Malignant hyperthermia (MH) is triggered by potent inhalation anesthetic agents and succinylcholine (SCh) and is diagnosed by the contracture response of biopsied skeletal muscle to halothane and/or caffeine. Masseter Muscle Rigidity (MMR) following SCh often precedes MH and is of higher incidence with halothane induction. The interaction of halothane with SCh will be examined in vitro on skeletal muscle from humans (control, MH susceptible, various neuromuscular disorders) and the rat diaphragm. Recent studies suggest that phospholipase A2 (PLA2) activity may be involved in MH. The role of PLA2 activity in contracture induction of muscle strips by halothane will be examined using PLA2 inhibitors and substrates and products of phospholipid metabolism. The phospholipids, neutral lipids and fatty acid release from preparations exhibiting contractures upon halothane and/or SCh challenge will be compared to those with no response to these agents. The effects on PLA2 activity of antagonists of the MH syndrome (dantrolene) and halothane- and/or SCh-induced contractures will be examined. Phospholipid distribution will be determined by lipid extraction, TLC separation and quantification of phosphorus. Cholesterol, free fatty acids and acylglycerols will be isolated by TLC. Fatty acids will be quantified by GC, and cholesterol and acylglycerides by colorimetric techniques. Fatty acid distribution will also be determined for individual phospholipids separated by TLC. Endogenous PLA2 activity will be studied using gas chromatographic analysis of free fatty acids. The long-term objectives of this study are to: 1) understand the relationship between MH and MMR, 2) develop a rat model for use in studies of MH and MMR, 3) examine mechanisms of the in vitro interaction of SCh and halothane and 4) clarify the role of lipid metabolism in abnormal responses to halothane and SCh, such as MH and MMR. Such information will be valuable for developing therapeutic agents, noninvasive diagnostic techniques for MH and screening anesthetic agents for use with MH susceptible. Since muscle will be obtained from some patients with neuromuscular disorders, these studies may aid in understanding the role of lipid metabolism in other forms of neuromuscular disease.
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