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.

Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

“…Consistent with earlier studies, we found almost no use-dependent inhibition by benzocaine 20,25,33,39 ( Supplementary Fig. S5), suggesting that a protonated amine is necessary for use-dependent inhibition.…”

Structural requirements for voltage‐dependent block of muscle sodium channels by phenol derivatives

“…Rapid recovery from inactivation explains the lack of use-dependent block at stimulating frequencies below 50 Hz. Lack of use-dependent block has equally been described for the structurally related local anaesthetic benzocaine (Quan et al, 1996). In contrast, lidocaine induces substantial use-dependent block, even at lower stimulating frequencies than those used in our experiments (Fan et al, 1996).…”

“…In contrast, lidocaine induces substantial use-dependent block, even at lower stimulating frequencies than those used in our experiments (Fan et al, 1996). Structure ± activity studies of dierent local anaesthetics and their derivatives have shown that the rate of dissociation from inactivated channels, which determines the accumulation of frequency-dependent block during repetitive stimulation, is related primarily to the size of the aliphatic side-chains (Quan et al, 1996), the molecular weight, and charge (Ehring et al, 1988). Thus, the lack of use-dependent block seen with all the phenol derivatives we have studied compared with lidocaine could be attributed to dierences in molecular weight.…”

Interaction of phenol derivatives with ion channels

“…The results on the kinetics of recovery from inactivated channel block explain the lack of use-dependent block at stimulating frequencies lower than 50 Hz seen with most phenolic compounds at concentrati ons below the IC 50 for rest block. Lack of use-dependent blockade has equally been described for the structurally related local anaesthetic benzocaine [63]. In contrast, lidocaine induces substantial use-dependent block, even at lower stimulating frequencies [18].…”

“…In contrast, lidocaine induces substantial use-dependent block, even at lower stimulating frequencies [18]. Structure-activity studies of different local anaesthetics and their derivatives have shown that the rate of dissociation from inactivated channels, which determines the accumulation of frequency-dependent block during repetitive stimulation, is related primarily to the size of the aliphatic side-chai ns [63], the molecular weight, and charge [2]. Thus, the lack of frequencydependent block seen with compounds with single substituents at the phenol ring compared with lidocaine could be attributed to differences in molecular weight.…”