title: Use-dependent inhibition of Na+ currents by benzocaine homologs.
abstract: Most local anesthetics (LAs) elicit use-dependent inhibition of Na+ currents when excitable membranes are stimulated repetitively. One exception to this rule is benzocaine, a neutral LA that fails to produce appreciable use-dependent inhibition. In this study, we have examined the use-dependent phenomenon of three benzocaine homologs: ethyl 4-diethylaminobenzoate, ethyl 4-ethoxybenzoate, and ethyl 4-hydroxybenzoate. Ethyl 4-hydroxybenzoate at 1 mM, like benzocaine, elicited little use-dependent inhibition of Na+ currents, whereas ethyl 4-diethylaminobenzoate at 0.15 mM and ethyl 4-ethoxybenzoate at 0.5 mM elicited substantial use-dependent inhibition--up to 55% of peak Na+ currents were inhibited by repetitive depolarizations at 5 Hz. Each of these compounds produced significant tonic block of Na+ currents at rest and shifted the steady-state inactivation curve (h infinity) toward the hyperpolarizing direction. Kinetic analyses showed that the decaying phase of Na+ currents during a depolarizing pulse was significantly accelerated by all drugs, thus suggesting that these drugs also block the activated channel. The recovery time course for the use-dependent inhibition of Na+ currents was relatively slow, with time constants of 6.8 and 4.4 s for ethyl 4-diethylaminobenzoate and ethyl 4-ethoxybenzoate, respectively. We conclude that benzocaine and 4-hydroxybenzoate interact with the open and inactivated channels during repetitive pulses, but during the interpulse the complex dissociates too fast to accumulate sufficient use-dependent block of Na+ currents. In contrast, ethyl 4-diethylaminobenzoate and ethyl 4-ethoxybenzoate dissociate slowly from their binding site and consequently elicit significant use-dependent block. A common LA binding site suffices to explain the presence and absence of use-dependent block by benzocaine homologs during repetitive pulses.
authors.affiliation: Department of Anesthesia Research Laboratories, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: C
authors.initials: C
authors.lastname: Quan
authors.forename: W M
authors.initials: WM
authors.lastname: Mok
authors.forename: G K
authors.initials: GK
authors.lastname: Wang
mesh_terms: D062365:Aminobenzoates / Q000494:pharmacology; D000779:Anesthetics, Local / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001566:Benzocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D055592:Biophysical Phenomena; D001703:Biophysics; D002460:Cell Line; D007700:Kinetics; D010226:Parabens / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D062366:para-Aminobenzoates
chemical_list: D062365:Aminobenzoates; D000779:Anesthetics, Local; D001565:Benzoates; D010226:Parabens; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D062366:para-Aminobenzoates; C099038:ethyl 4-diethylaminobenzoate; C012313:ethyl-p-hydroxybenzoate; C099039:ethyl 4-ethoxybenzoate; D001566:Benzocaine