Evidence for voltage-dependent block of cardiac sodium channels by tetrodotoxin

Clarkson, Craig W.; Matsubara, Tetsu; Hondeghem, Luc M.

doi:10.1016/0022-2828(88)90592-5

Cited by 18 publications

(13 citation statements)

References 32 publications

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“…Indeed, in the scientific literature, there are no experimental or simulation data describing this observation, which is an important contribution of the present study. The variation of peak I Na block by lidocaine with pH and stimulation rates obtained in our simulations was also in agreement with the scarce experimental data extracted from the scientific literature (11,23).…”

Section: Discussionsupporting

confidence: 86%

“…Several experimental studies developed in conditions in which the neutral drug form was present in a higher proportion have suggested that the use-dependent block of Na ϩ channels in cardiac tissue represents a balance between block development during depolarization (activated state) and incomplete recovery after repolarization (inactivated state) (11,23). On the other hand, Bean et al (3) found an initial blockade produced by lidocaine when a voltage-clamp protocol was applied, suggesting that the drug was bound in the resting state, although the binding was weaker than in inactivated or activated states.…”

Section: Methodsmentioning

confidence: 99%

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Exploring the role of pH in modulating the effects of lidocaine in virtual ischemic tissue

Cardona

Trénor

Moltó³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Lidocaine is a class I antiarrhytmic drug that blocks Na(+) channels and exists in both neutral and charged forms at a physiological pH. In this work, a mathematical model of pH and the frequency-modulated effects of lidocaine has been developed and incorporated into the Luo-Rudy model of the ventricular action potential. We studied the effects of lidocaine on Na(+) current, maximum upstroke velocity, and conduction velocity and demonstrated that a decrease of these parameters was dependent on pH, frequency, and concentration. We also tested the action of lidocaine under pathological conditions. Specifically, we investigated its effects on conduction block under acute regional ischemia. Our results in one-dimensional fiber simulations showed a reduction of the window of block in the presence of lidocaine, thereby highlighting the role of reduced conduction velocity and safe conduction. This reduction may be related to the antifibrillatory effects of the drug by hampering wavefront fragmentation. In bidimensional acute ischemic tissue, lidocaine increased the vulnerable window for reentry and exerted proarrhythmic effects. In conclusion, the present simulation study used a newly formulated model of lidocaine, which considers pH and frequency modulation, and revealed the mechanisms by which lidocaine facilitates the onset of reentries. The results of this study also help to increase our understanding of the potential antifibrillatory effects of the drug.

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Section: Discussionsupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Exploring the role of pH in modulating the effects of lidocaine in virtual ischemic tissue

Cardona

Trénor

Moltó³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Clarkson et al investigated possible state-dependent blocking activity of TTX in guinea pig papillary muscle at 37 °C [35]. Using V max of the action potential upstroke as indicator of Na + conductance the authors investigated possible state-dependent effects of TTX on guinea pig papillary muscles.…”

Section: Use-dependent Block By Guanidinium Toxinsmentioning

confidence: 99%

The Outer Vestibule of the Na+ Channel–Toxin Receptor and Modulator of Permeation as Well as Gating

et al. 2010

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The outer vestibule of voltage-gated Na+ channels is formed by extracellular loops connecting the S5 and S6 segments of all four domains (“P-loops”), which fold back into the membrane. Classically, this structure has been implicated in the control of ion permeation and in toxin blockage. However, conformational changes of the outer vestibule may also result in alterations in gating, as suggested by several P-loop mutations that gave rise to gating changes. Moreover, partial pore block by mutated toxins may reverse gating changes induced by mutations. Therefore, toxins that bind to the outer vestibule can be used to modulate channel gating.

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“…This may lead one to assume that the drug has a high affinity for the resting state of the sodium channel. However, this form of tonic block does not accurately reflect either the closed or rest-state drug binding since, at strong depolarizing pulses and at high drug concentrations, tonic block may result from open channel block (Clarkson et al, 1988). Our patch-clamp results suggest that PD117,302 may have a greater affinity for the active (open) or inactive (closed) form of the channel than for rested (closed) channels.…”

Section: Discussionmentioning

confidence: 91%