Local anesthetic block of sodium channels in normal and pronase-treated squid giant axons.
The inhibition of sodium currents by local anesthetics and other blocking compounds was studied in perfused, voltage-clamped segments of squid giant axon. When applied internally, each of the eight compounds studied results in accumulating "use-depnedent" block of sodium currents upon repetitive pulsing. Recovery from block occurs over a time scale of many seconds. In axons treated with pronase to completely eliminate sodium inactivation, six of the compounds induce a time- and voltage-dependent decline of sodium currents after activation during a maintained depolarization. Four of the time-dependent blocking compounds--procaine, 9-aminoacridine, N-methylstrychnine, and QX572--also induce altered sodium tail currents by hindering closure of the activation gating mechanism. Treatment of the axon with pronase abolishes use-dependent block completely by QX222, QX314, 9-aminoacridine, and N-methylstrychnine, but only partially be tetracaine and etidocaine. Two pulse experiments reveal that recovery from block by 9-aminoacridine or N-methyl-strychnine is greatly accelerated after pronase treatment. Pronase treatment abolishes both use-dependent and voltage-dependent block by QX222 and QX314. These results provide support for a direct role  of the inactivation gating mechanism in producing the long-lasting use-dependent inhibition brought about by local anesthetic compounds.
D000166:Acridines / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D005041:Etidocaine / Q000494:pharmacology; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D011343:Procaine / Q000494:pharmacology; D011402:Pronase / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D013331:Strychnine / Q000031:analogs & derivatives / Q000494:pharmacology; D013748:Tetracaine / Q000494:pharmacology
D000166:Acridines; D000779:Anesthetics, Local; D013748:Tetracaine; C017521:N-methylstrychnine; D011343:Procaine; D008012:Lidocaine; D012964:Sodium; D011402:Pronase; D013331:Strychnine; D005041:Etidocaine