The antagonist activities of some cyclohexylaralkylamines derived from perhexiline on the fast Na+ channel and slow Ca2+ channel in rat brain and rat heart were examined and compared to the antagonist activities of nifedipine, verapamil, prenylamine and perhexiline. Prenylamine, perhexiline and the cyclohexylaralkylamine derivatives inhibited the [3H]batrachotoxinin A 20-alpha-benzoate binding more than the [3H]nitrendipine binding in rat brain. The nature of the interaction of the cyclohexylaralkylamines with the binding of [3H]batrachotoxinin and [3H]nitrendipine was non-competitive. The synaptosomal 22Na uptake induced by protoveratrine B, a Na+ channel agonist, was also inhibited. Prenylamine, perhexiline and perhexiline derivatives were more potent on the fast Na+ channel than on the Ca2+ channel in contrast to nifedipine and verapamil. The inhibition of Na+ and Ca2+ channels was also shown in guinea pig left atria. Perhexiline, prenylamine and the perhexiline derivatives inhibited the protoveratrine B-induced contraction more than they inhibited that induced by CaCl2, in contrast with nifedipine and verapamil. Our results showed that prenylamine, perhexiline and its related cyclohexylaralkylamines inhibited the fast Na+ channel far more than the slow Ca2+ channel in rat brain, rat heart and guinea pig atria.