Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction.

Abstract

A B S T R A C T The properties of Na channels of the node of Ranvier are altered by neutral, amine, and quaternary local anesthetic compounds. The kinetics of the Na currents are governed by a composite of voltage-and time-dependent gating processes with voltage-and time-dependent block of channels by drug. Conventional measurements of steady-state sodium inactivation by use of 50-ms prepulses show a large negative voltage shift of the inactivation curve with neutral benzocaine and with some ionizable amines like lidocaine and tetracaine, but no shift is seen with quaternary QX-572. However, when the experiment is done with repetitive application of a prepulse-testpulse waveform, a shift with the quaternary cations (applied internally) is seen as well. 1-min hyperpolarizations of lidocaine-or tetracaine-treated fibers restore two to four times as many channels to the conducting pool as 50-ms hyperpolarizations. Raising the external Ca ++ concentration also has a strong unblocking effect. These manipulations do not relieve block in fibers treated with internal quaternary drugs. The results are interpreted in terms of a single receptor in Na channels for the different drug types. Lipid-soluble drug forms are thought to come and go from the receptor via a hydrophobic region of the membrane, while charged and less lipid-soluble forms pass via a hydrophilic region (the inner channel mouth). The hydrophilic pathway is open only when the gates of the channel are open. Any drug form in the channel increases the probability of closing the inactivation gate which, in effect, is equivalent to a negative shift of the voltage dependence of inactivation.

Mechanisms of Anesthesia: Towards Integrating Network, Cellular, and Molecular Level Modeling

“…The block has been shown to be state dependent (the modulated receptor hypothesis; Hille, 1977;Hondeghem and Katzung, 1977). Since the early 1970s the location of the binding site has been assumed to be in a postulated internal vestibule.…”

Quinidine‐induced open channel block of K+ current in rat ventricle

“…Nattel, 1991;Rosen et al, 1991). Although its ability to block sodium channels (class I antiarrhythmic actions) has been described in some detail as a use-dependent inhibition (Hille, 1977;Hondeghem & Katzung, 1977;Clarkson & Hondeghem, 1984), the action potential broadening, or class III actions of quinidine are less well understood (Singh & Nadamane, 1985;Hondeghem & Snyders, 1990;Colatsky et al, 1990;Lynch et al, 1992). Part of the reason for this is that in mammalian heart there is a relatively large number of quite diverse potassium (K+) currents (Colatsky et al, 1990;Baumgarten & Fozzard, 1991;Gintant et al, 1991).…”

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“…This result is to be expected if K channels are preferentially blocked by the anaesthetic in the open rather than in the resting state (see Hille, 1977).…”

“…According to the modulated receptor model for the action of local anaesthetics proposed by Hille (1977), this result can be interpreted by the assumption that alphaxalone preferentially binds to Na channels which are in the inactivated state. Therefore, the probability of Na channels being in the inactivated state would be increased in the presence of alphaxalone which, in effect, is equivalent to a negative shift of the voltage dependence of the steady-state inactivation of the peak Na current.…”