Inhibition of sarcoplasmic Ca²⁺-ATPase increases caffeine- and halothane-induced contractures in muscle bundles of malignant hyperthermia susceptible and healthy individuals

• Main Authors: Roewer Norbert, Hartung Edmund, Müller Rainer, Schuster Frank, Anetseder Martin
• Format: Article
• Language: English
• Published: BMC 2005-06-01
• Series: BMC Anesthesiology
• Online Access: http://www.biomedcentral.com/1471-2253/5/8

<p>Abstract</p> <p>Background</p> <p>Malignant 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.</p> <p>Methods</p> <p>With 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.</p> <p>Results</p> <p>Initial 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.</p> <p>Conclusion</p> <p>Inhibition 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.</p>