Journal Article

Intrinsic lidocaine affinity for Na channels expressed in <i>Xenopus</i> oocytes depends on α (hH1 vs. rSkM1) and β1 subunits

Jonathan C Makielski, James Limberis, Zheng Fan and John W Kyle

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 42, issue 2, pages 503-509
Published in print May 1999 | ISSN: 0008-6363
Published online May 1999 | e-ISSN: 1755-3245 | DOI:
Intrinsic lidocaine affinity for Na channels expressed in Xenopus oocytes depends on α (hH1 vs. rSkM1) and β1 subunits

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Objective: The affinity of lidocaine for the α-subunit of the Na channel has been reported to be greater for heart than for non-heart α-subunits, and also to be no different. Lidocaine block has a complex voltage dependence caused by a higher affinity for the inactivated state over the resting state. Inactivation kinetics, however, depend upon the α-subunit isoform and the presence of the auxiliary β1-subunit and will affect measures of block. Methods: We studied the voltage dependence of lidocaine block of Na currents by a two microelectrode voltage clamp in oocytes injected with RNA for the Na channel α-subunits of human heart (hH1a) or a rat skeletal muscle (rSkM1) alone, or coexpressed with the β1-subunit. Results: The midpoints of availability for a 25-s conditioning potential in control solutions were −65 mV for rSkM1, −50 for rSkM1+β1, −78 mV for hH1a and −76 for hH1a+β1. The Kd of tonic lidocaine block was measured at −90, −100, −110, −120 and −130 mV in the same oocytes. The apparent Kd for both isoforms ±β1 became greater with more negative holding potentials, but tended to reach different plateaus at −130 mV (Kd=2128 μM for rSkM1, 1760 μM for rSkM1+β1, 433 for hH1a, and 887 μM for hH1a+β1). Inactivated state affinities, assessed by fitting the shift in the Boltzmann midpoint of the availability relationship to the modulated receptor model, were 4 μM for rSkM1, 1 μM for rSkM1+β1, 7 μM for hH1a and 9 μM for hH1a+β1. Conclusion: The heart Na channel α-subunits expressed in oocytes have an intrinsically higher rest state affinity for lidocaine compared to rSkM1 after the voltage- and state dependence of block are considered. Coexpression with β1 modestly increased the rest affinity of lidocaine for rSkM1, but had the opposite effect for hH1a.

Keywords: Local anesthetics; Antiarrhythmic drugs; Sodium current; Modulated receptor model; Heart; Skeletal muscle; Ion channels

Journal Article.  5287 words.  Illustrated.

Subjects: Cardiovascular Medicine

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