Inhibition of the sodium channel by SK&F 96365, an inhibitor of the receptor-operated calcium channel,in mouse diaphragm

The effects of SK&F 96365, a blocker of the receptor-operated Ca²⁺ channel, on contractilities and the Na⁺ channel of mouse diaphragm were studied. SK&F 96365 (10–50 µM) reversibly inhibited twitches, tetanic contractions and muscle and nerve action potentials. The IC₅₀ was 17–24 µM. The inward Na⁺ current was suppressed and its recovery from inactivations delayed. Crotamine, a peptide toxin that binds to neurotoxin receptor site 3 of the muscle Na⁺ channel, enhanced the inhibitory effects of SK&F 96365 and reduced the IC₅₀ to about 4 µM. Veratridine had similar effects, although it was less effective than crotamine. On the other hand, the crotamine-induced membrane depolarizations and spontaneous discharges of muscle action potentials were inhibited by SK&F 96365 noncompetitively. The inhibitory effects of tetrodotoxin and tetracaine were additive with those of SK&F 96365 but were enhanced slightly by crotamine. The results suggested that SK&F 96365 acts on a distinct site and blocks the Na⁺ channel of excitable membranes at a concentration range that inhibits the receptor-operated calcium channel.