Saxitoxin and procaine act independently on separate sites of the sodium channel.

1. Voltage clamp experiments were done on single myelinated nerve fibres of the frog, Rana esculenta. 2. The time course of procaine action (1.0 mM at pH 7.2) was obtained from changes in INa on changing solutions during repetitive (1 HZ) depolarizing pulses of constant amplitude following hyperpolarizing prepulses. The mean half times of onset and offset of procaine block were 3.7 and 28 s, respectively. In the presence of 1.4 nM saxitoxin (STX) the corresponding times were virtually the same, 3.1 and 27 s. 3. Similarly, the time course of partial relief from procaine block that is obtained by increasing the frequency of the prepulse-test pulse pairs from 1-10 HZ was unaffected in the presence of STX. 4. Comparison of the equilibrium effects of procaine concentrations ranging from 0.03-1.0 mM suggest a one-to-one drug-receptor reaction. The fraction of Na channels blocked at equilibrium with 1.0 mM procaine, 1.4 nM STX, and 1.0 mM procaine + 1.4 nM STX was 0.81, 0.49, and 0.90, respectively. This result and the kinetic behaviour fully agree with the idea of two separate and independent receptors for procaine and STX.