In vitro muscle contracture investigations on the malignant hyperthermia like episodes in myotonia congenita

2013 ◽  
Vol 57 (8) ◽  
pp. 1017-1023 ◽  
Author(s):  
K. HOPPE ◽  
F. LEHMANN-HORN ◽  
S. CHAIKLIENG ◽  
K. JURKAT-ROTT ◽  
O. ADOLPH ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Myotonia Congenita ◽  
Muscle Contracture

Chlorocresol, an Additive to Commercial Succinylcholine, Induces Contracture of Human Malignant Hyperthermia-susceptible Muscles Via Activation of the Ryanodine Receptor Calcium sup 2+ Channel

1996 ◽  
Vol 84 (6) ◽  
pp. 1380-1385 ◽  
Author(s):  
Vincenzo Tegazzin ◽  
Erica Scutari ◽  
Susan Treves ◽  
Francesco Zorzato
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Muscle Relaxants ◽  
Commercial Preparation ◽  
Muscle Contracture ◽  
Malignant Hyperthermia Susceptible ◽  
Underlying Causes ◽  
Muscle Biopsies ◽  
Terminal Cisternae

Background A defect in the ryanodine (Ry1) receptor Ca2+ channel has been implicated as one of the possible underlying causes of malignant hyperthermia (MH), a pharmacogenetic disorder characterized by sustained muscle contracture. The disease is triggered by common halogenated anesthetics and skeletal muscle relaxants, such as succinylcholine. This study tested whether the functional properties of the Ry1 receptor Ca2+ channel are affected by chlorocresol, a preservative added to a commercial preparation of succinylcholine (Midarine) and other parenteral compounds. Methods In vitro contracture testing was carried out on muscle biopsies from malignant hyperthermia-susceptible (MHS) and -negative (MHN) individual according to the protocol of the European MH group. Ca2+ flux studies on isolated rabbit sarcoplasmic reticulum fractions were measured spectrophotometrically by following the A710-790 of the Ca2+ indicator antipyrylazo III. Results Chlorocresol causes muscle contracture in MHS muscles at a concentration of 25-50 microM and potentiates the caffeine contracture response in human MHS muscles. Sub-threshold (20 microM) concentrations of chlorocresol increase both the Kd and the Vmax of caffeine-induced Ca2+ release from isolated rabbit terminal cisternae. Conclusions These data suggest that, in muscle from MHS individuals, the enhanced Ca2+ released from the sarcoplasmic reticulum may not be due to the effect of succinylcholine alone but rather to the action of the preservative chlorocresol added to the drug.

An in-Vitro Model of Malignant Hyperthermia

1979 ◽  
Vol 23 (1) ◽  
pp. 31
Author(s):  
S. B. REED ◽  
G. E. STROBEL
Keyword(s):  
Malignant Hyperthermia ◽  
In Vitro Model ◽  
Vitro Model

4-Chloro-m-cresol Triggers Malignant Hyperthermia in Susceptible Swine at Doses Greatly Exceeding Those Found in Drug Preparations

1999 ◽  
Vol 90 (6) ◽  
pp. 1723-1732. ◽  
Author(s):  
Paul A. Iaizzo ◽  
Brooks A. Johnson ◽  
Kaoru Nagao ◽  
William J. Gallagher
Keyword(s):  
Malignant Hyperthermia ◽  
Blood Chemistry ◽  
Response Curves ◽  
End Tidal ◽  
In Vivo Effects ◽  
Higher Doses ◽  
End Tidal Co2 ◽  
Cardiovascular Reactions

Background Chlorocresols are used as preservatives in numerous commercial drugs that have been shown to induce myoplasmic Ca2+ release; the most potent isoform is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and (2) contrast in vivo versus in vitro dose-response curves. Methods Susceptible swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations in physiological responses, including end-tidal CO2, heart rate, blood pressure, blood chemistry, and temperatures. In the first animals studied, 4-chloro-m-cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and 9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95, 17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100 micromol). For comparison, in vitro rectus abdominis muscle preparations obtained from normal and susceptible swine were exposed to 4-chloro-m-cresol, at cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600 micromol; standard caffeine and halothane contracture testing was also performed. Results Episodes of malignant hyperthermia were not triggered in response to administration of low doses of 4-chloro-m-cresol, but transient cardiovascular reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed. Subsequently, episodes in these animals were triggered when halothane (0.87; 1 MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia that were fatal, when equivalent cumulative concentrations were greater than 1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased: e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m-cresol administration at concentrations > 200 micromol. In vitro, muscle from susceptible animals elicited contractures > 200 mg at 50-micromol bath concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not elicit such contractures until bath concentrations were > 800 micromol (n = 10). Conclusions 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine, but only when serum concentrations are far above those likely to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol, 50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has minimal effects due to the rapid decrease in its plasma levels.

Malignant Hyperthermia in a Child with Duchenne Muscular Dystrophy

PEDIATRICS ◽  
1983 ◽  
Vol 71 (1) ◽  
pp. 118-119
Author(s):  
HOWARD M. KELFER ◽  
WILLIAM D. SINGER ◽  
ROBERT N. REYNOLDS
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Side Effects ◽  
Muscular Dystrophy ◽  
Malignant Hyperthermia ◽  
Muscle Biopsy ◽  
Biopsy Specimen ◽  
Laboratory Findings ◽  
Anesthetic Agents ◽  
In Vitro Response

Patients with Duchenne muscular dystrophy (DMD) are susceptible to numerous adverse intraoperative and postoperative side effects of anesthetic agents. These include: hyperthermia and hyperkalemia,1,2 systemic acidosis,3 cardiac abnormalities (tachycardia, arrhythmia, arrest),2-5 rhabdomyolysis,2-6 as well as death.2,5 These clinical and laboratory findings are similar to those associated with malignant hyperthermia (MH).7,8 Until this time no one has confirmed the association of MH, as reflected by these clinical phenomena, in a patient with DMD. We present a patient who manifested many features of MH immediately following confirmatory muscle biopsy for DMD under general anesthesia. In vitro response to testing of a muscle biopsy specimen was consistent with a diagnosis of malignant hyperthermia.

In Vitro Diagnosis of Malignant Hyperthermia Susceptibility with Ryanodine-Induced Contractures in Human Skeletal Muscles

1996 ◽  
Vol 82 (6) ◽  
pp. 1230-1236 ◽  
Author(s):  
Frank Wappler ◽  
Norbert Roewer ◽  
Andreas Kochling ◽  
Jens Scholz ◽  
Markus Steinfath ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Skeletal Muscles ◽  
Malignant Hyperthermia Susceptibility ◽  
Human Skeletal Muscles ◽  
In Vitro Diagnosis

scholarly journals Impact of statin intake on malignant hyperthermia: an in vitro and in vivo swine study

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Asensio Gonzalez ◽  
Tinen L. Iles ◽  
Paul A. Iaizzo ◽  
Oliver Bandschapp
Keyword(s):  
Malignant Hyperthermia ◽  
Clinical Presentation ◽  
Sevoflurane Anesthesia ◽  
Short Term ◽  
Simvastatin Treatment ◽  
Simvastatin Therapy ◽  
Diagnostic Sensitivity And Specificity ◽  
Masseter Spasm

Abstract Background Statin intake is associated with muscular side effects, among which the unmasking of latent myopathies and of malignant hyperthermia (MH) susceptibility have been reported. These findings, together with experimental data in small animals, prompt speculation that statin therapy may compromise the performance of skeletal muscle during diagnostic in vitro contracture tests (IVCT). In addition, statins might reduce triggering thresholds in susceptible individuals (MHS), or exacerbate MH progression. We sought to obtain empirical data to address these questions. Methods We compared the responses of 3 different muscles from untreated or simvastatin treated MHS and non-susceptible (MHN) pigs. MHS animals were also invasively monitored for signs of impending MH during sevoflurane anesthesia. Results Muscles from statin treated MHS pigs responded with enhanced in vitro contractures to halothane, while responses to caffeine were unaltered by the treatment. Neither agent elicited contractures in muscles from statin treated MHN pigs. In vivo, end- tide pCO2, hemodynamic evolution, plasma pH, potassium and lactate concentrations consistently pointed to mild acceleration of MH development in statin-treated pigs, whereas masseter spasm and rigor faded compared to untreated MHS animals. Conclusions The diagnostic sensitivity and specificity of the IVCT remains unchanged by a short-term simvastatin treatment in MHS swine. Evidence of modest enhancement in cardiovascular and metabolic signs of MH, as well as masked pathognomonic muscle rigor observed under simvastatin therapy suggest a potentially misleading influence on the clinical presentation of MH. The findings deserve further study to include other statins and therapeutic regimes.

Caffeine stimulation of malignant hyperthermia-susceptible sarcoplasmic reticulum Ca2+ release channel

1994 ◽  
Vol 267 (5) ◽  
pp. C1253-C1261 ◽  
Author(s):  
N. H. Shomer ◽  
J. R. Mickelson ◽  
C. F. Louis
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Single Channel ◽  
Release Channel ◽  
Muscle Contracture ◽  
Malignant Hyperthermia Susceptible ◽  
Open Time ◽  
Pig Muscle ◽  
Channel Mutation ◽  
The Difference

The altered caffeine sensitivity of malignant hyperthermia-susceptible (MHS) muscle contracture is one basis of the diagnostic test for this syndrome. To determine whether the Arg615-to-Cys615 mutation of the porcine sarcoplasmic reticulum (SR) Ca2+ release channel is directly responsible for this altered caffeine sensitivity, the single-channel kinetics of purified MHS and normal pig Ca2+ release channels were examined. Initial studies demonstrated that decreasing the pH of the medium in either the cis- or trans-chamber decreased the Ca2+ release channel percent open time (Po). The half-inhibitory pH of MHS channels (6.86 +/- 0.04, n = 17) was significantly different from that of normal channels (7.08 +/- 0.07, n = 14). At pH 7.4, in either 7 or 0.12 microM Ca2+, MHS channel Po was not significantly different from that of normal channels over the range 0-10 mM caffeine. Although at pH 6.8 in 7 microM Ca2+ MHS channel Po was greater than that of normal channels over the range 0-20 mM caffeine, the difference could be eliminated by dividing each mean MHS Po by a scaling factor of 3.2. Thus the MHS Ca2+ release channel mutation does not appear to be directly responsible for the altered caffeine sensitivity of MHS pig muscle contracture. Rather, this altered caffeine sensitivity may result from an altered resting myoplasmic Ca2+ concentration or the altered pH and Ca2+ sensitivity of Ca2+ release channel Po of MHS muscle.

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