Sodium channel molecular conformations and antiarrhythmic drug affinity

Abstract

Class I cardiac antiarrhythmic drugs, for example, lidocaine, mexiletine, flecainide, quinidine, and procainamide, continue to play an important role in the therapy for cardiac arrhythmias because of the presence of use-dependent block. Lidocaine, as well as related drugs such as mepivacaine, bupivacaine, and cocaine, also belong to the class of medications referred to as local anesthetics. In this review, we will consider lidocaine as the prototypical antiarrhythmic drug because it continues to be widely used both as an antiarrhythmic drug (first used as an antiarrhythmic drug in 1950) as well as a local anesthetic agent. Both of these clinical uses depend upon block of sodium current (I(Na)), but it is the presence of use-dependent I(Na) block, that is, an increasing amount of block at faster heart rates, which enables a local anesthetic agent to be a useful antiarrhythmic drug. Although many early studies investigated the action of antiarrhythmic drugs on Na currents, the availability of site-directed mutant Na channels has enabled for major advances in understanding their mechanisms of action based upon molecular conformations of the Na channel.

Figure 1

Proposed location for lidocaine in the closed (A) and open/inactivated (B) Na channel pore. Lidocaine is shown as space-filled (green represents C atoms, blue represents N atoms, and red represents O atoms) docking in the interface of DIIIS6 and DIVS6 (both green ribbons). Amino acid residues making contacts with lidocaine are shown by blue (DIIIS6) and red (DIVS6) colors. Lidocaine is predicted to be oriented horizontally with its aromatic ring aligned with Phe1759 in the closed channel (shown below panel A). In contrast, the charged, tertiary amine of lidocaine is predicted to be oriented vertically in the open/inactivated channel (shown below panel B). (Adapted from Hanck et al. 2009).

Figure 2

Steady-state voltage-dependent Na channel availability curves for cells expressing NaV1.5a (WT) (A) and (B), and for F1759K mutant channels (C). The voltage protocol is shown as an insert to (B). Summary data for Na channel availability in WT (A) channels in control (□) and after exposure to lidocaine (0.5 mM (•), 1 mM (◆) from a holding potential (V_hp) of −150 mV. The right panel of (A) shows the shifts in V_½ of availability for cells exposed to four concentrations of lidocaine including cells exposed to 5 μM and 50 μM, concentrations at which little reduction in maximal I_Na was evident. (B) Data showing the effect of holding potential on tonic block in WT cells held at −135 mV (•) or -155 mV (■) exposed to 0.5 mM lidocaine. In control solutions steady-state voltage-dependent availability (○ and □) were not different. However, in the presence of lidocaine the amount of tonic block from a V_hp of −155 mV (■) was 0.36 while from a V_hp of −135 mV (•) it was 0.58, an amount almost twice as large. Furthermore, the leftward shift in V_½ was 10 mV greater with V_hp of −135 mV compared to −155 mV. (C) Data for cells expressing F1759K exposed to 1 mM (■), 3 mM (•), and 10 mM (◆). The right panel shows that the shift in V_½ is independent of lidocaine concentration. The ED₅₀'s calculated from the fitted asymptotes of the Na channel availability relationships were 0.78 mM for WT (A), and 2.2 mM for F7159K(C). (Adapted, in part, from (Hanck et al. 2009).