The pathophysiology of myotonia produced by aromatic carboxylic acids

Abstract

A series of nine related aromatic monocarboxylic acids (ACAs) previously shown to inhibit muscle membrane chloride conductance (GCl) selectively in the rat were studied for their ability to produce myotonia. All nine induced characteristic repetitive electrical activity and delayed relaxation in isolated muscle, although the concentrations required for this action varied widely. In each case, myotonia was observed at concentrations that correlated closely with previously determined half-maximal concentrations for inhibition of GCl. Intracellular recordings from muscle made myotonic with ACA revealed prolonged latencies at rheobase, multiple driven spikes, and self-sustaining repetitive activity similar to that previously reported in hereditary goat myotonia. Phase-plane diagrams of membrane action potentials recorded after exposure to the most effective of these compounds suggested little effect on the voltage-dependent sodium system. The changes seen could be duplicated by simple removal of chloride ion. The expression of repetitive electrical activity in the presence of low membrane GCl depends on ambient temperature and on the concentration of calcium ion. Increasing temperature and decreasing Ca++ predispose toward myotonic activity; converse conditions inhibit myotonia. Myotonia induced by ACA is inhibited by concentrations of diphenylhydantoin that are clinically effective in controlling hereditary myotonia in humans.