Title

 

Authors

T. Costanza

Doctorate School in Biochemical and Pharmacological Sciences
Dept. ofPharmaco-Biology, Section of Pharmacology - University of Bari, Italy

 

Abstract

The non-dystrophic myotonias (NDM) are a group of skeletal muscle disorders, characterized by clinical/electrical myotonia, defined as the prolongation of skeletal muscle relaxation time following sudden voluntary contraction or external mechanical stimulation. In these diseases a genetic defect in muscle chloride or sodium channel function leads to hyperexcitability [1]. Myotonia has been treated by various Na⁺ channel blockers, the class IB antiarrhythmic mexiletine being considering by many as the first choice. However, not all the patients respond to mexiletine and some others suffer from limiting side effects. In a previous study, we showed that the β2-adrenergic agonist clenbuterol produces a potent and use-dependent block of sodium current both in rat muscle fibers and in tsA201 cells transfected with the human muscle sodium channel isoform, in a manner reminiscent to mexiletine. Similar effects were obtained with the β-antagonist propranolol, whereas salbutamol (β2-agonist) and nadolol (β-antagonist) were ineffective due to the presence of OH groups on their aromatic moiety [2].In this study we tested the antimyotonic activity of these compounds compared to mexiletine in vivo using a pharmacological rat model of myotonia. In this model, myotonia is induced by i.p. injection of anthracene-9-carboxylic acid (9AC) and assessed by measuring the time of righting reflex (TRR), which is the time the animal needs to come back on his four legs after being put on his back [3]. The TRR is <0.5 s in control rats but lasts 3-5 s after 9-AC administration. Myotonia is observed immediately 10 minutes after administration, reaches a peak after 30 min and gradually decreases. Per os administration of mexiletine, clenbuterol or propranolol, 10 minutes after 9AC induced a dose dependent inhibition of myotonia, whereas nadolol and salbutamol had no effect. The ED₅₀ (mg/kg) were 11.5 ± 0.8 for mexiletine, 19.4± 1.0 for propranolol, and 22.6 ± 0.8 for clenbuterol. The highest dose tested (40 mg/kg) was well tolerated for mexiletine and propranolol, whereas clenbuterol induced rat discomfort. The time dependence of mexiletine and propranolol effects was tested by administrating 40 mg/kg of the drugs at various time intervals before 9AC injection. Antimyotonic activity of both drugs lasted up to two hours and strongly decreased then after. Based on these data, we propose propranolol as an alternative to mexiletine in the treatment of myotonic syndromes, also in consideration of its well-characterized, favourable risk-benefit profile.
Supported by Telethon-Italy (grant GGP10101) and the “Association Française contre les Myopathies”.
 
1) Platt D. et al.(2009)-Curr Opin Neurol. 22(5):524-31.
2) Desaphy J.-F. et al.(2003)- Mol Pharmacol. 63(3):659-70.
3) De Luca A. et al. (2004)- Neuromuscul Disord. 14(7):405-16.