1984
DOI: 10.1016/s0006-3495(84)83994-6
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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-a… Show more

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Cited by 319 publications
(184 citation statements)
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“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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].…”
Section: Sodium Channel Blockadementioning
confidence: 99%
“…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.…”
Section: Introductionmentioning
confidence: 99%