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.
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