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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The currently favored theory of pathogenesis of malignant hyperthermia (MH) implicates an abnormality in skeletal muscle calcium ion transport. During a MH crisis a profound lactic acidosis occurs and in MH-sensitive individuals a delayed recovery of venous lactate has been previously noted postexercise. We have used 31P magnetic resonance spectroscopy to follow noninvasively in vivo changes in muscle of intracellular pH and high-energy phosphate metabolites during rest, exercise, and recovery of MH-sensitive subjects. Eleven biopsy-positive MH-sensitive patients have been studied and compared to 26 normal subjects. The MH-sensitive subjects as a group prematurely dropped their intracellular pH during mild aerobic exercise and they demonstrated a marked delay before the recovery of pH after maximal exercise. PCr/(PCr + Pi) ratios also dropped early during exercise but recovered normally. The observed changes in pH and PCr/(PCr + Pi) are consistent with a myopathy in MH-susceptible individuals.
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PMID:Metabolic response to exercise in malignant hyperthermia-sensitive patients measured by 31P magnetic resonance spectroscopy. 237 3

This investigation sought to determine if the Ca2+ antagonist, TMB-8, alters the contracture responses of malignant hyperthermia susceptible (MHS) skeletal muscle to halothane and to caffeine. Muscle fiber bundles were excised from both MHS and normal pigs and exposed to TMB-8 (100 microM), halothane (3%) and caffeine (0.5-8.0 mM), administered alone and in combination. TMB-8 depressed tension developed during isometric twitches in both MHS and normal muscle but had no effect on resting tension (RT). Halothane, however, increased RT in MHS but not in normal muscle. TMB-8 failed to reduce the halothane contracture of MHS muscle but hastened its onset. Caffeine concentrations of greater than or equal to 2 mM increased RT in MHS whereas only 8 mM evoked contracture of normal muscle. These effects were also unaltered by TMB-8. Results suggest that TMB-8 does not inhibit halothane nor caffeine contractures of MHS muscle.
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PMID:Effects of the calcium antagonist, TMB-8 on halothane and on caffeine contractures of malignant hyperthermia susceptible skeletal muscle. 238 62

We tested the hypothesis that lymphocytes from swine with susceptibility to malignant hyperthermia (MH) had calcium extrusion activity higher than unaffected swine. Cytoplasmic concentration of ionized calicum was determined by use of dual emission spectrofluorometry and measurement of the ratio of free to calcium-bound form of the fluorescent calcium dye indo-1. Net calcium accumulation and unidirectional calcium extrusion rate were dependent on intracellular calcium concentration. Calcium extrusion from calcium-loaded lymphocytes was monitored while calcium influx was inhibited by suspending the cells in calcium-free medium with a calcium chelator. Net calcium accumulation of untreated lymphocytes was monitored in calcium-replete medium. A novel method of calculation of ionized calcium was used. This method confirmed our previous findings of lower ionized calcium concentration (86 +/- 40 and 370 +/- 216 nmol/L; P less than 0.01) and slower rates of calcium accumulation 39 +/- 16 and 127 +/- 52 nmol/L/min) in untreated lymphocytes from MH-susceptible swine compared with controls. These changes were attributable to calcium extrusion activity two- to three-fold higher in lymphocytes of MH-susceptible swine (154 +/- 36 and 408 +/- 47 nmol/L/min at 175 nmol/L; 972 +/- 111 and 1,690 +/- 505 nmol/L/min at 425 nmol/L). These data were compatible with our model of higher calcium extrusion activity being a compensatory adaptation of MH-susceptible swine lymphocytes to their hypersensitivity to stimuli that increase cytoplasmic calcium concentration.
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PMID:Compensatory increase in calcium extrusion activity of untreated lymphocytes from swine susceptible to malignant hyperthermia. 238 80

Malignant hyperthermia (MH) can be triggered in swine either by stress or by certain anesthetic agents. In humans, MH commonly occurs in patients previously exposed uneventfully to triggering anesthetics. This variability in expressivity of the MH syndrome is a combination of unknown genetic and environmental factors. A hypothesis was tested that a fall in rectal temperature following general anesthesia can prevent the MH syndrome in susceptible patients. Nine littermate Pietrain pigs with MH were exposed to halothane after their rectal temperatures were stabilized at 35 degrees, 36 degrees, and 37 degrees C during thiopental/nitrous oxide anesthesia. The in vivo MH metabolic, cardiopulmonary, and contracture responses were attenuated at the lower rectal temperatures. The effect of varying temperatures on biopsies of skeletal muscle from these animals showed a marked decrease in contracture response to halothane when the muscle was cooled to 25 degrees C. Studies on the Ca2+ uptake process and on Ca2+ channel-Ca2+ release properties of isolated sarcoplasmic reticulum (SR) membranes showed that increasing incubation temperatures from 25 degrees to 38 degrees C increased the Ca2+ uptake rate by the SR Ca2+ pump and also increased the probability of Ca2(+)-induced Ca2+ opening of a Ca2+ channel and the release of stored Ca2+. This study indicates that temperature can have a marked effect on the expressivity of the MH defect at the whole animal, isolated tissue, and fragmented membrane levels of organization. Since many surgical patients' temperatures decrease after induction and anesthesia, this may explain one environmental factor that determines the incidence, rate, and magnitude of the MH syndrome.
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PMID:Porcine malignant hyperthermia: critical temperatures for in vivo and in vitro responses. 239 29

Dantrolene sodium is a drug used in the treatment of spasticity and malignant hyperthermia. It is known to have a myorelaxant effect related to inhibition of the "release" of calcium by the sarcoplasmic reticulum of striated skeletal muscle. A direct cardiac effect which has only recently been suspected was demonstrated in vitro on isolated preparations of sheep Purkinje fibres and ventricular myocardium. Dantrolene caused a spectacular lengthening of the duration of the action potential of Purkinje fibres. This could be due either to an action on the slow calcium current or to stimulation of an ingoing sodium current sensitive to tetrodotoxin (TTX). This effect on the cardiac action potentials could explain the antiarrhythmic properties of dantrolene sodium during attacks of malignant hyperthermia.
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PMID:[In vitro electrophysiological effects of sodium dantrolene on isolated preparations of Purkinje fibers and ventricular myocardium of sheep]. 242 77

The role of sarcoplasmic reticulum (SR) in malignant hyperthermia (MH) was studied using the heavy microsomal fraction prepared from semitendinosus muscles of both normal and genetically MH-susceptible pigs. In the presence of ATP, SR was loaded with 70 nmol Ca2+/mg SR protein. Under these conditions, MH-SR demonstrated Ca2+-induced Ca2+ release (Ca-ICaR) and halothane-induced Ca2+ release (halothane-ICaR; halothane concentrations as low as 10 microM). Normal SR did not demonstrate these release phenomena. Dantrolene inhibited the halothane-ICaR, but did not inhibit the Ca-ICaR. Ruthenium red and tetracaine inhibited both types of Ca2+ release. From the measurement of passive Ca2+ efflux, it was shown that dantrolene did not affect the Ca2+ permeability of the SR itself, but suppressed only the halothane-induced increment of the permeability. The membrane order parameter of the SR, as measured by the spin-probe EPR technique, indicated that halothane disordered the lipid bilayer of MH-SR to a greater extent than it did of normal SR. This halothane disordering effect on MH-SR was antagonized by dantrolene. Ruthenium red and tetracaine did not antagonize the halothane disordering effect. These results raise the possibility that halothane could disturb the structure of the lipoprotein complex in MH-SR in such a way that it could open the Ca2+-release channels. The Ca2+ thus released further opens the channel through the Ca-ICaR mechanism in a positive feedback fashion, thus triggering the MH syndrome. The efficacy of dantrolene in ameliorating the MH syndrome might be related to the inhibition of this halothane effect.
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PMID:Abnormal membrane properties of the sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia: modes of action of halothane, caffeine, dantrolene, and two other drugs. 242 70

Malignant Hyperthermia is a specific potentially fatal condition which occurs in susceptible individuals in response to various triggering mechanisms, of which anesthetic agents have been found to be the most common offenders. Leading symptoms are generalized muscular rigidity and hyperpyrexia. The etiology seems to be associated with some inherited disturbance in muscle metabolism related to calcium regulation. This syndrome is known for 25 years, the mechanism of triggering, the genetics and the treatment have been able to get examined by animal model as malignant hyperthermia syndrome may occur in swine as well. Pharmacological in-vitro studies on biopsy specimen of muscle fragments are presently one of the most accepted means for pre-anesthetic diagnosis, the hydantoin derivate dantrolene sodium is the only known specific drug in treatment and prophylaxis. Neuroleptic Malignant Syndrome which occurs in patients treated with neuroleptics shows almost identical symptoms. Although the pathogenesis is still unknown, most authors believe a neuroleptic-induced alteration of central neuroregulatory mechanisms is involved. Alternative etiologic mechanisms are suggested by the striking similarities noted between the Neuroleptic Malignant Syndrome and Malignant Hyperthermia. Both disorders might be based on common pathophysiologic mechanisms and might be induced in susceptible patients by a variety of pharmacologic agents. The authors present and compare the actual knowledge concerning symptoms, course and therapy of both syndromes on the basis of 126 case studies of the Neuroleptic Malignant Syndrome from literature.
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PMID:[Malignant neuroleptic syndrome and malignant hyperthermia--a comparison]. 242 64

Preparing skeletal sarcoplasmic reticulum from both normal and malignant hyperthermia susceptible pigs, the effects of various drugs on the passive calcium permeability of these sarcoplasmic reticulum preparations were studied. It was found that, in the absence of halothane, the permeability of heavy sarcoplasmic reticulum prepared from malignant hyperthermia susceptible pigs was much higher than that of normal pigs. It was observed that halothane, at concentrations above 10 microM (well below anesthetic concentrations, which are on the order of 1 mM), increased the permeability of sarcoplasmic reticulum. The Hill coefficient of the effect of halothane ranged from 1.96 to 2.25, suggesting that some kind of cooperativity was involved in this reaction. The effects of caffeine were similar to those of halothane. Inhibitors, such as tetracaine and ruthenium red inhibited both the calcium permeability and the halothane-induced increment. The Hill coefficient of the effect of tetracaine was 1.75. The mode of inhibition suggests that tetracaine directly binds with the calcium channel to inhibit the calcium efflux. On the contrary, dantrolene did not affect the calcium permeability of the sarcoplasmic reticulum. However, it inhibited the halothane-induced and caffeine-induced increments of the permeability. The Hill coefficient of inhibition by dantrolene ranged from 2.3 to 3.9, suggesting that several molecules of dantrolene may interact cooperatively with one calcium release channel to inhibit the effect of halothane. These results suggest that dantrolene has a unique inhibitory action, which may be related to its efficacy in ameliorating the syndrome of malignant hyperthermia.
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PMID:Effects of halothane, caffeine, dantrolene and tetracaine on the calcium permeability of skeletal sarcoplasmic reticulum of malignant hyperthermic pigs. 243 28

The concept of the cytosolic homeostasis of calcium is presented, and the mechanisms by which a very low cytosolic concentration of Ca is maintained are considered. The transient increase of intracellular Ca2+ when muscles fibres are stimulated illustrates the role of Ca as an intracellular messenger. The author presents his own kinetic analysis of the interaction of Ca with several intracellular targets and describes the Ca translocations which take place. Two examples of deficiency in the control of the intracellular Ca2+ are examined: malignant hyperthermia and Duchenne muscular dystrophy.
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PMID:[Control and kinetics of intracellular calcium movement in striated muscle]. 248 52

Transverse tubule (TT) membrane vesicles have been isolated from the skeletal muscle of normal and malignant hyperthermia-susceptible (MHS) pigs. MHS and normal TT did not differ in the distribution of the major proteins, cholesterol, or phospholipid content, (Na+ + K+)-ATPase activity, [3H]ouabain binding, Ca2+-ATPase activity, Mg2+-ATPase activity, or [3H]saxitoxin binding. Furthermore, in the presence of micromolar Ca2+, MHS and normal TT did not differ significantly in the KD values for either [3H]nitrendipine binding (2.7 +/- 0.6 and 3.3 +/- 0.5 nM, respectively) or (-)-[3H]desmethoxyverapamil ([3H]D888) binding (7.2 +/- 0.9 and 6.4 +/- 0.6 nM, respectively). However, in contrast to normal TT, MHS TT exhibited a significantly decreased Bmax for both [3H]nitrendipine binding (26.4 +/- 5.4 for MHS versus 40.6 +/- 3.7 pmol/mg protein for normal TT) and [3H]D888 binding (17.8 +/- 7.0 for MHS versus 37.4 +/- 5.9 pmol/mg protein for normal TT). At calcium concentrations greater than 0.1 mM, there was a greater inhibition of [3H]nitrendipine binding to normal than to MHS TT such that binding was now similar for both preparations. As with purified TT, [3H]nitrendipine binding to MHS muscle homogenates was significantly less than to normal muscle homogenates (109 +/- 20 versus 211 +/- 19 fmol/mg protein, for MHS and normal TT, respectively); this difference was not apparent when 100 mM CaCl2 was included in the binding medium. We conclude that the altered MHS TT dihydropyridine receptor properties may reflect an adaptation of the TT voltage sensing mechanism to the abnormal sarcoplasmic reticulum calcium release channel regulation in MHS muscle.
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PMID:Altered transverse tubule dihydropyridine receptor binding in malignant hyperthermia. 253 21


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