Neuromuscular dysfunction of burn injury, evidenced as skeletal muscle weakness, results in hypoventilation, difficulties in weaning off respirators, decreased mobilization and/or muscle contractures. Concomitant, prolonged use of muscle relaxants (to facilitate mechanical ventilation) and/or additional stress (usually associated with further increases in catecholamines) has been implicated in the aggravation of this neuromuscular dysfunction. Adequate nerve function to conduct nerve impulses acetylcholine receptor (AChR) function to depolarize the neuromuscular junction, and Na channel (NaC) function to propagate the action potentials generated at the neuromuscular junction, are all necessary for muscle contraction. The muscle weakness of burns can therefore, be related to the prejunctional (nerve), junctional (AChR) or postjunctional (NaC) factors. The proposed experiments will use molecular pharmacologic and molecular biologic approaches to: 1. Identify the site of the neuromuscular dysfunction (as presynaptic, synaptic or postsynaptic). 2. Define the qualitative and quantitative changes in AChRs and NaCs and their mRNA levels, and their relationship to neuromuscular function. 3. Test the hypothesis that prolonged administration of muscle relaxants induce qualitative and quantitative changes in AChRs and NaCs, and their function. 4. Characterize the specific role of catecholamines in the neuromuscular changes of burns. In burned rats, increased levels of transcripts (mRNA levels) encoding the gamma-subunit of the AChR (quantitated by subunit specific cDNA probes) will indicate a nerve-mediated (presynaptic) neuromuscular dysfunction. Increased levels of transcripts of other AChR subunit proteins (alpha1, beta1, epsilon, delta), with absence of gamma-subunit mRNA levels, will indicate a synaptic or postsynaptic phenomenon. 125I-alpha-bungarotoxin or 3H-saxitoxin binding and/or the use of specific antibodies will assess the qualitative (mature vs. immature) and quantitative changes in AChRs and NaCs. The neuromuscular changes in function and biochemistry (AChRs and NaCs) associated with prolonged exposure to muscle relaxants will be examined in vivo (in burned and unburned rats) and in vitro (TE671 cells). The specific of effects of catecholamines on neuromuscular function and biochemistry will be studied in burned and unburned rats after administration of specific adrenoceptor agonists and antagonists. Delineation of the site of the neuromuscular dysfunction, as well as the changes in AChRs and NaCs associated with burns, and characterization of the contributory role of muscle relaxants and catecholamines, will provide a scientific basis for choice of therapeutic maneuvers, and agents to prevent and/or rectify the neuromuscular changes in burns.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031569-14
Application #
2391922
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1983-12-01
Project End
1998-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
14
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Kaneki, Masao; Fukushima, Yuji; Shinozaki, Shohei et al. (2013) iNOS inhibitor, L-NIL, reverses burn-induced glycogen synthase kinase-3? activation in skeletal muscle of rats. Metabolism 62:341-6
Nagashima, Michio; Yasuhara, Shingo; Martyn, J A Jeevendra (2013) Train-of-four and tetanic fade are not always a prejunctional phenomenon as evaluated by toxins having highly specific pre- and postjunctional actions. Anesth Analg 116:994-1000
Frick, Christiane G; Fink, Heidrun; Blobner, Manfred et al. (2012) A single injection of botulinum toxin decreases the margin of safety of neurotransmission at local and distant sites. Anesth Analg 114:102-9
Sugita, Michiko; Sugita, Hiroki; Kim, Minhye et al. (2012) Inducible nitric oxide synthase deficiency ameliorates skeletal muscle insulin resistance but does not alter unexpected lower blood glucose levels after burn injury in C57BL/6 mice. Metabolism 61:127-36
Frick, Christiane G; Helming, Marc; Martyn, J A Jeevendra et al. (2010) Continuous administration of pyridostigmine improves immobilization-induced neuromuscular weakness. Crit Care Med 38:922-7
Martyn, J A J; Fagerlund, M Jonsson; Eriksson, L I (2009) Basic principles of neuromuscular transmission. Anaesthesia 64 Suppl 1:1-9
Han, Tae-Hyung; Greenblatt, David J; Martyn, J A Jeevendra (2009) Propofol clearance and volume of distribution are increased in patients with major burns. J Clin Pharmacol 49:768-72
Han, T-H; Martyn, J A J (2009) Onset and effectiveness of rocuronium for rapid onset of paralysis in patients with major burns: priming or large bolus. Br J Anaesth 102:55-60
Shear, Torin D; Martyn, J A Jeevendra (2009) Physiology and biology of neuromuscular transmission in health and disease. J Crit Care 24:5-10
Martyn, Jeevendra; Durieux, Marcel E (2006) Succinylcholine: new insights into mechanisms of action of an old drug. Anesthesiology 104:633-4

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