The objective of this renewal application is to continue to investigate membrane mechanisms that underlie myotonia, a syndrome characterized by abnormal excitability leading to prolonged repetitive discharge of action potentials and abnormal contractions of skeletal muscle fibers. Electrophysiological and pharmacological methods will be used to study myotonic behavior of skeletal muscle fibers from myotonic goats and normal skeletal muscle of rats and frogs after induction of myotonia by chemical agents, ionic changes, or other treatments. Analysis will also be made of the action of drugs or of treatments such denervation which antagonize myotonia. Experiments will be made largely on biopsied muscle fiber bundles, single fibers or membrane vesicle preparations in vitro. The electrical measurements will include: membrane ionic currents and voltage dependent charge movement with a voltage clamp; membrane excitability and cable parameters with microelectrodes. The triple-vaseline-gap and the three-microelectrode voltage clamps will be used to monitor macroscopic ionic currents. Planar lipid bilayer and patch-clamp methods will be used to monitor single channel currents to answer questions concerning channel abnormalities. Extensive use will be made of the laboratory computer for analysis of these data and for testing of hypotheses through computer simulation of myotonic membrane behavior. Particular attention will be paid to the role of chloride conductance channels in the maintenance of normal excitability of skeletal muscle. The ultimate goals of this project are: 1) to increase our basic knowledge of the electrophysiological basis of myotonia to the level of membrane ionic channel function and 2) to provide rational bases for the control of myotonic syndromes in man.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Physiology Study Section (PHY)
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University of Cincinnati
Schools of Medicine
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Bryant, S H; Conte-Camerino, D (1991) Chloride channel regulation in the skeletal muscle of normal and myotonic goats. Pflugers Arch 417:605-10
Heiny, J A; Jong, D; Bryant, S H et al. (1990) Enantiomeric effects on excitation-contraction coupling in frog skeletal muscle by a chiral phenoxy carboxylic acid. Biophys J 57:147-52
Conte Camerino, D; Bryant, S H; Mambrini, M et al. (1990) The action of taurine on muscle fibers of normal and congenitally myotonic goats. Pharmacol Res 22 Suppl 1:93-4
Heiny, J A; Valle, J R; Bryant, S H (1990) Optical evidence for a chloride conductance in the T-system of frog skeletal muscle. Pflugers Arch 416:288-95
Conte Camerino, D; De Luca, A; Mambrini, M et al. (1989) The effects of taurine on pharmacologically induced myotonia. Muscle Nerve 12:898-904
Conte-Camerino, D; Mambrini, M; DeLuca, A et al. (1988) Enantiomers of clofibric acid analogs have opposite actions on rat skeletal muscle chloride channels. Pflugers Arch 413:105-7
Hitzemann, R; Kao, L; Hirschowitz, J et al. (1988) Lithium transport in human fibroblasts: relationship to RBC lithium transport and psychiatric diagnoses. Psychiatry Res 24:337-44
Conte-Camerino, D; Franconi, F; Mambrini, M et al. (1987) Effect of taurine on chloride conductance and excitability of rat skeletal muscle fibers. Adv Exp Med Biol 217:207-16
Guo, X T; Uehara, A; Ravindran, A et al. (1987) Kinetic basis for insensitivity to tetrodotoxin and saxitoxin in sodium channels of canine heart and denervated rat skeletal muscle. Biochemistry 26:7546-56
Walsh, K B; Bryant, S H; Schwartz, A (1987) Suppression of charge movement by calcium antagonists is not related to calcium channel block. Pflugers Arch 409:217-9

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