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 currents of frog skeletal muscle fibers recorded by means of the three vaseline 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 from the holding potential of -100 mV to -20 mV, with an IC50 of 43.9 +/- 1 microM, whereas the corresponding S-(+) enantiomer produced the same effects at about twofold higher concentrations. A similar steroselectivity was observed with tocainide enantiomers, but at about 5 fold higher concentrations. Both the R-(-) and S-(+) enantiomers of mexiletine and tocainide produced a further use-dependent block of sodium currents when the test pulse was applied repetitively at a frequency of 2 Hz. The use dependent behavior led to a significant lowering of the IC50 values with respect to the tonic block but the eudismic ratios ([IC50S-(+)]/[IC50R(-)]) and the relative potency between mexiletine and tocainide were maintained. All the tested compounds produced a left shift of the steady state inactivation curves (h infinity), suggesting a high-affinity interaction with the inactivated sodium channels. Again a stronger potency of R-(-) vs. S-(+) enantiomers and of mexiletine vs. tocainide was observed. The excitability characteristics recorded from the semitendinosus muscle by the two microelectrode technique were modified by the tested drugs in agreement with their ability to block sodium current. Thus a concentration-related increase in the threshold current required to elicit an action potential as observed along with a decrease in the amplitude and a shortening of the latency of action potential and a decrease in the firing capability of the membrane. Again the R-(-) isomers were more potent than the S-(+) ones and mexiletine was more effective than tocainide. These data corroborate the presence of a stereospecific site for these drugs on adult skeletal muscle sodium channels. The constant eudismic ratios between the enantiomers during both tonic and use-dependent block suggest that the increase in the apparent affinity of the receptor during state-dependent conformational changes of the channel does not enhance its stereospecificity. The decrease in effective concentration upon high frequency stimulation supports the potential usefulness of low doses of R-(-) mexiletine in the treatment of the abnormal hyperexcitability of the myotonic muscles, with a likely reduction of unwanted side effects.
De Luca
A
A
Unità di Farmacologia, Dipartimento Farmacobiologico, Bari, Italy.
Natuzzi
F
F
Lentini
G
G
Franchini
C
C
Tortorella
V
V
Conte Camerino
D
D
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008801:Mexiletine / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011893:Rana esculenta; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D016677:Tocainide / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D015222:Sodium Channels; D008801:Mexiletine; D016677:Tocainide