ca2+ concentration ([Ca2+]i) in intact swine skeletal muscle in a dose-dependent manner. However, the increase in [Ca2+]i was greater in malignant-hyperthermia-susceptible (MHS) fibers than in non-susceptible (MHN) fibers. Incubation of muscle fibers in low external Ca2+ solution or in the presence of L-type Ca2+ channel entry blockers, or intracellular microinjection of heparin or ruthenium red did not modify the effect of cADPR on [Ca2+]i. Dantrolene (50 microM), a known inhibitor of intracellular Ca2+ release, decreased resting [Ca2+]i and prevented the cADPR-induced increase in [Ca2+]i. These results provide evidence: (1) for the existence of Ca2+ release mechanisms occurring via non-ryanodine or inositol 1,4,5-trisphosphate (InsP3) receptor mechanisms; (2) that MHS skeletal muscles exhibit a higher responsiveness to cADP-ribose-induced release of Ca2+ and (3) that the ability of dantrolene to block cADP-ribose-induced release of Ca2+ could be related to its pharmacologic effect on resting [Ca2+]i.
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PMID:Cyclic ADP-ribose induces a larger than normal calcium release in malignant hyperthermia-susceptible skeletal muscle fibers. 1089 24

Dantrolene, a drug used to treat malignant hyperthermia, inhibits abnormal Ca2+ release from the sarcoplasmic reticulum. Glutathione reductase (Glutathione: NADP+ oxidoreductase, EC 1.8.1.7), a member of the pyridine-nucleotide disulfide oxidoreductase family of flavoenzymes, catalyzes the reduction of glutathione disulfide (GSSG) to reduced form (GSH) in the presence of nicotinamide adenine dinucleotide phosphate (NADPH). In the present study, the in vitro effects of dantrolene on human erythrocyte glutathione reductase were investigated. For this purpose, initially, human erythrocyte glutathione reductase was purified 2555.56 fold in a yield of 29.74% using both 2',5'-ADP Sepharose-4B affinity gel chromatography and Sephadex G-200 gel filtration chromatography. The purity of the enzyme was controlled by sodium dodecyle sulfate (SDS)-polyacrylamide gel electrophoresis (SDS-PAGE) which showed a single band. A constant temperature (+4 degrees C) was maintained during the purification process. Enzyme activity was determined with the Beutler method at 340 nm by means of a spectrophotometer. Dantrolene showed remarkable in vitro inhibitory effects on the enzyme. Ki constant and 50% inhibitory concentration (IC50) value for dantrolene were determined by Lineweaver-Burk graphs and plotting activity % vs. [I], respectively. Ki constant for dantrolene was found to be 0.1116+/-0.04 mM; IC50 value was 0.0523 mM. Dantrolene displayed non-competitive inhibition.
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PMID:Dantrolene inhibits human erythrocyte glutathione reductase. 1898 69


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