Journal of Cardiovascular Pharmacology and

Therapeutics
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The Influence of Extracellular Acidosis on the Effect of IKr Blockers

Congrong Lin, Xiaogang Ke, Ivana Cvetanovic, Vasant Ranade and John Somberg
J Cardiovasc Pharmacol Ther 2005; 10; 67
DOI: 10.1177/107424840501000108

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 J Cardiovasc Pharmacol Therapeut 10(1):67–76, 2005

The Influence of Extracellular Acidosis

on the Effect of IKr Blockers
Congrong Lin, MD, Xiaogang Ke, MD, Ivana Cvetanovic, MD,
Vasant Ranade, PhD, and John Somberg, MD

Background: Myocardial infarction causes the acidification of the cellular environment and
the resultant acidosis maybe arrhythmogenic. The effect of acidosis on the action of antiar-
rhythmic drugs, an important issue in the antiarrhythmic drug therapy after myocardial
infarction, remains to be studied.
Methods: To evaluate the effect of acidosis on rectifier potassium current (Ikr) blockers, the
human ether-a-go-go-related gene (HERG), which encodes IKr, was expressed in Xenopus
laevis oocytes. The two electrodes voltage clamp technique was used and the experiments
were performed at room temperature.
Results: Quinidine (10 µM) inhibited HERG tail current by 37% ± 5% at pH7.4. The block
decreased to 5% ± 2% with extracellular pH at 6.2. Dofetilide (0.3 µM) inhibited HERG tail
current by 34% ± 3% and 1% ± 2% at extracellular pH 7.4 and 6.2, respectively. Azimilide
(10 µM) inhibited HERG tail current by 59% ± 3% and 17% ± 3% at extracellular pH 7.4 and
6.2. There were significant differences in the HERG inhibition by quinidine, dofetilide, and
azimilide between pH 7.4 and pH 6.2 (P < .01). The drug concentration blocking 50% of cur-
rent (IC50) was 5.8 ± 0.3 µM for azimilide, 9.9 ±1.0 µM for quinidine, and 0.5 ± 0.02 µM for
dofetilide at pH 7.4. When extracellular pH was decreased from 7.4 to 6.2, the IC50 increased
to 95.5 ± 11.3 µM for azimilide, 203.2 ± 15.7 µM for quinidine, and 12.6 ± 1.2 µM for
dofetilide. Unlike quinidine, dofetilide, and azimilide, there was no significant difference in
the percentage of current block by amiodarone between pH 6.2 and 7.4. For amiodarone, the
IC50 was 38.3 ± 8.5 µM at pH 7.4 and 27.3 ± 1.6 µM at pH 6.2.
Conclusion: Our data show that the Ikr blocking effect of azimilide, dofetilide, and quinidine
was attenuated at acid pH, whereas this was not the case for amiodarone. These observations
may explain the efficacy of amiodarone in reducing arrhythmic death in patients after a
myocardial infarction compared with other IKr blockers.
Key words: acidosis, antiarrhythmic drugs, HERG channel.

Myocardial ischemia can cause a marked acidosis (1)
(more than 0.5 pH units) in the ischemic region due to
the accumulation of lactic acid and CO2, which can
increase fourfold during 30 minutes of ischemia (2). It
is well recognized that acidosis markedly affects the
From the Department of Pharmacology, Rush University Medical
Center, Chicago, IL.
Reprint requests: John Somberg, MD, Department of Pharma-
cology, Rush University, Chicago, IL 60612; e-mail: jsomberg
@rush.edu.
Copyright © 2005 Westminster Publications, Inc., 708 Glen Cove
Avenue, Glen Head, NY 11545, USA
function of cardiac muscle. Acidosis decreases heart
contractility (3) and alters the electrical activity of the
cell (4). Acidosis can depolarize the resting membrane
potential and produce abnormal cardiac repolarization
(5–7). The susceptibility of the heart to ventricular fib-
rillation is increased during metabolic acidosis (8,9).
Therefore, acidosis may have a role in arrhythmogen-
esis during myocardial ischemia.
It is important to understand the influence of acido-
sis on the action of the antiarrhythmic agents that are
frequently prescribed for patients after a myocardial
infarction; however, few studies have been reported in
this area and the results vary. The reduction in resting
potential, action potential amplitude, and Vmax by lido-

67

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68 Journal of Cardiovascular Pharmacology and Therapeutics Vol. 10 No. 1 2005
caine and quinidine were shown to be greater at a
more acid pH (10), whereas disopyramide was shown
to exert a smaller effect on myocardial contractility,
His-ventricular conduction time, and QT interval (11).
The rapidly activating component of the delayed
rectifier potassium current (IKr) is critical for cardiac
repolarization and is the important target for many
antiarrhythmic agents. In this study, we evaluated the
effect of extracellular pH on the action of the IKr-
blocking antiarrhythmic drugs. IKr was studied at
room temperature by using human ether-a-go-go-
related gene (HERG) expressed in Xenopus laevis
oocytes and the two electrodes voltage-clamp tech-
nique was used for recording. HERG expressed in
Xenopus oocytes and human embryonic kidney cells
encodes a K+ channel of biophysical and pharmaco-
logic characteristics similar to cardiac IKr (12, 13).
For this reason, HERG expressed in Xenopus oocytes
has been widely used to evaluate the effects of antiar-
rhythmic drugs on IKr.
Method
Xenopus laevis Oocytes Isolation
Female Xenopus laevis frogs (Nasco, Modesto, CA)
were anesthetized with 0.2% tricaine methanesul-
fonate (Sigma, St. Louis, MO). The ovarian lobes
were surgically removed and digested with 2.0 mg/mL
type IA collagenase (Sigma) for 2 hours in a Ca2+-free
solution containing (mmol/L) 88.0 NaCl, 1.0 KCl, 2.4
NaHCO3, 5.0 HEPES, 0.82 MgCl2 solution (pH 7.6
with NaOH) to remove the follicle layer. At the end of
collagenase treatment, the stage V and VI oocytes
were picked up and stored in modified Barth solution
containing (mmol/L) 88.0 NaCl, 1.0 KCl, 2.4
NaHCO3, 5.0 HEPES, 0.30 Ca(NO3)2, 0.40 CaCl2, 0.82
MgSO4, 2.5 pyruvic acid and gentamicin (50 ug/mL),
pH 7.6 with NaOH.
Expression of HERG in Oocytes
The HERG clone was a gift from Dr Gail Robertson
(University of Madison, Wisconsin) and the cDNA
was cloned into the pGH19 vector. The cDNA was lin-
eralized with NOT1 and in vitro transcription was
made with T7 mMessage Machine Kit (Ambion,
Austin, TX). One day after isolation, oocytes were
injected with 40 nL of 50 µg/µL of HERG cRNA
using a microinjector (Drummond Sientific,
Broomall, PA) and incubated at 18°C to 20°C in the
modified Barth solution.
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Electrophysiology
Currents were studied 2 to 7 days after injection by the
2 microelectrodes voltage-clamp technique at room
temperature (21°C to 23°C). The oocytes were voltage-
clamped with an amplifier (Warner OC-725 C oocyte
clamp, Warner Instruments, Hamden, CT). Current and
voltage electrodes were filled with 3 mol/L KCl and
had a resistance of 2 to 4 MΩ for voltage-recording
electrodes and 1 to 2 MΩ for current-passing elec-
trodes. The recording bath solution contained in
mmol/L: 96 Na Cl, 5.0 KCl, 2.0 CaCL2, 1.0 MgCl2, 5
HEPES; and the pH of solution was adjusted with
NaOH to 7.4 or 6.2. The pH 6.2 or lower has been stud-
ied by a number of investigators (14, 15). Additionally,
acidotic condition at this low pH has been observed in
human following aortic crossclamping (16).
Electrophysiologic recordings were made before
and after 10 minutes of the drug perfusion. The rela-
tive current at different concentrations of drug, calcu-
lated from the ratio Idrug/Icontrol of the peak tail current,
was normalized and fit with Hill function with the rel-
ative current = 1/[1+(D/IC50)h], where D is drug con-
centration and h is the Hill coefficient, and IC50 is the
drug concentration blocking 50% of current, which
was calculated from Hill equation. The percentage of
current block was calculated by (I control–I drug)/I control.
Drug Supplies
Quinidine anhydrous and amiodarone were purchased
from Sigma. Dofetilide was obtained from Pfizer
Global Research. Azimilide was obtained from Procter
& Gamble Pharmaceuticals. A 50-mM stock solution
of each drug was made by dissolving in dimethylsul-
foxide (DMSO) and kept at –20°C. Appropriate drug
dilution with 5K recording solution with various pH
levels was prepared shortly before the experiments.
The concentration of DMSO in the perfusion solutions
did not exceed 0.2% to avoid solvent effects.
Statistics
Data acquisition was made with pCLAMP software
(Axon Instruments, Foster City, CA). Experiments in
which the holding current was more than 200 nA at
–80 mV holding potential were excluded from analy-
sis. Statistical significance for the data was obtained
by the Student t test. When appropriate, data were
expressed as mean ± SEM.
Results
Xenopus oocytes, after injection of HERG cRNA,
expressed potassium current that had similar biophys-
 The Influence of Extracellular Acidosis on the Effect of IKr Blockers • Lin et al. 69

ical characteristics to IKr (12,13). The initial holding
potential was –80 mV, then stepped pulses from –60
mV to 40 mV in 10-mV increments (the stepped pulse
duration was 1200 ms) and returning to –40 mV of
potential (Fig. 1). HERG current was activated at a
potential of more than –40 mV by depolarizing pulse
from holding potential –80 mV. The amplitude of out-
ward currents grew larger as the membrane was depo-
larized, reached maximum around 0 mV, and then
decreased progressively with further depolarization,
showing a pronounced inward rectification of current-
voltage relationship. The outward tail currents devel-
oped when the membrane potential returned to –40
mV. The amplitude of tail current was larger than that
of the current during pulsing and increased as mem-
brane potential increased.
The effect of the Ikr-blocking drug quinidine at
extracellular acidosis was studied. The inhibitions of
currents by 10 µM quinidine at pH 7.4 and 6.2 are
shown in Fig. 2A and B, respectively. When pH was
changed from 7.4 to 6.2, the blocking effect of quini-
dine was greatly diminished at pH 6.2. The percentage
of current block at various concentrations of quinidine
is depicted in Fig. 2C. The percentage of current block
increased as quinidine concentration increased. The
dose-dependent inhibitory effect of quinidine was
greater at pH 7.4 than at 6.2. Quinidine at 10µM inhib-
ited HERG tail current by 37% ± 5% at pH7.4. The
inhibition was decreased to 4% ± 2% at pH 6.2. As the
extracellular H+ increased, the quinidine inhibitory
effect decreased. There were significant differences in
the current blockade between pH 6.2 and 7.4 at every
tested quinidine concentration (P < .01). The IC50 of
quinidine at pH 6.2 and 7.4 are shown in Fig. 2D. The
IC50 was 9.9 ± 1.0 µM at pH 7.4 and increased to 203.2
± 15.7 µM at pH 6.2.
The IKr inhibitory effect of dofetilide is also modi-
fied by extracellular acidosis (Fig. 3). The current
traces with and without 0.3 µM dofetilide at pH 7.4
are shown in Fig. 3A. The current traces before and
after 0.3µM dofetilide at pH 6.2 are shown in Fig. 3B.
The current was greatly inhibited by 0.3µM dofetilide
at pH 7.4. The current inhibition by the same concen-
tration of dofetilide was significantly less at pH 6.2
than that at pH 7.4. In Fig. 3C, the percentage of cur-
rent block is shown versus a series of concentrations
of dofetilide at different pH values. The dose-depen-
dent inhibitory effect of dofetilide was much less at
pH 6.2 than that at pH 7.4. As the concentration of
dofetilide increased, the inhibitory effect increased
much more at pH 7.4 than at pH 6.2. Dofetilide at
0.3µM inhibited HERG tail current by 34% ± 3% at
pH 7.4 and 1% ± 2% at pH 6.2. There were signifi-
cant differences in current inhibition between pH 6.2
and 7.4 at every tested dofetilide concentration (P <
.01). The IC50 was increased from 0.5 ± 0.02 to 12.6 ±
1.2 µM as extracellular pH decreased from 7.4 to 6.2
(Fig. 3D).

Fig. 1. The characteristics of HERG channels expressed in Xenopus oocytes. (A) The current traces elicited by depolar-
izing voltage pulses (1.2 seconds) in 10 mV steps (upper panel) from –60 mV to 40 mV, and returning to –40 mV. The ini-
tial holding potential was –80 mV. (B) Plot of the steady state current (measured at the end of depolarizing pulses) and the
peak tail current plotted against voltage. The data is presented as mean ± SEM, each data point was obtained from 5 cells.

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70 Journal of Cardiovascular Pharmacology and Therapeutics Vol. 10 No. 1 2005

●
●

Fig. 2. The effect of extracellular pH on the action of quinidine (Qui) on IKr. (A) Upper panel shows the voltage proto-
col. The lower panel shows the current traces from one cell at pH 7.4 as well as at 10 µM Qui. (B) The current traces from
one cell at pH 6.2 and at 10 µM Qui. (C) The percentage of current block by quinidine at different pHs. The peak tail cur-
rents at different pH levels without drug were taken as 1. (D) The IC50 of Qui at pH 7.4 (●) and 6.2 (●), n = 5–7.

The influence of extracellular pH on another Ikr-
blocking agent, azimilide, is shown in Fig. 4. The cur-
rent inhibitions by solution of 10 µM azimilide at pH
7.4 and 6.2 are shown in A and B, respectively. A large
portion of the current was inhibited by 10 µM azim-
ilide at pH 7.4, but the inhibitory effect dramatically
declined for azimilide when the pH was 6.2.
In Fig. 4C, the percentage of HERG inhibition by
various concentrations of azimilide at different pHs is
shown. As the dose of azimilide was increased, the
blocking effect at 7.4 increased much more than that
at pH 6.2. The dose-dependent inhibitory effect of
azimilide was more obvious at pH 7.4 than at pH6.2.
Azimilide at 10µM inhibited HERG tail current by
59% ± 3% and 17% ± 3% at pH 7.4 and 6.2, respec-
tively. The t test showed that there were significant
differences in current blockade between different pHs
at every tested azimilide concentration (P < 0.01).
The IC50 was increased from 5.8 ± 0.3 µM to 95.5 ±
11.3 µM as extracellular pH decreased from 7.4 to 6.2
(Fig. 4D).
Unlike dofetilide, quinidine, and azimilide, extra-
cellular acidification shows little impact on the effect
of amiodarone on the HERG channel. The effect of
extracellular pH on the IKr block of amiodarone is
shown in Fig. 5. The current traces with and without
10µM amiodarone at pH 7.4 and 6.2 solution are
shown in A, and B. The current was inhibited to the
similar extent by 10µM amiodarone at pH 7.4 and 6.2.
The percentage of current block by amiodarone at dif-
ferent pH levels is shown in Fig. 5C.
In contrast to quinidine, dofetilide and azimilide, as
the concentration of amiodarone increased, the slope
of increment in IKr block was similar at pH 6.2 and
7.4. Amiodarone at 10 µM inhibited HERG tail cur-
rent by 41% ± 7% at pH 6.2 and 43% ± 4% at pH 7.4.
Amiodarone at 100 µM decreased HERG tail current
by 62 ± 5 at pH 6.2 and by 55 ± 5 at pH 7.4. There was

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 The Influence of Extracellular Acidosis on the Effect of IKr Blockers • Lin et al. 71

●
●

Fig. 3. The effect of extracellular pH on HERG blockade by dofetilide (Dof). (A) Upper panel shows the voltage proto-
col. The lower panel shows the current traces from the same cell at pH 7.4 as well as at 0.3 µM Dof. (B) The current traces
from a cell at pH 6.2 and after 0.3µM Dof. (C) The percentage of current block at different concentrations of dofetilide at
various pH levels. (D) The IC50 of dofetilide at pH 7.4 (●) and 6.2 (●). Symbols with the error bars represent the mean ±
SEM, each data point obtained from 5 cells.

no significant difference in the percentage block Discussion

between pH 7.4 and 6.2 groups at every amiodarone
concentration tested (P > 0.05). Fig. 5D shows the IC50
of amiodarone at pH 7.4 and pH 6.2. The IC50 were
27.3 ± 1.6 µM at pH 6.2 and 38.3 ± 8.5 µM at pH 7.4.
The influence of extracellular acidosis on quini-
dine, dofetilide, azimilide, and amiodarone was fur-
ther compared as to the extent of change in the current
inhibition when lowering pH from 7.4 to 6.2. The
changes in current inhibition by these IKr blockers at
different pH levels (percentage of current block at pH
7.4 – percentage of current block at pH 6.2) is depict-
ed in Fig. 6. When the extracellular pH was acidified
from 7.4 to 6.2, there was little change in the percent-
age of current block by amiodarone, whereas there
were significant changes for the other IKr blockers.
The specific IKr blocker dofetilide shows the greatest
decrement in its blocking effect as extracellular (H+)
increases.
Ventricular arrhythmias are the major cause of death
after myocardial infarction. Metabolic acidosis gener-
ated in the acute ischemic myocardium is an important
factor that may result in arrhythmias. Considerable
efforts have been made to identify effective antiar-
rhythmic drugs that can reduce arrhythmic death after
myocardial infarction.
Many clinical trials with various type I antiarrhyth-
mic drugs (sodium-channel blockers) failed to sup-
press arrhythmias and prevent death in postmyocar-
dial infarction patients. The Cardiac Arrhythmia
Suppression Trial (CAST) showed that flecainide,
encainide, and moricizine actually increased mortality
(17). Data on calcium-channel blockers has not been
promising, but β-blockers have been demonstrated to
reduce mortality (18).

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72 Journal of Cardiovascular Pharmacology and Therapeutics Vol. 10 No. 1 2005

●
●

Fig. 4. The effect of azimilide (Azi) on HERG blockade at different pHs. (A) Upper panel shows the voltage protocol.
The lower panel shows the current traces from a cell at pH 7.4 as well as at 10µM azimilide perfusion. (B) The current
traces from a cell at pH 6.2 solution and after 10 µM azimilide. (C) The percentage of current block at different concen-
trations of azimilide at various pH levels. (D) The IC50 of azimilide at pH 6.2 (●) and pH 7.4 (●). Symbols with the error
bars represent the mean ± SEM, each data obtained from 6 cells.

It was hoped that type III antiarrhythmic agents
could reduce the cardiac mortality in a post myocar-
dial infarction population. Nevertheless, the Survival
With Oral d-Sotalol (SWORD) trial showed a signifi-
cantly higher mortality in the drug-treated patients
(19). The Azimilide Post Infarct Survival Evaluation
(ALIVE) trial demonstrates that azimilide does not
have a benefit on mortality, and the risk of arrhythmic
death is similar in azimilide and the placebo groups
(20).
The Danish Investigation of Arrhythmia and
Mortality on Dofetilide (DIAMOND) trials found no
significant difference in arrhythmic mortality between
dofetilide-assigned and placebo-assigned patients
(21).
Only clinical trials with amiodarone appear promis-
ing in myocardial infarction patients. The European
Myocardial Infarction Amiodarone Trial (EMIAT)
(22) and the Canadian Amiodarone Myocardial
Infarction Trial (CAMIAT) (23) support the use of
amiodarone in high-risk patients as an antiarrhythmic
therapy in the survivors of a myocardial infarction.
Amiodarone lacks proarrhythmic toxicity (24,25) and
may decrease arrhythmic death (26). Amiodarone has
been reported to possess the least proarrhythmic risk
among type III anti-arrhythmic agents (24,25), and
this has been believed due to its electrophysiologic
profile that may cause significant myocardial homo-
geneity (24,27).
In this study, we evaluated the effect of Ikr-block-
ing agents at low extracellular pH to mimic metabolic
acidosis in the ischemic myocardium. The important
finding of our study is that amiodarone retains its IKr
inhibitory effect at extracellular acidosis, but the effect

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 The Influence of Extracellular Acidosis on the Effect of IKr Blockers • Lin et al. 73

●
●

Fig. 5. The effect of extracellular pH on HERG blocking activity by amiodarone (Amio). (A) The current traces from one
cell at pH 7.4 solution as well as after 10µM amiodarone perfusion. (B) The current traces from a cell with and without
10 µM amiodarone at pH 6.2. (C) The percentage of current blockade at different concentrations of amiodarone at vari-
ous pH levels. (D) Comparison of the IC50 of amiodarone at pH 7.4 (●) and 6.2 (●). Symbols with the error bars represent
mean ± SEM, each data obtained from 6 to 7 cells.

Fig. 6. The change in the percentage of current inhibition when extracellular pH changed from 7.4 to
6.2. The change in the percentage of current inhibition was calculated as: percentage current blockade
at pH 7.4 – percentage current blockade at pH 6.2.

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74 Journal of Cardiovascular Pharmacology and Therapeutics Vol. 10 No. 1 2005
of quinidine, dofetilide, and azimilide was markedly
diminished with acidosis. We believe this is the first
report that extracellular acidosis has a differential
influence on amiodarone and other IKr blockers.
We observed a marked decrement in HERG inhibi-
tion by dofetilide in response to acidification, regard-
less of prepulsing rate (data not reported in this paper).
Both the current blockade with no prepulsing and at 1
HZ prepulsing showed a decline in effect with acido-
sis. West et al (28) reported that dofetilide demon-
strated a significantly reduced blockade of IKr with
acidosis in rabbit ventricular myocytes. A recent study
performed by Dong et al (29) also showed that lower-
ing pH decreased the inhibitory effect of quinidine and
azimilide on the HERG channel. But in contrast to our
result, they found an increased inhibitory effect of
dofetilide on the HERG channel after acidification.
This discrepancy may result from the different buffer
system used in the study. In Dong’s study, acidic solu-
tion was prepared with sodium acetate instead of sodi-
um chloride. Sodium acetate may change the extracel-
lular pH and intracellular pH, leading to different
results.
This study demonstrates for the first time that
unlike quinidine, azimilide and dofetilide, amiodarone
exerts the same degree of inhibition on the HERG
channel at acidic pH as that at normal pH. This pre-
served efficacy of IKr inhibition with acidosis may
underlie the mechanism by which amiodarone, rather
than other IKr blockers, is somewhat effective in pre-
venting arrhythmic death in myocardial infarct popu-
lation, demonstrated by the above clinical trials. The
attenuation of IKr inhibition by quinidine, azimilide,
and dofetilide at acidic conditions may explain the
lack of efficacy of these drugs in preventing arrhyth-
mias and reducing arrhythmic death in patients with
myocardial infarction.
It has been reported recently that there are multiple
proton binding sites in HERG, and extracellular pro-
tons bind rapidly and reversibly to affect both activa-
tion and deactivation (30). The binding of extracellu-
lar protons may reduce a drugs’ binding affinity,
resulting in an attenuated IKr block. The drug-binding
site for amiodarone may be different from that of
quinidine, dofetilide and azimilide, and thus it might
not be affected by the extracellular protons. This
hypothesis is supported by an interesting observation
that amiodarone and its analogue, Dronedarone, block
the HERG channel without a strong dependence on
Y652 and F565 (31). These two aromatic amino acids
on the inner (S6) helices are considered to be key con-
stituents of a high-affinity drug-binding site within the
HERG channel pore cavity (32–34). The extracellular
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protons may interact with these critical amino acids,
leading to the decreased binding affinity and dimin-
ished HERG inhibition by quinidine, dofetilide, and
azimilide. On the other hand, the blockade of HERG
by amiodarone lacks the strong dependency on these
amino acids, which may account for its unchanged
potency with acidosis.
Another possible explanation for the observed dif-
ferences is that the access of drugs to IKr channels
through the lipid membrane is modified by acidifica-
tion, particularly for dofetilide, quinidine, and azim-
ilide, because acidosis is likely to decrease lipophilic-
ity. Amiodarone, on the other hand, is extremely
lipophilic and would not be significantly affected by
acidosis, which preserves its IKr inhibitory effect.
The extracelluar acidosis may also change the pro-
portion of ionized to un-ionized drug and change the
accessibility of a drug to its binding site, contributing
to the diminished drug effect. But we believe that the
change in the ionization does not play a major role.
Since both quinidine (pK1, 5.4; pK2, 10.0) and azim-
ilide (pK1, 3.75; pK2, 8.06) have pK1 of less than 7.4
and pK2 of more than 7.4, switching extracellular pH
from 7.4 to 6.2 would not produce enough change in
the un-ionized portion of a drug to explain the signif-
icant decrease in the drugs’ Ikr-blocking action.
Additionally, amiodarone has a pKa value of 6.56 ±
0.06. The portion of un-ionized drug will increase as
the extracellular pH changes from 7.4 to 6.2, leading
to a greater IKr inhibition with acidic conditions.
However, the percentage of current blockade by amio-
darone shows little change as extracellular pH
decreased from 7.4 to 6.2.
We used HERG expressed on Xenopus oocytes as
the study model to investigate the influence of extra-
cellular acidosis on the effect of IKr blockers. Because
HERG expressed in Xenopus oocytes encodes a K+
channel of similar biophysical and pharmacologic
characteristics of cardiac IKr (12,13), it has been a fre-
quently used tool to evaluate the effects of antiar-
rhythmic drugs on IKr. When the oocyte expression
system is used, the potency of block by some drugs
has been noticed to be less than that observed on
mammalian cell lines (35–37). This difference may
result from the vitelline membrane surrounding the
oocyte, which might impede the access of compounds
to the ion channels expressed in the oocyte membrane.
Although the potency of drugs may exhibit difference
in oocyte model and mammalian cell lines, the studies
done on these different systems usually reflect similar
actions of the drugs but to a different extent. For
instance, the diminished IKr inhibition by dofetilide
after extracellular acidification has been observed
 The Influence of Extracellular Acidosis on the Effect of IKr Blockers
from HERG expressed on Xenopus oocytes in our
study and in other studies using the rabbit myocyte
model (28). Further studies confirming these observa-
tions are appropriate in mammalian cell lines as well
as evaluation of the effects at body temperature and at
temperatures observed in ischemic regions.
In conclusion, extracellular acidosis has different
effects on IKr inhibition by amiodarone from that of
other IKr blockers. IKr inhibition by amiodarone does
not decline at low pH, whereas the effects of other IKr
blockers are diminished with decreasing pH. This
unique property of amiodarone may explain the bene-
ficial effects of amiodarone reported in some patients
after myocardial infarction.
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