Page 43 - F. Cell biology

Regulation of hERG current and cardiac action potential
Department of Physiology, Institute of Bioscience and Biotechnology, BK21 plus Graduate Program, Kangwon National University
ABSTRACT
Pindolol is a beta blocker which is used in the treatment of
hypertension and angina pectoris. We studied the effects of
pindolol on a human K channel, human ether-a-go-go-
+
related gene (hERG), expressed in Xenopus oocytes and on
action potential of guinea pig ventricular myocytes. The
hERG encodes the pore-forming subunits of the rapidly-
activating delayed rectifier K channel, which has an
important role in regulation of action potential duration of
cardiac ventricle, resulting in changes in ECG wave.
Pindolol decreased hERG current amplitude at the end of
the voltage steps and hERG tail currents only at 1000 µM,
the highest concentration we tested. Pindolol did not
change the value of V 1/2
current, indicating the drug did not affect activation gating.
In guinea pig ventricular myocytes, pindolol did not
change the resting membrane potential, however, the drug
increased the action potential amplitude, action potential
duration (APD , APD , APD ), suggesting that pindolol
90
50
could affect cardiac electrophysiology, particularly in
overdose condition.
KEYWORDS
hERG channel; LQT; pindolol; action potential
FIG 1: Structure of pindolol.
by pindolol
Su-Hyun Jo
College of Medicine, Chuncheon 200-701, Korea
A B
+
C D
for activation curve of hERG tail
E
20
FIG 4: The effect of pindolol on human ether-a-go-go-related
gene (hERG) currents elicited by depolarizing voltage. A: Plot of the
normalized hERG current measured at the end of depolarizing pulses
(IhERG) against the pulse potential in the control and pindolol
conditions (n = 5). B : Plot of the normalized tail current measured at
FIG 2: Effects of pindolol exposure on action potential of guinea its peak just after repolarization. The peak amplitude of the tail current
pig ventricular myocytes. A: Time course of the effects of pindolol on in the absence of the pindolol was set as 1. Control data were fitted to
action potential duration at 90% of repolarization (APD ). B: Time the Boltzmann Equation, y = 1/ 1 + exp[(-V + V1/2)/dx] /, with V 1/2 of -
90
course of the effects of pindolol on action potential duration at 50% of 20.3 mV (n = 5).
repolarization (APD ). C:Time course of the effects of pindolol on
50
action potential duration at 20% of repolarization (APD ). D: Time
20
(mV)
course of the effects of pindolol on action potential amplitude (APA). [Drug] (µM) V -17.333
1/2
control (0)
E: Time course of the effects of pindolol on the resting membrane 30 -18.491
potential. Symbols with error bars represent mean ± S.E.M. (n = 3 - 5). 100 -18.191
-17.895
300
*P < 0.05. 1000 -17.029
TABLE 1: The effect of pindolol on the voltage for half-maximal
activation of human-ether-a-go-go-related gene (hERG) currents.
V 1/2 of the Boltzmann Equation, y = 1/ 1 + exp[(-V + V1/2)/dx] in the
absence and the presence of various concentrations of pindolol (n = 5).
SUMMARY
1. Pindolol, non-selective beta blocker, induced the
prolongation of APD , APD , and APD , however the drug
20
50
90
did not change APA and resting membrane potential.
2. The hERG current, which is overexpressed in Xenopus
oocytes, were not affected by pindolol at the relatively high
concentrations of the drug.
3. These results could indicate that pindolol can change
ventricular action potential possibly by changing other currents
through such as L-type Ca channel than hERG channel.
2+
FIG 3: The effect of pindolol on human-ether-a-go-go-related
gene (hERG) currents elicited by depolarizing voltage. A:
Superimposed current traces elicited by depolarizing voltage pulses (4
s) in 10 mV steps from a holding potential of -70 mV in the absence
of pindolol and in the presence of 1 mM pindolol for 15 min.