Page 37 - F. Cell biology
P. 37
Effects of acebutolol on cardiac action potential and
human ERG K Current
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Su-Hyun Jo
Department of Physiology, Institute of Bioscience and Biotechnology, BK21 plus Graduate Program, Kangwon National University
College of Medicine, Chuncheon 200-701, Korea
ABSTRACT A B
K channels are key components of the primary and
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secondary basolateral Cl pump systems, which are
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important for secretion from the salivary glands.
Acebutolol is a cardioselective beta blocker with ISA
(intrinsic sympathomimetic activity). We studied the
effects of acebutolol on a human K channel, human ether-
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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 C D
rapidly-activating delayed rectifier K channel in the heart.
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Mutations in hERG reduce I Kr and cause type 2 long QT
syndrome, a disorder that predisposes individuals to life-
threatening arrhythmias. Acebutolol decreased hERG
current amplitude at the end of the voltage steps, however,
the drug failed to induce a concentration-dependent
changes hERG tail currents. Acebutolol did not change the
value of V 1/2 for activation curve of hERG tail current,
indicating the drug did not affect activation gating. In E
guinea pig ventricular myocytes, acebutolol did not change
the resting membrane potential, however, the drug
increased the action potential amplitude, action potential
duration (APD , APD ), showing that acebutolol could FIG 4: The effect of acebutolol on human ether-a-go-go-related
90
20
change cardiac electrophysiology function. 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 acebutolol
conditions (n = 5). B : Plot of the normalized tail current measured at
KEYWORDS its peak just after repolarization. The peak amplitude of the tail current
FIG 2: Effects of acebutolol exposure on action potential of guinea in the absence of the acebutolol was set as 1. Control data were fitted to
hERG channel; LQT; acebutolol; action potential pig ventricular myocytes. A: Time course of the effects of acebutolol the Boltzmann Equation, y = 1/ 1 + exp[(-V + V1/2)/dx] /, with V 1/2 of -
on action potential duration at 90% of repolarization (APD ). B: Time 20.3 mV (n = 5).
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course of the effects of acebutolol on action potential duration at 50%
of repolarization (APD ). C:Time course of the effects of acebutolol
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on action potential duration at 20% of repolarization (APD ). D: Time [Drug] (µM) V 1/2 (mV)
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course of the effects of acebutolol on action potential amplitude (APA). control (0) -20.317
-19.379
100
E: Time course of the effects of acebutolol on the resting membrane 300 -18.948
potential. Symbols with error bars represent mean ± S.E.M. (n = 3 - 6). 1000 -19.415
*P < 0.05.
TABLE 1: The effect of acebutolol 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
acebutolol (n = 5).
SUMMARY
1. Acebutolol, cardioselective beta blocker, induced the
prolongation of APD and APD , however the drug did not
20
90
FIG 1: Structure of acebutolol. change APD , APA, the resting membrane potential.
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2. The hERG current, which is expressed in Xenopus oocytes,
were not affected by acebutolol at the relatively high
concentrations of acebutolol.
3. These results could indicate that acebutolol can change
ventricular action potential possibly by changing other than
hERG currents such as L-type Ca currents.
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FIG 3: The effect of acebutolol 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 acebutolol and in the presence of 1 mM acebutolol for 15 min.
