RESUMO
BACKGROUND: Mutations within the gene encoding the skeletal muscle calcium channel ryanodine receptor can result in malignant hyperthermia. Although it is important to characterize the functional effects of candidate mutations to establish a genetic test for diagnosis, ex vivo methods are limited because of the low incidence of the disorder and sample unavailability. More than 250 candidate mutations have been identified, but only a few mutations have been functionally characterized. METHODS: The human skeletal muscle ryanodine receptor complementary DNA was cloned with or without a disease-related variant. Wild-type and mutant calcium channel proteins were transiently expressed in human embryonic kidney-293 cells expressing the large T-antigen of simian virus 40, and functional analysis was carried out using calcium imaging with fura-2 AM. Six human malignant hyperthermia-related mutants such as R44C, R163C, R401C, R533C, R533H, and H4833Y were analyzed. Cells were stimulated with a specific ryanodine receptor agonist 4-chloro-m-cresol, and intracellular calcium mobility was analyzed to determine the functional aspects of mutant channels. RESULTS: Mutant proteins that contained a variant linked to malignant hyperthermia showed higher sensitivity to the agonist. Compared with the wild type (EC50=453.2 µM, n=18), all six mutants showed a lower EC50 (21.2-170.4 µM, n=12-23), indicating susceptibility against triggering agents. CONCLUSIONS: These six mutations cause functional abnormality of the calcium channel, leading to higher sensitivity to a specific agonist, and therefore could be considered potentially causative of malignant hyperthermia reactions.
Assuntos
Hipertermia Maligna/genética , Mutação/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Cálcio/metabolismo , DNA Complementar/genética , DNA Complementar/metabolismo , Imunofluorescência , Células HEK293 , Humanos , Hipertermia Maligna/fisiopatologia , Mutação/fisiologia , Neuroimagem , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologiaRESUMO
Hyperthermia is defined as an elevated body temperature due to failed thermoregulation. It can occur under physiological conditions such as intense exercise or due to pathology such as malignant hyperthermia and heat stroke. It has also been implicated as a cause for sudden infant death syndrome. High temperatures are also used in medical interventions - hyperthermic chemotherapy or radiofrequency ablation, for example, which have serious side effects. The effect of hyperthermia on the central nervous system has not been fully researched, but even less is known on the effects of hyperthermia on the peripheral autonomic nervous system. In this review we discuss how conditions such as malignant or therapeutic hyperthermia affect the central and peripheral components of the autonomic nervous system, smooth muscle, skeletal muscle and cardiac muscle. We conclude that there is sufficient evidence for the detrimental effect of hyperthermia on central nerves, and that these effects are long lasting, although the major mechanism for this remains unknown. Similarly, the direct damage of hyperthermia to the enteric nerves also seems to be long lasting. In contrast, the reduced contractility of cardiac muscle and gastrointestinal smooth muscle when exposed to hyperthermia is short-lived. The consensus is that inadequate calcium handling is the mechanism of heat damage to cardiac and skeletal muscle. There is no such consensus when dealing with smooth muscle. The mechanism of hyperthermic damage to autonomic end organs such as the gastrointestinal tract has yet to be elucidated and further research into both central and peripheral hyperthermia is necessary.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Febre/fisiopatologia , Sistema Nervoso Periférico/fisiopatologia , Antineoplásicos/uso terapêutico , Ablação por Cateter , Terapia Combinada , Trato Gastrointestinal/fisiologia , Humanos , Hipertermia Induzida , Hipertermia Maligna/fisiopatologia , Músculo Esquelético/fisiopatologia , Músculo Liso/fisiologia , Miocárdio , Fibras Simpáticas Pós-Ganglionares/fisiologiaRESUMO
BACKGROUND: Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different RYR1 variants are associated with quantitative differences in MH phenotype. METHODS: The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH. We then undertook the most extensive RYR1 genotype-phenotype correlation in MH to date using 504 individuals from 204 MH families and 23 RYR1 variants. We also determined the association between a clinical phenotype and both the laboratory phenotype and RYR1 genotype. RESULTS: We report a novel correlation between the degree of in vitro pharmacological muscle contracture responses and the onset time of the clinical MH response in index cases (P<0.05). There was also a significant correlation between baseline CK concentration and clinical onset time (P=0.039). The specific RYR1 variant was a significant determinant of the severity of each laboratory phenotype (P<0.0001). CONCLUSIONS: The MH phenotype differs significantly with different RYR1 variants. Variants leading to more severe MH phenotype are distributed throughout the gene and tend to lie at relatively conserved sites in the protein. Differences in phenotype severity between RYR1 variants may explain the variability in clinical penetrance of MH during anaesthesia and why some variants have been associated with exercise-induced rhabdomyolysis and heat stroke. They may also inform a mutation screening strategy in cases of idiopathic hyperCKaemia.
Assuntos
Hipertermia Maligna/genética , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Anestésicos Inalatórios/farmacologia , Cafeína/farmacologia , Creatina Quinase/sangue , Análise Mutacional de DNA/métodos , DNA Complementar/genética , Feminino , Predisposição Genética para Doença , Genótipo , Halotano/farmacologia , Humanos , Masculino , Hipertermia Maligna/enzimologia , Hipertermia Maligna/fisiopatologia , Contração Muscular/efeitos dos fármacos , Fenótipo , Inibidores de Fosfodiesterase/farmacologia , Técnicas de Cultura de TecidosRESUMO
Malignant hyperthermia (MH) is a metabolic myopathy with an abnormal release of calcium by the sarcoplasmic reticulum (SR), triggered by volatile anesthetics and succinylcholine. Similarly, caffeine enhances Ca(2+)release by the SR in vitro. In a prospective, randomized study, high-energy phosphates were studied by intramuscular 31-phosphorus magnetic resonance spectroscopy ((31)P-MRS) in 10 MH-susceptible (MHS) and 7 MH-nonsusceptible (MHN) subjects before and after injection of 0.5 ml caffeine (20 mM). Intramuscular energy balance, measured by the ratios of P(i)/PCr and P(i)/gamma-ATP, did not differ between MHS and MHN patients before and after intramuscular caffeine injection. However, within each group, P(i)/PCr and P(i)/gamma-ATP increased significantly only in the MHS group. Intramuscular caffeine injection seemed to impair the metabolic balance in MHS individuals. This may reflect a local calcium overload leading to consumption of high-energy phosphates and increase of inorganic phosphate. Intramuscular stimulation by caffeine and (31)P-MRS may provide a valuable tool to investigate MH-related metabolic disturbances.
Assuntos
Cafeína , Hipertermia Maligna/metabolismo , Doenças Metabólicas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Adulto , Fatores Etários , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Suscetibilidade a Doenças/diagnóstico por imagem , Suscetibilidade a Doenças/metabolismo , Suscetibilidade a Doenças/fisiopatologia , Feminino , Humanos , Injeções Intramusculares , Espectroscopia de Ressonância Magnética , Masculino , Hipertermia Maligna/diagnóstico por imagem , Hipertermia Maligna/fisiopatologia , Doenças Metabólicas/diagnóstico por imagem , Doenças Metabólicas/fisiopatologia , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Doenças Musculares/diagnóstico por imagem , Doenças Musculares/fisiopatologia , Fosfocreatina/metabolismo , Fósforo/metabolismo , Radioisótopos de Fósforo , Estudos Prospectivos , Cintilografia , Fatores SexuaisRESUMO
The objective of this research was to examine the impact of supplementation with creatine monohydrate (CMH) on the quality of various muscles from normal and heterozygous halothane carrier pigs. Twenty-nine crossbred pigs, 16 normal (NN) and 13 halothane carrier (Nn) genotypes, were supplemented with 0 or 25 g x pig(-1) x d(-1) of CMH for 5 d before slaughter. Supplemented pigs gained 2.26 kg more weight (P < 0.05) during 5 d of supplementation. There were trends (P < 0.10) toward higher objective marbling scores and lower cooking loss for supplemented pigs. The 45-min pH was 0.27 units higher (P < 0.05) for supplemented pigs in the semimembranosus; CMH supplementation did not influence (P > 0.05) drip loss or muscle composition. Supplementation with CMH also resulted in lower L* values in two ham muscles, semitendinosus (5.15 units) (P < 0.05) and semimembranosus (1.95 units) (P < 0.10) for Nn carcasses. Genotype had significant effects on most quality indicators, with Nn carcasses producing lower-quality lean as evidenced by less desirable subjective and objective color and higher drip losses. Genotype also affected the composition of several muscles, with the NN carcasses having more fat and less moisture.
Assuntos
Creatina/administração & dosagem , Hipertermia Maligna/veterinária , Carne/normas , Doenças dos Suínos/genética , Suínos/crescimento & desenvolvimento , Ração Animal , Animais , Temperatura Corporal , Culinária , Creatina/farmacologia , Suplementos Nutricionais , Feminino , Genótipo , Halotano/efeitos adversos , Heterozigoto , Concentração de Íons de Hidrogênio , Masculino , Hipertermia Maligna/genética , Hipertermia Maligna/fisiopatologia , Músculo Esquelético/química , Suínos/genética , Doenças dos Suínos/fisiopatologia , Aumento de Peso/efeitos dos fármacosRESUMO
Xenon has many characteristics of an ideal anaesthetic agent. It is not known whether xenon is a safe alternative to the potent inhalational anaesthetics in patients susceptible to malignant hyperthermia (MH). We investigated the effect of xenon, halothane and caffeine on muscle specimens of 31 individuals, referred to the MH Unit of the University of Ulm, and performed genetic epidemiology. Thirteen individuals were classified as MH susceptible and 18 as MH negative. Xenon 70% did not cause an increase in baseline tension of any MH-susceptible muscle specimen in contrast to halothane and caffeine. The evoked twitch response increased transiently in MH-susceptible and normal specimens indicating a mechanism independent of MH susceptibility. These results suggest that xenon, in concentrations up to 70% may be a safe anaesthetic for MH-susceptible patients.
Assuntos
Anestésicos Inalatórios/farmacologia , Hipertermia Maligna/fisiopatologia , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Xenônio/farmacologia , Cafeína/farmacologia , Técnicas de Cultura , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Predisposição Genética para Doença , Halotano/farmacologia , Humanos , Hipertermia Maligna/genética , Músculo Esquelético/fisiopatologia , Inibidores de Fosfodiesterase/farmacologiaRESUMO
Malignant hyperthermia (MH) has been reported as non-existent in children less than 1 yr old, although several unconfirmed reports have been published. A case report of MH in a 6-month-old child is presented, with confirmation of MH susceptibility by in vitro contracture testing of quadriceps muscle at 13 yr old. Genetic analysis revealed a novel RYR1 mutation that substitutes arginine 2452 for tryptophan in a region of the calcium channel mutated in several other MH pedigrees.
Assuntos
Predisposição Genética para Doença , Hipertermia Maligna/genética , Mutação , DNA Complementar/genética , Humanos , Lactente , Masculino , Hipertermia Maligna/fisiopatologia , Músculo Esquelético/fisiopatologia , Linhagem , Reação em Cadeia da PolimeraseAssuntos
Humanos , Masculino , Feminino , Pré-Escolar , Adolescente , Cuidados Pré-Operatórios , Pediatria , Estudo de Avaliação , Anestésicos/farmacologia , Consentimento Livre e Esclarecido , Infecções Respiratórias/complicações , Diagnóstico Clínico , Hipertermia Maligna/fisiopatologia , Hipertermia Maligna/complicações , Exame Físico , Prontuários Médicos/normas , Relações Médico-Paciente , Toxoide Tetânico , Psicoterapia de GrupoAssuntos
Humanos , Masculino , Feminino , Pré-Escolar , Adolescente , Anestésicos/farmacologia , Diagnóstico Clínico , Estudo de Avaliação , Consentimento Livre e Esclarecido , Hipertermia Maligna/complicações , Hipertermia Maligna/fisiopatologia , Pediatria , Exame Físico , Cuidados Pré-Operatórios , Infecções Respiratórias/complicações , Relações Médico-Paciente , Psicoterapia de Grupo , Prontuários Médicos/normas , Toxoide TetânicoRESUMO
Two primary hypotheses have been proposed to explain the pathophysiology of the neuroleptic malignant syndrome (NMS): 1) that NMS is produced by abrupt and extensive central dopamine receptor blockade by neuroleptics, particularly in nigrostriatal and hypothalamic pathways; and 2) that NMS, like malignant hyperthermia (MH), results from a preexisting defect in skeletal muscle metabolism that is unmasked or provoked by neuroleptic exposure. To evaluate these models, the authors review studies published since 1980 of the clinical features, epidemiology, risk factors, laboratory assessment, and relevant animal models of NMS and MH. Data from these studies suggest that although NMS and MH are clinically similar, they are pharmacologically distinct, implying that cross-reactivity between triggering agents is unlikely to occur.
Assuntos
Antipsicóticos/efeitos adversos , Hipertermia Maligna/fisiopatologia , Síndrome Maligna Neuroléptica/fisiopatologia , Animais , Antipsicóticos/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Hipertermia Maligna/diagnóstico , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Síndrome Maligna Neuroléptica/diagnóstico , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/fisiologia , Fatores de Risco , Substância Negra/efeitos dos fármacos , Substância Negra/fisiopatologiaRESUMO
We report a malignant hyperthermia-susceptible patient who required investigation for a large, symptomatic anterior mediastinal mass. Multiple attempts at tissue diagnosis under local anaesthesia were unsuccessful. Following awake fibreoptic tracheal intubation, general anaesthesia was administered using ketamine, midazolam, and nitrous oxide, maintaining spontaneous ventilation. Prophylactic dantrolene was not used, to avoid potential muscle weakness and respiratory compromise. Diagnostic mediastinotomy was performed without incident. We conclude that ketamine anaesthesia is appropriate for patients with anterior mediastinal masses, and is considered safe in malignant hyperthermia-susceptible patients.
Assuntos
Anestesia Intravenosa , Doença de Hodgkin/complicações , Ketamina , Hipertermia Maligna/complicações , Neoplasias do Mediastino/complicações , Adulto , Anestesia por Inalação , Anestesia Local , Feminino , Humanos , Intubação Intratraqueal , Lidocaína , Hipertermia Maligna/fisiopatologia , Midazolam , Óxido NitrosoRESUMO
The role of sarcolemma and sarcoplasmic reticulum in malignant hyperthermia was studied by the esr technique using the trapezius muscle membrane of both normal and genetically susceptible pigs. Normal and malignant hyperthermia membranes from sarcolemma as well as from sarcoplasmic reticulum did not show significant differences near the polar heads of the phospholipidic bilayer. In contrast, the fluidity and activation energy of normal membranes differed from those in malignant hyperthermia; in both sarcolemma and sarcoplasmic reticulum the mobility of the label was greater than the controls. The presence of halothane was examined, by inducing this disease anesthetically. The drug effect confirmed the above results, i.e. the disease affects mainly the hydrophobic core of the lipid bilayer of both sarcolemma and sarcoplasmic reticulum membranes.
Assuntos
Halotano/farmacologia , Hipertermia Maligna/fisiopatologia , Sarcolema/química , Retículo Sarcoplasmático/química , Suínos/fisiologia , Animais , Modelos Animais de Doenças , Espectroscopia de Ressonância de Spin Eletrônica , Temperatura Alta , Hipertermia Induzida , Fluidez de Membrana/fisiologia , Membranas/química , Modelos Químicos , Fosfolipídeos/química , Sarcolema/efeitos dos fármacos , Retículo Sarcoplasmático/efeitos dos fármacos , Propriedades de Superfície , Suínos/genéticaAssuntos
Anestesia , Temperatura Corporal/efeitos dos fármacos , Adulto , Idoso , Anestésicos/farmacologia , Regulação da Temperatura Corporal/efeitos dos fármacos , Humanos , Hipotálamo/fisiologia , Recém-Nascido , Hipertermia Maligna/fisiopatologia , Neurotransmissores/fisiologia , Salas Cirúrgicas , TermômetrosRESUMO
The caffeine contracture of normal human muscle, which has been used as a model for malignant hyperpyrexia, is greatly potentiated by halothane. Prior administration of procaine markedly reduces the halothane-potentiated caffeine contracture, and procaine given at the height of the contracture induces relaxation. Lignocaine, on the other hand, produces a variable response and sometimes increases the contracture.The muscle from a patient with an inherited susceptibility to malignant hyperpyrexia contracted spontaneously with halothane alone, and this contracture was reversed by procaine.These experiments support the therapeutic use of procaine in malignant hyperpyrexia.