Voltage-dependent action of tetrodotoxin in mammalian cardiac muscle

Abstract

TETRODOTOXIN (TTX) in many excitable membranes selectively blocks the transient change in sodium conductance which underlies the rising phase of the action potential. Electrophysiological and binding studies from nerve and skeletal muscle^1–5 indicate that a one-to-one binding reaction between toxin and Na channels with a dissociation constant of about 5 × 10⁻⁹ M can adequately describe the kinetic and steady-state actions of TTX on the Na conductance. Cardiac muscle is unusual in that it shows a marked insensitivity to TTX. A substantial reduction in the rate of rise of action potentials in ventricular trabeculae and Purkinje fibres does not occur until a TTX concentration of about 10⁻⁶ M is reached^6–8. We report here the results of a systematic study of the effects of TTX on mammalian cardiac muscle. The experiments were designed to determine whether the reported difference in sensitivity to TTX is an indication of basic differences in the TTX receptor of cardiac muscle as compared to nerve and skeletal muscle. Unlike any TTX effects reported in other tissues⁶, our results show a voltage dependence of TTX block. This suggests possible differences in the structure of the TTX binding site or of the Na channel itself.