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Cardiovascular Research 1999 42(2):503-509; doi:10.1016/S0008-6363(99)00024-3
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Intrinsic lidocaine affinity for Na channels expressed in Xenopus oocytes depends on {alpha} (hH1 vs. rSkM1) and β1 subunits

Jonathan C Makielski*, James Limberis1, Zheng Fan2 and John W Kyle1

Departments of Medicine and Physiology, University of Wisconsin, Madison, WI 53792, USA

jcm{at}medicine.wisc.edu

* Corresponding author. Present address: University of Wisconsin Clinics and Hospitals, 600 Highland Ave H6/349, Madison, WI 53792, USA. Tel.: +1-608-263-9648; fax: +1-608-263-0405

Objective: The affinity of lidocaine for the {alpha}-subunit of the Na channel has been reported to be greater for heart than for non-heart {alpha}-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 {alpha}-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 {alpha}-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 {alpha}-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

1 Present address: Department of Pharmacology and Physiology, University of Chicago, Chicago, IL 60637, USA.

2 Present address: Department of Physiology, University of Tennessee, College of Medicine, Memphis, TN 38163, USA.


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