Intestinal Energy Metabolism during Ischemia and Reperfusion

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Intestinal Energy Metabolism during Ischemia and Reperfusion1

Atsushi Sato,*,2 Yoshiyuki Kuwabara,* Masahiko Sugiura,* Yoshiteru Seo,† and Yoshitaka Fujii*

*Department of Surgery II, Nagoya City University Medical School, Nagoya, Japan; and †Department of Molecular Physiology,

ournal of Surgical Research 82, 261–267 (1999)rticle ID jsre.1998.5538, available online at http://www.idealibrary.com on

National Institute for Physiological Science, Okazaki, Japan

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Background. In order to evaluate acute ischemicamage in the small intestine induced by superioresenteric artery occlusion (SMAO) and subsequent

eperfusion, changes in ATP, ADP, and AMP wereeasured by high-performance liquid chromatogra-

hy, and changes in tissue blood flow were measuredfrom the serosal surface) by the laser doppler flow

eter in a rat model.Materials and methods. The superior mesenteric ar-

ery of the rat was occluded for 30, 60, 90, and 120 minnd then reopened. Core temperature was maintainedarefully at 37 6 0.3°C.Results. All rats that underwent 90 and 120 min of

MAO died within 2 days, but those with 30 and 60 minf SMAO survived. ATP (10.39 6 0.90 mmol/g dryeight), ADP (3.34 6 0.33), and total adenine nucleo-

ides (TAN; 14.08 6 0.86) decreased with longer SMAOimes. After 30 and 60 min of SMAO followed by reper-usion, recoveries of ATP and TAN were relativelyood and ADP levels remained fairly steady, but littler no recovery of these levels was observed after 90nd 120 min of SMAO followed by reperfusion. Thereere linear correlations between the levels of ATP andAN after 30 min of reperfusion and the time of SMAO.issue blood flow levels were constant during SMAO.fter reperfusion, those levels were recovered alongith the SMAO periods. But recovery rates comparedith control values were not related with those ofTP.Conclusions. ATP and TAN levels, particularly at 30in after reperfusion, seemed to be in good agreementith the tissue damage and the viability of the small

ntestine. We propose that the measurement of these

1 This work was supported in part by a grant from the Ministry of

nu(r

ducation, Science, and Culture of Japan (No. 04770879).2 To whom correspondence should be addressed at Department of

urgery II, Nagoya City University Medical School, 1 Kawasumi,izuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Fax: 81-52-853-

440.

261

on August 31, 1998

evels may be useful for the evaluation of intestinalamage and viability. © 1999 Academic Press

Key Words: small intestine; ischemia; reperfusion;uperior mesenteric artery occlusion (SMAO); energyetabolism; ATP; TAN; high-performance liquid chro-atography (HPLC).

INTRODUCTION

Small intestinal infarction resulting from acute su-erior mesenteric artery occlusion (SMAO) is a clinicalisorder with significant morbidity and a high mortal-ty rate [1–3]. One reason for the high morbidity and

ortality is the lack of a reliable, noninvasive exami-ation for diagnosing intestinal ischemia and viability.t is important to find a parameter with which to esti-ate tissue damage of the small intestine duringMAO and subsequent reperfusion and to predict via-ility of the organ.We have previously reported the ATP level of the

mall intestine measured by phosphorus-31 magneticesonance spectroscopy (31P-MRS) during 30 or 90 minf SMAO followed by reperfusion. The ATP level de-reased with longer SMAO times, and the recovery ratef ATP after reperfusion also decreased with longerMAO times [4]. The ATP level may thus provide alinical parameter of intestinal damage and organ vi-bility of patients with mesenteric ischemia.However, knowledge of the time course of the energyetabolism during intestinal ischemia and subsequent

eperfusion remains insufficient [5–10]. It is controver-ial whether intestinal viability or individual survivalollowing intestinal ischemia is linked to recovery ofhe energy metabolism. We have extended our previoustudy and report here in detail the levels of adenine
ucleotides during SMAO and subsequent reperfusionsing high-performance liquid chromatographyHPLC) in a rat model where special care was taken toeduce the variability of the measurements.
0022-4804/99 $30.00Copyright © 1999 by Academic Press

All rights of reproduction in any form reserved.

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MATERIALS AND METHODS

Male Wistar rats weighing 160 to 180 g were divided into tworoups: one to determine the survival rate (20 rats) and the other totudy adenine nucleotide metabolism (96 rats). The care of thesenimals was in compliance with the “Guide for the Care and Use ofaboratory Animals” (NIH Publication No. 80-23, revised 1985). Theats were starved overnight but allowed to drink water freely andhen initially anesthetized with sodium pentobarbital at 12.5 mg/kgy intraperitoneal injection. Animals spontaneously breathed roomir. The tail vein was cannulated, and anesthesia was maintained bydministration of sodium pentobarbital at 12.5 mg/kg/h and Ringer’sactate solution at 10 ml/kg/h by infusion pump (STC-525, Terumo,okyo, Japan) to ensure a constant anesthetic level and blood pres-ure [5].Through a midline laparotomy, the superior mesenteric artery was

xposed, and a 3-0 nylon thread was passed loosely around its origin.ach end of the ligature was brought out of the abdominal wall.Each animal was placed in a supine position on a carrier in whicharm water was perfused from a BZ-21 water bath and a BF-41ump with a thermostatic control (Yamato, Tokyo, Japan) to main-ain its intraperitoneal temperature at 37 6 0.3°C. The temperatureas measured continuously with a CTM-204 temperature monitor

Terumo). The abdominal incision was not closed, but covered witharafilm (American National Can., Greenwich, CT) to prevent heatoss and desiccation.

Four different SMAO times were used: 30 (SMAO30), 60SMAO60), 90 (SMAO90), and 120 min (SMAO120). This was doney pulling each end of the ligature tightly with 160-g weights. Reper-usion was performed by removing the ligature by manipulation fromutside the abdominal cavity and was confirmed by return of theolor and visible pulsation in the mesentery.Five rats in each group were used to determine the survival. The

bdominal incision was closed after 150 min from the start of thexperiment. The rats were allowed to take food and water freely. Thenimals were followed for 7 days.Specimens of the intestine were taken at appropriate intervals and

quashed by bronze tongs that had been cooled in liquid nitrogen,aking care not to include any mesenteric fat or stools in the smallntestine. They were immediately frozen and stored in liquid nitro-en until lyophilization. A part of the small intestine was taken forematoxylin–eosin staining to determine histological changes. Afterhe specimen was obtained, the animal was sacrificed by pentobar-ital sodium injection. Eight rats were used to determine the levelsf adenine nucleotides at each time point. The squashed tissue wasyophilized for 48 h and then extracted with 1 N perchloric acid. Aftereing filtered through a 0.45-mm Millipore filter (Millipore, Tokyo,apan), the neutralized perchloric acid extracts were analyzed toetermine the concentrations of ATP, ADP, and AMP by HPLC [11].oreover, total adenine nucleotides (TAN) and energy charge (EC)ere calculated from the analyzed values of adenine nucleotides as

ollows [12]:

TAN 5 ATP 1 ADP 1 AMP

EC 5 ~ATP 1 0.5 ADP!/TAN.

HPLC was performed on a mBondasphere C18-100 Å, 3.9 3 150-mmolumn (Waters, Tokyo, Japan) attached to a SCL-6A pump (Shi-adzu, Kyoto, Japan), equipped with a variable wavelength UV

etector, LC-6A (Shimadzu), adjusted to 260 nm. The solvent was

62 JOURNAL OF SURGICAL RESEA

.03 M phosphate buffer, which was brought to pH 7.2 with tri-thylamine. Reference solutions of ATP, ADP, and AMP were pre-ared according to dissolving standards (Boehringer Mannheim,annheim, Germany, BRD).For tissue blood flow measurement, two experimental groups were

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ivided. One group of five rats had SMAO maintained for 30 minSMAO30) and another one underwent SMAO for 90 min (SMAO90).

The probe of 1-mm diameter was placed on the serosal surfacegainst the antimesenteric border and away from visible blood ves-els. The probe was connected to a laser doppler perfusion monitorALF21N, Advance, Japan) precalibrated to an instrument readingf milliliters per 100 g of tissue per minute. Control blood flow waseasured after a 10- to 20-min stabilization period. Care was taken

o that the probe did not compress the bowel and to ensure a goodlectrical contact at all times. After control flow measurements, SMAas ligated, and the measurements were constantly repeated.None of the 106 rats died during the surgery or during the SMAO

r reperfusion period. No animal was excluded from the study be-ause of surgical complications or premature death.Student’s t test was used to analyze correlation between two

ariables, and analysis of variance and multiple comparison (Fish-r’s protected least significant difference) were used to determine theignificance of the difference between the groups.

RESULTS

Figure 1 gives the survival of animals that under-ent different periods of the SMAO and subsequent

eperfusion. Although all animals survived in theMAO30 and SMAO60 groups, no one survived in theMAO90 and SMAO120 groups. Most animals werexamined within a few hours after death. There wereo apparent signs of peritonitis or perforation of small

ntestine but necrosis was apparent in all the deadnimals.The ATP level of the small intestine before SMAO

control value) was 10.39 6 0.90 mmol/g dry weightFig. 2). The ATP level decreased rapidly after the startf SMAO; after 30 min of SMAO, it was 3.14 6 0.21mol/g dry weight (30% of control value). After that,TP decreased relatively slowly during SMAO. After

FIG. 1. Survival of rats after various periods of SMAO. Theuperior mesenteric artery was occluded by 3-0 nylon ligature for thendicated times, after which the ligature was removed and the ab-ominal incision was closed.

H: VOL. 82, NO. 2, APRIL 1999

20 min of SMAO, ATP decreased to 1.70 6 0.49mol/g dry weight (16% of control value). ATP levelshowed a significant difference between SMAO groupsP 5 0.027 between the SMAO60 and SMAO120

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roups, P 5 0.0054 between the SMAO30 andMAO60 groups, and P , 0.0001 for other compari-ons, respectively) except between the SMAO60 andhe SMAO90 groups and between the SMAO90 and theMAO120 groups (Fig. 2 solid line). Recoveries of theTP levels after episodes of SMAO followed by reper-

usion were incomplete in all groups. The ATP recoveryfter 30 min of reperfusion was less for longer SMAO.TP levels after 30, 60, and 90 min of SMAO followedy 30 min of reperfusion were 6.52 6 0.56 (63% ofontrol value), 4.89 6 0.56 (47%), and 3.47 6 0.42mol/g dry weight (33%), respectively. No recovery ofTP was observed after SMAO120 followed by 30 minf reperfusion (Fig. 2). The ATP levels after 30 min ofeperfusion showed significant differences between theMAO groups (P , 0.0001 for comparisons betweenach group). Additionally, there was a linear correla-ion between the ATP levels after 30 min of reperfusionnd the duration of SMAO (r 5 20.966, P , 0.0001).The ADP level before SMAO (control value) was

.34 6 0.33 mmol/g dry weight. The ADP level duringMAO decreased more slowly than the ATP level. Aftereperfusion, the ADP levels remained fairly steady andid not show the recovery that the ATP levels did. TheDP level after 90 min of SMAO followed by 30 min of

eperfusion showed no difference when compared withhat after 120 min of SMAO. Moreover, the ADP levelfter 120 min of SMAO continued to decrease during0 min of reperfusion (P , 0.0001) (Fig. 3). The ADPevels after 30 min of reperfusion showed significantifferences between the SMAO groups (P , 0.0001 foromparisons between each group). Additionally, thereas a linear correlation between the ADP levels after0 min of reperfusion and the duration of SMAO (r 50.966, P , 0.0001).The AMP level before SMAO (control value) was

FIG. 2. Level of ATP in the rat small intestine after variouseriods of SMAO and reperfusion. Each value is the average of eightats and the bar is one standard deviation.

SATO ET AL.: INTESTINAL

.35 6 0.06 mmol/g dry weight. With hydrolysis of ATPn the initial period of SMAO, the AMP level increasedut then decreased slowly to 1.01 6 0.41 mmol/g dryeight after 120 min of SMAO. After reperfusion, AMP

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ecreased to less than its control value in all SMAOroups. There was no correlation among the AMP con-ent, SMAO duration, and reperfusion period (Fig. 4).

The TAN level before SMAO (control value) was4.08 6 0.86 mmol/g dry weight (Fig. 5). The TAN levelecreased rapidly after the start of SMAO; after 60 minf SMAO, its level reached 5.64 6 0.40 mmol/g dryeight (40% of control value). After that, TAN de-

reased relatively slowly during SMAO. After 120 minf SMAO, TAN decreased to 4.16 6 0.98 mmol/g dryeight (30% of control value). TAN levels showed a

ignificant difference between the SMAO groups (P 5.003 between the SMAO60 and the SMAO120roups, P , 0.0001 for other comparisons, respec-ively) except between the SMAO60 and the SMAO90roups (Fig. 5 solid line). Recovery of the TAN levelsfter episodes of SMAO followed by reperfusion wasncomplete in all groups. The TAN recovery after 30

in of reperfusion was less for longer SMAO. TANevels after 30 and 60 min of SMAO followed by 30 minf reperfusion were 9.52 6 0.63 (68% of control value)nd 7.28 6 0.73 mmol/g dry weight (52%), respectively.

FIG. 3. Level of ADP in the rat small intestine after variouseriods of SMAO and reperfusion. Each value is the average of eightats and the bar is one standard deviation.

263HEMIA STUDIED BY HPLC

FIG. 4. Level of AMP in the small intestine after various periodsf SMAO and reperfusion. Each value is the average of eight rats andhe bar is one standard deviation.

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o recovery of TAN was observed after 90 min ofMAO followed by 30 min of reperfusion. After 30 minf reperfusion, the TAN level was significantly lowerhan that after 120 min of SMAO (P 5 0.0003) (Fig.). The TAN levels after 30 min of reperfusion showedignificant differences between the SMAO groups (P ,.0001 for comparisons between each group). Addi-ionally, there was a linear correlation between theAN levels after 30 min of reperfusion and the dura-ion of SMAO (r 5 20.972, P , 0.0001).

The EC level before SMAO (control value) was.86 6 0.02. EC decreased rapidly to 0.52 6 0.03 until0 min of SMAO and then remained fairly steady asMAO was extended. After 30, 60, 90, and 120 min ofMAO followed by 30 min of reperfusion, EC levelsere 0.83 6 0.01, 0.82 6 0.01, 0.83 6 0.01, and 0.78 6.03, respectively. Thus, the EC levels after reperfu-ion showed almost perfect recovery to pre-SMAO lev-ls, regardless of the duration of SMAO (Fig. 6).The tissue blood flow level of the small intestine

efore SMAO (control value) was 42.0 6 3.4 ml/100/min. The tissue blood flow level decreased immedi-tely after the start of SMAO to 4.7 6 1.4 ml/100 g/minnd was constant during occlusion. Recoveries of tissuelood flow levels after episodes of SMAO followed byeperfusion were incomplete in both groups. In bothroups, the tissue blood flow level recovered andeached a plateau within 10 min of reperfusion. Tissuelood flow levels after 30 and 90 min of SMAO followedy 30 min of reperfusion were 23.6 6 4.4 (53% ofontrol value) and 17.7 6 0.6 ml/100 g/min (39%), re-pectively. The recovery rate of the tissue blood flowfter 10 min of reperfusion was lower than that of ATPn the SMAO30 group (P 5 0.051), and in the

FIG. 5. Level of total adenine nucleotides (TAN) in the rat smallntestine after various periods of SMAO and reperfusion. TAN is aum of ATP, ADP, and AMP. Each value is the average of eight ratsnd the bar is one standard deviation.


MAO90 group, it was significantly higher than that ofTP (P 5 0.026) (Fig. 7).Histologically, ischemic changes of the intestinalucosa were worse in groups with longer SMAO. After

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0 min of SMAO, the tops of the villi fell off, andemorrhage of the mucosa was seen. Moreover, edemaf the mucosa was apparent after reperfusion. After 90in of SMAO, the mucosa fell off, including its crypt

ayer, and hemorrhage was severe. After 120 min ofMAO, transmural necrosis was seen. But these find-

ngs were observed only in the limited area whereschemic damage appeared most severe. Degrees ofistological tissue damage varied in different parts ofhe intestine. Ischemic changes of smooth muscle layerannot be appreciated.

DISCUSSION

The energy metabolism during ischemia has beenidely studied in the heart and in some other tissues

13–17]. Those studies revealed that the recovery ratef the reduced ATP during reperfusion after ischemiaould be used as an indication of tissue damage andiability. But in the small intestine, the time course of

FIG. 6. Level of energy charge (EC) in the rat small intestinefter various periods of SMAO and reperfusion. Each value is theverage of eight rats and the bar is one standard deviation.

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FIG. 7. Level of blood flow in the rat small intestine after variouseriods of SMAO and reperfusion. Each value is the average of fiveats and the bar is one standard deviation.

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he energy metabolism during ischemia and subse-uent reperfusion has been less extensively studied,nd only a few studies with controversial results haveeen reported [4–10]. It remains unclear whether in-estinal viability or individual survival following intes-inal ischemia and subsequent reperfusion is linked tohe recovery of the energy metabolism.

One reason for the controversial results is that stud-es of energy metabolism in other tissues have beenerformed in isolated perfused models, but studies inhe small intestine have been done in in vivo models. Insolated perfused models, the velocity and the pressuref the perfusate and the temperature of the isolatedrgan were maintained at a constant level. Moreover,he influence of general anesthesia did not have to beonsidered. We found that it was essential to maintainhe general condition of the experimental animals. So,e maintained constant not only the anesthetic levelnd the blood pressure but also the core temperature.ontinuous intravenous infusion of sodium pentobar-ital at 12.5 mg/kg/h and lactate Ringer’s solution at 10l/kg/h was thought sufficient to maintain anesthetiz-

ng levels and arterial blood pressure [5]. If the coreemperature is reduced, the intestinal blood flow wille preferentially distributed to the splanchnic vasculared, and intestinal oxygen uptake and consumptionould be decreased [18]. In the present study, weaintained the core temperature carefully at 37 6

.3°C. In this way, the ATP level of the sham-operatednimals of our experimental models was stable for 360in from the start of the experiment (unpublished

ata).In our investigation, ATP and TAN decreased with

onger SMAO times, and their recovery after 30 min ofeperfusion was less in groups with longer duration ofMAO where no animal survived (SMAO90 andMAO120). This may suggest that recovery from isch-mic damage in the small intestine depends on theapacity for ATP synthesis, and the absence of ade-uate recovery after prolonged ischemia is attributedo dysfunction and damage to mitochondria on whichost of the cell functions depend. Mitochondria are

ensitive to ischemia and are damaged from the earlyoments of ischemia [19–22]. Our results also indicate

hat ATP and TAN can be useful parameters for tissueamage and organ viability of the small intestine dur-ng SMAO and reperfusion. Their levels after 30 min ofeperfusion seem to be a critical indicator of tissueurvival.Because all the experimental animals that under-ent 90 min of SMAO died within 2 days from intes-

inal infarction and its sequelae but the rats with 60


in of SMAO survived, the critical time that limits theiability of the ischemic intestine is between 60 and 90in of SMAO. After 90 min of SMAO followed by 30in of reperfusion, no TAN recovery was observed, and

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he ADP level was not different from that after 120 minf SMAO. These results indicate that ATP synthesis isost after 90 min of SMAO. Therefore, it may suggesthat intestinal viability was lost when the ATP levelecreased to less than about 20% of the control valueuring ischemia or when it failed to recover to about5% of the control value after reperfusion.Even after 30 min of SMAO followed by 30 min of

eperfusion, the ATP level recovered only to 63% of theontrol value. According to Werner et al. [7], after 30in of SMAO, ATP rapidly decreased from 10.4 of the

ontrol value to 3.7 nmol/mg of protein, but adenosinend inosine monophosphate still remained intact andnosine increased. In another rat small intestine

odel, the adenosine concentration was stable at only/20 of the myocardial level [8]. These results suggesthat the pathway from AMP to inosine monophosphates relatively inactive in the rat small intestine, anddenosine is maintained at low concentrations due tots rapid deamination to inosine. Adenine nucleotidealvage pathways that lead back to AMP are slow andequire much energy. Therefore, it seems that the re-overy of ATP was relatively low even after 30 min ofMAO because of the rapid degradation of AMP to

nosine.EC has been suggested to be the best parameter of

he energy level required for cell survival [12, 23–25].owever, we found that its decrements did not changeith longer SMAO times. Also even in an irreversiblelyamaged small intestine (after 90 and 120 min ofMAO), the level of EC recovered almost to the controlalue. Similar results have been reported by Canada etl. using rat intestinal segments [6], and by Yamada etl. using rat small intestinal grafts [26]. Warnick andazarus concluded from their results in ischemia andeperfusion of the rat kidney that mitochondria con-inue to function even after ischemia, resulting in func-ional cell death [27]. As Kristensen suggested [28], itight be reasonable to consider that no simple corre-

ation exists between EC and tissue viability. EC the-ry may not hold under conditions where the equilib-ium between the consumption and the formation ofTP has collapsed. We suggest that EC is an unsuit-ble parameter for tissue damage and organ viabilityf the small intestine during SMAO and reperfusion.Tissue blood flow has been reported to be suitable for

iagnosing intestinal ischemia and viability [29, 30].ut because tissue blood flow levels were close to zero

n all the SMAO groups during ischemia, these levelso not reflect the extent of intestinal damage. More-ver, the recovery rate of the tissue blood flow wasower than that of ATP in the SMAO30 group (P 5


.051) and higher in the SMAO90 group (P 5 0.026).oreover, according to our previous study, ATP recov-

red immediately to reach a plateau after 10 min ofeperfusion in the SMAO30 group. But in the SMAO90

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roup, ATP recovered relatively slowly and needed 30in of reperfusion to reach a plateau. There also was a

ifference in duration to reach a relative plateau be-ween both groups [4]. But in tissue blood flow levels,here was no difference in both groups. So these levelsannot demonstrate the intestinal damage during isch-mia and viability after reperfusion. Also tissue bloodow had no correlation with the intestinal energy me-abolism during ischemia and subsequent reperfusion.

Histology is thought to be a good standard for thessessment of ischemia-reperfusion injury of the smallntestine, and microscopic criteria in the grading intes-inal injury have been used [31, 32]. But this gradingan be applied only to the mucosal damage, and isch-mic damage of the smooth muscle layer is difficult tovaluate microscopically [33]. Also in this study, isch-mic changes were more severe in groups with longerimes of SMAO, but these findings were observed onlyn the limited mucosal area. After 30 min of SMAO,hough histological changes were slight, tissue ATPemarkably decreased. Changes in intestinal energyetabolism were thought to be more sensitive and

arlier than histological changes. Moreover, tissueamples must be harvested for histological examina-ion. Thus we find that histological examination wasot suitable for quantitative and objective evaluationf intestinal damage and viability.Recently, noninvasive and nondestructive observa-

ion of the change of tissue ATP has been accomplishedn vivo by 31P-MRS [4, 5, 10]. Because the presentesults with HPLC demonstrate that ATP changes inhe ischemic intestine reflect the duration of ischemia,he ATP change measured by 31P-MRS may be suitables a new clinical parameter when applied to humans.In summary, changes in ATP and TAN levels during

MAO and reperfusion may be a useful clinical param-ter of tissue damage and organ viability.

ACKNOWLEDGMENTS

The authors are most grateful to Dr. Hiroshi Watari and Dr.asataka Murakami (Department of Molecular Physiology, Na-

ional Institute for Physiological Science) for their assistance. Wehank Mrs. Shinobu Makino for her technical assistance.

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Intestinal Energy Metabolism during Ischemia and Reperfusion

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