Extract
Note: Please read the complete
full text with Figures and Tables at
Introduction
Numerous reports have demonstrated the
pro-arrhythmic effects of antipsychotic
drugs[1,2], among which, haloperidol, a butyrophenone antipsychotic with established
efficacy, exhibits adverse effects on the cardiovascular
system, including the alteration of superficial
electrocardiogram (ECG) configuration. The most severe forms of ECG
abnormalities elicited by haloperidol are shown as Q-T
interval prolongation, ST segment depression
and torsade de pointes (Tdp) in more severe
cases[3-7]. Cardiac arrhythmias under hypoxia are common. It was reported that action
potential duration (APD) shortening under myocardial
hypoxia might result in cardiac arrhythmias and was one of
the major factors that causes Tdp[8,9]. Monique and
colleagues reported that cardiac arrhythmias and Tdp were
associated with antipsychotic dosage, physiological, and
pathological conditions of patients[10]. Nonetheless, no
systematic study has been conducted regarding
haloperidol-induced arrhythmias with a special focus on hypoxic
condi-tions. Therefore, the aim of this study was to evaluate the
pro-arrhythmic risk of haloperidol under ischemia, in
order to provide some indication for the clinical use of these
antipsychotics.
Materials and methods
Preparation of samples Purkinje fiber samples: Male
New Zealand albino rabbits, weighing 2.0±0.3 kg, were
stunned by a blow to the back of the neck. The hearts were
rapidly removed and placed in high potassium Tyrode's
solution with 99.9% oxygen. The left ventricle was opened and
a 5-mm Purkinje fiber with cardiac tissue at both ends was
isolated and fixed at the bottom of a thermostatic bath
(5 mL). Then the fiber received an excessive high
potassium Tyrode's solution perfusion (velocity about 3
mL·min-1). After 30 min, the fiber was perfused with modified Tyrode's
solution bubbled with 99.9% oxygen at a temperature of 36.0±0.5 oC.
Papillary muscle samples: Male guinea pigs, weighing
200±50 g, were stunned by a blow to the back of the neck.
The hearts were rapidly removed and placed in modified
Tyrode's solution with 99.9% oxygen. The papillary muscle
of the right ventricle was isolated and fixed at the bottom of
a thermostatic bath. The muscle was superfused with
modified Tyrode's solution (about 3
mL·min-1) bubbled with 99.9% oxygen at a temperature of 36.0±0.5
oC.
The solutions included modified Tyrode's solution (in
mmol/L): NaCl 147.0, KCl 4.0, CaCl2 1.8,
MgCl2 0.5, Tris 1.2, and glucose 5.5, pH 7.35±0.05; excessive high potassium
Tyrode's solution (in mmol/L): NaCl 147.0, KCl 27.0,
CaCl2
1.8, MgCl2 0.5, Tris 1.2, glucose 55.0, and 99.9%
O2, pH 7.35±
0.05; and simulated ischemic fluid
(mmol/L)[11,12]: NaCl 147.0, KCl
4.0, CaCl2 1.8, MgCl2 0.5, Tris 1.2, and sodium lactate 22.0
saturated with 99.0%N2, pH 6.50.
Experimental protocols The samples received a 1 Hz
stimulation (stimulation potency was 150% of the threshold
potency) and were stabilized in modified Tyrode's solution
for 30 min. Then a glass microelectrode (filled with 3 mol/L
KCl and with a resistance of 20±10 MΩ) was inserted in the
samples to give the action potential curve. The signals were
amplified and recorded with a RM6240B image processing
system (Chengdu Instruments Factory, Sichuan, China). The
sampling frequency was 100 kHz. The entire experiment was
conducted in the same myocyte.
The Purkinje fibers were supervised with simulated
ischemic fluid for 50 min. The action potential curves at 0,
10, 20, 30, 40, and 50 min were obtained, respectively, under
1 Hz frequency.
Different concentrations of haloperidol (0.1, 0.3, 1, 3, and
10 µmol/L) were prepared with simulated ischemic fluid.
Haloperidol was added to the perfusion chamber from low to
high concentrations. The effects of each concentration were
observed for 10 min.
The action potential parameters were: the action
potential amplitude (APA), phase 0 maximum upstroke velocity
(Vmax), action potential amplitude at 90% of repolarization
(APD90); and effective refractory period (ERP).
Statistical analysis Data were expressed as mean±SD.
Statistical comparisons of data obtained under different
testing conditions were obtained by using paired
t-tests. Significant differences were fixed at
P<0.05.
Results
Effects of simulated ischemic fluid on the action
potentials of rabbit Purkinje fibers After simulated ischemic
fluid perfusion, a time-dependent decrease was observed in
the APA of Purkinje fibers with a statistical significance after
10 min. The decrease in the
Vmax and ERP also showed time-dependency and became significant at 30 min. Although
there was a decrease in APD90, no significant difference was
observed (Figure 1).
Effects of haloperidol on the action potential properties
of rabbit Purkinje fiber The Purkinje fibers were treated
with different concentrations of haloperidol and simulated
ischemic fluid simultaneously. The results showed that the
decrease in the APA revealed a concentration
dependency (P<0.05 starting from 3 µmol/L);
Vmax also showed a concentration dependency
(P<0.01, 1 µmol/L); and there was a
tendency of ERP prolongation, although no statistical
significance was reached. When the haloperidol concentration
was increased to10 µmol/L, a significant decrease in ERP
(P<0.05) was observed. In addition,
APD90 was prolonged by haloperidol in a concentration-dependent manner with a
threshold of significance at 3 µmol/L (Figure 2).
Effects of simulated ischemic fluid on the action
potentials of papillary muscles in guinea pigs
Ten minutes after simulated ischemic fluid perfusion, the decrease in the APA
in papillary muscles showed a time-dependency and had a
significant difference (P<0.01).
Vmax also showed a time-dependent effect; the effect was significant after 20 min of
perfusion (P<0.01). The concentration-dependent
shortening of ERP and APD90 also had significance after the cells
were exposed to ischemic fluid for 20 min
(P<0.01, Figure 3).
Effects of different concentrations of haloperidol on the
action potential characteristics of guinea pig papillary
muscles under ischemic conditions Guinea pig papillary
muscle cells were perfused with different concentrations of
haloperidol solutions prepared with simulated ischemic fluid.
The results showed a significant concentration-dependent
decrease in the Vmax; this effect was initiated after 0.3
µmol/L haloperidol solution was perfused
(P<0.05). Both ERP and APD90 showed a concentration-dependent decrease which
were initiated after 1 µmol/L haloperidol solution was added
(P<0.05, Figure 4).
Discussion
In recent years, it has been realized that the prolonging
or shortening of the Q-T interval would induce arrhythmia
and even sudden death. Using the antipsychotic drug,
haloperidol, and myocardial ischemia can result in the
changing of the Q-T interval. In this study, we observed the
effects on the action potential of two kinds of cardiac
myocytes superimposed under these two factors and
discovered that haloperidol prolonged the shortening of APD
produced by supervising simulated ischemic fluid, we
presume that the effect of haloperidol may be due
to suppression of outflow of K+ induced by ischemia. We will
make further studies to verify it.
Simulated ischemia for tissues was produced by
supervising Tyrode's solution containing no glucose, no
O2, at low pH levels. The results showed that after 10 min perfusion,
the APA of rabbit Purkinje cells was significantly different
from the normal group. Then APA further decreased with
increasing the duration of ischemia. At the same time, we
observed a decrease in both Vmax and ERP, which had
significant difference in the normal group after 30 min perfusion
with ischemic fluid. Although APD90 tended to decrease, the
difference was not significant. These results are in
accordance with Arita who reported that ischemia might affect
depolarizing Na+ currents and result in a decrease in APA
and Vmax, which in turn causes an increase in
K+ efflux, and thus shortening ERP and
APD90[9]. It has been proven that
myocardial ischemia may cause the shortening of APD, which
is owed to a lack of ATP caused by ischemia, to open the
channel of KATP and to cause an outflow of
K+[13]. It has been suggested that inhibition of the inflow of
Ca2+ will protect cardiac myocytes from ischemia which caused
vasodilatation and depressed the overloads of
Ca2+ induced by ischemia.
Our results showed that different concentrations of
haloperidol perfusion also caused a decrease in
Vmax,; however, there were no significant changes in the APA with 0.1, 0.3,
and 1 µmol/L of haloperidol. Significant differences
compared to the control were only observed at 3 µmol/L
haloperidol. Thus, we presumed that haloperidol may also
affect the sodium channels during phase 0 depolarization,
and it might be concentration-dependent.
After exposure to the simulated ischemic fluid
containing different concentrations of haloperidol, ERP and
APD90 levels of the Purkinje fibers were prolonged and showed a
concentration-dependency with haloperidol at 0.1, 0.3, 1, and
3 µmol/L. This result indicates that haloperidol prolongs
APD shortening induced by ischemia in rabbit Purkinje fibers.
KATP channel may be one the target of haloperidol to
suppress K+ efflux during ischemia. The site of action of this
effect needs further investigation using patch-clamp
techno-logy.
We also investigated the effects of different
concentrations of haloperidol on the action potential characteristics of
papillary muscle cells under simulated ischemic conditions.
As described earlier, papillary muscle cells possess higher
sensitivity to ischemia than Purkinje fibers for the following
reasons: (i) the volume of Purkinje fiber cells is larger, and
the storage of ATP is perhaps more than that of papillary
muscle cells, so it is not sensitive to ischemia; and (ii) the
quantity of the KATP channel protein distributed on these
two cell types is different. After 10 min superfusion with
ischemic fluid, both the APA and
Vmax of papillary cells showed a significant decrease compared with the normal
group. All of the parameters of the action potentials were
significantly decreased after 20 min perfusion. After adding
haloperidol to the simulated ischemic fluid, the parameters
tended to decrease, but to a lower scale.
It is necessary to notice that it is not profitable to cardiac
myocytes that haloperidol prolonged the shortening of APD
induced by ischemia, because the APD prolongation of the
drug in the pathological state actually increases the risk of
overloads of Ca2+ of cardiac myocytes. Meanwhile, higher
dosages of haloperidol also depress
Vmax and the APA of phase 0 to inhibit conductivity, and then aggravate the
conduction blockade of ischemic regions to increase the
probability of re-entry. Thus, patients suffering from myocardial
ischemia should be careful when applying haloperidol.
References
1 Gury C, Canceil O, Iaria P. Antipsychotic drug and
cardiovascular safety: current studies of prolonged Q-T interval and risk of
ventricular arrhythmia. Encephale 2000; 26: 62_72.
2 Lathers CM, Lipka LJ. Cardiac arrhythmia, sudden death and
psychoactive agents. Clin Pharmacol 1987; 27: 1_14.
3 Franco-Bronson K, Gajwani P. Hypotension associated with
intravenous haloperidol and imipenem. J Clin Psychopharmacol
1999; 19: 480_1.
4 Hatta K, Takahashi T, Nakamura H, Yamashiro H, Asukai N,
Matsuzaki I, et al. The association between intravenous
haloperidol and prolonged QT interval. J Clin Psychopharmacol
2001; 21: 257_61.
5 Kriwisky M, Perry GY, Tarchitsky D, Gutman Y, Kishon
Y. Haloperidol-induced torsades de
pointes. Chest 1990; 98: 482_4.
6 Douglas PH, Block PC. Corrected QT interval prolongation
associated with intravenous haloperidol in acute coronary
syndromes. Catheter Cardiovasc Interv 2000; 50: 352_5.
7 Zee-Cheng CS, Mueller CE, Seifert CF, Gibbs
HR. Haloperidol and torsades de
pointes. Ann Int Med 1985; 102: 418.
8 Wang YG, Lipsius SL. β-adrenergic stimulation induced
acely-chline to activate ATP-sensitive K+
channel in cat atrial myocytes. Circ Res 1995; 77: 565_74.
9 Arita M, Sato T, Ishida H, Nakazawa H. Celluar
electrophysiological basis of proarrhymic and antiarrhythmic effects of
ischemia related lipid metabolites. Cardiovasc Res 1997; 35:
256_72.
10 Adamantidis MM, Kerram P, Caron JF, Dupuis BA. Droperidol
exerts dual effects on repolarization and induces early
afterdepo-larization and triggered activity in rabbit Purkinje fibers. J
Pharmacol Exp Ther 1993; 266: 844_93
11 Zhang JJ, Hu DY, Liu XL. Effect of ischemic preconditioning on
action potential of anoxic reoxygenated papillary muscle of
SD rats. Chin J Cardiac Pacing Electrophysiol 1999; 13: 178_81.
12 Qi SY, Yang L, He ZS. Effects of simulated ischemia on the
transient outward potassium current heterogeneity of myocytes
from rabbit left ventricular free wall. J Bethune Milit Med Coll
2006; 4: 65_7.
13 Hu K, Duan D, Li GR. Protein kinase C activates ATP sensitive
K+ current in human and rabbit ventricular myocytes. Circ Res
1996; 78: 492_8.
|
