Download C57BL/6J和BALB/c繁育方式及子代生长发育的比较研究

组胺拮抗剂在小鼠 ATP-敏感性钾离子通道上的影响
朴伶华 1，姜圣男 3，柳贤德 2*
（1. 海南医学院基础医学部，海口，海南 571199；2. 海南大学农学院，海口，海南 570228；3. 海南省
海口市人民医院，海口，海南 570109）
【摘要】目的：观察比较 3 种组胺拮抗剂对缺血性心肌细胞的 ATP-敏感性钾离子通道中的影响。方法：
利用急性酶解法分离小鼠心室肌细胞。结果：pyrilamine、chlorpheniramine 及 diphenhydramine 均可抑制
ATP-敏感性钾离子通道的活性，抑制程度为 pyrilamine > chlorpheniramine > diphenhydramine。组胺对 KATP
通道活性无影响。结论：第一代的组胺拮抗剂（pyrilamine 、 chlorpheniramine 及 diphenhydramine）对
KATP 通道活性有抑制作用，其抑制作用与膜上 H1 受体无关。
【关键词】
组胺拮抗剂；膜片钳；ATP-敏感性钾离子通道
【中图分类号】R332
【文献标识码】
【文章编号】YX2012231
Effect of Antihistaminic Agents on the ATP-sensitive Potassium Channel Activity
in Isolated Mouse Ventricular Cardiomyocytes
PIAO LINGHUA1, JIANG SHENGNAN 3, LIU XIANDE 2*
(1Hainan medical university department of preclinical medicine, Haikou 571199; 2 Hainan university college of
agriculture, Haikou, 570228; 3 Haikou people’s hospital department of nuclear medicine, Haikou, 570109)
【Abstract】
.
Objective: The present study was undertaken to clarify the effect of the first generation histamine
H1 receptor antagonists on the adenosine triphosphate-sensitive potassium (KATP) channel in the
isolated mouse ventricular cardiomyocytes using excised inside-out and cell-attached patch clamp
techniques.
Methods:
In
the
excised
inside-out
patch
configuration,
H1-antihistaminic
agents
(chlorpheniramine, pyrilamine and diphenhydramine), doses ranging from 1 to 100 μmol/L,
inhibited KATP channel activity in a dose-dependent manner. The potency order reducing the
channel activity was pyrilamine > diphenhydramine > chlorpheniramine.
Results: All the antihistamines (100 μmol/L) also inhibited the pinacidil-induced KATP channel
activity in the cell-attached patch configuration. The potency order of the 3 antihistamines
inhibiting KATP channel activity is pyrilamine > chlorpheniramine > diphenhydramine in the
1
cell-attached configurations. Histamine did not affect the pinacidil-induced KATP channel activities
by itself, in addition, did not influence the effects elicited by the 3 antihistamines on the
pinacidil-induced KATP channel acitivities in the cell-attached patches.
Conclusion: From these results, it concluded that the first generation histamine H1 receptor
antagonists are involved in the regulation of the ATP-sensitive potassium channel activities in the
mouse cardiac ventricular myocytes, and that the inhibitory actions of the antihistaminic agents on
the channels are not dependent on the H1-receptors.
【Key words】antihistamine; patch clamp; ATP-sensitive potassium channel
[作者简介] 朴伶华（1980−）
，女，研究方向：医学生理学。E-mail: [email protected]。
[通讯作者] 柳贤德（1979−）
，男，研究方向：动物医学。Email: [email protected]。
2
Introduction
Numerous antihistaminic agents are used for the treatment of allergic diseases, but their use is
sometimes restricted because of their adverse effects on the central nervous system, like
somnolence and diminished alertness[1]. However, terfenadine, one of the most widely used
antihistaminics, has been found that it exerts cardiovascular actions including life-threatening
tachyarrythmias[2]. In addition, Jackman[3]reported that the prologation of QT interval precedes
these arrhythmias, and therefore attention has been paid to the effects of the antihistaminic on the
K+ currents that cause the action potential repolarization.
In the cardiac muscles, adenosine triphosphate-sensitive K+ (KATP) channels are thought to
play a role in the phenomenon of ischemic preconditioning in the heart, and the activation of these
channels may improve recovery of regional contractile function of stunned myocardium by
shortening action potential duration and attenuating membrane depolarization, thus decreasing
contractility and preserving energy during ischemia. In addition, there are several types of K+
currents, which are involved in the action potential repolarization, such as the delayed rectifier IK1
and IKir. However, under pathological conditions of myocardial ischemia, a decrease in the
intracellular adenosine triphosphate concentrations induces another K+ current IK,ATP within the
plateau potential range of the ventricular action potentials[4,5]. Activation of this currents during
acute ischemia shortens the action potential duration （APD) to protect the energy consumption and
facilitates the ischemic preconditioning[6]. The K+ efflux due to these currents cause extracellular
K＋ accumulation[7]and may elicit arrythmia during cardiac ischemia.
Despite the important roles of IK,ATP under pathological conditions, the effect of
antihistaminics on the IK,ATP has not been clearly elucidated yet, and there also has been known
that some antihistaminic agents are more likely to cause tachyarrhythmia in patients with
underlying cardiac diseases, such as ischemic heart disease and congestive heart failure[2],
indicating modulation of IK,ATP is involved in the cardiovascular side effects of the
antihistaminics.
Therefore, the aim of this study was to elucidate the relationships between the effects of
antihistaminics and ATP-sensitive potassium channel activities in the enzymatically isolated mouse
ventricular cardiac myocytes using inside-out and cell-attached patch clamp techniques.
1
Materials and Methods
1.1 Isolation of single mouse cardiac ventricular myocytes
Single ventricular myocytes were isolated from adult mouse heart by the enzymatic dissociation
procedure described previously[8]. In brief, the heart was cut from the ICR mouse which was kill
by cervical disloation. And then after mounting the heart on a Langendorff apparatus, the organ was
perfused for 5 min with a normally 1 mmol/L Ca2+-Tyrode's solution. The composition of Tyrode's
solution was (in mmol/L) 137 NaCl, 5.4 KCl, 10
HEPES, 1 MgCl2, 0.33 NaH2PO4, 10 Glucose,
10 CaCl2 (pH 7.4 with NaOH). Ca2+-free Tyrode's solution was perfused for 10 min and Ca2+-free
Tyrode's solution containing 1.5 mg/mL collagenase (Worthington Chemical Co.) was perfused for
25 min thereafter and then rinsed with a high K+, low Cl- kraftsbrühe (KB) solution contained (in
3
mmol/L) Taurine 20, L-Glutamic acid 70, KCl 25, KH2PO4 10, MgCl2 3, EGTA 0.5, HEPES 10,
Glucose 10. The temperature of all the perfusion solutions was maintained at 37℃. The solution
was bubbled with 100% O2. After the heart perfusion with the solution, the ventricular free wall
was cut into small pieces, and isolated ventricular cells were stored in the KB solution then the
isolated cells were observed under the microscope.
1.2 Electrophysiological recordings and solutions
Single-channel recording was conducted in both the cell-attached and excised inside-out patch
configurations[9]in the single mouse ventricular cardiac myocytes. Electrodes were fabricated from
patch glass (Warner Instrument Co.) in two steps on an electrode puller (PP-83, Narishige Scientific
Instruments). Pipette having a relatively high resistance (between 3 and 5 MΩ) were used to record
as small number of channels in the patch as possible. The pipette was heat-polished immediately
before use, and its shank was coated with Sylgard (Corning Co.).
In this experiment,
K-5 solution constituting (in mmol/L): KCl 118.5, MgCl2 2, KOH 21.5,
EGTA 5, HEPES 10) was used for the bath and pipette recording solutions. S-(+)-Chlorpheniramine
malate salt, dipheniramine hydrochloride, pyrilamine maleate salt, histamine, pinacidil,
glibaenclamide and ATP were all obtained from Sigma Chemical Co. For stock solutions were
initially dissolved in distilled water besides the pinacidil which was dissolved in DMSO.
1.3 Data acquisition and analysis
In experiments, the currents data, obtained through a patch clamp amplifier (AxoPatch-1D,
Axon Instruments), were filtered at 2 kHz, and stored on a video tape using a video data recorder.
For the analysis of single channel activity, the data were transferred to a computer with pClamp
(version 7.0, Axon Instruments) through an analog-to-digital converter interface (Digidata-1200,
Axon
Instruments). The open probability (Po) was calculated using the formula which was
introduced by Spruce [10]:
N
Po=(Σtjj)/Td n
j=1
where tj is the time spent at current levels corresponding to j=0, 1, 2... N channels in the open state.
4
Td is the duration of the recording and N is the number of channels active in the patch. Po is
calculated for over 30-sec records. To measure the magnitude of the inhibition by the antihistaminic
agents, the experimental results was fitted as follows,
Relative activity (%) = (Po antihistamine / Po control) X 100
Relative activity 100% represents the channel activity for 30 secs of the control channel activity.
1.4 Quantification and Statistics
Results are expressed as mean±S.E. of the N cells, The students t-test was used to determine the
significance of differences between set of data. p<0.01 was considered statistically significant.
2 Results
2.1 Ascertain the ATP-sensitive K+ channel activity in the excised inside-out and cell-attached
patches
At -60 mV holding potential in excised inside-out patch configuration, channel activity
appeared immediately after making excised inside-out patch, under the superfusion of ATP-free
bath solution and 1 mmol/L ATP inhibited the channel activity almost completely. Channel activities
resumed when the ATP was wash out. Glibenclamide (50 μmol/L), a KATP channel blocker,
inhibited the channel activities again (Fig. 1).
图 1. ATP（1 mM）及格列本脲（20 μM）在膜内向外方式中对小鼠心室肌细胞 KATP 通道的
影响
Figure 1. A trace showing the typical ATP-sensitive K+ channel activities in the excised inside-out
configuration at -60mV holding potential (HP) in isolated mouse ventricular myocytes. Channel
activity appeared immediately after making excised inside-out patch and ATP (1 mM) inhibited the
channel activity almost comletely. Channel activity revived when ATP was washed out, and
Glibenclamide (20 μM) inhibited the channel activity again.
At -60 mV holding potential in the cell-attached patch configuration, scanty channel activities
5
were developed in cell-attached patch configuration under the superfusion of ATP-free bath solution.
Pinacidil (200 μmol/L), a K+ channel opener, induced a plenty of channel activities and the
pinacidil-induced channel activities were reduced by glibenclamide (50 μmol/L) (Fig. 2).
图 2.格列本脲（50 μM）在细胞吸附法中对小鼠心室肌细胞 KATP 通道的影响
Figure 2. A trace showing the typical KATP channel activities in the cell-attached patch at -60mV
holding potential (HP) in the isolated mouse ventricular myocytes. Pinacidil (200 μM) induced the
channel activity and glibenclamide (50 μM) inhibited the channel activity.
From the results of these experiments, it was ascertained that the channel activities in the present
study are ATP-sensitive K+ channel activities in the excised inside-out and cell-attached patches
respectively.
2.2 Effect of antihistamines on the KATP channel activity in the excised inside-out patches
The antihistaminic agents, used in the present study, generally inhibited KATP channel activity
in the excised inside-out patches under the superfusion of ATP-free solution. The relative activities
of the channel by 1, 10 and 100 μmol/L chlorpheniramine were 48.3±7.91, 16.5±2.13, 3.3±1.80%,
respectively (Fig. 3).
图 3. chlorpheniramine 在膜内向外方式中对小鼠心室肌细胞 KATP 通道的影响
6
Figure 3. Effect of chlorpheniramine (CPM) on the KATP channel activity in the excised inside-out
patch configuration at -60 mV holding
potential (HP). A: CPM attenuated KATP channel
activities in a dose-dependent manner. B: Histogram shows its inhibition at different concentration.
Relative activity 100% represents the channel activity for 30 secs of the control channel activity. (*
p<0.01 significant difference from the control.)
Diphenhydramine (DPH) also attenuated the KATP channel activity in a dose-dependent manner in
the excised inside-out patch. Relative activities by 1, 10 and 100 ?mol/L DPH were 42.3±6.99,
22.8±4.60 and 5.2±1.29%, respectively (Fig. 4).
图 4. diphenhydramine 在膜内向外方式中对小鼠心室肌细胞 KATP 通道的影响
Figure 4. Effect of diphenhydramine (DPH) on the KATP channel activities in the excised
inside-out patch configuration at -60 mV holding
potential (HP). A: DPH attenuated KATP
channel activity in a dose-dependent manner. B: Histogram shows its inhibition at different
concentration. Relative activity 100% represents the channel activity for 30 secs of the control
channel activity. (* p<0.01 significant difference from control).
An another histamine antagonist pyrilamine (PYL) inhibited KATP channel activity in the
excised inside-out patch at -60 mV holding potential, similar fashion to those of the CPM and DPH,
a relative activities by 1, 10 and 100 ?mol/L were 35.7±11.05, 10.9±3.25 and 1.0±0.29%
respectively (Fig. 5). The potency rank order of the 3 antihistamines inhibiting KATP channel
activity in the excised inside-out patch was PYL > DPH > CPM (Fig. 6).
7
图 5. pyrilamine 在膜内向外方式中对小鼠心室肌细胞 KATP 通道的影响
Figure 5. Effect of pyrilamine (PYL) on the KATP channel activities in the excised inside-out patch
configuration at -60 mV holding potential (HP). A: PYL attenuated KATP channel activity in a
dose-dependent manner. B: Histogram shows its inhibition at different concentration. Relative
activity 100% represents the channel activity for 30 secs of the control channel activity. (* p<0.01
significant difference from control).
图 6. 比较 3 种抗组胺药物对 KATP 通道的影响程度
Figure 6. Dose-response curves of antihistamines for the inhibition of KATP channel activities in
the excised inside-out patch configuration at -60 mV of holding potential. The potency order of
antihistamines (10 and 100 μM) was PYL>CPM>DPH but was PYL > DPH > CPM at 1 μM in the
mouse cardiac ventricular myocytes.
8
2.3 Effect of Antihistamines on the KATP channel activity in the cell-attached patches
In the cell-attached patch configuration, KATP channel activities were not spontaneously
developed at -60 mV holding potential. The pinacidil artificially opens the channel by altering its
sensitivity to ATP, and therefore pinacidil (200 μmol/L) was used for activition of the KATP
channel. All the 3 antihistamines (CPM, DPH and PYL; 100 μmol/L) inhibited the
pinacidil-induced KATP channel activity in the cell-attached patches, and the rank order of potency
was PYL > CPM > DPH, as seen in the relative channel activities 3.9±2.27, 10.8±9.09 and
29.0±8.44% respectively (Fig. 7 and 8).
图 7. 3 种抗组胺药物（chlorpheniramine，diphenhydramine 及 pyrilamine）在细胞吸附法中对
小鼠心室肌细胞 KATP 通道的影响
Figure 7. Effects of antihistamines on the KATP channel activity in the cell-attached patch at -60
mV holding potential in the mouse cardiac ventricular myocytes. Chlorpheniramine (CPM),
diphenhydramine (DPH) and pyrilamine (PYL) inhibited pinacidil-induced KATP channel
activities.
9
图 8. 3 种抗组胺药物在细胞吸附试验中对 KATP 通道影响程度比较，p<0.01
Figure 8. Effects of antihistamine (100 μM) on the pinacidil-induced KATP channel activity in the
cell-attached
configuration
at
-60
mV
holding
potential.
Diphenhydramine
(DPH),
chlorphenhydramine (CPM) and pyrilamine (PYL) inhibited the pinacidil-induced channel
activities. Relative activity 100% represents the channel activity for 30 secs of the control channel
activity. (* p<0.01 significant difference from control.)
2.4 Influence of histamine on the antihistamins' inhibitory effects of pinacidil-induced channel
activity in the cell-attached patches
It was examined whether the antihistamine's inhibitory effects of KATP channel activity was
through the histamine receptors or not. Firstly, the histamine was added to the bath solution which
contains pinacidil. Histamine itself did not affect the pinacidil-induced channel activities (Fig. 9),
and the antihistamines (CMP, DPH and PYL; 100 μmol/L), added to the bath solution, still inhibited
the pinacidil-induced channel activities even in the presence of histmaine (Fig. 10). Relative activity
by the 3 antihistamines (CMP, DPH and PYL; 100 μmol/L) under both histamine and pinacidil
superfusion was 13.3±11.73, 7.6±2.49 and 3.0±1.79%, respectively (Fig. 11).
10
图 9. 组胺在细胞吸附法中对小鼠心室肌细胞 KATP 通道的影响
Figure 9. Effect of histamine (100 μM) on the pinacidil-induced KATP channel activity in the
cell-attached configuration at -60 mV holding potential in isolated mouse ventricular myocytes.
Histamine have no effect on the pinacidil-induced channel activity.
图 10. 组胺和 3 种抗组胺药物在细胞吸附法对心室肌细胞 KATP 通道影响关系
Figure 10. Influence of histamine on the antihistamins' inhibitiory effect of the pinacidil-induced
channel activity at -60 mV holding potential in the cell-attached patch configuration in isolated
mouse ventricular myocytes. Histamine did not affect the antihistamins' inhibitiory effect on the
pinacidil-induced channel activities.
11
图 11. 组胺和 3 种抗组胺药物在细胞吸附法对心室肌细胞 KATP 通道影响关系比较，p<0.01
Figure 11. Effects of histamine on the pinacidil-induced channel activity in the cell-attached patch
configuration. Histamine (100 μM) has no effect on the channel activity inhibitory effect of the
antihistamins. Relative activity 100% represents the channel activity for 30 secs of the control
channel activity. (* p<0.01 significant difference from control.)
3 Discussion
The present study demonstrates that the first generation antihistaminics (chlorpheniramine,
diphenhydramine and pyrilamine) inhibited the ATP-sensitive potassium (KATP) channel activities
in the mouse ventricular myocytes, indicating antihistaminic agents are involved in the ischemia
pathophysiology.
This is the first result to show that antihistaminics could inhibit the KATP channel activities at
both inside and outside of the cells. During the ischemia and cardiac failure, the activation of the
KATP channels by deletion of ATP would shorten the action potential duration (APD).
Simultaneously, the hyperpolarization of membrane might reduce Ca2+ influx into the
metabolically the disturbed cell, and limit further myocardial damages. These actions would
contribute to the prevention of calcium overload related arrhythmias[11]. Antihistaminics could
inhibit KATP channel activities, and therefore inhibited the K+ efflux, making the plateau phase
prolonged and increase of the Ca2+ influx. This would be harmful effect for the ischemic
myocardium, due to the positive inotropic and chronotropic action of antihistaiminics. In addition to
the result of present study, other recent evidence suggests that mitochondrial KATP channels
mediate cardioprotection in ischemic preconditioning[12,13].
In the present study, it was found that the rank order of potency inhibiting KATP channel
12
activities by the 3 antihistaminics was PYL > DPH > CPM in the case of excised inside-out patch
configuration, and was PYL > CPM > DPH in the case of cell-attached patch configration
respectively. The reason why the potency order of the 3 antihistaminics is not just same in the two
patch configurations could not be understood only with this study, but it indicates that the
subcellular action mechanisms inhibiting KATP channel activity in the two configurations are not
the same.
As seen in the present study, antihistamines inhibited the KATP channel activities in general.
However, it is clear whether this antihistaminics' effect on the KATP channel regulation is from the
action through the histamine receptor or not. Not only histamine did not affect the KATP channel
itself but also did not affect the antihistaminics' KATP channel inhibitory effects, indicating no
connection with the H1-receptors. It could be supposed that the antihistaminics' KATP channel
inhibition is not from the action through the histamine receptor, but rather, from the action directly
to the channel moiety.
It has been reported that terfenadine, a histamine antagonist, blocks pancreatic β-cell KATP
channels via binding to the cytoplasmic side of the pore-forming subunit[14]. In this experiment,
the antihistaminics inhibited the KATP channel in the excised inside-out and cell-attached patches
in the isolated mouse ventricular myocytes. Though it is not defined the effect of the IK,ATP
activation on the arrhythmias either early or delayed afterdepolarization[15,16], the prolongation of
action potential due to the IK,ATP blockage in the ischemic zone would attenuate the dispersion of
the refactory period. It has been also reported that blockade of IK,ATP contributed to the
antihistaminic actions of antiarrhythmic agents[17,18]. Although IK,ATP play a key role in the
ischemic preconditioning[6,19], some patient had porarrhythmic events and sudden death were
developed in some patients, with some of antihistaminic agents, inhibiting IK,ATP[20,21].
In summary, some first generation antihistmainic agents are involved in the regulation of
ATP-sensitive potassium channel activity in the myocardium, and the inhibitory effects of the
agents on the KATP channel are not from the actions through the classical H1-histamine receptors,
would be harmful to ischemic myocardium.
It was examined the effects of first generation H1 histamine receptor antagonists
(chlorpheniramine, pyrilamine and diphenhydramine) on the ATP-sensitive potassium (KATP)
channel activity in the isolated mouse ventricular cardiac myocytes.
13
Single cardiac myocytes were isolated from the ventricle of adult mouse with enzymatic
dissociation, and the excised insede-out and cell-attached patch clamp techniques were used to
measure the ATP-sensitve K+ channel activities.
In the excised inside-out patch configuration, H1-antihistaminic agents (chlorpheniramine,
pyrilamine and diphenhydramine), doses ranging from 1 to 100 μmol/L, inhibited KATP channel
activity respectively in a dose-dependent manner and the potency order of these is pyrilamine >
diphenhydramine > chlorpheniramine.
All the antihistamines (100 μmol/L) also inhibited the pinacidil-induced KATP channel activity
in the cell-attached patch configuration. The potency order of the 3 antihistamines inhibiting KATP
channel activity is pyrilamine > chlorpheniramine > diphenhydramine in the cell-attached patches.
Histamine did not affect the pinacidil-induced KATP channel activities by itself, in addition,
histamine did not affect the effects by the 3 antihistamines on the pinacidil-induced KATP channel
acitivities in the cell-attached patches.
From these results, it concluded that the first generation histamine H1 receptor antagonists
blocks the ATP-sensitive potassium channel in the mouse cardiac ventricular myocytes, and that the
inhibitory effects of the antihistamines are not from the actions through the H1-receptors.
References
1. Simons F.E.R. and Simons K.J., (1994). The pharmacology and use of H1-receptor-antagonist
drugs. N Engl J Med, 330:1663-1670.
2. Woosley R.L., Chen Y., Freiman J.P. and Gillis R.A., (1993). Mechanism of the cardiotoxic
actions of terfenadine. JAMA, 269:1532-1536.
3. Jackman W.M., Clark M., Friday K.J., Aliot E.M., Andrson J. and Lazzara R., (1984). Ventricular
tachyarrhythmics in the long QT syndrome. Mes Clin North Am, 68(5):1079-1109.
4. Noma A., (1983). ATP-regulated K+ channels in cardiac muscle. Nature, 305:147-148.
5. Nichols C.G. and Lederer W.J., (1991). Adenosine triphosphate-sensitive potassium channels in
the cardiovascular system. Am J Physiol, 261:H1675-1686.
6. Parret J.R. and Kane K.A., (1994). KATP channels in ischaemic preconditioning. Cardiovasc Res,
28:783-787.
7. Wilde A.A.M. and Janse M.J., (1994). Electrophysiological effects of ATP sensitive potassium
channel modulation: implications for arrhythmogenesis. Cardiovasc Res, 28:16-24.
14
8. Doepner B., Thierfelder S., Hirche H. and Benndorf K., (1997). 3-Hydroxybutyrate blocks the
transient K+ outward current in myocardial mouse cells in a stereoselective fashion. J Physiol,
500:85-94.
9. Hamill O.P., Arty A., Neher E., Sakmann B. and Sigworth F.J., (1981). Improved patch-clamp
techniques for high-resolution current recording from cells and cell-free membrane patches.
Pflügers Arch, 391:85-100.
10. Spruce A.E., Standen N.B. and Stanfield P.R., (1985). Voltage-dependent ATP-sensitive
potassium channels of skeletal muscle membrane. Nature, 316:736-738.
11. Satoh H., (1993). Effect of ATP-sensitive K+ channel openers on pacemaker activity in isolated
single rabbit sino-atrial node cells. J Caediovasc Pharmacol, 22:863-868.
12. Liu Y., Sato T., O'Rourke B. and Marban E., (1998). Mitochondrial ATP-dependent potassium
channels: novel effectors of cardioprotection. Circulation, 23;97(24):2463-9.
13. Liu Y., Sato T., Seharaseyon J., Szewczyk A., O'Rourke B. and Marban E., (1999).
Mitochondrial ATP-dependent potassium channels. Viable candidate effectors of ischemic
preconditioning. Ann N Y Acad Sci, 30;874:27-37.
14. Zunkler B.J., Kuhne S., Rustenbeck I. and Ott T., (2000). Mechanism of terfenadine block of
ATP-sensitive channels. Br J Pharmcol, 130(7):1571-1574.
15. Spinelli W., Sorota S., Siegal M. and Hoffman B.F., (1991). Antiarrhythmic actions of the
ATP-regulated K+ activated by pinacidil. Circ Res, 68:1127-1137.
16. Carlsson L., Abrahamsson C., Drews L. and Duker G., (1992). Antiarrhythmic effects of
potassium channel openers in thythm abnormalities realted to delayed repolarization. Circulation,
85:1491-1500.
17. Horie M., Hayashi S., Yuzuki Y. and Sasayama S., (1992). Comparative studies of ATP sensitive
potassium channels in heart and pancreatic β cells using Vaugham-Williams class Ia antiarrhythmics.
Cardiovasc Res, 26:1087-1094.
18. Wu B., Sto T., Kiyosue T. and Arita M., (1992). Blockage of 2,4-dinitrophenol induced
antiarrhythmic drugs. Cardiovasc Res, 26:1095-1101.
19. Knopp A., Thierfelder S., Koopmann R., Biskup C., Böhle T. and Benndorf K., (1999). Anoxia
generates rapid and massive opening of KATP channels in ventricular cardiac myocytes.
Cardiovasc Res, 41:629-640.
15
20. Burkhart G.A., Freiman J., (1995). The risk of life-threatening cardiocascular events with
terfenadine. Am J Cardiol, 75:213-214.
21. Broadhurst P., Nathan A.W., (1993). Cardiac arrest in a young woman with
the long QT
syndrome and concomitant astemizole ingestion. Br Heart J. 70:469-470.
16