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.