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(Circulation Research. 2009;105:492.)
© 2009 American Heart Association, Inc.

Cellular Biology

Using Lidocaine and Benzocaine to Link Sodium Channel Molecular Conformations to State-Dependent Antiarrhythmic Drug Affinity

Dorothy A. Hanck, Elena Nikitina, Megan M. McNulty, Harry A. Fozzard, Gregory M. Lipkind, Michael F. Sheets

From the Department of Internal Medicine (Cardiology) (D.A.H., E.N., M.M.M., H.A.F., G.M.L., M.F.S.), University of Chicago, Ill; and the Department of Internal Medicine (M.F.S.), The Nora Eccles Harrison Cardiovascular Research and Teaching Institute, University of Utah, Salt Lake City.

Correspondence to Dorothy A. Hanck, Cardiology (MC6094), University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637. E-mail dhanck{at}uchicago.edu

Rationale: Lidocaine and other antiarrhythmic drugs bind in the inner pore of voltage-gated Na channels and affect gating use-dependently. A phenylalanine in domain IV, S6 (Phe1759 in Na_V1.5), modeled to face the inner pore just below the selectivity filter, is critical in use-dependent drug block.

Objective: Measurement of gating currents and concentration-dependent availability curves to determine the role of Phe1759 in coupling of drug binding to the gating changes.

Methods and Results: The measurements showed that replacement of Phe1759 with a nonaromatic residue permits clear separation of action of lidocaine and benzocaine into 2 components that can be related to channel conformations. One component represents the drug acting as a voltage-independent, low-affinity blocker of closed channels (designated as lipophilic block), and the second represents high-affinity, voltage-dependent block of open/inactivated channels linked to stabilization of the S4s in domains III and IV (designated as voltage-sensor inhibition) by Phe1759. A homology model for how lidocaine and benzocaine bind in the closed and open/inactivated channel conformation is proposed.

Conclusions: These 2 components, lipophilic block and voltage-sensor inhibition, can explain the differences in estimates between tonic and open-state/inactivated-state affinities, and they identify how differences in affinity for the 2 binding conformations can control use-dependence, the hallmark of successful antiarrhythmic drugs.

Key Words: antiarrhythmic drug • voltage clamp • gating currents • lidocaine • benzocaine • local anethestic