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Vol. 301, Issue 1, 234-240, April 2002
-Estradiol on Reperfusion
Arrhythmias and Infarct Sizes in Canine Hearts
Departments of Surgery (C.-H.T.) and Internal Medicine (T.-M.L.), Cardiology Section, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan; College of Medicine (S.-F.S.), National Cheng Kung University, Tainan, Taiwan; and Department of Surgery (T.-F.C.), Municipal Jen-Ai Hospital, Taipei, Taiwan
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
Conclusions
References
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We have demonstrated the effects of estrogen on modulation of
ATP-sensitive K+ channels; however, the subcellular
location of these channels is unknown. The purpose of the present study
was to investigate the role of the sarcolemmal and mitochondrial
ATP-sensitive K+ channels in a canine model of myocardial
infarction after stimulation with 17
-estradiol. Anesthetized dogs
were subjected to 60 min of the left anterior descending coronary
artery occlusion followed by 3 h of reperfusion. Infarct size was
markedly reduced in estradiol-treated dogs compared with controls
(14 ± 6 versus 42 ± 6%, P < 0.0001), indicating the effective dose of estradiol administrated. Pretreatment with the mitochondrial ATP-sensitive K+ channel antagonist
5-hydroxydecanoate completely abolished estradiol-induced cardioprotection. The sarcolemmal ATP-sensitive K+ channel
antagonist
1-15-12-(5-chloro-o-anisamido)ethyl-methoxyphenyl)sulfonyl-3-methylthiourea (HMR 1098) did not significantly attenuate estradiol-induced
infarct size limitation. In addition, estradiol administration
significantly reduced the incidence and duration of reperfusion-induced
ventricular tachycardia and ventricular fibrillation. Although
5-hydroxydecanoate alone caused no significant effect on the incidence
of reperfusion arrhythmias in the presence or absence of estradiol, the
administration of HMR 1098 abolished estrogen-induced improvement of
reperfusion arrhythmias. Pretreatment with the estrogen-receptor
antagonist faslodex (ICI 182,780) did not alter estrogen-induced
infarct-limiting and antiarrhythmic effects. These results demonstrate
that estrogen is cardioprotective against infarct sizes and fatal
reperfusion arrhythmias by different ATP-sensitive K+
channels for an estrogen receptor-independent mechanism. The infarct
size-limiting and antiarrhythmic effects of estrogen were abolished by
5-hydroxydecanoate and HMR 1098, suggesting that the effects may result
from activation of the mitochondrial and sarcolemmal ATP-sensitive
K+ channels, respectively.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusions
References
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Epidemiological
studies showed that women appear to have a lower incidence of
arrhythmia-related sudden death than men (Sourander et al., 1998
).
Estrogen can decrease cardiovascular mortality primarily in sudden
cardiac death in postmenopausal women (Sourander et al., 1998).
However, the mechanism involved is not completely known. Fatal
reperfusion arrhythmia occurring in the absence of heart failure or
hypotension is a common complication of acute myocardial infarction
(Volpi et al., 1987). Estrogen has been shown previously to
attenuate reperfusion-induced ventricular arrhythmias in the dog
(McHugh et al., 1995). The antiarrhythmic effects of estrogen have been
attributed to antioxidants (McHugh et al., 1998), resulting in a
reduction of free radicals during reperfusion. We have previously
demonstrated that there is an association of estrogen and ATP-sensitive
K+ channels in patients with syndrome X by
analyzing the changes of electrocardiographic QT parameters (Lee et
al., 1999). However, no previous study has addressed this issue on the
effects of estrogen on ATP-sensitive K+ channels
and the incidence of arrhythmias during myocardial reperfusion.
Cardioprotection via ATP-sensitive K+ channels
may be an integral player in ischemic preconditioning (IP), where brief
periods of ischemia and reperfusion before a sustained ischemic stress protects the heart. We have previously demonstrated that estrogen can
activate mitochondrial ATP-sensitive K+
(mit-KATP) channels and mimicked IP to reduce
myocardial infarct size in anesthetized dogs (Lee et al., 2000).
Cardiac myocytes contain two distinct ATP-sensitive
K+ channels with one subtype located in the
sarcolemma (sar-KATP) and the other in the inner
membrane of the mitochondria (mit-KATP) (Liu et
al., 2001). mit-KATP channels share some
pharmacological properties with sar-KATP channels
while possessing a distinct pharmacological response.
sar-KATP channels are selectively blocked by HMR
1098, whereas mit-KATP channels are specifically
inhibited by 5-hydroxydecanoate (Liu et al., 2001). The involvement of
the two types of ATP-sensitive K+ channels in
estradiol-induced infarct size and antiarrhythmias during ischemic and
reperfusion remained unknown. Although there is an emerging consensus
that the activation of mit-KATP channels reduces
infarct size, there are widely divergent views regarding whether
sar-KATP channels act in an antiarrhythmic role
during reperfusion. Activation of sar-KATP
channels can theoretically be antiarrhythmic, because shortening of the
action potential duration by opening these channels would suppress
triggered activity, which is an important mechanism of reperfusion
arrhythmias (Wilde and Janse, 1994). However, several studies have
demonstrated a decrease in arrhythmic severity with ATP-sensitive
K+ channel blockers (Dhein et al., 2000). This
discrepancy may stem from different species (dogs, pigs, rabbits,
rats), collateral flow measurements (microspheres versus others), model
studies (isolated heart versus in vivo), and different arrhythmic
quantitative methods (arrhythmic score versus incidence) used in the
studies. Small animals did not provide a good model to assess the
pharmacological effects on arrhythmias because their hearts are too
small to sustain arrhythmias (Sakamoto et al., 1999). Such tests are
performed better in large animals. Thus, this study investigated
whether pretreatment with 17-estradiol in physiological
concentrations provides cardioprotection against infarct size and fatal
reperfusion arrhythmias in a canine model of acute myocardial
infarction. We have also investigated whether the observed antinecrotic
and antiarrhythmic effects of 17-estradiol are due to the activation of mit- and sar-KATP channels by the use of
5-hydroxydecanoate and HMR 1098, specific mit- and
sar-KATP channel blockers, respectively. Besides,
to assess whether the estrogen-induced effects are related to
activation of estrogen receptors, we used a specific estrogen receptor
antagonist ICI 182,780.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusions
References
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Preparation
All experiments were conducted on male mongrel dogs,
weighing 10 to 15 kg. Because we have previously demonstrated that
estrogen provided the similar magnitude of cardioprotection in both
sexes of canine hearts (Lee et al., 2000), we used male animals in this study. The experimental preparation and techniques have been previously described (Lee et al., 2000). Pentobarbital-anesthetized dogs were
instrumented. Fluid replacement, plasma [K+]
and [Ca2+], and basic physiological conditions
were controlled as described (Lee et al., 2000).
Near the base of the heart, the left anterior descending artery
proximal to the first diagonal branch was encircled with a 4-0 silk
suture. Because the degree of preceding ischemia is one determinant of
the severity of infarct size and reperfusion arrhythmias (Jugdutt et
al., 1981), we intended to produce similar ischemia by monitoring
collateral blood flow at baseline and during ischemia. Collateral
coronary blood flow was detected by intracoronary Doppler flow wire as
previously described (Lee et al., 2000). All procedures were in
accordance with the Guide for the Care and Use of Laboratory Animals
(National Institutes of Health Publication 85-23, revised 1996) and
approved by the Animal Subjects Committee of National Taiwan University.
Experimental Protocol
Protocol 1 (n = 95)
The dogs
were randomized to one of six groups (Fig.
1). All animals were subjected to a
60-min coronary occlusion followed by 180 min of reperfusion. The doses
of estradiol were chosen to achieve serum levels in the range of 200 to
500 pg/ml, levels equivalent to those in human females during midcycle.
The dose of 5-hydroxydecanoate (5 mg/kg, serum level around 100 µM
when extracellular space is assumed to be 20% of body weight) was used to selectively block mit-KATP channels and to avoid to
affect sar-KATP channels, which are insensitive to 500 µM
of 5-hydroxydecanoate (Hu et al., 1999). 5-Hydroxydecanoate was
administered 5 min before prolonged coronary occlusion, which has been
shown to be maximally effective in inhibiting cardioprotection (Fryer
et al., 2000). HMR 1098 was administered at the dose of 3 mg/kg, which
was an optimal dosage to determine the effectiveness of inhibiting the sar-KATP channels in IP (Fryer et al., 2000).
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Protocol 2 (n = 45).
To assess whether the
estradiol-induced effects were of nongenomic origin, we performed
another four groups randomly allocated to either placebo or estrogen
administration in the presence or absence of intravenous infusion of
ICI 182,780 at a dose of 2.5 mg/kg, a classical estrogen receptor
antagonist, 5 min before a 60-min coronary occlusion. The dosage
administered was chosen on the basis of data from previous studies
(Robertson et al., 2001), suggesting that the dose of ICI 182,780 is
sufficient to block estrogen receptors.
Measurements of Infarct Size
Infarct size was determined as previously described (Lee et al.,
2000) using 1% triphenyltetrazolium chloride (Sigma, St. Louis, MO) in
phosphate buffer (pH 7.4). Left ventricular area at risk and the area
of infarcted tissue were measured by an independent, blinded observer
using computer planimetry.
To verify the reproducibility of the computer-assisted planimetry, a second measurement was performed by another, blinded investigator. The correlation between the two measurements was excellent (r = 0.992 for ischemic area).
Arrhythmia Analysis
The acquired single-lead electrocardiographic tracing was
continuously displayed. All arrhythmic events were classified by the
observer according to the guidelines provided by "the Lambeth conventions" (Walker et al., 1988). Ventricular tachycardia (VT) was
defined as less than or equal to four consecutive ventricular premature
beats. Ventricular fibrillation (VF) was defined as a signal that
changed from beat to beat in rate and configuration (Fig.
2). Reference was made to the blood
pressure signal to confirm which type of ectopic activity was
occurring, particularly to distinguish between polymorphic VT and VF.
When the former occurs, the pressure trace is usually still pulsatile,
whereas with VF the blood pressure falls rapidly toward zero and is no
longer pulsatile. The onset, durations, and incidence of VT and VF were measured occurring within the whole reperfusion period. Measurements of
all variables were performed in a blinded manner.
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Laboratory Measurements
17-Estradiol concentrations were quantified by enzyme-linked
immunoassay (Diagnostic Products Corporation, Los Angeles, CA) before
and at the end of the study. The detection limit was 20 pg/ml for estradiol.
Exclusion Criteria
Animals were omitted from analysis for infarct size: 1) if
intractable VF occurred or arrhythmia needed antiarrhythmic agents to
correct; 2) if such severe hypotension was observed that the experiment
could not be continued successfully for the duration of the protocol;
or 3) if heart worms were present. Because of influence of collateral
circulation on infarct sizes (Jugdutt et al., 1981), we excluded
collateral flow >20% of baseline coronary blood flow to make our
study animals homogeneous. Dogs with VF during reperfusion were
resuscitated and converted to a stable rhythm by internal electric
shocks (3 × 10 W). The low energy did not result in more cell
necrosis (de Lorgeril et al., 1990). We calculated survival percentage
as (number of dogs that survived)/(number of originally assigned
dogs 
number of dogs with heart worms or collaterals > 20%) × 100.
Statistics
All values are expressed as mean ± S.D. Differences among groups in hemodynamics, coronary blood flow, infarct size, and area at risk were compared using one-way analysis of variance followed by Student-Newman-Keuls test. Differences in the incidence of arrhythmias among the groups were determined by the chi-square test and Fisher's exact test if case number < 5. Difference in the VT and VF durations among the groups was tested by the Mann-Whitney test because of no Gaussian distribution. A value of P < 0.05 was considered to be significant.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusions
References
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Intravenous injection of 10 µg/kg 17-estradiol resulted in
increases of plasma estradiol concentration (Table
1) equivalent to those in human females
during midcycle. Concentration of arterial blood gas, calcium, sodium,
and potassium were fairly stable throughout the study.
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Mortality and Exclusions.
A total of 95 animals were enrolled
in the protocol 1, and 72 successful experiments were completed. Six
dogs were excluded because of intractable VF (two in control; one in
5-hydroxydecanoate, HMR 1098, 17-estradiol + 5-hydroxydecanoate, and
17-estradiol + HMR 1098). Ten dogs were excluded from analysis
because collateral circulation exceeded 20% of baseline (two in
control, 17-estradiol, 5-hydroxydecanoate, and HMR 1098; one in
17-estradiol + 5-hydroxydecanoate and 17-estradiol + HMR 1098).
Six dogs were excluded because of intractable hypotension (two in
control and HMR 1098; one in 5-hydroxydecanoate and 17-estradiol + HMR 1098). One dog was excluded because of the presence of heart worms
(one in 17-estradiol). The remaining dogs were randomly assigned to
each group of 12.
Hemodynamic Variables. The hemodynamic data are summarized in Table 1. Heart rate, mean blood pressure, and rate-pressure product were not significantly different among the six groups.
Baseline coronary blood flow measured with intracoronary Doppler flow wire was nonsignificantly different among the six groups (Table 1). Five minutes after occlusion, collateral blood flow in the center of the ischemic region was very low in the six groups, and increased only slightly with time. Blood flow of the left anterior descending artery among the six groups was similar during coronary occlusion, suggesting that collateral flow to the ischemic region may be not altered by treatment assignment. Coronary blood flow during hyperemic responses and reperfusion was also similar among the six groups.Infarct Size and Area at Risk.
There was no significant
difference in area at risk expressed as a percentage of the left
ventricle among the groups, indicating a comparable degree of ischemic
risk (Fig. 3). Infarct size in control
animals averaged 42 ± 6% of the risk region, compared with
14 ± 6% of the risk region in estrogen-treated dogs
(P < 0.0001), indicating that an effective dose was
used in this study. Pretreatment with 5-hydroxydecanoate completely
abolished estrogen-pretreatment (14 ± 6 to 38 ± 6% of the
risk region, P < 0.0001) cardioprotection. HMR 1098 did not significantly attenuate infarct size in the presence of
estrogen. These data suggest a mit-KATP
channel-sensitive, sar-KATP channel-insensitive
mechanism as a mediator of estradiol-induced infarct size limitation.
|
-estradiol, suggesting a nongenomic cardioprotective
effect (Table 3).
Reperfusion Arrhythmias.
As summarized in Table
2, 100% of the control dogs developed
reperfusion VT, and 83% of them deteriorated into VF. 17-estradiol administration reduced the incidence of VT by 83% and VF by 83%. Duration of VT in the estrogen-treated heart was significantly shorter
than in the control (129 ± 45 versus 1054 ± 221 s,
P < 0.0001). Either HMR 1098 or 5-hydroxydecanoate
alone did not produce significant increase of fatal reperfusion
arrhythmias compared with the control group. However, the
antiarrhythmic properties of estradiol were abolished with the use of
HMR 1098 in terms of the incidence and duration of VT and the incidence
of VF. The reduced reperfusion arrhythmic incidence and durations
induced by estrogen was not significantly altered by ICI 182,780 (Table 3).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusions
References
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Our present results clearly showed for the first time that estrogen at physiological doses exerts its beneficial effect on infarct sizes and reperfusion arrhythmias at different subcellular location through a nongenomic mechanism in anesthetized dogs. There is a separate mechanism modulating infarct size and reperfusion arrhythmias. The infarct size-limiting effect of estrogen was abolished by 5-hydroxydecanoate, suggesting that the cardioprotective effect of estrogen may result from activation of myocardial mit-KATP channels. Estradiol effectively attenuates the incidence and durations of reperfusion-induced VT and VF. This antiarrhythmic effect was abolished by HMR 1098 at the dose to selectively block sar-KATP channels, implying that beneficial effects appear to be mediated through the opening of myocardial sar-KATP channels. Our findings imply an important difference in the mechanism of these two channels on cardioprotection.
Estrogen and ATP-Sensitive K+ Channels.
The
mechanisms by which activation of ATP-sensitive
K+ channels by estradiol protected the heart
against infarct sizes and reperfusion arrhythmias remain to be defined.
Clearly, estrogen did not exert any hemodynamic effects and was not
associated with an increase in myocardial blood flow at the dose used
in this study. Rate pressure product, an index of myocardial oxygen
consumption, was similar throughout the study among the groups,
indicating that changes in myocardial metabolism cannot be a mechanism
for beneficial effect of the drug. The finding was consistent with the
result of McHugh et al. (1995), showing the unchanged hemodynamics throughout ischemia reperfusion in dogs treated with estrogen at a
physiological dose. Collateral blood flow during coronary occlusion
among the six groups was similar, demonstrating that the differences in
infarct sizes and arrhythmic incidence were not explained by collateral
blood flow.
).
However, whether myocardial response to estrogen can be mediated by
estrogen binding to a cell surface form of estrogen receptor remained unknown.
17-Estradiol has been shown to activate
K+ channels in some (Sudhir et al., 1995; Hugel
et al., 1999) but not all studies (Nakajima et al., 1999; Tanabe et
al., 1999). The ATP-sensitive K+ channel, a
member of the superfamily of Kir channels, is a heteromultimer composed
of a pore-forming K+ channel core and a
regulating ATP-binding cassette protein (Jovanovic et al., 1999).
However, a Kir blocker terikalant has no effect on the current of
ATP-sensitive K+ channel (Escande, 1989). Thus,
it is not surprising that although 17-estradiol did not exert any
effect on Kir channels (Nakajima et al., 1999; Tanabe et al., 1999), it
can activate ATP-sensitive K+ channels. Many
agonists have been shown to trigger the opening of ATP-sensitive
K+ channels, including adenosine, bradykinin,
opioids, and free radicals (Downey and Cohen, 1997). Estradiol
increased adenosine levels, opioid sensitivity, bradykinin
concentrations, and nitric oxide, which may increase the open-state
probability of ATP-sensitive K+ channels as
measured by patch-clamp technique (Downey and Cohen, 1997). Multiple
numbers of the triggers intensify the downstream signals to activate
the two types of ATP-sensitive K+ channels.
First, mit-KATP channel activation was
involved in the mechanism modulating estradiol-induced infarct size
reduction demonstrated by the fact that infarct sizes increased by
administering 5-hydroxydecanoate in the presence of estradiol. Because
5-hydroxydecanoate alone did not alter infarct size, the abrogation of
infarct size limitation cannot be ascribed to a detrimental effect of
this agent. Opening of mit-KATP channels results
in K+ influx in to the mitochondrial matrix
(Sakamoto et al., 1998). Mitochondrial membrane depolarization induced
by K+ influx would lead to a reduction in the
driving force responsible for Ca2+ uptake and/or
activation of Ca2+ release (Holmuhamedov et al.,
1999; Jovanovic et al., 1999). Besides, mitochondrial
Ca2+ overload during ischemia-reperfusion can be
reversed by mit-KATP channel agonists
(Holmuhamedov et al., 2001). The attenuated mitochondrial Ca2+ overload has been closely correlated with
the preservation of cell integrity. Thus, it suggests that the opening
of mit-KATP channels may have been associated
with reduced infarct sizes by attenuated Ca2+
overload. The result was consistent with previous finding (Liu et al.,
1998), showing that mit-KATP channels, but not
sar-KATP channels, modulate cell viability.
Second, sar-KATP channel activation was involved
in the mechanism modulating estradiol-induced reduction of reperfusion
arrhythmia demonstrated by the fact that fatal arrhythmias worsened
after the administration of HMR 1098. Although the antiarrhythmic
effects of sar-KATP channel antagonists has been
documented during ischemia, there were controversial in vivo data of
the literature supporting either proarrhythmic or antiarrhythmic
effects (Baczko et al., 1997; Rioufol et al., 1997; Kita et al., 1998;
Wirth et al., 1999; Table 4). Different
agonists and antagonists including specific and nonspecific agents were
used to assess anti- and pro-arrhythmic effects of ATP-sensitive
K+ channels. Because of many other effects in
nonspecific agents, it is difficult to compare these studies. For
example, glibenclamide was able to prevent accumulation of free
arachidonic acid released from the reperfused cell membrane (Picard et
al., 1998). Because accumulated free fatty acids can induce arrhythmias
(Oliver and Opie, 1994), an indirect antiarrhythmic action of
glibenclamide cannot be excluded. Besides, prolonged ischemia results
in much greater increases in intracellular calcium concentrations and produces triggered arrhythmias. Shortening of action potential duration
by sar-KATP channel agonists might diminish this
type of arrhythmia by decreasing intracellular calcium concentrations. Furthermore, there are variable amounts of myocardial ATP-sensitive K+ channels in different species. The amount of
sar-KATP channels is expressed at high levels in
rat and mouse (Inagaki et al., 1995). The different amount of
sar-KATP channels explained, at least in part,
why estradiol only produced an antiarrhythmic effect at 10-fold the
physiological doses in rats (Li et al., 2000), which contrasted with
our finding in dogs at physiological doses. Taken together, different
species, different specificity of drugs, and experimental models of
different myocardial ischemic durations may explain the inconsistent
data of roles of ATP-sensitive K+ channels in
arrhythmias.
|
).
sar-KATP channel agonists have been shown to aggravate reentry-type arrhythmias but to inhibit triggered-type arrhythmias (Chi et al., 1990). Our result showed that the
sar-KATP channel antagonist HMR 1098 exerts a
proarrhythmic effect in the presence of estradiol. The proarrhythmic
effect could not be due to hypoglycemia, vasoconstriction, or a
reduction in coronary flow, which are common confounding factors in
using sulfonylurea. Opening of sar-KATP channels
enhances the shortening of the action potential duration by
accelerating repolarization, which would inhibit calcium entry into the
cells (Jovanovic et al., 1999). Because reperfusion arrhythmia may
occur secondary to calcium overload (Li and Ferrier, 1992), activation
of sar-KATP channels may protect against
arrhythmias by attenuating calcium overload during reperfusion.
Estradiol has been shown to prolong action potential duration
(Tanabe et al., 1999), which was in contrast to the notion that activation of estradiol-induced sar-KATP channels
enhances the shortening of the action potential duration. The
repolarization phase of the action potential is formed by several ionic
channels, including inward Ca2+ current,
transient outward K+ current, and delayed outward
K+ current, which overlap each other with similar
time courses (Nakajima et al., 1999). Previous studies have shown that
estradiol inhibited inward Ca2+ current, which
shortens the action potential duration in guinea pig ventricular
muscles (Nakajima et al., 1999). However, the inhibition of
estradiol-induced transient outward K+ current
(Berger et al., 1997) and delayed outward K+
current (Tanabe et al., 1999) prolongs the action potential duration in
rat hearts. Our result show that estradiol activates
sar-KATP channels, which shortens the action
potential duration. However, because multiple ion channel responses
occur concomitantly, it is not possible to elucidate the specific
contributions of changes in coupling to action potential duration.
Thus, our result may not necessarily indicate that estrogen exhibits
shortening of action potential duration.
Other Mechanisms.
Although the present study suggests
that the mechanisms of estrogen-induced antiarrhythmia may be related
to opening of ATP-sensitive K+ channels, other
potential mechanisms need to be studied. 17-Estradiol may reduce
arrhythmia by attenuating catecholamine-induced injury. Aupetit et al.
(1998) showed that the adrenoceptor blockade protects against
reperfusion arrhythmia after prolonged ischemia. Myocardial infarction
can alter the control of sympathetic tone, which has been linked to an
increased extent of infarction and sudden cardiac death after
myocardial infarction (Aupetit et al., 1998). It appears that
modification of autonomic tone of estrogen may have an impact on
electrical stability. However, HMR 1098 blocked the antiarrhythmic effects of estrogen, arguing against a significant role of other factors that might be altered by estrogen. Therefore, we believe that
other mechanisms mediated by estrogen would not be a critical factor to
attenuate fatal reperfusion arrhythmia.
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Conclusions |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusions
References
|
|---|
This study demonstrates that estrogen at physiological concentrations effectively limits infarct sizes and diminishes fatal reperfusion-induced ventricular arrhythmias by different ATP-sensitive K+ channels for a nongenomic mechanism in the canine heart. The infarct size-limiting effect of estrogen was abolished by 5-hydroxydecanoate, suggesting that the effects may result from activation of the mit-KATP channels. The antiarrhythmic effect of estrogen during reperfusion was associated with the activation of sar-KATP channels because estrogen-mediated antiarrhythmic effect was inhibited by the blocker of sar-KATP channels, HMR 1098.
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Footnotes |
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Accepted for publication January 11, 2002.
Received for publication June 4, 2001.
This work was supported by Grant NSC89-2314-B002-186 from the National Science Council, (Taiwan, Republic of China) and by Grant NTUH89S1026 from National Taiwan University Hospital.
Address correspondence to: Dr. Chang-Her Tsai, Department of Surgery, Cardiology Section, National Taiwan University Hospital, 7 Chung-Shan S. Road, Taipei, Taiwan, Republic of China. E-mail: tmlee{at}ha.mc.ntu.edu.tw
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Abbreviations |
|---|
IP, ischemic preconditioning; mit-KATP, mitochondrial KATP; sar-KATP, sarcolemmal KATP; VF, ventricular fibrillation; VT, ventricular tachycardia; HMR 1098, 1-15-12-(5-chloro-o-anisamido)ethyl-methoxyphenyl)sufonyl-3-methylthiourea; ICI 182,780, faslodex.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusions
References
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-adrenergic receptor antagonist, propranolol, in preventing ischaemic ventricular fibrillation: dependence on heart rate and ischaemia duration.
Cardiovasc Res
37:
646-655-estradiol on action potentials and ionic currents in male rat ventricular myocytes.
Naunyn Schmiedebergs Arch Pharmacol
356:
788-796[CrossRef][Medline].-estradiol in the isolated perfused rat heart.
J Cardiovasc Pharmacol
33:
852-858[CrossRef][Medline].-estradiol produced by activation of mitochondrial ATP-sensitive K+ channels in canine hearts.
J Mol Cell Cardiol
32:
1147-1158[CrossRef][Medline].-estradiol in rat heart treated with isoproterenol: involvement of a cyclic AMP-dependent pathway.
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429-440[CrossRef][Medline].
-[9-(4,4,5,5,5-pentafluoropentysulfinyl)-nonyl]estra-1,3,5,(10)-triene-3-17-diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer.
Cancer Res
61:
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 J. D. McCully, A. J. Rousou, R. A. Parker, and S. Levitsky Age- and Gender-Related Differences in Mitochondrial Oxygen Consumption and Calcium With Cardioplegia and Diazoxide Ann. Thorac. Surg., March 1, 2007; 83(3): 1102 - 1109. [Abstract] [Full Text] [PDF]
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T.-M. Lee, M.-S. Lin, C.-H. Tsai, and N.-C. Chang Effect of pravastatin on left ventricular mass in the two-kidney, one-clip hypertensive rats Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2705 - H2713. [Abstract] [Full Text] [PDF]
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J. D. McCully, Y. Toyoda, H. Wakiyama, A. J. Rousou, R. A. Parker, and S. Levitsky Age- and gender-related differences in ischemia/reperfusion injury and cardioprotection: effects of diazoxide. Ann. Thorac. Surg., July 1, 2006; 82(1): 117 - 123. [Abstract] [Full Text] [PDF]
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E. A. Booth, N. R. Obeid, and B. R. Lucchesi Activation of estrogen receptor-{alpha} protects the in vivo rabbit heart from ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2039 - H2047. [Abstract] [Full Text] [PDF]
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 T.-M. Lee, M.-S. Lin, T.-F. Chou, C.-H. Tsai, and N.-C. Chang Adjunctive 17{beta}-estradiol administration reduces infarct size by altered expression of canine myocardial connexin43 protein Cardiovasc Res, July 1, 2004; 63(1): 109 - 117. [Abstract] [Full Text] [PDF]
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 E. A. Booth, M. Marchesi, E. J. Kilbourne, and B. R. Lucchesi 17{beta}-Estradiol as a Receptor-Mediated Cardioprotective Agent J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 395 - 401. [Abstract] [Full Text] [PDF]
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 T.-M. Lee and T.-F. Chou Impairment of Myocardial Protection in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 531 - 537. [Abstract] [Full Text] [PDF]
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 T.-M. Lee, T.-F. Chou, and C.-H. Tsai Differential Role of KATP Channels Activated by Conjugated Estrogens in the Regulation of Myocardial and Coronary Protective Effects Circulation, January 7, 2003; 107(1): 49 - 54. [Abstract] [Full Text] [PDF]
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, P < 0.05 versus animals treated with
HMR 1098.