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- but not 
-opioid receptors mediate effects of
ischemic preconditioning on both infarct and arrhythmia in
rats
Department of Physiology and Institute of Cardiovascular Sciences and Medicine, Faculty of Medicine, University of Hong Kong, Hong Kong
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Two
series of experiments were performed in the isolated perfused rat heart
to determine the role of 
- and 
-opioid receptors (OR) in
cardioprotection of ischemic preconditioning (IP). In the first series
of experiments, it was found that IP with two cycles of 5-min regional
ischemia followed by 5-min reperfusion each reduced infarct size
induced by 30-min ischemia, and the ameliorating effect of IP on
infarct was attenuated with blockade of either 5 × 10
6 mol/l nor-binaltorphimine (nor-BNI), a
selective -OR antagonist, or 5 × 106 mol/l
naltrindole (NTD), a selective -OR antagonist. The second series
showed that U50,488H, a selective -OR agonist, or
D-Ala2-D-leu5-enkephalin
(DADLE), a selective -OR agonist, dose dependently reduced the
infarct size induced by ischemia, which mimicked the effects of IP. The
effect of 105 mol/l U50,488H on infarct was significantly
attenuated by blockade of protein kinase C (PKC) with specific PKC
inhibitors, 5 × 106 mol/l chelerythrine or 8 × 107 mol/l calphostin C, as well as by blockade of
ATP-sensitive K+ (KATP) channels with blockers
of the channel, 105 mol/l glibenclamide or
104 mol/l 5-hydroxydecanoate. IP also reduced arrhythmia
induced by ischemia. Nor-BNI, but not NTD, attenuated, while U50,488H, but not DADLE, mimicked the antiarrhythmic action of IP. In conclusion, the present study has provided first evidence that -OR mediates the
ameliorating effects of IP on infarct and arrhythmia induced by
ischemia, whereas -OR mediates the effects only on infarct. Both PKC
and KATP channels mediate the effect of activation of -OR on infarct.
opioid receptor; protein kinase C; ATP-sensitive potassium channel
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ISCHEMIC
PRECONDITIONING (IP) is a phenomenon in which brief exposures of
the myocardium to ischemia protect the heart against subsequent severe
ischemia (28). Cardioprotection is manifested in a
reduction in infarct size, which is used as the prevailing measure
(9). Antiarrhythmic action of IP has also been reported in
rats (44, 53), dogs (53), and humans
(30). Both adenosine and -opioid receptors (OR) have
been shown to mediate the protective effect of IP (21,
40). A previous study in our laboratory (57) showed
that the binding affinity of the -OR, the predominant OR in the
heart (46, 51), is decreased during reperfusion after
ischemia in rats subjected to IP, which correlates with an increase in
ventricular fibrillation threshold. The observation suggests a role of
the receptor in cardioprotection of IP. In support of the suggestion,
another recent study in our laboratory (56) showed that
-OR mediates protection of metabolic inhibition preconditioning
against severe metabolic inhibition insult in the single ventricular
myocyte. In view of the fact that preconditioning with other insults
(such as hypoxia, metabolic inhibition, and high calcium) also provides
protection to the heart against subsequent severe ischemic insults
(2, 34, 61), a cross-tolerance phenomenon, it is therefore
highly likely that the -OR mediates cardioprotection of IP.
Both protein kinase C (PKC) (17, 24) and ATP-sensitive
K+ (KATP) channels, which are phosphorylated by
PKC (18, 20), have been shown to mediate the
cardioprotection of IP. It has also been shown that PKC mediates
cardioprotection of metabolic inhibition preconditioning and
pretreatment with U50,488H, a -OR agonist (56). In
addition, -OR stimulation activates PKC in the heart
(4). It is possible that -OR may mediate
cardioprotection of IP via PKC and KATP channels.
The purpose of this study was, first, to determine the role of -OR
in the cardioprotection of IP and, secondly, to delineate the
underlying signaling mechanism. First, we determined the effects of IP
and stimulation of -OR with its selective agonist in the absence and
presence of its antagonist on infarct induced by ischemia in the
isolated perfused rat heart. The effect of stimulation of -OR, which
has previously been shown to mediate cardioprotection of IP (19,
39, 42), was also studied for comparison. Second, we studied the
effects of pretreatment with a -OR agonist on infarct on blockade of
PKC or KATP channels with respective blockers. Finally, we
determined the roles of - and -ORs in the antiarrhythmic action
of IP. We found that -OR mediated the ameliorating effects of IP on
both infarct and arrhythmia, whereas -OR mediated the effects only
on infarct. Both PKC and KATP channels were
involved in cardioprotection (reduced infarct size) of pretreatment
with a -OR agonist.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Langendorff-perfused isolated rat heart preparation. The Langendorff-perfused isolated rat heart preparation was used (57). In brief, male Sprague-Dawley rats weighing 300-350 g were killed by decapitation with a guillotine. The heart was removed immediately and perfused retrogradely with a Krebs-Ringer solution containing (in mM) 115 NaCl, 5 KCl, 1.2 MgSO4, 1.2 KH2PO4, 1.25 CaCl2 , 25 NaHCO3, and 11 glucose. The solution was aerated with 95% O2-5% CO2, pH 7.4, under a constant pressure of 100 cmH2O. The temperature of the perfusion solution was maintained at 36°C. Total coronary arterial flow was measured by timed collection of the coronary venous effluent in a graduated cylinder. A 2-0 silk thread was passed around the left main coronary artery close to its origin with a taper needle, and the ends were passed through a small vinyl tube to form a snare. The coronary artery was occluded by pulling the snare. Myocardial ischemia was confirmed by regional cyanosis and a substantial fall in coronary flow (CF). Reperfusion was achieved by releasing the snare. In the first 15 min of perfusion, the heart was allowed to stabilize, and any heart exhibiting arrhythmia during this period was discarded.
Experimental protocol.
After an initial stabilization period of 15 min, the heart was
subjected to 30-min regional ischemia and 120-min reperfusion. IP
was produced by two cycles of 5-min regional ischemia followed by 5-min
reperfusion (Fig. 1). Figure 1 also shows
the experimental protocol for the study on the effect of OR blockade on
cardioprotection of IP. In this series of experiment, 5 × 106 mol/l nor-binaltorphimine (nor-BNI), a selective
-OR antagonist (32), or 5 × 106
mol/l naltrindole (NTD), a selective -OR antagonist
(33), was perfused for a period of 10 min before the first
ischemic episode to 10 min after the second ischemic episode. To
determine whether pretreatment with OR agonist mimicked the effect of
IP, a selective -OR agonist, U50,488H (52), or a
selective -OR agonist,
D-Ala2-D-Leu5-enkephalin
(DADLE) (13), was infused for two cycles of 5 min, as
shown in Fig. 1. Figure 2 shows the
experimental protocol for the study on the roles of PKC and
KATP channels. Phorbol 12-myristate 13-acetate (PMA;
107 mol/l), an activator of PKC (23), was
perfused for 10 min before 30-min ischemia. The inhibitors of PKC,
5 × 106 mol/l chelerythrine (Che) (18)
and 8 × 107 mol/l calphostin C (Calph)
(48), and the KATP channel blockers, 105 mol/l glibenclamide (Glib) (12) and
104 mol/l 5-hydroxydecanoate (5-HD) (3),
were infused for the period of 10 min before the first ischemic episode
to 10 min after the second ischemic episode.
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Measurement of ischemic (risk) zone and infarct size. At the end of the experiment, the silk snare was securely tightened, and 0.25% Evans blue was then infused into the heart to determine the myocardial risk zone. The heart was weighed, frozen, and cut into 2-mm slices. After removal of the right ventricle and connective tissue, we incubated the slices in 1% 2,3,5-triphenyltetrazolium chloride (TTC) in pH 7.4 buffer for 15 min at 37°C. The slices were immersed in 10% formalin overnight. The areas of infarct (TTC negative) and risk zone (TTC stained) were determined by a computerized planimetry technique (SigmaScan program 4). Volumes of left ventricle, infarct size, and risk zone were calculated by multiplying each area with slice thickness and summing products. Infarct size was expressed as a percentage of the risk zone.
Evaluation of arrhythmias. Fine platinum electrodes were placed on the right atrium and the apex of the left ventricle, allowing an epicardial electrogram to be recorded. A typical electrocardiographic trace consists of a P wave and QRS complex, which occurred at regular intervals. Both premature ventricular contraction (PVC) and ventricular tachycardia (VT) were the main arrhythmias observed within 30-min ischemia. VT was defined as a successive run of at least six PVCs of uniform QRS complex. In this study, the incidence of PVC and duration of VT were determined.
Drugs and chemicals. U50,488H, DADLE, Che, PMA, Glib, TTC, and Evans blue were purchased from Sigma Chemical; nor-BNI from Tocris Cookson; and Calph, 5-HD, and NTD from Research Biochemicals International. All chemicals were dissolved in distilled water except Glib, Calph, and PMA, which were dissolved in DMSO to a final concentration <0.1%, at which no effect was observed.
The concentrations of NTD (37), nor-BNI (43), Che (58), Calph (48), Glib (7), and 5-HD (8) used in this study were based on previous studies. At the concentrations used, the OR antagonists, PKC inhibitors, and KATP channel blockers, which themselves had no effect, blocked the effects of the respective OR agonists, PKC, and KATP channels.Exclusions. Rat hearts were excluded for the following reasons: five hearts were excluded during the stabilization period because of a CF > 15 ml/min, and nine hearts were excluded as a consequence of irreversible ventricular fibrillation (more than 2 min; 3 control, 1 IP, 2 DADLE, 2 DADLE + NTD, and 1 NTD heart). Three hearts were excluded due to an excessively large risk volume >0.550 mm3 (2 nor-BNI + IP and 1 control heart) at the end of experiment.
Statistical analysis. Data were expressed as means ± SE. One-way ANOVA was used to detect differences between groups. Paired t-test was used for within-group analyses to test drug effects on hemodynamic parameters before ischemia. When multiple comparisons with t-tests were performed, Bonferroni's correction was adopted. P < 0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamic data.
Heart rate and CF data were summarized in Table
1. Heart rate and CF were comparable in
all groups under baseline conditions. Pretreatment with
105 mol/l U50,488H or 3 × 107 mol/l
DADLE induced a transient reduction in heart rate, which was measured
at 2 min after the treatment. The heart rate in both groups recovered
before ischemia (data not shown). Che (5 × 106
mol/l) caused an increase in CF, whereas Glib (105 mol/l)
led to a reduction in CF (Table 1). Coronary artery occlusion resulted
in a marked reduction in CF in all of the experimental groups. On
reperfusion, CF was restored to normal immediately (data not shown).
There were no significant differences in heart rate and CF among groups
at the end of reperfusion.
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Effects of IP or pretreatment of - or -OR agonist on infarct
caused by ischemia in isolated perfused rat hearts.
There was no significant difference in the risk area among all groups.
Ischemia induced myocardial infarct. In agreement with a previous
finding (22), exposure to two cycles of 5-min ischemia each reduced the infarct size caused by ischemia (Table
2). In the presence of either 5 × 106 mol/l nor-BNI or NTD, which themselves had no effect
at all, the ameliorating effect of IP on infarct was significantly
attenuated (Table 2).
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-OR agonist, or DADLE, a selective -OR agonist, concentration dependently reduced the infarct size induced by ischemia
(Fig. 3). The effect of the agonists at
the highest concentrations of the concentration ranges used in this
study was abolished by their respective antagonists (Fig. 3).
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Effects of IP or pretreatment of - or -OR agonist on
arrhythmia induced by ischemia in isolated perfused rat hearts.
Ischemia induced mainly PVC and VT. IP significantly reduced the number
of PVCs and duration of VT (Fig. 4).
Interestingly, the ameliorating effect of IP was attenuated in the
presence of 5 × 106 mol/l nor-BNI but not 5 × 106 mol/l NTD (Fig. 4). It is important to note
that, at the concentrations used, both OR antagonists, which had no
effects on arrhythmia (Fig. 4), attenuated the effects of IP on infarct
(Table 2).
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6-105
mol/l also concentration dependently attenuated the arrhythmogenic
effects of ischemia (Fig. 5). On the
other hand, pretreatment with DADLE at a similar concentration range
(3 × 107-105 mol/l) had no
effect on arrhythmia at all (Fig. 5).
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Effects of pretreatment with U50,488H on infarct and arrhythmia on
blockade of PKC in isolated perfused rat hearts.
As shown in Fig. 6, the ameliorating
effect of pretreatment with U50,488H on infarct was mimicked by
107 mol/l PMA, an activator of PKC, and completely
blocked by selective PKC inhibitors, 5 × 106 mol/l
Che or 8 × 107 mol/l Calph. On the other hand,
blockade of PKC with either of the two selective inhibitors did not
alter the effect of pretreatment with U50,488H on arrhythmia (Fig.
7).
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Effects of pretreatment with U50,488H on infarct with blockade of KATP channel in isolated perfused rat hearts. As shown in Fig. 6, the ameliorating effect of U50,488H on infarct induced by ischemia was abolished on blockade of KATP channel with two inhibitors, Glib and 5-HD, which themselves had no effect at all (Fig. 6). The effects on arrhythmia were not studied because the inhibitors of the KATP channel themselves induced arrhythmia.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The most interesting observations in this study are 1)
the -OR antagonist, nor-BNI, attenuated the ameliorating effects of IP on infarct and arrhythmia induced by ischemia in the isolated perfused rat heart and 2) pretreatment with a -OR
agonist, U50,488H, reduced the effects of ischemia on infarct and
arrhythmia, which mimicked the effect of IP. These observations
provided evidence indicating that -OR mediates cardioprotection and
the antiarrhythmic action of IP. This extends the previous findings
that the affinity of the -OR binding site is decreased during
reperfusion after ischemia in rats subjected to IP (57)
and that -OR mediates cardioprotection of metabolic inhibition
preconditioning (56). The findings are not in agreement
with the results of previous studies, which showed that nor-BNI does
not antagonize the ameliorating effects of hypoxic preconditioning on
survival time in mice (25), and of IP on infarct in the
anesthetized Wistar rat (42) and in an isolated perfused
rat heart (1), respectively, suggesting that -OR is not
involved in protection of preconditioning with either hypoxia or
ischemia. However, nor-BNI has been shown not to be sufficiently active
in vivo previously in two studies (6, 29). The
concentration of nor-BNI used in the isolated rat heart study was
3 × 108 M (1), much lower than the
concentration (5 × 106 M) required to block the
cardioprotection of IP in the same preparation, as demonstrated in this
study. In addition, the findings in this study are not in agreement
with the finding that 30 nmol/l bremazocine and 1 µmol/l DADLE
increased the infarct size in the isolated rat heart subjected to
ischemia, and the effects were antagonized by nor-BNI
(1). These observations suggest that -OR stimulation exacerbated the ischemia-induced infarct rather than producing protection. It should be noted that bremazocine is a nonselective -OR agonist with a preference for the 2-OR subtype
(47, 60), whereas DADLE is a -OR agonist. The
concentration of bremazocine (30 nmol/l) used in the previous study was
much lower than the concentration range (1-10 µmol/l) used in
this study. Further study is needed to clarify the discrepancies in the
two studies.
In this study, we also obtained evidence that -OR is involved in the
ameliorating effect of IP on infarct. This is in agreement with the
previous finding that -OR mediates cardioprotection of IP (41,
42). Interestingly, unlike -OR, -OR is not involved in the
antiarrhythmic effect of IP. The fact that effects of stimulation of
- and -ORs are similar on infarct but different on arrhythmia also supports the suggestion that different mechanisms may be involved
for these two parameters (31, 50).
The observation that -OR mediates the ameliorating effects of IP on
infarct and arrhythmia, whereas -OR mediates the effect only on
infarct, indicates that -OR agonists may provide more protection
against injury and arrhythmia than that on injury alone with a -OR
agonist. So -OR agonists may be more useful for the treatment of cardiac disorders. On the other hand, the -OR agonist produces cardioprotection at a concentration range of
108-3 × 107 mol/l, which is much
lower than that of the -OR agonist,
106-105 mol/l. The observation
indicates that a much higher concentration of -OR agonist may be
needed to produce cardioprotection. The high concentration needed for
-OR agonist to produce cardioprotection means more undesirable effects.
In our previous studies, we found that administration of -OR
agonists, dynorphin1-13 (16) and U50,488H at
106-105 mol/l, induces arrhythmias in
the isolated perfused rat heart (5, 54, 55). The
arrhythmogenic action of -OR stimulation may not be beneficial. On
the other hand, we have also shown that U50,488H at as low as
108-106 mol/l attenuates arrhythmias
induced by low flow and augmented by 
-adrenoceptor stimulation in
the isolated perfused rat heart, an effect antagonized by nor-BNI
(59), suggesting that -OR stimulation may also produce
antiarrhythmic action during ischemia. So in the in vivo situation,
-OR stimulation may have both arrythmogenic and antiarrhythmic actions.
In this study, we also observed that the ameliorating effect of
pretreatment with U50,488H on infarct was attenuated by blockade of PKC
with two selective inhibitors, Che and Calph, and that activation of
PKC with a selective PKC activator, PMA, mimicked the effect of
pretreatment with U50,488H. A previous study (26) showed
that morphine produces early cardioprotection similar to that of IP and
that the protection of morphine is blocked by naloxone in the isolated
rabbit heart. The protective effect of morphine is also blocked by
blockade of PKC with a selective inhibitor, suggesting that PKC
mediates the effect of OR stimulation (26). Similarly, Wu
et al. (56) also showed that the -OR agonist U50,488H
produces similar cardioprotection as metabolic inhibition preconditioning and that nor-BNI blocks the effects of metabolic inhibition preconditioning and U50,488H, suggesting that -OR mediates the delayed cardioprotection of metabolic inhibition preconditioning via PKC in the rat ventricular myocyte. The
observations are in agreement with the finding of this study. It is
important to note that PKC also mediates cardioprotection of IP
(17, 24) and that stimulation of the adenosine
A1 receptor (21) and bradykinin receptor
(11), which activate PKC, mimics cardioprotection of IP,
as does OR. The observations from the present and previous studies
suggest that PKC may be the central mechanism mediating cardioprotection of IP. On the other hand, PKC inhibitors have also
been reported to fail to block the cardioprotection of IP in
anesthetized dogs and pigs (45, 49).
Interestingly, blockade of PKC with the same inhibitors did not
affect the ameliorating effects of pretreatment with U50,488H on
arrhythmia, indicating that the messenger does not mediate the action
of pretreatment with a -OR agonist on arrhythmia. These observations
indicate that different mechanisms are involved in mediating the action
of pretreatment with a -OR agonist on infarct and arrhythmia.
Previous studies have demonstrated that both - and
-ORs activate K+ channels, which are linked to G protein
(15). KATP channel blockers have been shown to
abolish both early and delayed cardioprotection of -OR stimulation
(10, 39) and morphine pretreatment (38). In
the present study, we also observed that blockade of the
KATP channels also attenuated the ameliorating effect of
pretreatment with U50,488H on infarct, indicating that the
KATP channel mediates the effect of pretreatment with
U50,488H. So the signaling pathway activated on -OR stimulation
during IP includes PKC and KATP channels. Whether -OR
stimulation directly activates the KATP channel via a
pertussis toxin-sensitive G protein or activation of PKC needs further
study. Glib is a nonselective inhibitor of KATP channels
(14), whereas 5-HD is considered a selective mitochondrial KATP channel inhibitor by some (36) but not
others (27, 35). The result from this study does not
provide sufficient evidence on the role of sarcolemmal and
mitochondrial KATP channel.
In this study, we found that Che increased CF, whereas another PKC inhibitor, Calph, had no effect. Glib reduced CF, whereas another blocker of KATP channels had no effect. All of these agents, which themselves had no effect on infarct, attenuated the ameliorating effect of U50,488H on infarct induced by ischemia. It is unlikely that the effect of these drugs on CF has any correlation with their effect on infarct.
In conclusion, this study has provided evidence for the first
time that -OR mediates the ameliorating effects of IP on infarct and
arrhythmia, whereas -OR mediates the effect only on infarct. Pretreatment with a -OR agonist, U50,488H, may provide more
beneficial effects than pretreatment with a -OR agonist, DADLE.
However, a higher concentration is required for the -OR agonist to
produce cardioprotection. Both PKC and KATP channels are
involved in the cardioprotection (reduced infarct size), whereas PKC is
not involved in the antiarrhythmic action of -OR stimulation.
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ACKNOWLEDGEMENTS |
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We thank Dr. H. Ballard and Dr. I. Bruce for advice on the use of English and C. P. Mok for technical assistance.
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FOOTNOTES |
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The study was supported by a grant from the Research Grants Council, Hong Kong.
Address for reprint requests and other correspondence: T.-M. Wong, Dept. of Physiology, Faculty of Medicine, Univ. of Hong Kong, Li Shu Fan Bldg., Sassoon Rd., Hong Kong (E-mail:wongtakm{at}hkucc.hku.hk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4 April 2000; accepted in final form 27 July 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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