Kinetic analysis of phasic inhibition of neuronal sodium currents by lidocaine and bupivacaine

Chernoff, Daniel M.

doi:10.1016/s0006-3495(90)82353-5

Cited by 55 publications

(37 citation statements)

References 39 publications

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“…However, as the frequencydependent block, observed with lidocaine, is also due to changes in binding kinetics of lido caine to sodium channels during membrane depolarization [21], the influence of the HAP on impulse propagation cannot be clearly dis tinguished in the present experiments.…”

Section: Effects O F Clonidine and Lidocaine On Afterpotentialsmentioning

confidence: 71%

Hyperpolarizing Afterpotentials in C Fibers and Local Anesthetic Effects of Clonidine and Lidocaine

Gaumann

Brunet²,

Jirounek³

1994

Pharmacology

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Effects of clonidine and lidocaine on the hyperpolarizing after-potential (HAP) and frequency-dependent block in C fibers were examined on desheathed rabbit vagus nerves, using the sucrose gap technique. A single action potential (AP) was followed by a fast and a slow HAP. Clonidine, at concentrations from 0.05 to 50 µmol/l, decreased the fast HAP, while the AP amplitude was unchanged. At a 500 µmol/l concentration of clonidine, the fast HAP amplitude was similar to control, the slow HAP was increased, and the AP amplitude decreased. Lidocaine at 500 µmol/l delayed and broadened the HAP, making a distinction between fast and slow HAP impossible, and decreased and delayed the AP amplitude. In the presence of lidocaine (500 µmol/l), clonidine at concentrations from 0.05 to 500 µmol/l decreased the HAP amplitude, without modifying the lidocaine-induced shape of the HAP. The modifications of the HAP, however, do not contribute to the local anesthetic effects of clonidine, as the addition of clonidine (0.5 and 500 µmol/l) to Locke or lidocaine (500 µmol/l) solution does not enhance the frequency-dependent block (3 and 10 Hz) observed with either Locke or lidocaine solution alone.

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Section: Effects O F Clonidine and Lidocaine On Afterpotentialsmentioning

confidence: 71%

Hyperpolarizing Afterpotentials in C Fibers and Local Anesthetic Effects of Clonidine and Lidocaine

Gaumann

Brunet²,

Jirounek³

1994

Pharmacology

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“…Such compounds include bupivacaine, imipramine, carbamazepine, and diphenhydramine. 13,43 Thus, based on this collective evidence, an assay that measures open state block theoretically should approximate EP K i values relatively well. Nonetheless, under natural conditions, the open state of the NaCh is extremely transient (1-2 msec); most compounds are thought not to bind this rapidly.…”

Section: Discussionmentioning

confidence: 92%

State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR Vm Dye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

Benjamin

Pruthi²,

Olanrewaju³

et al. 2006

SLAS Discovery

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Voltage-gated sodium channels (NaChs) are relevant targets for pain, epilepsy, and a variety of neurological and cardiac disorders. Traditionally, it has been difficult to develop structure-activity relationships for NaCh inhibitors due to rapid channel kinetics and state-dependent compound interactions. Membrane potential (V m ) dyes in conjunction with a high-throughput fluorescence imaging plate reader (FLIPR) offer a satisfactory 1st-tier solution. Thus, the authors have developed a FLIPR V m assay of rat Na v 1.2 NaCh. Channels were opened by addition of veratridine, and V m dye responses were measured. The IC 50 values from various structural classes of compounds were compared to the resting state binding constant (K r ) and inactivated state binding constant (K i ) obtained using patch-clamp electrophysiology (EP). The FLIPR values correlated with K i but not K r . FLIPR IC 50 values fell within 0.1-to 1.5-fold of EP K i values, indicating that the assay generally reports use-dependent inhibition rather than resting state block. The Library of Pharmacologically Active Compounds (LOPAC, Sigma) was screened. Confirmed hits arose from diverse classes such as dopamine receptor antagonists, serotonin transport inhibitors, and kinase inhibitors. These data suggest that NaCh inhibition is inherent in a diverse set of biologically active molecules and may warrant counterscreening NaChs to avoid unwanted secondary pharmacology. (Journal of Biomolecular Screening 2006: 29-39)

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“…Apparently, the dissociation of these drugs from closed channels was extremely slow, as if the drugs were trapped within the channels when they closed. One possible explanation for these observations is that the channel activation and/or inactivation gates act as physical barriers, preventing drug access to and escape from the receptor site (19,20 (21,22). Thus, the concentration dependence of the steady-state level of frequencydependent block by these drugs gives an estimate of K., the dissociation constant for drug binding to the open state of the channel.…”

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confidence: 99%

Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.

Ragsdale

McPhee

Scheuer

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

457

422

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Voltage-gated Na+ channels are the molecular targets of local anesthetics, class I antiarrhythmic drugs, and some anticonvulsants. These chemically diverse drugs inhibit Na+ channels with complex voltage-and frequencydependent properties that reflect preferential drug binding to open and inactivated channel states. The site-directed mutations F1764A and Y1771A in transmembrane segment IVS6 of type IIA Na+ channel ai subunits dramatically reduce the affinity of inactivated channels for the local anesthetic etidocaine. In this study, we show that these mutations also greatly reduce the sensitivity of Na+ channels to state-dependent block by the class Ib antiarrhythmic drug lidocaine and the anticonvulsant phenytoin and, to a lesser extent, reduce the sensitivity to block by the class Ta and Ic antiarrhythmic drugs quinidine and flecainide. For lidocaine and phenytoin, which bind preferentially to inactivated Na+ channels, the mutation F1764A reduced the affinity for binding to the inactivated state 24.5-fold and 8.3-fold, respectively, while Y1771A had smaller effects. For quinidine and flecainide, which bind preferentially to the open Na+ channels, the mutations F1764A and Y1771A reduced the affinity for binding to the open state 2-to 3-fold. Thus, F1764 and Y1771 are common molecular determinants of state-dependent binding of diverse drugs including lidocaine, phenytoin, flecainide, and quinidine, suggesting that these drugs interact with a common receptor site. However, the different magnitude of the effects of these mutations on binding of the individual drugs indicates that they interact in an overlapping, but nonidentical, manner with a common receptor site. These results further define the contributions of F1764 and Y1771 to a complex drug receptor site in the pore of Na+ channels.Voltage-gated Na+ channels are responsible for the initiation and propagation of action potentials in both nerve and muscle cells (1, 2). The main structural component of Na+ channels is the 260-kDa a subunit, which forms the Na+ selective pore and other structures necessary for channel function. In mammalian Na+ channels, the a subunit associates with one or two smaller auxiliary subunits designated 131 and ,32. Na+ channel function is regulated by voltage-dependent transitions among three sets of functionally distinct conformational states. At hyperpolarized membrane potentials, most Na+ channels are in closed resting states. In response to membrane depolarization, channels rapidly convert to an open state that conducts Na+ ions and then to a nonconducting, inactivated state. The opening and subsequent inactivation of Na+ channels results in a transient inward current that inactivates within a few milliseconds.Class I antiarrhythmic drugs such as lidocaine, quinidine, and flecainide (3, 4) as well as some anticonvulsants including phenytoin and carbamazepine (5) act by inhibiting ionic currents through voltage-gated Na+ channels. Tertiary amine local anesthetics, like procaine and etidocaine, which are chemically related...

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Kinetic analysis of phasic inhibition of neuronal sodium currents by lidocaine and bupivacaine

Cited by 55 publications

References 39 publications

Hyperpolarizing Afterpotentials in C Fibers and Local Anesthetic Effects of Clonidine and Lidocaine

Hyperpolarizing Afterpotentials in C Fibers and Local Anesthetic Effects of Clonidine and Lidocaine

State-Dependent Compound Inhibition of Nav1.2 Sodium Channels Using the FLIPR Vm Dye: On-Target and Off-Target Effects of Diverse Pharmacological Agents

Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.

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