J Pharmacol Exp Ther 1981 Jul 01;2181:175-81.

Barbiturates: active form and site of action at node of Ranvier sodium channels.

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Barbiturate sodium channel block was investigated in the voltage-clamped amphibian node of Ranvier. Internal pH was manipulated by diffusion of buffers from the cut internodes. Like local anesthetics and volatile general anesthetics, barbiturates shift the voltage dependence of inactivation in the hyperpolarizing direction. A barbiturate anion, 5-phenyl barbituric acid, blocks sodium channels when applied externally or internally. On external application, block is of very slow onset. The barbiturate anion, like the local anesthetic cation, thus appears to bind to a receptor site on the axoplasmic side of the membrane. Unlike local anesthetics, however, phenobarbital exerts a frequency-dependent block which is modified by changes in internal pH and is not affected by changes in external pH. In addition, barbiturate frequency dependence is apparently more exclusively involved with channel inactivation. The results suggest a barbiturate sodium channel binding site closer to the axoplasm than the local anesthetic binding site is and also suggest that there is a proton barrier between the two sites.

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