Abstract
BackgroundMalignant hyperthermia (MH) is triggered by halogenated anaesthetics and depolarising muscle relaxants, leading to an uncontrolled hypermetabolic state of skeletal muscle. An uncontrolled sarcoplasmic Ca2+ release is mediated via the ryanodine receptor. A compensatory mechanism of increased sarcoplasmic Ca2+-ATPase activity was described in pigs and in transfected cell lines. We hypothesized that inhibition of Ca2+ reuptake via the sarcoplasmic Ca2+-ATPase (SERCA) enhances halothane- and caffeine-induced muscle contractures in MH susceptible more than in non-susceptible skeletal muscle.MethodsWith informed consent, surplus muscle bundles of 7 MHS (susceptible), 7 MHE (equivocal) and 16 MHN (non-susceptible) classified patients were mounted to an isometric force transducer, electrically stimulated, preloaded and equilibrated. Following 15 min incubation with cyclopiazonic acid (CPA) 25 μM, the European MH standard in-vitro-contracture test protocol with caffeine (0.5; 1; 1.5; 2; 3; 4 mM) and halothane (0.11; 0.22; 0.44; 0.66 mM) was performed. Data as median and quartiles; Friedman- and Wilcoxon-test for differences with and without CPA; p < 0.05.ResultsInitial length, weight, maximum twitch height, predrug resting tension and predrug twitch height of muscle bundles did not differ between groups. CPA increased halothane- and caffeine-induced contractures significantly. This increase was more pronounced in MHS and MHE than in MHN muscle bundles.ConclusionInhibition of the SERCA activity by CPA enhances halothane- and caffeine-induced contractures especially in MHS and MHE skeletal muscle and may help for the diagnostic assignment of MH susceptibility. The status of SERCA activity may play a significant but so far unknown role in the genesis of malignant hyperthermia.
Highlights
Malignant hyperthermia (MH) is triggered by halogenated anaesthetics and depolarising muscle relaxants, leading to an uncontrolled hypermetabolic state of skeletal muscle
9 female and 21 male, with a mean age of 28 (15 – 32) years and a mean weight of 74 (62 – 87) kg were studied. 7 patients were classified as MH susceptible (MHS), 7 as MHEh and 16 as more than in non-susceptible (MHN) according to the criteria of the European Malignant Hyperthermia group diagnostic protocol
Muscle bundles used for the invitro contracture test (IVCT) and cyclopiazonic acid (CPA)-IVCT did not differ regarding to length, weight, maximum twitch height, predrug resting tension and predrug twitch height (Table 1)
Summary
Malignant hyperthermia (MH) is triggered by halogenated anaesthetics and depolarising muscle relaxants, leading to an uncontrolled hypermetabolic state of skeletal muscle. Due to MH-associated mutations in the ryanodine receptor, triggering agents such as halogenated anaesthetics cause an excessive Ca2+ release from the SR resulting in intracellular hypermetabolism, increased mitochondrial energy-turnover and metabolic failure with a deficiency of adenosine-triphosphate [2]. This may lead to energetic exhaustion of the SERCA, the main transporter for Ca2+ ions across the sarcoplasmic membrane. The mycotoxin cyclopiazonic acid (CPA) is a selective inhibitor of SR Ca2+ reuptake [4] that has been used previously to study SERCA in different tissues [5,6]
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