Muscle membrane chloride conductance and the myotonic syndromes

The myotonic syndrome of delayed relaxation in striated muscle associated with repetitive membrane electrical activity is characteristic of a number of hereditary disorders in animals and man. This state of pathologic membrane hyperexcitability is also seen as a consequence of intoxication with several classes of chemicals. In most of these states an increase in muscle membrane resistance due to a specific reduction in sarcolemmal GCl can be demonstrated. Computer simulations have indicated that such a reduction in GCl alone could account for the observed repetitive electrical activity. Controlled reduction of GCl in normal muscle, using aromatic monocarboxylic acids, produces a myotonic syndrome. This myotonia resembles that seen in hereditary disease in its contractile characteristics, its intracellular electrical behavior and its response to diphenylhydantoin and procainamide. The effects of variations in temperature and divalent cation concentration seen in this system parallel those predicted by computer models of myotonia based on the chloride hypothesis. Comparison of the behavior of this and similar model systems with the hereditary myotonias of man and goat allow conclusions to be drawn concerning the underlying pathophysiologic mechanisms at work in the hereditary disorders. The concept of an abnormally reduced GCl as the final common factor in many of these disorders emerges as the most tenable hypothesis, although the mechanism by which this conductance is altered may be unique in each case.