Abstract

Malignant Hyperthermia (MH) is an anesthetic reaction that occurs in certain individuals during surgery. In this syndrome certain anesthetic agents and depolarizing muscle relaxants trigger a rise in body temperature and muscle spasm (rigidity). The result can be fatal. The precise aetiology of this syndrome is unknown and the metabolic changes that occur during the acute response have not been described adequately. The systematic study of MH requires the use of a suitable animal model and for this a purebred strain of MH Pietrain pigs will be used. The biochemical experiments that are proposed in this project will test the hypothesis that calcium regulation is defective in MH muscle. It follows that sarcoplasmic ionized calcium concentration would be abnormally elevated during MH crisis. The project proposes to determine whether the regulation of calcium by the sarcolemma and T-tubule membranes is abnormal in MH muscle. Calcium regulation by these membranes will be determined using isolated sarcolemma and T-tubule vesicles derived from control and MH muscle. In addition, the biochemical changes that are responsible for some of the features of MH crisis will be defined. This will be determined using isolated muscle strips that can be prefused with different anaesthetics and Mh-triggering or blocking drugs. Possible modifications in the calcium permeability of non-muscle cell membranes will also be examined in these MH pigs using red blood cell membranes. These different approaches should provide a description of the molecular defect(s) responsible for the onset of MH crisis. An understanding of the nature of this disease will be of great assistance in the future identification, management of patients, and treatment of MH crisis. In addition the results should lead to the development of a reliable test for MH individuals that does not involve surgical intervention. Furthermore, the results should provide basic information regarding the regulation of calcium by both muscle and non-muscle membranes. This understanding will be important in the future elucidation of the mechanisms of many other muscle diseases in which calcium metabolism is abnormal.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031382-05
Application #
3279362
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1984-04-01
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Type
Schools of Veterinary Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Fruen, Bradley R; Balog, Edward M; Schafer, Janet et al. (2005) Direct detection of calmodulin tuning by ryanodine receptor channel targets using a Ca2+-sensitive acrylodan-labeled calmodulin. Biochemistry 44:278-84
Fruen, Bradley R; Black, D J; Bloomquist, Rachel A et al. (2003) Regulation of the RYR1 and RYR2 Ca2+ release channel isoforms by Ca2+-insensitive mutants of calmodulin. Biochemistry 42:2740-7
Balog, Edward M; Norton, Laura E; Bloomquist, Rachel A et al. (2003) Calmodulin oxidation and methionine to glutamine substitutions reveal methionine residues critical for functional interaction with ryanodine receptor-1. J Biol Chem 278:15615-21
Louis, C F; Balog, E M; Fruen, B R (2001) Malignant hyperthermia: an inherited disorder of skeletal muscle Ca+ regulation. Biosci Rep 21:155-68
Balog, E M; Fruen, B R; Shomer, N H et al. (2001) Divergent effects of the malignant hyperthermia-susceptible Arg(615)-->Cys mutation on the Ca(2+) and Mg(2+) dependence of the RyR1. Biophys J 81:2050-8
Zhao, F; Li, P; Chen, S R et al. (2001) Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity. J Biol Chem 276:13810-6
Balog, E M; Fruen, B R; Kane, P K et al. (2000) Mechanisms of P(i) regulation of the skeletal muscle SR Ca(2+) release channel. Am J Physiol Cell Physiol 278:C601-11
Palnitkar, S S; Mickelson, J R; Louis, C F et al. (1997) Pharmacological distinction between dantrolene and ryanodine binding sites: evidence from normal and malignant hyperthermia-susceptible porcine skeletal muscle. Biochem J 326 ( Pt 3):847-52
Fruen, B R; Mickelson, J R; Louis, C F (1997) Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors. J Biol Chem 272:26965-71
Fruen, B R; Kane, P K; Mickelson, J R et al. (1996) Chloride-dependent sarcoplasmic reticulum Ca2+ release correlates with increased Ca2+ activation of ryanodine receptors. Biophys J 71:2522-30

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