Although lidocaine block of cardiac Na+ current (I(Na)) has been extensively studied in animal tissues, very little is known about its actions on human cardiac I(Na). We studied the effects of lidocaine (0.01-10 mM) on human atrial I(Na) in single myocytes using whole-cell patch-clamp techniques. The dose-response relationship for lidocaine block at a low frequency (0.2 Hz, 'tonic' block) indicated that lidocaine blocked Na+ channels by one-to-one binding with an apparent K(d) of 291 μM. Lidocaine (200 μM) shifted the steady-state I(Na) availability curve by -11 mV, but did not change the slope factor (n = 5). Lidocaine also induced use-dependent block that increased directly with increases in drug concentration (0.01-1 mM) and pulse duration (3-100 msec) and inversely with interpulse interval (2-0.33 sec). The time constant for onset of lidocaine (200 μM) block of I(Na) displayed both a fast (τ(f) = 3.6 ± 0.4 msec) and a slow (τ(s) = 168 ± 21 msec) exponential component (n = 10). In addition, lidocaine slowed the rate of I(Na) recovery after a 1-sec conditioning pulse to -20 mV, recovery was biexponential at a low drug concentration (20 μM), but had only a single slow phase at a high drug concentration (200 μM). These characteristics of lidocaine block suggest that lidocaine binds to both inactivated and activated Na+ channels in human atrial cells and that use-dependent block of I(Na) by lidocaine is dependent on drug concentration, interpulse interval and pulse duration, findings similar to those reported for other mammalian species. The similarity of these results to those obtained from atrial as well as ventricular cells from other species suggests that some source other than differential drug action on atrial and ventricular I(Na) underlies differential drug efficacy against supraventricular and ventricular dysrhythmias.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1993|
ASJC Scopus subject areas
- Molecular Medicine