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[3H]Batrachotoxinin-A benzoate ([3H]BTX-B) binds with high affinity to sites on voltage sensitive sodium channels in synaptoneurosomes from guinea pig cerebral cortex. Local anesthetics competitively antagonize the binding of [3H]BTX-B. An irreversible local anesthetic, procaine isothiocyanate (PRIT) and a tritiated derivative [( 3H]PRIT) have been prepared. PRIT inhibits the binding of [3H]BTX-B in a noncompetitive, irreversible manner (apparent Ki = 13 microM) whereas the parent compound, procaine, inhibits in a competitive, reversible manner (Ki = 40 microM). The dissociation rate of [3H]BTX-B from sites on the sodium channel is greatly accelerated in a concentration dependent manner in the presence of PRIT. A 50% increase in the dissociation rate of [3H]BTX-B is achieved in the presence of 0.98 microM PRIT. [3H]PRIT binds irreversibly to three proteins in synaptoneurosomes with apparent molecular weights of 20, 42, and 68 kDa. Protection studies with procaine and other local anesthetics suggest that only the 68 kDa species was related to local anesthetic binding.