© 1999 American Heart Association, Inc.
Original Contribution |
Cardioprotection of Preconditioning by Metabolic Inhibition in the Rat Ventricular Myocyte
Involvement of 
-Opioid Receptor
From the Department of Physiology and Institute of Cardiovascular Science and Medicine, Faculty of Medicine, The University of Hong Kong, China.
Correspondence to T.M. Wong, PhD, Department of Physiology, Faculty of Medicine, The University of Hong Kong, Li Shu Fan Building, Sassoon Rd, Hong Kong, China. E-mail wongtakm{at}hkucc.hku.hk
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Abstract |
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Abstract—To determine whether opioid receptors (ORs) are involved in the delayed cardioprotection of ischemic preconditioning (IP), the effect of severe metabolic inhibition (MI) with a glucose-free buffer that contained sodium cyanide and 2-deoxy-D-glucose on the viability of isolated rat ventricular myocytes was first determined 20 hours after preconditioning with a sublethal metabolic inhibition (MIP) with a glucose-free buffer that contained 2-deoxy-D-glucose and lactate for 30 minutes in the presence of OR antagonists. With the use of trypan blue exclusion as an index of cell viability, severe MI killed >60% of the cells and the value increased significantly after MIP. In the presence of 5x10-6 mol/L nor-binaltorphimine (nor-BNI), a selective
-OR antagonist, but not 5x10-6
mol/L CTOP, a selective µ-OR antagonist, or
5x10-6 mol/L naltrindole, a selective 
-OR
antagonist, the cardioprotection of MIP was significantly
attenuated. To verify the role of -OR, we studied the effects of
severe MI after pretreatment with the -OR agonist U50,488H (UP) for
30 minutes. U50,488H at 3x10-6 to 1x10-4
mol/L increased cell viability concentration-dependently with an
EC50 of 3.311x10-6 mol/L. In the presence of
5x10-6 nor-BNI, the cardioprotection of UP
(3x10-5 mol/L) was blocked. A time course study showed
that UP-induced cardioprotection occurred in 2 windows: the first
occurred 
1 hour later and the other occurred 16 to 20 hours later.
Additional studies on cell contraction and intracellular
Ca2+ ([Ca2+]i) revealed that both
UP and MIP attenuated the inhibitory effects of severe MI
on contractility and electrically induced
[Ca2+]i transient in single
ventricular myocytes. On blockade of protein kinase C, the
delayed cardioprotections of UP and MIP were significantly attenuated.
In conclusion, the results of the present study have provided
evidence that -OR mediates the cardioprotection of MIP, which may
involve protein kinase C and [Ca2+]i.
Key Words: receptor • contractility • Ca2+ • myocyte • protein kinase
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Ischemic preconditioning (IP), which is defined as previous exposure to transient myocardial ischemia, provides protection to subsequent severe insults in the heart. Early studies show that the protection occurs immediately and wanes within 1 to 2 hours.1 This is called classic IP. More recently, it was found that IP can also trigger a delayed cardioprotection 12 to 72 hours later, which is called second window of IP.2 The longer cardioprotection in the second window may be more useful clinically. In addition to ischemia, preconditioning with other insults such as hypoxia,3 metabolic inhibition (MI),4 and high Ca2+5 also provide protection against subsequent severe ischemic insults, a cross-tolerance phenomenon.
Opioid receptors (ORs) have been suggested to be involved in
immediate6 7 and delayed8 9 cardioprotection
of IP. More recent studies show that the -receptor may be
involved.10 A previous receptor binding study showed that
IP, which elevated the ventricular fibrillation
threshold,11 reduced the binding affinity of the -OR,
the predominant OR in the heart,12 13 which suggests that
the -OR may also be involved in cardioprotection of IP. However,
findings from a receptor binding study are not conclusive.
Therefore, the purpose of the present study was to determine
whether any subtypes of OR are involved in the cardioprotection of IP,
and, if so, the possible mechanisms involved. We concentrated on
delayed cardioprotection for 2 reasons. First, the longer duration of
protection was considered more useful clinically. Second, the
mechanisms of delayed cardioprotection are less understood. We adopted
a procedure used by Nayeem and colleagues14 who
preconditioned isolated ventricular myocytes with mild MI
(MIP), which produced a delayed cardioprotection similar to that of IP.
An advantage of the isolated myocyte model was that we not only could
study the viability and functional status of the cells but also the
intracellular events such as the intracellular
Ca2+
([Ca2+]i) response, which
provides information on
[Ca2+]i homeostasis in
the heart. In the present study, we determined the viability,
[Ca2+]i, and contraction
of the ventricular myocytes that were subjected to MIP with
or without the blockade or activation of OR subtypes. We also
determined the cardioprotection of MIP and pretreatment with an opioid
agonist when protein kinase C (PKC), known to mediate the
cardioprotection of IP15 and the effects of OR
stimulation,16 17 was blocked. The results of the
present study show that -OR mediates the cardioprotection of MIP
and that both [Ca2+]i and
PKC may be involved in the delayed cardioprotection of MIP and
pretreatment with a -opioid agonist.
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Materials and Methods |
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Isolation and Culture of Rat Ventricular Myocytes
Myocytes were isolated from hearts of adult Sprague-Dawley rats with a collagenase method described previously.18 The level of viable myocytes, as indicated by trypan blue exclusion, was
76% of total cells. The cells were
incubated in a CO2 incubator (95% air/5%
CO2, 28°C) for 1 to 28 hours in culture dishes
in 5 mL of MEM that contained 1x10-3 mol/L
Ca2+, 0.2% BSA,
1x10-8 mol/L insulin, 100 U/mL of penicillin G,
and 100 µg/mL of streptomycin according to the method of Sheng and
colleagues.19 The percentages of nonblue cells were
70.7%, 69.7%, 64.8%, 62.1%, and 51.5% after 1, 6, 16, 20, and 28
hours of incubation in normal medium, respectively.
Experimental Protocol
After the ventricular myocytes had been
separated, they were allowed to stabilize for 30 minutes before the
experiment started. We used the procedures described by Nayeem and
colleagues14 (Figure 1A
). Cells were subjected
either to MIP with a glucose-free Krebs buffer (pH 6.6) that contained
2x10-2 mol/L lactate and
1x10-2 mol/L 2-deoxy-D-glucose
(2-DOG), an inhibitor of glycolysis, or to pretreatment
with an OR agonist for 30 minutes in the presence of an
OR-antagonist (5 minutes before and throughout MIP) or an
inhibitor of PKC (1 hour before MIP began). In the control
groups, the cells were subjected to pretreatment with vehicle (VP) for
30 minutes or an OR antagonist or PKC inhibitor
alone for 35 minutes or 1 hour, respectively. Myocytes were washed
several times after pretreatment to ensure that the cells were free of
any drug. They were then incubated in normal MEM for 20 hours, except
in the experiments that involved time course study, in which the cells
were cultured for 1, 6, 16, 20, and 28 hours (Figure 3A).
Finally, the cells were subjected to severe MI for 5 minutes with
1.5x10-3 mol/L sodium cyanide and
2x10-2 mol/L 2-DOG, followed by washout and
replacement with normal solution reperfusion.
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Myocytes incubated for 20 hours were more sensitive to severe MI than the fresh cells as indicated by the fact that only 22% of the cells were alive after 20 hours of culture compared with 43% in the fresh cells at 10 minutes into reperfusion after severe MI.
Trypan Blue Exclusion and Cell Morphology
Trypan blue exclusion was used as an index of the viability of
the myocytes.3 20 After the live cells were incubated with
0.4% trypan blue dye for 3 minutes, they were unstained and called
nonblue cells. Approximately 200 cells in each of 8 cultures were
examined for each group. Cells were counted in a hemocytometer chamber
under a light microscope.
Cell morphology was determined by microscopic examination.3 4 Both rod-shaped (length/width ratio, >3:1) and square (length/width ratio, <3:1, >1:1) cells were examined. Only the results from rod-shaped cells were presented, because the conclusion remained the same with or without the results from square cells. Approximately 100 cells in each of 5 cultures were determined for each group.
Measurement of Contraction and Electrically Induced
[Ca2+]i Transient in the Single
Ventricular Myocyte
Myocytes incubated for 20 hours after
preconditioning/pretreatment were placed in a chamber and superfused
with a bicarbonate Krebs solution that contained (mmol/L) 118 NaCl, 5
KCl, 1.2 MgSO4, 1.2
KH2PO4, 1
CaCl2, 25 NaHCO3, and 11
glucose gassed with 95% O2/5%
CO2 at pH 7.2 in room temperature. At 5 minutes
into reperfusion, after severe MI, the surviving myocytes were
electrically stimulated at 0.2 Hz. The amplitude of contraction was
measured with an automatic video analyzer
system.21 For the measurement of the electrically induced
[Ca2+]i transient, cells
were first loaded with fura-2/AM as a Ca2+
indicator, and [Ca2+]i
transient was determined by a spectrofluorometric method described
previously.21 22 The fluorescence ratio of 340 nm
(F340) over 380 nm (F380) was used as an index of
[Ca2+]i because changes
in the fluorescence ratio were considered to accurately reflect
the fluctuations in the cytosolic Ca2+ of the
contraction-relaxation cycle.23
Drugs and Chemicals
CTOP, naltrindole, and nor-binaltorphimine (nor-BNI), selective
antagonists of µ-,24 -,25
and -OR,26 27 respectively; U50,488H, a selective
-OR agonist28 29 ; and chelerythrine, an
inhibitor of PKC,30 were used. In the
present study, the concentration range of U50,488H was
3x10-6 to 1x10-4
mol/L because, at a similar range, this drug has been shown to
activate the phospholipase C/Ca2+
pathway,31 which leads to the mobilization of
Ca2+ from its intracellular
store.17 19 32 The effects were antagonized by
5x10-6 mol/L nor-BNI,22 31 33
which itself had no effect. The concentrations of
naltrindole,34 35 CTOP,36 37
nor-BNI,22 31 33 and chelerythrine38 39 used
in this study were based on previous studies, which showed that at the
concentrations used, the OR antagonists and the PKC
inhibitor, which themselves had no effect at all, blocked
the effects of the respective OR agonists and PKC.
U50,488H, fura-2/AM, type 1 collagenase, sodium cyanide, 2-DOG, chelerythrine, and trypan blue dye were purchased from Sigma Chemical Co. Nor-BNI was purchased from Tocris Cookson Ltd, and naltrindole and CTOP were purchased from Research Biochemicals International. All chemicals were dissolved in distilled water except chelerythrine and fura-2/AM, which were dissolved in DMSO at a final concentration <0.1%, at which no effect was observed.
Statistical Analysis
Data were expressed as mean±SEM. One-way ANOVA was used to
determine the differences among the multiple groups. For
analysis of drug effects, the nonparametric
Kruskal-Wallis test was used. P<0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effects of MIP on Trypan Blue Exclusion in Isolated Ventricular Myocytes in the Presence of OR Antagonists
This series of experiments was undertaken to determine which of the 3 OR subtypes may be involved in the mediation of delayed cardioprotection of MIP (Figure 1A
).
After 20 hours of incubation followed by 5 minutes of severe MI, the
percentage of the nonblue cells per the total number of cells at 10
minutes into reperfusion in the MIP group was 38%; this was
significantly higher than the 22% found in the VP group (Figure 1B). In the presence of nor-BNI, the nonblue cells were 25% of
total cells, which was significantly lower than 38% in the MIP group.
On the other hand, in the presence of CTOP or naltrindole, the effect
of MIP was not attenuated.
Effects of Pretreatment With U50,488H on the Viability of
Ventricular Myocytes
This second series of experiments was designed to determine
whether pretreatment with U50,488H (UP) produced cardioprotection
similar to that observed with MIP. The same experimental procedure as
in the first series of experiments was used except that the
ventricular myocytes were pretreated with
3x10-6 to 1x10-4 mol/L
U50,488H for 30 minutes. The percentage of nonblue cells at 10 minutes
into reperfusion was significantly higher than that of the VP group
when U50,488H was at 1x10-5 mol/L, and the
maximum response was reached when the concentration of U50,488H
was 3x10-5 mol/L (Figure 2A). We used the concentration
3x10-5 mol/L for all experiments.
EC50 was 3.311x10-6
mol/L.
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In the presence of 5x10-6 mol/L nor-BNI, which
in itself had no effect, the percentages of the nonblue cells in both
MIP and UP were significantly reduced (Figure 2B, top).
To compare the responses in terms of myocyte viability and cell shape,
the rod-shaped cells were counted 10 minutes into reperfusion. Only
11% of the cells were rod-shaped in the VP group, although the
percentage of rod-shaped cells increased to 30% and 24% in the MIP
and UP groups, respectively (Figure 2B, bottom). Nor-BNI
significantly attenuated (19%) and completely abolished (12%) the
effects of MIP and UP, respectively (Figure 2B, bottom).
To study the time course of cardioprotection of UP, we determined the
viability of myocytes incubated for different periods of time (1, 6,
16, 20, and 28 hours) after 30 minutes of UP (Figure 3A). The nonblue cells that were found 10
minutes into reperfusion after 1 hour of incubation and severe MI,
composed only 35% of the total cells in the VP group. Myocyte
viability decreased as the incubation time increased. A plateau of
20% was reached at 16 hours. The viability of the UP groups was
significantly higher than that in the corresponding VP groups at 1, 16,
and 20 hours, with the greatest difference at the 20-hour point (36%
versus 22%; Figure 3B).
Effects of MIP and UP on Contraction and Electrically Induced
[Ca2+]i Transient in Single Surviving
Myocytes
To determine the functional status of the cells after MIP and UP,
both contraction and electrically induced
[Ca2+]i transient during
reperfusion and after 20 hours of incubation and severe MI were
determined. Measurements were made at 5 minutes into reperfusion
because the difference in contraction among the groups at this time was
most obvious as shown in the previous40 and present
studies. In the VP group, the amplitude of contraction was only 13% of
baseline (100%; Figure 4A, top, and
4B). The amplitudes in the MIP and UP groups were significantly
increased; MIP was 65% and UP was 42% (Figure 4A and 4B) of baseline. When the myocytes were subjected to MIP or UP
in the presence of 5x10-6 mol/L nor-BNI, which
itself had no effect, the amplitude returned to the level of the VP
group (Figure 4B).
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Similar to the measurement of contractility, the
electrically induced
[Ca2+]i transient was
also measured 5 minutes into reperfusion. In the same manner as the
response in contraction, the
[Ca2+]i transient was
significantly reduced by severe MI in the VP group (Figure 5A, top), which was in agreement with the
previous study.41 MIP (Figure 5A, middle, and 5B) and UP (Figure 5A, bottom, and 5B)
significantly attenuated the effects of severe MI. The effects of MIP
and UP (Figure 5B) were significantly attenuated and completely
abolished with 5x10-6 mol/L nor-BNI, which
itself had no effect (Figure 5B).
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Effects of MIP and UP on Trypan Blue Exclusion With Blockade
of PKC
The goal of this series of experiments was to determine whether
PKC mediated the delayed cardioprotection of MIP and UP. In the
presence of 5x10-6 mol/L chelerythrine, a PKC
inhibitor that by itself had no effect, the cell viability
was significantly reduced in both MIP and UP groups (Figure 6) when determined 10 minutes into
reperfusion after preconditioning/pretreatment, 20 hours of incubation,
and severe MI.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The most interesting observations of the present study are (1) blockade of the
-OR with selective -OR
antagonist nor-BNI obstructed the cardioprotective effects
of MIP, and (2) -OR stimulation with specific -OR agonist
U50,488H provided similar cardioprotective effects of MIP. The
observations indicate that -OR mediates the cardioprotection of MIP.
The finding extends the previous observations in our
laboratories11 and other6 7 that suggest that
OR is involved in cardioprotection of IP. Our results also suggest that
neither µ- nor -OR is involved in the cardioprotection of MIP.
Thefindings are consistent with our previous observations
that -OR but not µ- or -OR is involved in cardiac responses to
ischemia/reperfusion.42 However, the findings are
not in agreement with recent reports that suggest that
-9 10 but not -OR43 may be the subtype
of OR involved in the cardioprotection of IP. The discrepancies might
be related to the animal models and experimental procedures used and
the windows studied in different studies.
Results on time-course study showed that there were 2 windows of
cardioprotection by UP, which occurred at 1 hour and 16 to 20 hours,
respectively. Similarly, IP produced PKC-inhibitor
immediate (1 to 2 hours)1 and delayed (12 to 72
hours)2 cardioprotection; however, the length of the
window of delayed protection was different from the one we achieved. In
the present study, an isolated and cultured myocyte preparation was
used, whereas in the previous studies,1 2 a perfused heart
or anesthetized animal model was used.
It has been well established that ischemia causes
hypoxia/anoxia, MI, acidosis, hyperkalemia, and
Ca2+ overload in the heart.44
Ca2+ overload, which is secondary to MI, is one
of the most important causes of cell injury during myocardial
ischemia.44 45 In isolated myocytes, an elevation
of extracellular calcium
([Ca2+]o) from
1x10-3 to 5x10-3 mol/L
induced a marked increase in
[Ca2+]i and cessation of
[Ca2+]i transient, which
was followed by cell death.5 In myocytes that were
pretreated with high
[Ca2+]o the damage by
subsequent severe high
[Ca2+]o on cell viability
and contractility was abolished, which indicates that
Ca2+ may play an important role in protection by
preconditioning.5 46 In the present study, the
Ca2+ response was altered in parallel with the
changes of viability, morphology, and contractility in
the cardiomyocytes that were subjected to MI, with or
without MIP and UP. These observations suggest that
[Ca2+]i may play an
important role in cell injury and cardioprotection of MIP and UP, which
is consistent with the results of previous studies that
indicate that [Ca2+]i
overload induces cardiac injury5 18 44 and
Ca2+ is a mediator of IP.46 Because
-OR stimulation has been shown to increase the level of
[Ca2+]i47 48 and
affects Ca2+
homeostasis17 33 49 in adult rat
cardiomyocytes, it is possible that pretreatment with
a -OR agonist may produce cardioprotection via alterations of
Ca2+ homeostasis in a manner similar to
Ca2+ preconditioning.5 46 Additional
studies are needed to verify this.
Another important finding of the present study is that the delayed
cardioprotection of both MIP and UP was attenuated by PKC blockade,
which indicates the involvement of PKC. This is consistent with
the observations in our laboratories17 and
others16 that the actions of -OR stimulation involve
PKC, presumably via a pertussis toxin–sensitive G-protein and
phospholipase C.33 In fact, PKC is known to
activate the ATP-sensitive potassium channel,50
which has been shown to inhibit the L-type Ca2+
channel and be involved in cardioprotection, and to mediate the
cardioprotection of IP.15 More studies are needed to
delineate the signaling pathway of UP.
We used isolated myocytes instead of an isolated heart or in vivo preparations because the model is a simple preparation that would enable us to study the intracellular signaling process, in particular, the Ca2+ response. Results showed that the isolated and cultured myocyte preparation is a useful model to delineate intracellular mechanisms. Like other authors,41 we used MI for cell pretreatment because it is one of the consequences of ischemia44 45 and MIP produces cardioprotection similar to that by IP,14 presumably because of the well-known cross-tolerance phenomenon.
In the present study, we found that the patterns of change in trypan blue exclusion and rod-shaped cells basically agreed with each other, although the number of nonblue cells was greater than that of rod-shaped cells. Therefore, cell morphology may also be used to confirm the conclusion made on the basis of trypan blue exclusion.
In conclusion, the present study has provided evidence for the
first time that -OR may mediate cardioprotection of IP and that PKC
and [Ca2+]i may be
involved in delayed cardioprotection. Additional studies are needed to
investigate the importance of
[Ca2+]i homeostasis and
signal-transduction mechanisms in -OR mediated cardioprotection.
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Acknowledgments |
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This study was supported by grants from the Research Grant Council, Hong Kong, and L.C.S.T. (Holding Ltd) to T.M.W., and from the Faculty of Medicine, Hong Kong University to the "Mechanisms of Disease" group. We thank I.C. Bruce for his advice on the English and C.P. Mok for his assistance.
Received November 12, 1998; accepted March 31, 1999.
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