Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics

Abstract

Many local anesthetics promote reduction in sodium current during repetitive stimulation of excitable membranes. Use-, frequency-, and voltage-dependent responses describe patterns of peak INa when pulse width, pulse frequency, and pulse amplitude are varied. Such responses can be viewed as reflecting voltage-sensitive shifts in equilibrium between conducting, unblocked channels and nonconducting, blocked channels. The modulated-receptor hypothesis postulates shifts in equilibrium as the result of a variable-affinity receptor and modified inactivation gate kinetics in drug-complexed channels. An alternative view considers drug blocking in the absence of these two features. We propose that drug binds to a constant-affinity channel receptor where receptor access is regulated by the channel gates. Specifically, we view channel binding sites as guarded by the channel gate conformation, so that unlike receptors where ligands have continuous access, blocking agent access is variable during the course of an action potential. During the course of an action potential, the m and h gates change conformation in response to transmembrane potential. Conducting channels with both gates open leave the binding site unguarded and thus accessible to drug, whereas nonconducting channels, with gates in the closed conformation, act to restrict drug access to unbound receptors and possibly to trap drug in drug-complexed channels. We develop analytical expressions characterizing guarded receptors as "apparently" variable-affinity binding sites and predicting shifts in "apparent" channel inactivation in the hyperpolarizing direction. These results were confirmed with computer simulations. Furthermore, these results are in quantitative agreement with recent investigations of lidocaine binding in cardiac sodium channels.

Tonic Block of the Sodium and Calcium Currents by Ketamine in Isolated Guinea Pig Ventricular Myocytes.

“…In the present study quinidine but not ketamine produced UDB of I Na . It is well-established that class I antiarrhythmic drugs inhibit max in a use-dependent manner [5,16,25], and several models have been proposed to explain the interaction between the class I antiarrhythmic drugs and the cardiac Na channel [15,16,27]. According to the modulated receptor hypothesis [16], the affinity of the Na channel blocker to the binding site is determined by the electrophysiologic state of the Na channel, i.e., resting, activated, and inactivated states, and the drug-associated channels do not conduct Na ion even when activated.…”

Treatment of patients with cocaine‐induced arrhythmias: bringing the bench to the bedside

“…The upstroke of the action potential is delayed with resultant prolongation of conduction and impaired myocardial contractility. Heart rate and acid-base status are significant modulators of the effects of cocaineincreases in heart rate and decreases in pH both increase the degree of sodium channel blockade [10,11].…”

Markov models for ion channels: versatility versus identifiability and speed

“…State-dependent drug interactions can obviously be implemented using MMs (e.g. Armstrong 1971), but are also possible using HH formulations (Starmer et al 1984). The latest review on MMs (Rudy & Silva 2006) has emphasized these advantages of MMs, but has not covered the numerical issues with parameter estimation and model layout, which we discuss in this paper.…”