Molecular Pharmacology, Vol 20, 533-542, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Pharmacological Properties of Sodium Channels in Cultured Rat Heart Cells

¹ Department of Pharmacology, University of Washington, Seattle, Washington 98195

The action of specific neurotoxins on sodium channels in cultured rat heart cells has been studied using ion flux methods under conditions where ²²Na⁺ influx is proportional to sodium permeability. Myocardial sodium channels are activated by batrachotoxin and veratridine. Batrachotoxin is a full agonist in this respect, whereas veratridine is a partial agonist. Aconitine and veratridine block the activation of sodium channels by batrachotoxin, consistent with their action as partial agonists at a common receptor site with batrachotoxin. The polypeptides scorpion toxin and sea anemone toxin II enhance persistent activation of sodium channels by alkaloid toxins. The concentration dependence of enhancement by scorpion toxin is hyperbolic with K_0.5 = 130 nM. In contrast, the enhancement of veratridine action by sea anemone toxin II is biphasic with K_0.5 values of 4 nM and 38 nM. Sea anemone toxin II increases the fraction of sodium channels activated by the partial agonists veratridine and aconitine and reduces K_0.5 for sodium channel activation by all three alkaloid toxins. Activation of sodium channels by batrachotoxin is not voltage-dependent, but enhancement of batrachotoxin activation of sodium channels by the polypeptide toxins is highly voltage-dependent. K_0.5 for sea anemone toxin II is increased 40-fold by depolarization of the cells in 135 mM K⁺. Sodium channels activated by alkaloid and polypeptide neurotoxins are inhibited by saxitoxin with K_0.5 = 50 nM and tetrodotoxin with K_0.5 = 1 µM. The results show that, relative to neuronal sodium channels, myocardial sodium channels have greatly reduced toxin-binding affinity at the tetrodotoxin/saxitoxin receptor site and altered binding specificity at the polypeptide toxin receptor site. The pharmacological profile of myocardial sodium channels is essentially identical with that of the tetrodotoxin-insensitive sodium channels in denervated and uninnervated rat skeletal muscle. A pharmacological classification of sodium channel subtypes in the rat is proposed.

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