Résumé :
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The therapy of myotonia is based on the use of sodium channel blockers able to inhibit the high-frequency discharges of action potentials in skeletal muscle. Mexiletine (Mex) is widely considered as the first choice drug, but a number of myotonic patients did not take any benefits from Mex because of limited efficacy and/or side effects. Moreover, Mex was recently withdrawn from the market except in Japan, pushing the community toward the search of new drugs.In a previous study, we demonstrated that some drugs known as beta-adrenergic receptor ligands are able to block skeletal muscle sodium currents in a manner reminiscent to class I antiarrhythmic drugs such as Mex (Desaphy et al., Mol. Pharmacol. 2003). In particular, the beta-agonist clenbuterol and the beta-antagonist propranolol were very potent and use-dependent blockers of sodium channels, whereas salbutamol and nadolol had no effect on sodium currents due to the presence of hydroxyl groups on their aromatic moiety.In the present study, we developed an animal model of myotonia congenita to compare in vivo these compounds to mexiletine. Myotonia was induced in adult rats by i.p. injection of 9-anthracen-carboxylic acid (9-AC), which is a potent blocker of skeletal muscle chloride ClC-1 channels. Loss-of-function mutations of this channel are responsible for recessive and dominant myotonia congenita in humans, mice, goats, and dogs. In rats, myotonia was monitored by measuring the time of righting reflex (TRR), which is the time needed by the rat to turn back on his four legs after being put on his back. In control rats, the TRR is less than 0.5 s, whereas 30 minutes after 9-AC injection, the TRR lasted for 2-3 seconds. Mex, given per os 10 minutes after 9-AC injection, reduced the TRR in a dose-dependent manner (range 5-40 mg/kg). Both clenbuterol and propranolol exerted an antimyotonic action with efficacy comparable to Mex, although clenbuterol was less well tolerated at the highest dose of 40 mg/kg. In contrast, nadolol and salbutamol showed limited benefits on TRR, confirming the relationship between sodium channel blockade in vitro and antimyotonic activity in vivo. Additional experiments are ongoing to compare the duration of antimyotonic effect between Mex and propranolol. The results presented here suggest that propranolol, a widely used antiarrhythmic drug with limited side effects, may prove beneficial in myotonic patients.Supported by AFM (grant #15020).
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