Use-dependent inhibition of Na+ currents by benzocaine homologs

• Published in: Biophysical journal 1996, Vol.70 (1), p.194-201
• Main Authors: Quan, C., Mok, W.M., Wang, G.K.
• Format: Article
• Language: English
• Subjects: Aminobenzoates - pharmacology; Anesthetics, Local - metabolism; Anesthetics, Local - pharmacology; Animals; Benzoates - pharmacology; Benzocaine - analogs & derivatives; Benzocaine - metabolism; Benzocaine - pharmacology; Binding Sites; Biophysical Phenomena; Biophysics; Cell Line; Kinetics; para-Aminobenzoates; Parabens - pharmacology; Rats; Sodium Channel Blockers; Sodium Channels - metabolism
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(96)79563-2

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.