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 in vitro contracture test determines the sensitivity of freshly obtained skeletal muscle specimens to caffeine or halothane applied to a bathing solution. Muscles from persons susceptible to malignant hyperthermia have lower contracture thresholds for these agents than do normal muscle. Thus, known concentrations of these agents must be accurately administered. We describe a system in which the bath concentrations of halothane (0 to 3%) are reproducible within 0.2% halothane from month to month. With use of this system, which includes an on-line gas analyzer, the measured halothane concentration within the bathing solution was independent of the performance of the vaporizer. The system is inexpensive and stable. The methods used to determine the bath concentrations of halothane and caffeine are reviewed. Finally, experimental equipment and a new recording system are described.
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PMID:In vitro contracture testing for determination of susceptibility to malignant hyperthermia: a methodologic update. 183 2

In vitro pharmacological responses of fresh biopsy specimens of human skeletal muscle were used as indicators of some intrinsic muscle properties. The measured parameters that were utilized for the current study were contractures induced in vitro by caffeine or by caffeine plus halothane. The opportunity to study such specimens arose from clinical testing for diagnosing the genetic predisposition to malignant hyperthermia, a potentially fatal complication of anaesthesia. The current analysis covers data from over 1,000 subjects, most of whom were clinical suspects and relatives of these. Responsiveness of the muscle specimens varied over two orders of magnitude. The frequency distribution curves suggest that the variation does not represent a continuum but that there are three or more clusters of functional variants. Muscle specimens from males were on average more responsive to caffeine than were those from females. Correlations within father-son and brother-brother pairs indicated complete heritability of responsiveness; this might have been expected but the surprise was a lack of correlation within mother-daughter pairs. There was an intermediate correlation in father-daughter pairs. The sex difference in heritability could be due to gender-related modifying genes or due to secondary modification of the muscle response in females by sex-related, perhaps hormonal factors. Among the effects of age appeared to be poor development in early childhood of the potentiation of the caffeine contracture by halothane.
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PMID:Pharmacogenetics of caffeine and caffeine-halothane contractures in biopsies of human skeletal muscle. 184 76

The effects of caffeine, halothane, succinylcholine, phenylephrine and isoproterenol on force of contraction were studied in electrically driven (0.2 Hz) trabeculae isolated from the right ventricles of the hearts of malignant hyperthermia susceptible (MHS) and healthy control (nMHS) swine. Caffeine (0.1-10 mmol/l) had positive inotropic effects, amounting to 275 +/- 35% of control in nMHS and 268 +/- 34% in MHS (n = 16). Halothane (0.25-4 vol%) decreased the force of contraction maximally to 52 +/- 4% in nMHS and 51 +/- 5% of control in MHS (n = 16). Propranolol did not change these effects. Succinylcholine (0.1-10000 mumol/l) had a small positive inotropic effect in both groups, which was blocked by propranolol. Phenylephrine (0.1-300 mumol/l) increased the force of contraction maximally to 188 +/- 24% of control in nMHS and to 193 +/- 23% in MHS (n = 16). The inotropic effect was blocked by prazosin but not by succinylcholine (1 mmol/l). Isoproterenol (0.01-10 mumol/l) had a positive inotropic effect of maximally 275 +/- 21% of control in nMHS and 396 +/- 31% in MHS (n = 17) (P less than 0.05). Succinylcholine potentiated this effect, and propranolol shifted the concentration-response curves to the right. We conclude that caffeine, halothane, succinylcholine and phenylephrine have similar inotropic effects in the hearts of nMHS and MHS, whereas isoproterenol has a significantly greater effect in MHS than in nMHS.
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PMID:Effects of caffeine, halothane, succinylcholine, phenylephrine and isoproterenol on myocardial force of contraction of malignant hyperthermia susceptible swine. 185 93

A 5-year-old boy with acute lymphatic leukemia in remission developed signs of malignant hyperthermia (MH) during general anesthesia for removal of a central venous access port. The anesthetic procedure for implantation of the port 17 months before had been uneventful despite use of the same triggering agents, halothane and succinylcholine. Meanwhile, the patient had received chemotherapy (COALL-03-85). The first sign of MH was masseter spasm following succinylcholine; then tachycardia, acidosis, myoglobinuria, and CPK elevation (8953 IU) appeared. There was only moderate temperature elevation to 37.8 degree C. Rapid improvement and complete recovery occurred after dantrolene i.v. The patient's father was found to have undiagnosed muscle pain and an elevated CPK level. An in vitro contracture test with halothane and caffeine revealed susceptibility to MH and supported the patient's diagnosis and genetic predisposition. Referring to several other cases in the literature concerning MH in patients with lymphomas and leukemias, a possible correlation between the two diseases is discussed. As the MH crisis in our patient was most probably genetic in origin, a common acquired cause such as a viral infection seems less probable. We do not believe the chemotherapy our patient received between the two anesthetics was the cause since about one-half of the patients in the literature had not had chemotherapeutic pretreatment at the time of the MH crisis. We believe that a common genetic predisposition is the most likely link between the two diseases. In any case, patients with leukemias and lymphomas should be monitored very carefully for symptoms of MH.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Malignant hyperthermia in a child with acute lymphatic leukemia]. 186 72

The binding properties of [3H]ryanodine, a specific ligand of the receptor complex that forms the Ca2+ release channel of sarcoplasmic reticulum, were studied in normal (N) and malignant hyperthermia-susceptible (MH) human skeletal muscle. Integrity of the solubilized ryanodine receptor was demonstrated by single-channel recordings in planar bilayers and by the changes produced by activators and inhibitors of the Ca2+ release channel on the binding properties of [3H]ryanodine. N and MH receptors were capable of binding [3H]ryanodine in a Ca(2+)-dependent manner. Scatchard analysis showed that a single binding site for [3H]ryanodine was present in either N or MH muscle. Binding affinity was approximately the same in N and MH (Kd approximately 7 nM), when the Ca2+ concentration was greater than 30 microM. At 0.3 microM Ca2+, MH receptors displayed a higher affinity for [3H]ryanodine (Kd = 4.1 +/- 1.0 nM) than N receptors (Kd = 7.1 +/- 0.8 nM). The presence of a single Kd for [3H]ryanodine in MH muscle, distinct from that of N muscle, indicated that MH muscle does not have detectable levels of N receptors. Ca2+ dependence of [3H]ryanodine binding further suggested that MH receptors had a higher affinity for Ca2+ (Kd[Ca2+] = 120 +/- 50 nM) than N receptors (Kd[Ca2+] = 250 +/- 80 nM). Caffeine increased [3H]ryanodine binding at submicromolar [Ca2+], and the effect was larger in MH. Apparent affinity constants for caffeine were 13 +/- 1.8 mM in N and 6 +/- 0.8 mM in MH receptors. Evidently, the ryanodine receptor of MH-susceptible human skeletal muscle has an unusually high sensitivity to Ca2+ which is augmented by caffeine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered binding site for Ca2+ in the ryanodine receptor of human malignant hyperthermia. 187 69

Different in vitro halothane testing procedures have been used in the European malignant hyperthermia (MH) Group Protocol (EMHGP) and the North American MH Group Protocol (NAMHGP), whereas the caffeine-testing protocols are very similar. The present study compares the two halothane-testing protocols in ten MH susceptible swine and in four control swine. Halothane contracture testing was conducted in vitro 12-52 days following the barnyard challenge that established the MH susceptibility of the swine. There was one false positive and one false negative halothane test by the EMHGP. The MH-equivocal category in the EMHGP, which is treated clinically as MH-susceptible, affords a margin of safety in such cases. In contrast, there were no false halothane tests by the NAMHGP. While some skeletal muscle strips from MH pigs were normal by both protocols (NAMHGP 30%; EMHGP 10%), the outcome of halothane testing by the NAMHGP was unaffected. The response to halothane 3% is reduced if preceded by the EMHGP, suggesting that simply adding halothane 3% to the end of the EMHGP does not permit a direct quantitative comparison to the NAMHGP. However, the diagnostic outcomes of the two approaches are similar.
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PMID:Comparison of North American and European malignant hyperthermia group halothane contracture testing protocols in swine. 189 41

The aim of the present study was to investigate whether the three different caffeine preparations--caffeine citrate, caffeine benzoate and the free base--used for in vitro diagnosis of malignant hyperthermia susceptibility--produced the same amount of contracture in rat diaphragm. At equimolar caffeine concentrations, the pure base generated more tension in the rat diaphragm muscle than caffeine benzoate or caffeine citrate. The citrate lowers the pH and the free Ca2+ concentration of the test bath and thus suppresses the caffeine contracture. The benzoate is believed to inhibit the caffeine contracture by its carbonyl group in a way similar to the effect of benzocaine.
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PMID:The caffeine contracture test for malignant hyperthermia: caffeine citrate, caffeine benzoate or caffeine free base? 189 51

Malignant hyperthermia (MH) is a potentially lethal condition in which sustained muscle contracture, with attendant hypercatabolic reactions and elevation in body temperature, are triggered by commonly used inhalational anaesthetics and skeletal muscle relaxants. In humans, the trait is usually inherited in an autosomal dominant fashion, but in halothane-sensitive pigs with a similar phenotype, inheritance of the disease is autosomal recessive or co-dominant. A simple and accurate non-invasive test for the gene is not available and predisposition to the disease is currently determined through a halothane- and/or caffeine-induced contracture test on a skeletal muscle biopsy. Because Ca2+ is the chief regulator of muscle contraction and metabolism, the primary defect in MH is believed to lie in Ca2+ regulation. Indeed, several studies indicate a defect in the Ca2+ release channel of the sarcoplasmic reticulum, making it a prime candidate for the altered gene product in predisposed individuals. We have recently cloned complementary DNA and genomic DNA encoding the human ryanodine receptor (the Ca2(+)-release channel of the sarcoplasmic reticulum) and mapped the ryanodine receptor gene (RYR) to region q13.1 of human chromosome 19 (ref. 14), in close proximity to genetic markers that have been shown to map near the MH susceptibility locus in humans and the halothane-sensitive gene in pigs. As a more definitive test of whether the RYR gene is a candidate gene for the human MH phenotype, we have carried out a linkage study with MH families to determine whether the MH phenotype segregates with chromosome 19q markers, including markers in the RYR gene. Co-segregation of MH with RYR markers, resulting in a lod score of 4.20 at a linkage distance of zero centimorgans, indicates that MH is likely to be caused by mutations in the RYR gene.
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PMID:Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. 196 23

Malignant hyperthermia (MH) is a potentially fatal, anesthetic-induced syndrome. Currently, the only accurate means of diagnosing susceptibility to this syndrome is the testing of biopsied skeletal muscle for its contracture response to halothane and caffeine. A less invasive means of diagnosis is needed. The authors previously reported that MH-susceptible patients studied by in vivo phosphorus nuclear magnetic resonance (31P NMR) spectroscopy demonstrated a higher resting inorganic phosphate (Pi) to phosphocreatine (PCr) ratio in their skeletal muscle, as well as a slower postexercise recovery of PCr/Pi, when compared to normal controls. In the present blinded study, the authors compared in vivo 31P NMR determination of resting Pi/PCr and recovery rate of PCr/Pi in forearm muscles to in vitro halothane/caffeine contracture test results in 42 patients. Forty-three control subjects were studied to establish normal NMR values of resting Pi/PCr and recovery rate of PCr/Pi. Their findings were compared with those of 27 patients shown to be MH-susceptible and 15 patients MH-negative by contracture testing. The MH-susceptible group had a significantly (P less than 0.005) higher resting Pi/PCr value (0.202 +/- 0.044) than either the MH-negative (0.152 +/- 0.043) or the control (0.141 +/- 0.026) group. The MH-susceptible group also had a significantly (P less than 0.02) slower postexercise recovery rate of PCr/Pi (1.50 +/- 0.872 PCr.Pi-1.min-1) than either the MH-negative (2.11 +/- 1.07 PCr.Pi-1.min-1) or control (2.25 +/- 0.828 PCr.Pi-1.min-1) group. Twenty-six of the 27 MH-susceptible patients demonstrated abnormal NMR test results (a resting Pi/PCr greater than or equal to 0.18 or recovery rate less than 1.0 PCr.Pi-1.min-1), and 13 of the 15 MH-negative patients had normal NMR results. Although neither NMR parameter alone was diagnostically reliable, an NMR test utilizing both parameters was quite accurate. The NMR test and contracture test demonstrated an overall agreement of 93% with a copositivity of 96% and conegativity of 87%. The sensitivity and specificity of the NMR test is estimated to be 98.8% +/- 11.8% and 95.3% +/- 20.3%, respectively. The role of 31P NMR in the diagnosis of MH susceptibility and possible mechanisms underlying the observations are discussed.
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PMID:A blinded comparison of noninvasive, in vivo phosphorus nuclear magnetic resonance spectroscopy and the in vitro halothane/caffeine contracture test in the evaluation of malignant hyperthermia susceptibility. 185 40

Platelets from normal and malignant hyperthermia (MH)-susceptible pigs were evaluated for differences in 45calcium uptake in the absence or presence of caffeine (2-16 mM), halothane (0.05-0.5%), or halothane and caffeine together. There were no statistically significant differences in basal or halothane-inhibited calcium uptake by platelets from either source. There was a small statistically significant difference in calcium uptake between platelets from normal and MH-susceptible pigs in the presence of 16 mM caffeine and 0.5% halothane. Calcium uptake by platelets from one pedigree of MH-susceptible pigs were stimulated in a concentration-dependent manner by caffeine. These data suggest that exposure of platelets to caffeine may have potential for identifying MH-susceptibility.
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PMID:Calcium handling by platelets from normal and malignant hyperthermia-susceptible pigs. 201 Oct 50


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