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Departments of
¹ Anaesthesiology
² Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA

Upon prolonged depolarizations, voltage-dependent Na⁺ channels open and subsequently inactivate, occupying fast and slow inactivated conformational states. Like C-type inactivation in K⁺ channels, slow inactivation is thought to be accompanied by rearrangement of the channel pore. Cysteine-labelling studies have shown that lidocaine, a local anaesthetic (LA) that elicits depolarization-dependent (‘use-dependent’) Na⁺ channel block, does not slow recovery from fast inactivation, but modulates the kinetics of slow inactivated states. While these observations suggest LA-induced stabilization of slow inactivation could be partly responsible for use dependence, a more stringent test would require that slow inactivation gating track the distinct use-dependent kinetic properties of diverse LA compounds, such as lidocaine and bupivacaine. For this purpose, we assayed the slow inactivation-dependent accessibility of cysteines engineered into domain III, P-segment (µ1: F1236C, K1237C) to sulfhydryl (MTSEA) modification using a high-speed solution exchange system. As expected, we found that bupivacaine, like lidocaine, protected cysteine residues from MTSEA modification in a depolarization-dependent manner. However, under pulse-train conditions where bupivacaine block of Na⁺ channels was extensive (due to ultra-slow recovery), but lidocaine block of Na⁺ channels was not, P-segment cysteines were protected from MTSEA modification. Here we show that conformational changes associated with slow inactivation track the vastly different rates of recovery from use-dependent block for bupivacaine and lidocaine. Our findings suggest that LA compounds may produce their kinetically distinct voltage-dependent behaviour by modulating slow inactivation gating to varying degrees.

(Received 17 December 2004; accepted after revision 24 January 2005; first published online 27 January 2005)
Corresponding author P. C. Viswanathan: 560, Preston Research Building, 2220 Pierce Avenue, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA. Email: prakash.viswanathan{at}vanderbilt.edu

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