Antimyotonic effects of tocainide enantiomers on skeletal muscle fibers ofcongenitally myotonic goats

Tocainide is effective in the symptomatic treatment of myotonic syndromes f or its ability to reduce the high Frequency discharges of action potentials typical of the disease, by blocking voltage-gated sodium channels. However , its use is restricted by serious side effects. In spite of its chiral str ucture, tocainide is clinically used as a racemic mixture. Since the optica l isomers may differ in their efficacy and toxicity, the present study was aimed at evaluating the antimyotonic activity of the pure R(-) and S(+) ena ntiomers of tocainide, on the abnormal membrane hyperexcitability of extern al intercostal muscle fibers of congenitally myotonic goats. The excitabili ty parameters were recorded in vitro by means of the standard two-microelec trode current-clamp technique before and after the addition of the compound s. The R(-) enantiomer of tocainide at concentrations as low as 10 mu M pot ently counteracted the abnormal excitability of myotonic fibers, by increas ing the threshold current, and decreasing the latency of the action potenti al and firing capability. Also, this concentration of R-(-) tocainide almos t completely abolished the abnormal spontaneous electrical activity occurri ng in about 70-80% of the myotonic fiber. The S(+) enantiomer was remarkabl y Less potent since up to 100 mu M did not restore the normal excitability pattern. The results show that most of the antimyotonic activity of tocaini de resides in the R(-) enantiomer suggesting that its clinical use may allo w a significant reduction of the doses and possibly of the side effects. (C ) 2000 Elsevier Science B.V. All rights reserved.