STEREOSELECTIVE EFFECTS OF MEXILETINE ENANTIOMERS ON SODIUM CURRENTS AND EXCITABILITY CHARACTERISTICS OF ADULT SKELETAL-MUSCLE FIBERS

The effects of the enantiomers of mexiletine were tested on sodium cur rents of frog skeletal muscle fibers recorded by means of the three va seline gap voltage clamp method and compared with the effects produced by tocainide enantiomers. The R-(-) mexiletine produced a tonic block of the sodium current, elicited by single depolarizing test pulses fr om the holding potential of - 100 mV to - 20 mV, with an IC50 of 43.9 +/- 1 mu M, whereas the corresponding S-(+) enantiomer produced the sa me effects at about twofold higher concentrations. A similar stereosel ectivity was observed with tocainide enantiomers, but at about 5 fold higher concentrations. Both the R-(-) and S-(+) enantiomers of mexilet ine and tocainide produced a further use-dependent block of sodium cur rents when the test pulse was applied repetitively at a frequency of 2 Hz. The use dependent behaviour led to a significant lowering of the IC50 values with respect to the tonic block but the eudismic ratios ([ IC50S-(+)]/[IC(50)R(-)]) and the relative potency between mexiletine a nd tocainide were maintained. All the tested compounds produced a left shift of the steady state inactivation curves (h(infinity)), suggesti ng a high-affinity interaction with the inactivated sodium channels. A gain a stronger potency of R-(-) vs. S-(+) enantiomers and of mexileti ne vs. tocainide was observed. The excitability characteristics record ed from the semitendinosus muscle by the two microelectrode technique were modified by the tested drugs in agreement with their ability to b lock sodium current. Thus a concentration-related increase in the thre shold current required to elicit an action potential was observed alon g with a decrease in the amplitude and a shortening of the latency of action potential and a decrease in the firing capability of the membra ne. Again the R-(-) isomers were more potent than the S-(+) ones and m exiletine was more effective than tocainide. These data corroborate th e presence of a stereospecific site for these drugs on adult skeletal muscle sodium channels. The constant eudismic ratios between the enant iomers during both tonic and use-dependent block suggest that the incr ease in the apparent affinity of the receptor during state-dependent c onformational changes of the channel does not enhance its stereospecif icity. The decrease in effective concentration upon high frequency sti mulation supports the potential usefulness of low doses of R-(-) mexil etine in the treatment of the abnormal hyperexcitability of the myoton ic muscles, with a likely reduction of unwanted side effects.