Different Ability of Clenbuterol and Salbutamol to Block Sodium Channels Predicts Their Therapeutic Use in Muscle Excitability Disorders

Abstract

Activation of muscle ␤ 2 -adrenergic receptors successfully counteracted sarcolemma inexcitability in patients suffering from hyperkalemic periodic paralysis (HPP), a hereditary disease caused by mutations in the gene encoding the skeletal muscle sodium channel. Looking for potential modulation of these channels by ␤ 2 -adrenergic pathway using patch-clamp technique, we found that clenbuterol blocked sodium currents (I Na ) in rat skeletal muscle fibers and in tsA201 cells transfected with the human channel isoform, whereas salbutamol did not. The effects of clenbuterol were independent of ␤-adrenoceptor stimulation. Instead, clenbuterol structure and physicochemical characteristics as well as I Na blocking properties resembled those of local anesthetics, suggesting direct binding to the channels. Similar experiments with the chemically similar ␤-antagonists propranolol and nadolol, suggested the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. Importantly, clenbuterol use-dependently inhibited action potential firing in rat skeletal muscle fibers, owing to ␤-adrenoceptorindependent I Na block. From a clinical point of view, our study defines the rationale for the safe use of salbutamol in HPP patients, whereas clenbuterol may be more indicated in patients suffering from myotonic syndromes, a condition characterized by sarcolemmal overexcitability, because use-dependent I Na block can inhibit abnormal runs of action potentials.

Skeletal muscle Na+ channel disorders

“…This therapeutic effect enhances sodium channel inactivation and shifts the voltage dependence of steady state inactivation in a hyperpolarizing direction and slows the recovery from inactivation. In most cases, Na v 1.4 mutations increased mexiletine sensitivity however, this was found to be dependent on the Na v 1.4 mutation as in some cases mexiletine sensitivity was reduced contributing to the heterogeneity of clinical symptoms observed with mexiletine treatment (Fan et al, 1996; Featherstone et al, 1998; Takahashi and Cannon, 2001; Desaphy et al, 2003). …”

Enhancement of hybrid-fiber types in rat soleus muscle after clenbuterol administration during hindlimb unloading

“…CB was chosen for its anabolic effects, which have been described in numerous studies (for review, see Kim and Sainz 1992). Salbutamol has been proposed for the treatment of human pathologies (Desaphy et al 2003), because the effects of short-term administration are so beneficial in case of short-term administration (Duncan et al 2000).…”

Molecular Dissection of Lubeluzole Use–Dependent Block of Voltage-Gated Sodium Channels Discloses New Therapeutic Potentials

“…The halfmaximum inhibitory concentrations (IC 50 ) were about 35 mM at 0.1 Hz and 1.8 mM at 10 Hz. Lubeluzole appears among the more efficient and use-dependent sodium channel blockers tested so far in these experimental conditions (Desaphy et al, 2003(Desaphy et al, , 2004(Desaphy et al, , 2009(Desaphy et al, , 2010. Since no stereoselective activity was discerned, the next experiments were performed using the racemic R,S-lubeluzole only.…”

“…Blocking of sodium channels by riluzole is likely involved in the clinical efficacy of the drug in amyotrophic lateral sclerosis (Benoit and Escande, 1991;Hebert et al, 1994;Song et al, 1997;Wang et al, 2008). Propranolol induces a use-dependent block of various sodium channel subtypes in a manner reminiscent of local anesthetics (Fischer, 2002;Desaphy et al, 2003;Wang et al, 2010). We thus decided to analyze in detail the effects of lubeluzole, its R isomer, a racemic mixture, the aforementioned isolated lubeluzole moieties, and riluzole on human voltage-gated sodium channels expressed in a mammalian cell line.…”