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)

Although consideral information is available concerning the structural and biochemical changes in the skeletal muscles of patients with malignant hyperthermia, little is known of the cardiac changes in this disease. However, ventricular fibrillation and cardiac arrest are frequent in these patients. In 3 patients with malignant hyperthermia, contraction bands and foci of myofiberlysis were found in the heart at necropsy. Ultrastructurally, areas of myofiber overstretching adjacent to contraction bands and foci of extensive myofiberlysis were associated with disruptions of the sarcolemma. Similar ultrastructural findings have been reported in the skeletal muscles of these patients and are thought responsible for the hyperkalemia which is a constant feature of malignant hyperthermia. Our findings suggest that the ventricular arrhythmias, frequent in this disease, are the result of direct damage to cardiac muscle rather then secondary to elevated plasma levels of potassium.
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PMID:Myocardial changes in malignant hyperthermia. 33 38

A dramatic case of anaesthetic-induced malignant hyperpyrexia is described. The treatment (ice packs, treatment of acidosis, glucose-insulin, methylprednisolone, lidocaine, verapamil, muscular relaxation and oxygen breathing) was effective. In the discussion, the pharmacological effects on the cardiac muscle are considered predominantly.
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PMID:[A further case of malignant hyperpyrexia and its treatment with lidocaine, methylprednisolone and verapamil (iproveratril) (author's transl)]. 126 20

We have studied the question of the possible role of sarcoplasmic reticulum (SR) in the interaction of volatile anesthetics (such as halothane, enflurane and isoflurane) with muscle. We used two cardiac muscle models, i.e., isolated rat myocytes and Langendorff perfused rat hearts. We compared the results with those for skeletal muscle SR from rabbits, rats and pigs susceptible to malignant hyperthermia (MH). In both skeletal and cardiac muscle SR, volatile anesthetics enhanced the calcium release from the SR. In cardiac muscle, these agents are known to decrease contractility (negative inotropism). We found that caffeine, a well-known agent which releases calcium from the SR, also had a negative inotropic effect in cardiac muscle, raising the possibility of an unexpected link between the potentiation of calcium release and mechanism underlying the observed negative inotropism. Current understanding of anesthetic mechanisms does not include this possibility. We further found that both volatile anesthetics and caffeine decrease the content of calcium in the SR, suggesting that the increase of calcium permeability results in the decrease of calcium ions in the SR which are available for excitation-contraction (E-C) coupling. In MH-susceptible skeletal muscle, a similar increase in calcium permeability does not cause a decrease of contractility, but rather may contribute to a fatal syndrome of temperature increase provoked by abnormal contracture. This difference may be because in skeletal myoplasm calcium ions recycle internally, while in the cardiac muscle cell they are in dynamic equilibrium with extracellular calcium ions.
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PMID:Why does halothane relax cardiac muscle but contract malignant hyperthermic skeletal muscle? 176 5

The sarcoplasmic reticulum (SR) ryanodine receptor was studied in SR vesicles isolated from the vastus intermedius skeletal muscle and cardiac muscle of malignant hyperthermia-susceptible (MHS) and normal pigs. MHS and normal heavy SR preparations isolated from the vastus intermedius muscle had similar yields, polyacrylamide gel electrophoretic patterns, Ca2(+)-ATPase activities, mitochondrial enzyme activities, calsequestrin contents, and maximal [3H]ryanodine-binding activities. However, while half-maximal calcium concentrations (Ca0.5) for stimulation of MHS and normal vastus intermedius SR [3H]ryanodine binding were not significantly different, the Ca0.5 for inhibition of [3H]ryanodine binding to MHS vastus intermedius SR (76 +/- 17 microM) was significantly greater than to normal SR (16 +/- 9 microM). MHS vastus intermedius SR also exhibited a significantly lower Kd value (62 +/- 15 nM) for [3H]ryanodine binding compared with normal SR (Kd = 284 +/- 102 nM). These values for MHS and normal vastus intermedius SR are similar to those reported using SR isolated from a muscle composed of predominantly fast-twitch fibers, indicating the similarity of the ryanodine receptor in fast- and slow-twitch skeletal muscles. In contrast, there were no differences in the properties of the ryanodine receptor of porcine cardiac SR isolated from MHS and normal pigs. We therefore conclude that there is a defect in the SR ryanodine receptor of both slow- and fast-twitch skeletal muscle fiber types but not in cardiac muscle of MHS individuals.
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PMID:Ryanodine receptor in different malignant hyperthermia-susceptible porcine muscles. 182 8

Mechanisms and their pharmacology of Ca ion mobilization in skeletal, cardiac and smooth muscles are reviewed. In skeletal muscle, it is very likely that depolarization of T-tubule membrane causes conformational changes of dihydropyridine (DHP) receptors in the T-membrane, which in turn, most probably through some kind of protein-protein interaction, open the Ca2+ release channel in the sarcoplasmic reticulum (SR), the ryanodine receptor. Both the DHP receptor and ryanodine receptor have already been purified and sequenced, but the nature of the information transduction between these proteins still remains to be solved. Both of these proteins appear to have dual functions: the DHP receptor as a voltage sensor as described above and as a voltage-dependent Ca2+ channel and the ryanodine receptor as a physiological Ca2+ release channel and as a Ca2(+)-induced Ca2+ release (CICR) channel, an abnormality of which is known to cause malignant hyperthermia. In cardiac muscle, Ca2+ influx is essential not as the main Ca2+ source but to release Ca2+ from the SR, probably not through the CICR mechanism in the narrow sense but through a mechanism dependent on both Ca2+ and T-tubule depolarization. Several mechanisms of Ca2+ mobilization are used in smooth muscles and their features, different from those in striated muscles, are briefly reviewed.
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PMID:[Mechanisms and their pharmacology of mobilization of calcium ion in muscle cells]. 269 57

Malignant hyperthermia has been an iatrogenic syndrome which was usually fatal. The syndrome occurs when certain physiologically active compounds act on defective skeletal and cardiac muscle cells. The syndrome consists of a soaring fever, severe acidosis, tachycardia, tachypnea, and usually myoclonic spasms. Cardiac arrhythmias, shock, bleeding disorders, and death soon follow. Malignant hyperthermia has characteristically complicated the administrations of anesthesiologists, but is being triggered by drugs used in other diagnostic and therapeutic activities. This paper reports a fatal case which followed the infusion of iodinated contrast media. The increased release of epinephrine and the production of fibrin split products seen in an iodinated contrast media reaction suggest certain commonalities between it and a malignant hyperthermia reaction which may be triggered be epinephrine and is complicated by disseminated vascular clotting and bleeding disorders. The potential for successful treatment has greatly improved with the availability of dantrolene. Increased awareness of the syndrome, temperature monitoring, early diagnosis, and rapid treatment should make this malignant disorder less threatening.
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PMID:Malignant hyperthermia following intravenous iodinated contrast media. Report of a fatal case. 701 55

The key factor in malignant hyperthermia does not seem to be a defect in the calcium-storing membrane of the skeletal and cardiac muscle cells. The primary cause would appear to be deficiency of adenylate kinase.
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PMID:[New aspects in the clinical picture of malignant hyperthermia (author's transl)]. 745 84

The Arg615 to Cys615 mutation of the sarcoplasmic reticulum (SR) Ca2+ release channel of malignant hyperthermia susceptible (MHS) pigs results in a decreased sensitivity of the channel to inhibitory Ca2+ concentrations. To investigate whether this mutation also affects the ion selectivity filter of the channel, the monovalent cation conductances and ion permeability ratios of single Ca2+ release channels incorporated into planar lipid bilayers were compared. Monovalent cation conductances in symmetrical solutions were: Li+, 183 pS +/- 3 (n = 21); Na+, 474 pS +/- 6 (n = 29); K+, 771 pS +/- 7 (n = 29); Rb+, 502 pS +/- 10 (n = 22); and Cs+, 527 pS +/- 5 (n = 16). The single-channel conductances of MHS and normal Ca2+ release channel were not significantly different for any of the monovalent cations tested. Permeability ratios measured under biionic conditions had the permeability sequence Ca2+ >> Li+ > Na+ > K+ > or Rb+ > Cs+, with no significant difference noted between MHS and normal channels. This systematic examination of the conduction properties of the pig skeletal muscle Ca2+ release channel indicated a higher Ca2+ selectivity (PCa2+:Pk+ approximately 15.5) than the sixfold Ca2+ selectivity previously reported for rabbit skeletal (Smith et al., 1988) or sheep cardiac muscle (Tinker et al., 1992) Ca2+ release channels. These results also indicate that although Ca2+ regulation of Ca2+ release channel activity is altered, the Arg615 to Cys615 mutation of the porcine Ca2+ release channel does not affect the conductance or ion selectivity properties of the channel.
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PMID:Ion selectivity of porcine skeletal muscle Ca2+ release channels is unaffected by the Arg615 to Cys615 mutation. 794 78

The tissue distribution of mRNA for ryanodine receptor (ryr) isoforms in various porcine tissues has been determined using the reverse transcription-polymerase chain reaction (RT-PCR). First strand cDNA was synthesized from total tissue RNA with reverse transcriptase and random hexamer primers. PCR primers were selected to amplify an approximately 500-base pair segment from homologous regions near the 5' end of the skeletal (ryr1), cardiac (ryr2), or brain (ryr3) ryr cDNA sequences. The specific amplification of each of the ryr isoforms was confirmed by restriction enzyme mapping and DNA sequencing. A ryr1 RT-PCR product was identified in skeletal muscle and esophagus, a ryr2 RT-PCR product was identified in cardiac muscle, aorta and esophagus, and a ryr3 RT-PCR product was identified in skeletal and cardiac muscle, aorta, esophagus, adrenal gland, small intestine, and lung. All three ryr isoforms were identified throughout the brain, including the parietal, frontal, and temporal lobes of the cerebrum, thalamus/hypothalamus, cerebellum, and brain stem. The normal (Arg615) and mutant (Cys615) ryr1 alleles were expressed in the brains of normal and malignant hyperthermia susceptible pigs, respectively. These results thus demonstrate expression of two ryr isoforms in each type of striated muscle, and all ryr isoforms in a number of regions of the nervous system. The wide distribution of ryr1 in the brain provides a possible neurogenic etiology of malignant hyperthermia.
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PMID:Tissue distribution of ryanodine receptor isoforms and alleles determined by reverse transcription polymerase chain reaction. 798 22

Recent findings on the ryanodine receptor of vertebrates, a Ca-release channel protein for the caffeine- and ryanodine-sensitive Ca pools, are reviewed in this article. Three distinct genes, i.e., ryr1, ryr2, and ryr3, express different isoforms in specific locations: Ryr1 in skeletal muscle and Purkinje cells of cerebellum; Ryr2 in cardiac muscle and brain, especially cerebellum; Ryr3 in skeletal muscle of nonmammalian vertebrates, the corpus striatum, and limbic cortex of brain, smooth muscles, and the other cells in vertebrates. While only one isoform (Ryr1) is expressed in mammalian skeletal muscles, two isoforms (alpha- and beta-isoforms expressed by ryr1 and ryr3, respectively) are found in nonmammalian vertebrate skeletal muscles. Although the coexistence of two isoforms may merely be related to differentiation and specialization, the biological significance remains to be clarified. Ryanodine receptors in vertebrate skeletal muscles are believed to mediate two different modes of Ca release: Ca(2+)-induced Ca release and action potential-induced Ca release. All results obtained so far with any isoform of ryanodine receptor are related to Ca(2+)-induced Ca release and show very similar characteristics. Ca(2+)-induced Ca release, however, cannot be the underlying mechanism of Ca release on skeletal muscle activation. Susceptibility of the ryanodine receptor's ryanodine-binding activity to modification by physical factors, such as osmolality of the medium, might be related to action potential-induced Ca release. A hypothesis of molecular interaction in view of the plunger model of action potential-induced Ca release is discussed, suggesting that the model could be compatible with Ryr1 and Ryr3, but incompatible with Ryr2. The functional relevance of ryanodine receptor isoforms, especially Ryr3, in brain also remains to be clarified. Among ryr1 gene-related diseases, malignant hyperthermia was the first to be identified; however, there is still the possibility of involvement of the other genes. Central core disease has been added to the list recently. A molecular approach for the diagnosis and treatment of diseases is now in progress.
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PMID:Role of ryanodine receptors. 800 96


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