© 1995 American Heart Association, Inc.
Articles |
Determinants of Antiarrhythmic Drug Action
Electrostatic and Hydrophobic Components of Block of the Human Cardiac hKv1.5 Channel
From the Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Abstract The molecular basis of antiarrhythmic drug action is
still poorly understood. We recently reported that block of the human
cardiac hKv1.5 channel by quinidine displayed similarity with internal
quaternary ammonium block of squid and Shaker potassium
channels. To gain further insight into the molecular determinants of
the affinity and the stereoselectivity of antiarrhythmic drug action,
we studied the effects of quinine (a diastereomer of quinidine),
clofilium (a quaternary ammonium class III agent), and
tetrapentylammonium (TPeA, a biophysical reference probe for the
internal quaternary ammonium binding site). For all compounds, block
was voltage dependent, with a steep increase over the voltage range of
channel opening and a superimposed weaker voltage dependence at more
positive potentials. The latter electrostatic component was similar for
all drugs, consistent with a binding reaction sensing 
20%
of the transmembrane electrical field. Clofilium and TPeA displayed a
higher apparent affinity (0.15 and 0.28 µmol/L, respectively), and
quinine displayed a lower one (21 µmol/L) compared with quinidine
(6.2 µmol/L). Block development upon depolarization was time
dependent for clofilium and TPeA but slow compared with quinidine. A
time-dependent component was difficult to resolve for quinine, but the
time course of deactivating tail currents was slower than in the
control condition. The resulting crossover phenomenon was also observed
for the quaternary drugs. Compared with TPeA alone, the combined
application of quinine and TPeA resulted in a reduced current that
decayed slower, consistent with competition. When a bimolecular
model for open-channel block was used, the apparent association rate
constants for these drugs were found to be similar [range, 4.5 to 7.7
(µmol/L)-1 · s-1]. The apparent
dissociation rate constants for clofilium (1.9 s-1) and
TPeA (3.6 s-1) were smaller compared with quinidine (34
s-1), whereas that for quinine was faster (
125
s-1). This large range in dissociation rate constants
could explain the differences between these drugs both in kinetics and
affinity. The results are consistent with a general model in
which these agents act as cationic open-channel blockers but with an
affinity largely determined by the intrinsic stability of the
drug-receptor complex. Hydrophobic interactions are most likely
involved in this stabilization of binding.
Key Words: K+ channels • antiarrhythmia agents • quaternary ammonium • quinidine • clofilium
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