EVALUATION OF THE ANTIMYOTONIC ACTIVITY OF MEXILETINE AND SOME NEW ANALOGS ON SODIUM CURRENTS OF SINGLE MUSCLE-FIBERS AND ON THE ABNORMAL EXCITABILITY OF THE MYOTONIC ADR MOUSE

To search for use-dependent sodium channel blockers to selectively sol ve skeletal muscle hyperexcitability in hereditary myotonias, mexileti ne (MEX; compound I) and its newly synthetized analogs, 2-(4-chloro-2- methylphenoxy)-benzenethanamine (compound II) and (-)-S-3-(2,6-dimethy lphenoxy)-2-methylpropanamine (compound III), were tested on intercost al muscle fibers from the myotonic ADR mouse through use of the standa rd current-clamp microelectrode technique. in parallel, the effects of these compounds on the sodium channels were measured on frog muscle f ibers under voltage-clamp conditions. The tonic and use-dependent bloc ks of peak sodium currents (I-Namax) produced by each compound were ev aluated by using a single depolarizing pulse and a pulse train at 10 H z frequency, respectively. At 10 and 50 mu M, MEX decreased the occurr ence of spontaneous excitability in myotonic muscle fibers; 100 mu M w as required to decrease the amplitude of the action potential and the stimulus-induced firing of the membrane as well as to increase the thr eshold for generation of action potential. At 300 mu M, MEX decreased the latency of the action potential and increased the threshold curren t to elicit a single action potential. MEX produced a tonic block of I -Namax with an half-maximal concentration (IC50) of 83 mu M, but the I C50 value for use-dependent block was 3-fold lower. Compound III, whic h differs from MEX in that it has a longer alkyl chain, similarly bloc ked first the spontaneous and then the stimulus-evoked excitability of myotonic muscle fibers but at 2-fold lower concentrations than MEX. C ompound III was less potent than MEX in producing a tonic block of I-N amax (IC50 = 108 mu M) but was a strong use-dependent blocker with an IC50 close to 15 mu M. The more lipophylic compound II irreversibly bl ocked both spontaneous and stimulus-evoked membrane excitability at co ncentrations as low as 10 mu M and shortened the latency of the action potential in a concentration-dependent fashion. Compound II produced a potent tonic block of I-Namax (IC50 = 30 mu M), and its potency incr eased 2-fold during high-frequency stimulation. Both of the new analog s (compound II in particular), but not MEX, were less effective on the excitability parameters of striated fibers of healthy vs. ADR mice, a characteristic that increases their interest as potential antimyotoni c agents.