Biomedical Engineering Reference
In-Depth Information
NS1643: A diphenylurea compound i.e., 1,3-bis-(2-hydroxy-5-trifluoromethyl-
phenyl)-urea (NS1643) also increases the activity of
hERG
channels expressed in
Xenopus laevis
oocytes. NS1643 (Table
1
) (EC
50
-10.5
M) increased both steady-
state and tail current at all voltages tested in the
hERG
expressed in
Xenopous
and
hERG
channels expressed in mammalian HEK 293 cells [
64
]. In guinea pig
cardiomyocytes, NS1643 significantly activated delayed rectifier potassium current
and decreased the action potential duration. This effect were reversed after appli-
cation of the specific
hERG
channel inhibitor 4
0
-[[1-[2-(6-methyl-2-pyridyl)ethyl]-
4-piperidinyl]carbonyl]-methanesulfonanilide (E-4031).
NS3623
:
N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-
N
0
-(3
0
-trifluoromethylphenyl)
urea (NS3623) also has the ability to activate
hERG
channels expressed in Xenopus
oocytes. Exposure of NS3623 affects the voltage-dependent release from inactiva-
tion, resulting in a half-inactivation voltage is rightward-shifted in
Xenopus
oocytes
[
65
]. Moreover, the compound affects the time constant of inactivation, leading to a
slower onset of inactivation of the macroscopic
hERG
currents [
65
]. Application of
NS3623 to
hERG
mutants did not result in increased
hERG
current. In contrast,
applications of NS3623 to the mutant F656M have shown to increase
hERG
current
to a larger extent as compared with wild-type
hERG
1 channels. NS3623 (Table
1
)
also has the ability to shorten action potential durations in guinea pig papillary
muscle.
Mallotoxin: Mallotoxin (MTX) is recently introduced as a naturally occurring
hERG
channel activator. MTX increases both step and tail
hERG
currents. MTX
leftward shifted the voltage dependence of
hERG
channel activation to less
depolarized voltages [
66
]. MTX also increased
hERG
deactivation time constants
without altering the half-maximal inactivation voltage of
hERG
channel, but it
reduced the slope of voltage-dependent inactivation curve. All of these factors
contribute to the enhanced activity of
hERG
channels. Application of MTX
increases the flow of potassium ions through
hERG
channels (Table
1
).
m
4.2 hERG Inhibitors
Amiodarone: Amiodarone is an antiarrhythmic drug used to treat ventricular and
supraventricular (atrial) arrhythmias, the IC
50
is around 0.7
M. It prolongs QT of
cardiac ECG (Table
2
). It shows beta-adrenoreceptor and potassium channel
blocking action on sinoatrial and atrioventricular node, which increases effective
refractory period via sodium and potassium channel that subsequently reduce
conduction of cardiac action potential. So it may lead to polymorphic ventricular
arrhythmia [
67
].
Astemizole: A non-sedating and selective H1-receptor antagonist, astemizole,
causes acquired longQT syndrome (Table
2
). Astemizole blocks the rapidly activating
delayed rectifier K
+
current I
Kr
and the
hERG
K
+
channels that underlie it. The
principal metabolite is desmethylastemizole and norastemizole. Desmethylastemizole
m
