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

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Abstract
Activation of muscle β2-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 β2-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 β-adrenoceptor stimulation. Instead, clenbuterol structure and physicochemical characteristics as well asI Na blocking properties resembled those of local anesthetics, suggesting direct binding to the channels. Similar experiments with the chemically similar β-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 β-adrenoceptor-independent 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-dependentI Na block can inhibit abnormal runs of action potentials.

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