The objectives of this proposal are: 1) to study sodium channel inactivation in rat skeletal muscle, and 2) to investigate rat model of human muscle myotonic disorders in which membrane excitability may be impaired. Two hypotheses about sodium channel gating will be tested. First, that sodium currents are increased by treatments which produce myotonia in rat skeletal muscle. Second, that the increase in sodium current density is due to an alteration in voltage-dependent sodium channel inactivation. The techniques employed are: 1) the loose-patch voltage clamp will be used to measure sodium currents, and 2) the fiber type of single fibers will be determined by histochemical staining and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The experiments measure sodium currents in control and myotonic muscle using techniques developed in this laboratory that permit stable current recordings of cells for several hours. Myotonia in rat muscle will be produced by: 1) bathing a fiber in a chloride- deficient solution, 2) treating fibers with aromatic carboxylic acids to reduce chloride conductance, and 3) treating rats with 20, 25-diazacholesterol. The voltage dependence of sodium channel fast and slow inactivation will be studied to examine whether changes in sodium current density can be attributed to alterations in fast or slow inactivation. These projects will provide 1) new information on the excitability of mammalian skeletal muscle; and 2) possibly new information on the pathophysiology of different forms of myotonia.
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