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From the * Department of Anesthesiology, We used patch clamp techniques to study the inhibitory effects of pentobarbital and barbital on nicotinic acetylcholine receptor channels from BC3H-1 cells. Single channel recording from outside-out patches reveals that both drugs cause acetylcholine-activated channel events to occur in bursts. The mean duration of gaps
within bursts is 2 ms for 0.1 mM pentobarbital and 0.05 ms for 1 mM barbital. In addition, 1 mM barbital reduces
the apparent single channel current by 15%. Both barbiturates decrease the duration of openings within a burst
but have only a small effect on the burst duration. Macroscopic currents were activated by rapid perfusion of
300 µM acetylcholine to outside-out patches. The concentration dependence of peak current inhibition was fit
with a Hill function; for pentobarbital, Ki = 32 µM, n = 1.09; for barbital, Ki = 1900 µM, n = 1.24. Inhibition is
voltage independent. The kinetics of inhibition by pentobarbital are at least 30 times faster than inhibition by barbital (3 ms vs. <0.1 ms at the Ki). Pentobarbital binds Department of Physiology and Biophysics, University at Stony Brook, Stony Brook, New
York 11794-8480; and || Klinik für Anästhesiologie, Universität Bonn, Bonn 53105, Germany
10-fold more tightly to open channels than to closed channels; we could not determine whether the binding of barbital is state dependent. Experiments performed with
both barbiturates reveal that they do not compete for a single binding site on the acetylcholine receptor channel protein, but the binding of one barbiturate destabilizes the binding of the other. These results support a kinetic
model in which barbiturates bind to both open and closed states of the AChR and block the flow of ions through
the channel. An additional, lower-affinity binding site for pentobarbital may explain the effects seen at >100 µM
pentobarbital.
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