Blockade of cardiac sodium channels. Competition between the permeant ion and antiarrhythmic drugs.

Barber, Michael J.; Wendt, David; Starmer, C. Frank; Grant, Augustus O.

doi:10.1172/jci115871

Cited by 32 publications

(19 citation statements)

References 37 publications

(52 reference statements)

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“…Thus, it probably reverses, at least in part, the bupivacaine sodium channel blockade. Our results differ from those obtained with lidocaine, which showed no protective effect with hypertonic saline (30,31). Both drugs bind to the sodium channel during the inactivated state; however, different binding sites or properties may prevent competition between extracellular sodium and lidocaine but not bupivacaine.…”

Section: Discussioncontrasting

confidence: 99%

Effects of hypertonic sodium chloride solution on the electrophysiologic alterations caused by bupivacaine in the dog heart

Scalabrini

Corregiari

Silva

2003

Braz J Med Biol Res

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The effects of various hypertonic solutions on the intraventricular conduction, ventricular repolarization and the arrhythmias caused by the intravenous (iv) injection of bupivacaine (6.5 mg/kg) were studied in sodium pentobarbital-anesthetized mongrel dogs. Hypertonic solutions, given iv 5 min before bupivacaine, were 7.5% (w/v) NaCl, 5.4% (w/v) LiCl, 50% (w/v) glucose (2,400 mOsm/l, 5 ml/kg), or 20% (w/v) mannitol (1,200 mOsm/l, 10 ml/kg). Bupivacaine induced severe arrhythmias and ventricular conduction and repolarization disturbances, as reflected by significant increases in QRS complex duration, HV interval, IV interval and monophasic action potential duration, as well as severe hemodynamic impairment. Significant prevention against ventricular electrophysiologic and hemodynamic disturbances and ventricular arrhythmias was observed with 7.5% NaCl (percent increase in QRS complex duration: 164.4 ± 21.8% in the non-pretreated group vs 74.7 ± 14.1% in the pretreated group, P<0.05; percent increase in HV interval: 131.4 ± 16.1% in the non-pretreated group vs 58.2 ± 7.5% in the pretreated group, P<0.05; percent increase in monophasic action potential duration: 22.7 ± 6.8% in the non-pretreated group vs 9.8 ± 6.3% in the pretreated group, P<0.05; percent decrease in cardiac index: -46 ± 6% in the non-pretreated group vs -28 ± 5% in the pretreated group, P<0.05). The other three hypertonic solutions were ineffective. These findings suggest an involvement of sodium ions in the mechanism of hypertonic protection.

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Section: Discussioncontrasting

confidence: 99%

Effects of hypertonic sodium chloride solution on the electrophysiologic alterations caused by bupivacaine in the dog heart

Scalabrini

Corregiari

Silva

2003

Braz J Med Biol Res

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“…Hence, external Na + ions do not reduce benzocaine binding. This result is in sharp contrast with the binding of tertiary and quaternary LAs with Na ÷ channels reported before in squid axons, in lipid bilayers, and in cardiac myocytes (Cahalan and Almers, 1979;Wang, 1988;Barber, Wendt, Starmer, and Grant, 1992) as well as in GH3 cells (Wang, G.K., unpublished observation).…”

Section: Lack Of Reduction Of Benzocaine Binding By External Na + Ionscontrasting

confidence: 98%

Binding of benzocaine in batrachotoxin-modified Na+ channels. State-dependent interactions.

Wang

1994

The Journal of General Physiology

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Hille (1977. Journal of General Physiology. 69:497-515) first proposed a modulated receptor hypothesis (MRH) to explain the action of benzocaine in voltage-gated Na+ channels. Using the MRH as a framework, we examined benzocaine binding in batrachotoxin (BTX)-modified Na+ channels under voltage-clamp conditions using either step or ramp command signals. We found that benzocaine binding is strongly voltage dependent. At -70 mV, the concentration of benzocaine that inhibits 50% of BTX-modified Na+ currents in GH3 cells (IC50) is 0.2 mM, whereas at +50 mV, the IC50 is 1.3 mM. Dose-response curves indicate that only one molecule of benzocaine is required to bind with one BTX-modified Na+ channel at -70 mV, whereas approximately two molecules are needed at +50 mV. Upon treatment with the inactivation modifier chloramine-T, the binding affinity of benzocaine is reduced significantly at -70 mV, probably as a result of the removal of the inactivated state of BTX-modified Na+ channels. The same treatment, however, enhances the binding affinity of cocaine near this voltage. External Na+ ions appear to have little effect on benzocaine binding, although they do affect cocaine binding. We conclude that two mechanisms underlie the action of local anesthetics in BTX-modified Na+ channels. Unlike open-channel blockers such as cocaine and bupivacaine, neutral benzocaine binds preferentially with BTX-modified Na+ channels in a closed state. Furthermore, benzocaine can be modified chemically so that it behaves like an open-channel blocker. This compound also elicits a use-dependent block in unmodified Na+ channels after repetitive depolarizations, whereas benzocaine does not. The implications of these findings for the MRH theory will be discussed.

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“…These results indicate that GA is more effective in blocking late I Na than peak I Na . Although peak I Na and late I Na were measured at a different external Na + concentrations (20 and 96 mM, respectively), some reduction of GA-induced peak I Na blockade should be expected at physiological Na + concentrations since increases in [Na + ] o have been shown to attenuate the Na + -channel blocking action of class I antiarrhythmic drugs (Barber et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Glycyrretinic acid blocks cardiac sodium channels expressed in Xenopus oocytes

Zhang

et al. 2009

Journal of Ethnopharmacology

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Blockade of cardiac sodium channels. Competition between the permeant ion and antiarrhythmic drugs.

Cited by 32 publications

References 37 publications

Effects of hypertonic sodium chloride solution on the electrophysiologic alterations caused by bupivacaine in the dog heart

Effects of hypertonic sodium chloride solution on the electrophysiologic alterations caused by bupivacaine in the dog heart

Binding of benzocaine in batrachotoxin-modified Na+ channels. State-dependent interactions.

Glycyrretinic acid blocks cardiac sodium channels expressed in Xenopus oocytes

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