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© 1999 American Heart Association, Inc.
Rapid Communication |
Opioid-Induced Second Window of Cardioprotection
Potential Role of Mitochondrial KATP Channels
From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wis.
Correspondence to Garrett J. Gross, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wis. E-mail ggross{at}post.its.mcw.edu
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Abstract |
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Abstract—Opioids have been previously shown to confer short-term cardioprotection against a prolonged ischemic insult. Therefore, the present study was designed to determine whether opioids can induce a delayed or "second window" of cardioprotection and to assess the potential involvement of the mitochondrial KATP channel. All rats were subjected to 30 minutes of ischemia and 2 hours of reperfusion (I/R). Control animals, injected with saline 24 hours before I/R, elicited an infarct size/area at risk (IS/AAR) of 62.9±3.4. TAN-67, a
1-opioid
receptor agonist, was administered 10 or 30 mg/kg IP 12, 24, 48, or 72
hours before I/R. TAN-67 (10 mg/kg) 12- or 24-hour pretreatment did not
significantly reduce IS/AAR (62.1±6.3 and 43.3±7.3, respectively).
Similarly, 12-hour pretreatment with TAN-67 (30 mg/kg) did not reduce
IS/AAR (60.0±5.6); however, 24-hour pretreatment significantly reduced
IS/AAR (34.5±5.9). Forty-eight–hour pretreatment with TAN-67
maximally reduced IS/AAR (29.2±7.0), and opioid-induced
cardioprotection was lost after 72-hour pretreatment (61.7±3.8).
TAN-67–induced cardioprotection could be abolished by pretreatment
with the selective 1-opioid receptor
antagonist 7-benzylidenenaltrexone, BNTX, administered
either 30 minutes before TAN-67 given 48 hours before I/R or 10 minutes
before I/R in rats previously treated for 48 hours with TAN-67
(59.6±3.1 and 58.7±3.5, respectively). The involvement of the
KATP channel was investigated with 2
inhibitors: glibenclamide, a nonselective KATP
channel inhibitor, and 5-hydroxydecanoic acid, selective
for the mitochondrial KATP channel in rabbits.
Glibenclamide, administered 30 minutes before I/R in 48-hour
TAN-67–pretreated rats, completely abolished cardioprotection
(60.4±3.2). Similarly, 5-hydroxydecanoic acid, administered 5 minutes
before I/R in rats pretreated 48 hours previously with TAN-67,
completely abolished cardioprotection (57.8±2.5). These results
suggest that 1-opioid receptor stimulation, 24 to 48
hours before an ischemic insult, produces a delayed
cardioprotective effect that is possibly the result of mitochondrial
KATP channel activation.
Key Words: quinolines • cardioprotection • mitochondria • receptors, opioid
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Opioids have been widely used as therapeutic agents for the treatment of pain; however, our laboratory has recently demonstrated that opioids also produce cardioprotection in the in vivo rat heart against a prolonged ischemic insult and subsequent reperfusion.1 We demonstrated that this cardioprotective effect is the result of
1-opioid receptor
activation and is elicited through a Gi/o
protein-mediated mechanism and subsequent opening of the ATP-sensitive
potassium channel (KATP channel).2
Similarly, Miki et al3 have recently demonstrated that in
the rabbit heart, morphine mimics ischemic preconditioning
through the activation of protein kinase C (PKC). Ischemic preconditioning (IPC), a phenomenon in which brief episodes of ischemia and reperfusion before a prolonged ischemic event limit myocardial cellular damage, has been shown to elicit both an acute and delayed phase of cardioprotection or a second window of protection.4 Short-term protection as a result of IPC provides immediate protection to the myocardium against a prolonged ischemic insult for 30 to 90 minutes after stimulus depending on the species studied. Baxter et al and others5 6 have demonstrated a second window of protection as a result of a previous IPC stimulus and have shown that an adenosine A1 receptor agonist also produces delayed cardioprotection. These investigators demonstrated that IPC and a selective adenosine A1 agonist can limit cell death as a result of a prolonged ischemic event in the rabbit heart 24, 48, or 72 hours after brief ischemia or pharmacological intervention. However, this delayed cardioprotection was not observed 12 hours after IPC and usually disappeared 72 to 96 hours after IPC.7 Baxter et al8 have also demonstrated that delayed cardioprotection produced by IPC is mediated by both PKC and tyrosine kinase8 9 activation. It has been hypothesized that this delayed protection may result from the translocation of PKC to the nucleus4 ; increased transcription and subsequent synthesis of cardioprotective proteins such as the small heat shock protein, hsp 27,10 other stress proteins4 ; and endogenous antioxidant enzymes.4
Although no work has been done concerning delayed cardioprotection due to opioids, Ventura et al11 have shown that the nucleus of hamster ventricular myocardial cells contain opioid binding sites and that cardiomyopathic cells had increased basal levels of opioid gene transcription. Opioids have been shown to activate other pathways thought to be involved in the protective effect of IPC-induced delayed protection. Gutstein et al12 have examined the involvement of opioids on the mitogen-activated protein kinase signaling cascade and have demonstrated that opioids may induce activation of both extracellular signal-related kinase and p38. As previously mentioned, opioids may activate PKC to confer cardioprotection in acute IPC.3 Similarly, PKC-signaling events have been demonstrated in delayed cardioprotection due to IPC.8 Evidence exists that implicates the mitochondrial KATP channel as the end effector of acute IPC13 14 15 ; however, controversy exists as to the importance of either the sarcolemmal and/or mitochondrial KATP channel to confer delayed cardioprotection due to IPC. Recently, Liu et al have identified a mitochondrial selective KATP channel antagonist, 5-hydroxydecanoic acid, in isolated rabbit myocardial cells.
Therefore, the present study sought to examine the possibility of
opioid-induced delayed cardioprotection in a rat model of
ischemia/reperfusion injury and examined the potential
involvement of the KATP channel in this
protection. We hypothesize that 1-opioid
receptor activation can initiate a delayed cardioprotective effect to a
prolonged ischemic insult in the rat and that the mitochondrial
KATP channel may be the end effector of this
cardioprotection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study was performed in accordance with the guidelines of the Animal Care Committee of the Medical College of Wisconsin, which is accredited by the American Association of Laboratory Animal Care.
General Surgical Preparation
Male Wistar rats (Harlan Sprague-Dawley, Indianapolis,
Ind), 350 to 450 g, were used for all phases of this study. Rats
were administered a drug or saline 1, 12, 24, 48, or 72 hours before
the surgical protocol through intraperitoneal
injection. Subsequently, rats were anesthetized via
intraperitoneal administration of thiobutabarbital
sodium (Inactin, Research Biochemical International; 100 mg/kg). A
tracheotomy was performed, and the trachea was intubated with a cannula
connected to a rodent ventilator (model CIV-101, Columbus Instruments,
or model 683, Harvard Apparatus). Rats were ventilated with
room air supplemented with O2 at 60 to 65 breaths
per minute. Atelectasis was prevented by maintaining a positive
end-expiratory pressure of 5 to 10 mm H2O.
Arterial pH, PCO2, and
PO2 were monitored at control, 15 minutes
of occlusion, and 60 and 120 minutes of reperfusion by a blood gas
system (AVL 995 pH/blood gas analyzer, AVL Medical Instruments)
and maintained within a normal physiological range
(pH 7.35 to 7.45; PCO2 25 to 40
mm Hg; and PO2 80 to 110 mm Hg) by
adjusting the respiratory rate and/or tidal volume. Body temperature
was maintained at 38°C by the use of a heating pad, and bicarbonate
was administered intravenously as needed to maintain
arterial blood pH within normal
physiological levels.
The right carotid artery was cannulated to measure blood pressure and heart rate via a Gould PE50 or Gould PE23 pressure transducer connected to a Grass (model 7) polygraph. The right jugular vein was cannulated for saline, bicarbonate, and drug infusion. A left thoracotomy was performed at the fifth intercostal space followed by a pericardiotomy and adjustment of the left atrial appendage to reveal the location of the left coronary artery. A ligature (6-0 prolene) was passed below the coronary artery from the area immediately below the left atrial appendage to the right portion of the left ventricle. The ends of the suture were threaded through a propylene tube to form a snare. The coronary artery was occluded by pulling the ends of the suture taut and clamping the snare onto the epicardial surface with a hemostat. Coronary artery occlusion was verified by epicardial cyanosis and a subsequent decrease in blood pressure. Reperfusion of the heart was initiated via unclamping the hemostat and loosening the snare and was confirmed by visualizing an epicardial hyperemic response. Heart rate and blood pressure were allowed to stabilize before the experimental protocols were initiated.
Study Groups and Experimental Protocols
Rats were randomly divided into 16 groups (Figure 1
). Control rats were administered saline
24 hours before 30 minutes of regional ischemia and 2 hours of
reperfusion (I/R). To reconfirm the effect of opioid-induced acute
cardioprotection, TAN-67 was administered 1 hour before a prolonged
ischemic insult. To determine whether opioid stimulation
elicits delayed cardioprotection against an acute ischemic
insult, TAN-67, a selective 1-opioid receptor
agonist,2 was administered at a level of 10 or 30 mg/kg
either 12 or 24 hours before I/R (TAN 10 mg/kg at 12 hours, TAN 10
mg/kg at 24 hours, TAN 30 mg/kg at 12 hours, and TAN 30 mg/kg at 24
hours). TAN-67 was also administered at a level of 30 mg/kg either 48
or 72 hours before I/R (TAN 30 mg/kg at 48 hours and TAN 30 mg/kg at 72
hours). We examined the effects of 1-opioid
receptor inhibition in the absence or presence of TAN-67 with the
selective 1-opioid receptor
antagonist, 7-benzylidenenaltrexone (BNTX). BNTX 3 mg/kg
was administered intravenously to either the control rats
or those treated with TAN 30 mg/kg at 48 hour 10 minutes before I/R.
Similarly, to examine the effect of BNTX given before TAN-67, we
administered BNTX 6 mg/kg IP 48 hours before I/R and 30 minutes before
saline in control rats and in those treated with TAN-67. To examine the
effect of inhibition of the KATP channel in
opioid-induced delayed cardioprotection, either glibenclamide or
5-hydroxydecanoic acid (5-HD) were used. Glibenclamide 1 mg/kg was
administered during either the control or TAN 30 mg/kg 48-hour protocol
30 minutes before I/R. Similarly, 5-HD 10 mg/kg was administered during
either the control or TAN 30 mg/kg at 48-hour protocol 5 minutes
before I/R.
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Determination of Infarct Size
On completion of the above protocols, the coronary
artery was reoccluded, and the area at risk (AAR) was determined by
negative staining with patent blue dye administered via the jugular
vein. The rat was euthanized with a 15% KCl solution. The heart was
excised, and the left ventricle was dissected from the remaining tissue
and subsequently cut into 6 thin, cross-sectional pieces. This allowed
for the delineation of the normal area, stained blue, versus the AAR,
which subsequently remained pink. The AAR was excised from the
nonischemic area, and the tissues were placed in separate vials
and incubated for 15 minutes with 1.0%
2,3,5-triphenyltetrazolium chloride (TTC)
stain in 100 mmol/L phosphate buffer (pH 7.4) at 37°C. TTC is an
indicator of viable and nonviable tissue. TTC is reduced by
dehydrogenase enzymes present in viable myocardium and
results in a formazan precipitate, which induces a deep red color,
whereas the infarcted area remains gray.16 Tissues were
stored in vials of 10% formaldehyde overnight, and the infarcted
myocardium was dissected from the AAR under the
illumination of a dissecting microscope (Cambridge Instruments).
Infarct size (IS), AAR, and left ventricular weight
(LV) were determined by gravimetric analysis. AAR was
expressed as a percentage of the LV (AAR/LV), and IS was expressed as a
percentage of the AAR (IS/AAR).
Exclusion Criteria
A total of 106 rats successfully completed the above protocols.
Rats were excluded from data analysis if they exhibited severe
hypotension (<30 mm Hg systolic blood pressure) or if we
were unable to maintain adequate blood gas values within a normal
physiological range because of
metabolic acidosis or alkalosis. Exclusion of animals from
the present study were evenly distributed among the protocol
groups.
Statistical Analysis of Data
All values are expressed as mean±SEM. One-way ANOVA with
Bonferroni's test was used to determine whether any significant
differences existed among groups for hemodynamics, IS,
and AAR. Significant differences were determined at
P<0.05.
Drugs
Thiobutabarbital sodium (Inactin) and 5-HD were purchased from
Research Biochemical International. TTC and glibenclamide were
purchased from Sigma Chemical Co. BNTX and TAN-67 were synthesized and
furnished by Dr Hiroshi Nagase of Toray Industries (Kanagawa, Japan).
Inactin was dissolved in distilled water. TAN-67 and 5-HD were
dissolved in 0.9% saline. BNTX was dissolved in a 1:10 cocktail of
polyethylene glycol 400 and dH20. Glibenclamide
was dissolved in polyethylene glycol 400, 0.1N NaOH, 95% EtOH, and
0.9% saline in a 1:1:1:2 cocktail mixture. This vehicle has been
previously shown to have no effect on infarct size in this
model.14 All drugs were administered in 
0.9 mL of
vehicle. The maximally effective timing and dose of
glibenclamide14 and 5-HD (R.M.F., G.J.G., unpublished
observation, 1998) were previously determined in our
laboratory.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hemodynamics
The Table
summarizes heart rate,
mean arterial blood pressure, and rate-pressure product
in all groups, determined at baseline, 15 minutes of coronary
artery occlusion, and 120 minutes of reperfusion. Blood pressure in the
inhibitor protocols were maintained at baseline values
after inhibitor treatment. No significant differences
existed in the hemodynamics of all groups versus the
control group; however, the rate-pressure product was significantly
increased in the glibenclamide control protocol versus control at 2
hours of reperfusion (45±4 versus 30±3, respectively).
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Infarct Size and Area at Risk
IS/AAR for all groups is shown in Figures 2 through 4. AAR/LV
was not significantly different in any group versus the control
(control, 50.7±2.4, rest of data not shown). Figures 2, 3, and 4 show IS/AAR for each group. The average IS/AAR
in control rats was 62.9±3.4. TAN-67 administration 1 hour before
ischemia significantly reduced IS/AAR (23.6±5.3). However,
administration of TAN-67 at a level of 10 or 30 mg/kg, 12 hours before
I/R, was not cardioprotective (62.1±6.3 or 60.0±5.6, respectively).
Administration of TAN-67, 10 and 30 mg/kg, 24 hours before I/R reduced
IS/AAR versus IS/AAR in control animals in a dose-dependent manner
(43.3±7.3 and 34.5±5.9, respectively), which was significant at 30
mg/kg versus control. Injection of TAN-67 (30 mg/kg) 48 hours before
I/R maximally reduced IS/AAR (29.2±7.0); however, cardioprotection was
lost at 72 hours (61.7±3.8). In the absence of TAN-67 treatment, when
BNTX (3 and 6 mg/kg) was administered either 48 hours or 10 minutes
before I/R, it did not significantly affect IS/AAR versus control.
However, when BNTX (3 or 6 mg/kg) was administered in the presence of
TAN-67 either 48 hours or 10 minutes before I/R, TAN-67–induced
cardioprotection was abolished (59.6±3.1 and 58.7±3.5).
Inhibition of the KATP channel with glibenclamide
or 5-HD in the absence of opioid pretreatment did not significantly
affect IS/AAR (53.0±5.6 and 62.6±4.1, respectively). However,
inhibition of the KATP channel 30 or 5 minutes
before I/R with glibenclamide or 5-HD, respectively, after 48 hours of
opioid pretreatment, completely abolished opioid-induced
cardioprotection (60.4±3.2 and 57.8±2.5, respectively).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These experiments demonstrate for the first time that stimulation of the
1-opioid receptor induces delayed
cardioprotection to the ischemic myocardium 24 or
48 hours after treatment. We also demonstrate that this
cardioprotection is mediated via activation of the
KATP channel and suggest that the mitochondrial
KATP channel may mediate this
cardioprotection.
IS/AAR was not affected by 12-hour pretreatment with TAN-67 at a level
of 10 or 30 mg/kg or 24-hour TAN-67 (10 mg/kg) pretreatment. However,
24- or 48-hour pretreatment with TAN-67 (30 mg/kg) significantly
reduced infarct size compared with control animals at 24 and 48 hours.
This reduction was maximal with 48-hour pretreatment, and
cardioprotection was lost with a 72-hour delay. Therefore, these data
suggest that delayed protection to the ischemic
myocardium can be mediated via
1-opioid receptor stimulation. These data are
consistent with the observations of Yellon and Baxter,
who showed in the rabbit model that pharmacological stimulation of the
adenosine A1 receptor could induce
delayed cardioprotection beginning 24 hours after a single pretreatment
with the selective adenosine A1 agonist
CCPA. However, opioid-induced cardioprotection in our study faded at 72
hours, whereas CCPA stimulation of the adenosine
A1 receptor began to fade at 96 hours
pretreatment.17
Our laboratory was the first to demonstrated that
1 but not µ- or 
-opioid receptors were
involved in mediating the cardioprotective effects of ischemic
preconditioning to reduce myocyte cell death after a prolonged
ischemic insult and subsequent reperfusion.18
Similarly, we have previously demonstrated that TAN-67 selectively acts
through 1-receptor activation to confer acute
cardioprotection in the in vivo rat because this effect was completely
abolished by the 1-opioid receptor
antagonist, BNTX.2 Similarly, the results of
the present study demonstrate that BNTX pretreatment can abolish
the TAN-67–induced second window of cardioprotection and are the first
to demonstrate that 1-opioid receptors can
mediate delayed cardioprotection.
BNTX abolished cardioprotection induced by 48-hour TAN-67 pretreatment
when administered either 30 minutes before TAN-67 pretreatment or 48
hours after TAN-67 treatment but 10 minutes before I/R. These data
suggest that opioid-receptor stimulation may elicit signal transduction
mechanisms necessary for delayed cardioprotection such as protein
synthesis. However, because BNTX administered 10 minutes before I/R
could abolish TAN-67 induced cardioprotection, these data suggest that
reoccupation of 1-opioid receptors may also be
important in producing delayed cardioprotection during the lethal
ischemic period.
Opioid receptor activation is thought to confer cardioprotection to an acute ischemic insult via coupling with a Gi/o protein.2 Evidence suggests that cardioprotection may subsequently signal through PKC,3 which may activate the KATP channel.19 Data from our laboratory are indicative of similarities between both acute and delayed cardioprotection due to opioid-receptor stimulation. With the use of both the nonselective KATP channel inhibitor glibenclamide and the putative mitochondrial KATP channel inhibitor 5-HD, we demonstrate for the first time that opioid receptor stimulation confers delayed cardioprotection from ischemia and reperfusion injury via activation of the KATP channel and suggest that the mitochondrial KATP channel may play a role in this cardioprotection. However, 5-HD has been shown to be specific only in the rabbit model, and the possibility exists that this agent may not exhibit the same selectivity in the rat model.
Acute protection afforded to the ischemic
myocardium via opioid receptor stimulation also appears to
be due to KATP channel activation.2
Similarly, preliminary evidence by Bell et al20
demonstrates a role for the mitochondrial KATP
channel in both preconditioning and opioid-induced cardioprotection in
human cardiac tissue. As demonstrated by Baxter et al,21
acute cardioprotection due to ischemic preconditioning may
disappear 2 hours after stimulus. This may be due to a decrease in
activated protein kinase second messengers or possible
inactivation of the KATP channel. Extensive
evidence exists to suggest the involvement of both
PKC8 22 23 and the KATP
channel13 14 15 in ischemic preconditioning. In this
regard, Light et al19 have demonstrated that PKC can
directly activate the KATP channel. The
present study also demonstrates cardioprotection from an
ischemic insult 1 hour after opioid treatment; however,
cardioprotection was lost at 12 hours. The subsequent reappearance of
cardioprotection 24 to 72 hours after ischemic preconditioning
may be due to PKC translocation into the nucleus and subsequent induced
transcription and synthesis of effector proteins.4
Similarly, the subsequent reappearance of cardioprotection 24 to 48
hours after opioid receptor stimulation may result from PKC signaling,
because PKC has been demonstrated to be involved in opioid-induced
acute cardioprotection in rabbits.3
Considerable debate exists as to the specific KATP channel involved in cardioprotection. There are arguments both pro and con for the involvement of the sarcolemmal KATP channel. Opening of the KATP channel under conditions of ischemic stress and depletion of ATP from cells may effectively hyperpolarize the membrane and shorten phase 3 of the action potential. These actions may lead to decreased sodium and calcium entry into the cell. Subsequent decreases in calcium-induced calcium release and therefore decreased excitation-contraction coupling may conserve necessary ATP within the cell used to salvage vital mechanisms important for cellular homeostasis.
In contrast, the physiological role of the mitochondrial KATP channel is still unknown. KATP channels are present on both the sarcolemmal membrane and the inner mitochondrial membrane,24 25 26 and some studies have implicated the mitochondrial KATP channel in cardioprotection,15 27 28 possibly mediated by PKC.29 Activation of the mitochondrial KATP channel has been shown to increase the influx of potassium into mitochondria, which results in both matrix expansion and mitochondrial depolarization.27 30 Recent studies in isolated cardiac mitochondria, in response to KATP channel activators, have demonstrated mitochondrial depolarization, increased rate of mitochondrial respiration, and decreased rate of ATP synthesis.31 32 As a compensatory response to this decreased ATP synthesis, it has been suggested that matrix expansion due to mitochondrial KATP channel opening stimulates electron transport and fatty acid oxidation.32 33 We speculate that increased respiratory chain activity and the possible increase in reactive oxygen species may confer delayed cardioprotection because it has been previously demonstrated that ROS can induce delayed cardioprotection in the ischemic heart.34 Alternatively, mitochondrial depolarization secondary to KATP channel activation may decrease the driving force for mitochondrial calcium uptake, which results in a reduction in mitochondrial calcium overload. Obviously, future studies are necessary to determine the mechanisms by which mitochondrial KATP channels elicit cardioprotection and to determine the selectivity of 5-HD for the mitochondrial KATP channel in other species.
In summary, these data demonstrate the involvement of the
KATP channel to confer delayed cardioprotection
against irreversible ischemia/reperfusion injury due to
1-opioid receptor stimulation. The potential
therapeutic benefits of opioids as cardioprotective agents justifies
further probing of the in vivo and in vitro mechanisms of
opioid-induced protection.
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Acknowledgments |
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This work was supported by the National Heart, Lung, and Blood Institute grant HL-08311.
Received December 3, 1998; accepted February 5, 1999.
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