USE-DEPENDENT INHIBITION OF NA+ CURRENTS BY BENZOCAINE HOMOLOGS

Most local anesthetics (LAs) elicit use-dependent inhibition of Na+ cu rrents when excitable membranes are stimulated repetitively. One excep tion to this rule is benzocaine, a neutral LA that fails to produce ap preciable use-dependent inhibition. In this study, we have examined th e use-dependent phenomenon of three benzocaine homologs: ethyl 4-dieth ylaminobenzoate, 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-diethylaminobenz oate at 0.15 mM and ethyl 4-ethoxybenzoate at 0.5 mM elicited substant ial use-dependent inhibition-up to 55% of peak Na+ currents were inhib ited by repetitive depolarizations at 5 Hz. Each of these compounds pr oduced significant tonic block of Na+ currents al rest and shifted the steady-state inactivation curve (h(infinity)) toward the hyperpolariz ing direction. Kinetic analyses showed that the decaying phase of Nacurrents during a depolarizing pulse was significantly accelerated by all drugs, thus suggesting that these drugs also block the activated c hannel, The recovery time course for the use-dependent inhibition of N ai currents was relatively slow, with time constants of 6.8 and 4.4 s for ethyl 4-diethylaminobenzoate and ethyl 4-ethoxybenzoate, respectiv ely. We conclude that benzocaine and 4-hydroxybenzoate interact with t he open and inactivated channels during repetitive pulses, but during the interpulse the complex dissociates too fast to accumulate sufficie nt use-dependent block of Na currents. In contrast, ethyl 4-diethylami nobenzoate and ethyl 4-ethoxybenzoate dissociate slowly from their bin ding site and consequently elicit significant use-dependent block. A c ommon LA binding site suffices to explain the presence and absence of use-dependent block by benzocaine homologs during repetitive pulses.