This study shows that Ca 2+ reversed the nerve-blocking actions of procaine, lidocaine, procainamide, imipramine, chlorpromazine, tetrodotoxin, hexanol, heptanol, benzyl alcohol, thymol, sodium barbital, and sodium pentobarbital. Using the rat phrenic nerve, it was found that an elevation of external Ca 2+ (from 0.22 mM to 4.4 mM) restored the blocked compound action potential of the nerve by around 30% for all three types of drugs: cationic, anionic, and uncharged.The high Ca 2+ level of 4.4 mM displaced chlorpromazine from brain synaptosome membranes, but did not displace heptanol, pentobarbital, or lidocaine. Since there was no relation between blockade reversal and drug displacement by Ca 2+ , the data do not support the idea that Ca 2+ and drugs compete for membrane-binding sites. Since approximately the same magnitude of reversal occurred with different drugs, as well as with tetrodotoxin, it is concluded that Ca 2+ may cause a physiological kind of allosteric antagonism of the drug-blocked Na + channel, or a direct augmentation of the Na + conductance.
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Seeman et al. (1974) studied this question.