Biophys J, January 2000, p. 200-210, Vol. 78, No. 1

Isoform-Specific Lidocaine Block of Sodium Channels Explained by Differences in Gating

H. Bradley Nuss, Nicholas G. Kambouris,^* Eduardo Marbán, Gordon F. Tomaselli, and Jeffrey R. Balser^*

 ^*Division of Cardiac Anesthesia, Department of Anesthesiology and Critical Care Medicine, and  Section of Molecular and Cellular Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland USA

When depolarized from typical resting membrane potentials (V_rest ~ 90 mV), cardiac sodium (Na) currents are more sensitive to local anesthetics than brain or skeletal muscle Na currents. When expressed in Xenopus oocytes, lidocaine block of hH1 (human cardiac) Na current greatly exceeded that of µ1 (rat skeletal muscle) at membrane potentials near V_rest, whereas hyperpolarization to 140 mV equalized block of the two isoforms. Because the isoform-specific tonic block roughly parallels the drug-free voltage dependence of channel availability, isoform differences in the voltage dependence of fast inactivation could underlie the differences in block. However, after a brief (50 ms) depolarizing pulse, recovery from lidocaine block is similar for the two isoforms despite marked kinetic differences in drug-free recovery, suggesting that differences in fast inactivation cannot entirely explain the isoform difference in lidocaine action. Given the strong coupling between fast inactivation and other gating processes linked to depolarization (activation, slow inactivation), we considered the possibility that isoform differences in lidocaine block are explained by differences in these other gating processes. In whole-cell recordings from HEK-293 cells, the voltage dependence of hH1 current activation was ~20 mV more negative than that of µ1. Because activation and closed-state inactivation are positively coupled, these differences in activation were sufficient to shift hH1 availability to more negative membrane potentials. A mutant channel with enhanced closed-state inactivation gating (µ1-R1441C) exhibited increased lidocaine sensitivity, emphasizing the importance of closed-state inactivation in lidocaine action. Moreover, when the depolarization was prolonged to 1 s, recovery from a "slow" inactivated state with intermediate kinetics (I_M) was fourfold longer in hH1 than in µ1, and recovery from lidocaine block in hH1 was similarly delayed relative to µ1. We propose that gating processes coupled to fast inactivation (activation and slow inactivation) are the key determinants of isoform-specific local anesthetic action.

Biophys J, January 2000, p. 200-210, Vol. 78, No. 1
© 2000 by the Biophysical Society   0006-3495/00/01/200/11  $2.00

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