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 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

The differences observed among rat strains in both basal [Na+]i and the several cation transport systems seem to be due to the different genetic background as clearly shown in F2 populations or after bone marrow transplantation in MHS. The same may be true for humans. In spite of all the caution taken in interpreting the data, because of the great possibility of methodological errors, it is likely that the differences observed in many laboratories are due to uneven genetic or ethnic composition of the samples studied, as shown by Dagher and Canessa. One intriguing observation is that most reports of "low Na-K cotransport" values in hypertensive patients are from Mediterranean countries (Italy, France, and Spain), whereas most reports of "high," or "not low Na-K cotransport," or very high values of countertransport came from populations originating from North Europe (Denmark, USA, South African whites). We are not aware of any study on erythrocyte Na-K cotransport performed in Great Britain (the greatest source of American immigrants). Indeed the difference in cotransport values between North and South European hypertensives might be due to different environmental factors, but if this is so, the difference does not depend on the salt consumption or plasma lipids that are similar in our high and low Na-K cotransport hypertensives (Cusi D et al, submitted). The picture seems relatively less confusing for calcium. The most consistent alterations in different models of hypertension is a decreased Ca-pump in SHR, MHS, and DOCA rats, reduced calcium binding in SHR and MHS, and reduced microsomal ATP dependent calcium uptake in SHR and DOCA rats. [Ca++]i, which is increased in established hypertension in man and rats, is normal in young prehypertensive rats and humans, and returns to normal values after pharmacological treatment of hypertension. This pattern of changes suggests that genetic control of these transport systems is weaker, and probably much influenced by different environmental conditions. However, because of the pivotal role of calcium in vascular smooth muscle cell concentration, its intracellular increase may be the common pathway of the different forms of hypertension. What remains unclear is the relation, if any, between calcium and sodium. Blaustein tried to find a link between them, but his hypotheses have yet to be confirmed.
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PMID:Role of cellular sodium and calcium metabolism in the pathogenesis of essential hypertension. 329 35

In malignant hyperpyrexia susceptible (MHS) porcine skeletal muscle, a low concentration (100 mumol/l) of the calcium ion antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) inhibited KCl-induced contractures, but potentiated contractures induced by halothane, caffeine and succinylcholine. Higher concentrations of TMB-8 (333 mumol/l to 1 mmol/l) contracted MHS muscle, but had little effect on muscle tension in control preparations. Treatments which inhibit excitation-contraction coupling abolished TMB-8-induced hyper-reactivity in MHS muscle. TMB-8 (50 mumol/l and 1 mmol/l) did not alter 45Ca2+ levels in actively loaded microsomal preparations from MHS swine. These results suggest that in malignant hyperpyrexia the primary abnormality occurs proximal to the release of calcium from the sarcoplasmic reticulum, probably at the level of excitation-contraction coupling.
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PMID:The effect of the calcium ion antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate on malignant hyperpyrexia-susceptible porcine skeletal muscle. 664 Oct 19

In skeletal muscle, halothane affects the functions of several Ca2+-regulatory membrane proteins involved in the excitation-contraction-relaxation cycle. To investigate the mechanism by which this volatile anesthetic interferes with Ca2+-homeostasis, we studied potential changes in protein-protein interactions by halothane. Using comparative immunoblotting of microsomal muscle proteins separated on native and denaturing gels, we show here that halothane induces oligomerization of the terminal cisternae Ca2+-binding protein calsequestrin, the junctional ryanodine receptor Ca2+-release channel and the transverse-tubular alpha1-dihydropyridine receptor. This agrees with previous reports on the modulation of Ca2+-release activity by halothane since interactions between the voltage-sensing alpha1-dihydropyridine receptor, the ryanodine receptor and the luminal Ca2+-reservoir might result in a rapid release of Ca2+-ions. Furthermore, this study supports the idea that specific protein sites are involved in the action of inhalational anesthetics and that halothane might trigger abnormal Ca2+-homeostasis in malignant hyperthermia via oligomerization of the mutated ryanodine receptor.
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PMID:Complex formation of skeletal muscle Ca2+-regulatory membrane proteins by halothane. 998 27

Malignant hyperthermia (MH) susceptibility is conferred by inheriting one of >60 missense mutations within the highly regulated microsomal Ca(2+) channel known as ryanodine receptor type 1 (RyR1). Although MH susceptible patients lack overt clinical signs, a potentially lethal MH syndrome can be triggered by exposure to halogenated alkane anesthetics. This study compares how non-coplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95), a congener identified in environmental and human samples, alters the binding properties of [(3)H]ryanodine to RyR1 in vitro. Junctional sarcoplasmic reticulum (SR) was isolated from skeletal muscle dissected from wild type pigs ((Wt)RyR1) and pigs homozygous for MH mutation R615C ((MH)RyR1), a mutation also found in humans. Although the level of (Wt)RyR1 and (MH)RyR1 expression is the same, (MH)RyR1 shows heightened sensitivity to activation and altered regulation by physiological cations. We report here that (MH)RyR1 shows more pronounced activation by Ca(2+), and is less sensitive to channel inhibition by Ca(2+) and Mg(2+), compared to (Wt)RyR1. In a buffer containing 100nM free Ca(2+), conditions typically found in resting cells, PCB 95 (50-1000nM) enhances the activity of (MH)RyR1 whereas it has no detectable effect on (Wt)RyR1. PCB 95 (2microM) decreases channel inhibition by Mg(2+) to a greater extent in (MH)RyR1 (IC(50) increased nine-fold) compared to (Wt)RyR1 (IC(50) increased by 2.5-fold). PCB95 reduces inhibition by Ca(2+) two-fold more with (MH)RyR1 than (Wt)RyR1. Our data suggest that non-coplanar PCBs are more potent and efficacious toward (MH)RyR1 than (Wt)RyR1, and have more profound effects on its cation regulation. Considering the important roles of Ca(2+) and Mg(2+) in regulating Ca(2+) signals involving RyR channels, these data provide the first mechanistic evidence that a genetic mutation known to confer susceptibility to pharmacological agents also enhances sensitivity to an environmental contaminant.
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PMID:Ryanodine receptor type 1 (RyR1) possessing malignant hyperthermia mutation R615C exhibits heightened sensitivity to dysregulation by non-coplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95). 1702 49