ORIGINAL RESEARCH

International Journal of Surgery 11 (2013) 96e100

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International Journal of Surgery

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Original research

The protective effects of dexmedetomidine on the liver and remote

organs against hepatic ischemia reperfusion injury in rats
_
Adnan Tfek a, *, Orhan Tokgz a, Ibrahim Aliosmanoglu b, Ulas Alabalik c, Osman Evliyaoglu d,
Taner ifti a, Abdlmenap Gzel a, Zeynep Baysal Yldrm a
a
Department of Anesthesiology, Faculty of Medicine, Dicle University, Diyarbakr, Turkey
b
Department of General Surgery, Medical Faculty, Dicle University, Diyarbakr, Turkey
c
Department of Pathology, Medical Faculty, Dicle University, Diyarbakr, Turkey
d
Department of Biochemistry, Medical Faculty, Dicle University, Diyarbakir, Turkey

a r t i c l e i n f o a b s t r a c t

Article history: Aim: To investigate the protective effects of dexmedetomidine against hepatic ischemia/reperfusion (IR)
Received 15 October 2012 injury and hepatic IR induced remote organ injury.
Received in revised form Methods: Forty Wistar albino rats were divided into the following four groups: sham, dexmedetomidine,
27 November 2012
IR, and IR dexmedetomidine. Hepatic ischemia was created by the Pringle maneuver for 30 min fol-
Accepted 3 December 2012
Available online 20 December 2012
lowed by a 30 min reperfusion period in the IR and IR dexmedetomidine groups. The dexmedeto-
midine and IR dexmedetomidine groups were administered dexmedetomidine (100 mg/kg, single dose)
intraperitoneally after the anesthesia insult. Blood samples and hepatic, renal, and lung tissue specimens
Keywords:
Dexmedetomidine
were obtained to measure serum and tissue total oxidative activity (TOA), total antioxidant capacity
Hepatic ischemia reperfusion injury (TAC), paraoxonase (PON-1), and oxidative stress index (OSI) after 60 min in all groups.
Rat Results: According to the biochemical analyses of the samples taken from the serum and the liver, lung,
and kidney tissues, when comparing the sham group and the IR group, TOA and OSI values were higher
in the IR group, while TAC and PON-1 values were lower (p < 0.05). It was observed that TOA and OSI
values were signicantly lower, while TAC and PON-1 values increased with dexmedetomidine treatment
(p < 0.05). In addition, dexmedetomidine ameliorated hepatic histopathological changes inducing IR, but
there were no signicant histopathological changes in the remote organs.
Conclusion: This study demonstrated that dexmedetomidine markedly reduced the oxidative stress in
serum, liver, and remote organs induced by hepatic IR injury, and ameliorated the histopathological
damage in the liver.
2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

1. Introduction sustained during reperfusion.2e4 Hepatic ischemia/reperfusion (IR)

The Pringle maneuver (spaced cleavage of the portal triad), used
during lung surgery to control bleeding, may cause ischemia in the
liver, depending on the occlusion of the livers blood ow.1 Liver
ischemia may also originate from a fall in the oxygenation of the liver
during situations such as trauma or liver transplantation. Although
hepatic ischemia may cause severe cell damage, the cell damage
agents originating from the ischemia process may undergo changes
during reperfusion; many chemical substances interact with one
another and cause reactive oxygen species (ROS) which is respon-
sible for the reperfusion damage to release. Thus, the real damage is
* Corresponding author. Tel.: 90 412 248 8004; fax: 90 412 2488523.
E-mail address: adnantufek@hotmail.com (A. Tfek).
injury induces a systemic response and releases harmful substances
that may affect remote organs such as the lung and kidney. In order
to prevent IR damage, new treatment strategies using various
antioxidant-like agents have been suggested; however, these agents
never made it to the routine clinical implementation. In studies
conducted using experimental IR models, it has been shown that
dexmedetomidine a highly selective and potent a2-adrenergic
agonist has antioxidant properties and cures IR damage.5e8
Recently, total oxidant activity (TOA), total antioxidant capacity
(TAC), paraoxonase-1 (PON-1), and oxidative stress index (OSI) have
the most commonly used markers for indicating the level of the IR
damage in tissues.9 Paraoxonase-1 is a calcium-dependent esterase,
closely associated with high-density lipoprotein (HDL) that can
prevent oxidation of low-density lipoprotein (LDL). The histopath-
ological display of variables such as local hemorrhage and necrosis,

1743-9191/$ e see front matter 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijsu.2012.12.003
 ORIGINAL RESEARCH
A. Tfek et al. / International Journal of Surgery 11 (2013) 96e100
neutrophil inltration, congestion, sinusoidal extension, and local
hepatocellular vacuolization are widely used when evaluating
hepatic IR damage.10,11 In this study, we aimed to investigate the
protective effects of dexmedetomidine against hepatic and remote
organ ischemia/reperfusion injury via analyzing PON-1, TAC, TOA,
OSI and histopathological variables.
2. Materials and methods
2.1. Experimental animals
Forty male Wistar albino rats with mean weight of 250e300 g were included in
the study at Dicle University Health Sciences Application and Research Center. The
study protocol was approved (2010e40) by the Committee of Experimental Animals
of Dicle University. All experimental procedures complied with the Guide for the
Care and Use of Laboratory Animals. Rats were housed in an air-conditioned room
with 12 h light and dark cycles, and a constant temperature (22  2  C). The rats
were housed in cages, and allowed free access to standard rat chow and water before
the experiments. The animals were fasted overnight before the experiments, but
were given free access to water.
2.2. Experimental protocol
Rats were anesthetized with 80 mg/kg ketamine hydrochloride (Ketalar, Parke
Davis, Eczacibasi, Istanbul, Turkey) via intramuscular injection and the experimental
procedure was initiated. A 10% povidone iodine solution (Betadine) was performed
for shaved skin cleansing. A midline incision was performed and rats underwent
either sham surgery or ischemia/reperfusion. Ischemia was induced with the Pringle
maneuver and sustained for 30 min. After this time, the ischemic liver was reper-
fused, and this was sustained for a further 30 min. At the end of this period, the
animals were sacriced by taking blood from the heart.
The animals were divided into four groups:
 S group (sham): Only hepatoduodenal ligament dissection was performed and
no drug was given.
 Dex group (dexmedetomidine): Hepatoduodenal ligament dissection was
performed and dexmedetomidine was given at a dose of 100 mg/kg (1 ml)
intraperitoneally right after anesthesia was administered.
 IR group (Ischemia and reperfusion): Thirty minutes after the Pringle
maneuver, reperfusion was generated for 30 min and no drug was given.
 IR Dex group: Dexmedetomidine was given at a dose of 100 mg/kg (1 ml)
intraperitoneally after anesthesia was performed. Thirty minutes after the
Pringle maneuver, reperfusion was generated for 30 min.
At the end of the procedures, blood and tissue samples from the liver, lung, and
kidney were obtained for biochemical analyses and histopathological examination.
Serum was obtained from the centrifugation of the blood and rapidly transferred to
plastic, Eppendorf-covered tubes for biochemical analyses and stored at 80  C in
a deep freezer. Sampled tissues were prepared for biochemical analyses; foreign
tissue residues and blood were removed by washing with saline, and thereafter,
tissues were transferred to plastic tubes with Eppendorf covers for biochemical
analyses, stored at 80  C in the freezer. In addition, the tissues taken for histo-
pathological evaluation were put into plastic containers, which included 10%
formaldehyde solution.
2.3. Biochemical analyses
TOA, TAC, and PON-1 analysis were performed in blood and hepatic, renal, and
lung tissue samples. In addition, the OSI was calculated.
2.4. Homogenization of tissues
Tissues stored at 80  Cwere removed from the deep freezer and brought to the
laboratory in dry ice. About 0.30e0.50 g of tissue pieces were transferred into the
tube and 2 ml of TriseHCl buffer was added. Tissues in the tube, which was placed in
an ice-lled plastic container, were processed in 50 mM pH 7.0 phosphate buffered
saline (PBS) for 1e3 min on 14,000 rpm in a homogenizer (Ultra Turrax Type T8, IKA
Labortechnic, Germany). Homogenate was centrifuged for 30 min at 40 C. Samples
were obtained from supernatant for TOA and TAC analysis.
2.5. Measurement of the paraoxonase (PON-1)
Serum PON-1 activity was measured spectrophotometrically using a modied
Eckerson method.12 The results are expressed in terms of U/L.
97
2.6. Measurement of total oxidant activity (TOA)
TOA of supernatant fractions was determined using a novel automated
measurement method developed by Erel.13 The assay is calibrated with hydrogen
peroxide and the results are expressed in terms of mmol H2O2 equiv./L.
2.7. Measurement of the total antioxidant capacity (TAC)
TAC of the supernatant fractions was determined using a novel automated
measurement method developed by Erel.14 Here, the antioxidative effect of the
sample against the potent-free radical reactions, as initiated by the produced
hydroxyl radical, is measured. The results are expressed as mmol Trolox equiv./L.
2.8. Oxidative stress index (OSI)
OSI is a parameter indicating the degree of oxidative stress; its formulation is as
follows: OSI (arbitrary units) [TOA/TAC]  100.14
2.9. Histopathological evaluation
Tissue specimens were xed in 10% formalin for 48 h, then embedded in parafn
and cut into 5 mm sections. Slides were stained with hematoxylineeosin. The
sections were examined under a light microscope using 200 magnication for
assessment of the degree of liver injury by a liver pathologist blinded to the grouping
of the animals.
Hepatic injury was graded as follows: grade 0: minimal or no evidence of injury;
grade 1: mild injury characterized by cytoplasmic vacuolization and focal nuclear
pyknosis; grade 2: moderate injury exhibiting cytoplasmic vacuolization, conuent
areas of hepatocyte ballooning but no frank necrosis, sinusoidal dilatation and
congestion, and blurring of intercellular borders; grade 3: moderate to severe injury
with areas of coagulative necrosis, cytoplasmic hypereosinophilia, extensive sinu-
soidal dilatation and congestion; grade 4: severe injury consisting of severe
conuent coagulative necrosis, and disintegration of and hemorrhage into hepatic
chords leading to the loss of tissue architecture.15
Renal injury was graded as follows: grade 0: no diagnostic change; grade 1:
tubular cell swelling, brush border loss and nuclear condensation, with up to 1/3 of
the tubular prole showing nuclear loss; grade 2: as grade 1, but greater than 1/3
and less than 2/3 of tubular prole showing nuclear loss; and grade 3: greater than
2/3 of tubular prole showing nuclear loss.16
Lung injury was evaluated using an ordinal scale as follows: grade 0: no change;
grade 1: mild neutrophil leukocyte inltration and mild to moderate interstitial
congestion; grade 2: moderate neutrophil leukocyte inltration, perivascular edema
formation, and disintegration of the structure; and grade 3: dense neutrophil
leukocyte inltration and destruction of pulmonary structure.17
2.10. Statistical analysis
Statistical analysis was performed using SPSS for Windows 11.5 (SPSS Inc.,
Chicago, IL, USA). Data were presented as mean  standard deviation (SD) values.
Groups were compared using the nonparametric KruskaleWallis test. The Manne
Whitney U test was used for binary comparisons. Spearman correlation test was
used for evaluation of the relationships between the variables. A p value of less than
0.05 was considered signicant.
3. Results
All of the animals completed the study procedure. Liver, kidney,
lung tissue, and blood samples were taken from the animals that
were sacriced at the end of the study.
3.1. Comparison of total oxidant activity and oxidative stress index
According to the biochemical analyses of the serum and the
samples taken from the liver, lung, and kidney tissues, the IR group
had higher TOA and OSI values and lower TAC and PON-1 values
compared with the sham group. When dexmedetomidine was
applied to IR group, it was observed that TOA and OSI values
became signicantly lower, (Table 1).
3.2. Comparison of paraoxonase and total antioxidant capacity
According to the biochemical analyses of the serum and the
samples taken from the liver, lung, and kidney tissues, the IR group
had lower TAC and PON-1 values compared with the sham group.
 ORIGINAL RESEARCH

98 A. Tfek et al. / International Journal of Surgery 11 (2013) 96e100

Table 1
Oxidative and antioxidative parameters in rats according to the groups.

Groups Sham (mean  SD) Dexmedetomidine (mean  SD) IR (mean  SD) IR Dex (mean  SD)
Serum PON-1 127.72  20.84 128.16  11.99 99.35  8.64a,c 125.84  19.59h
TAC 1.79  0.39 1.65  0.23 0.97  0.04a,c 1.52  0.27g
TOA 33.13  12.62 35.87  13.68 99.39  47.22a,d 39.71  19.48h
OSI 1899.27  712.74 2230.43  946.07 10,305.01  4946.10a,c 2716.25  1509.62g
Hepatic PON-1 18.83  2.18 18.25  2.98 13.96  1.36a,c 17.27  3.56f
TAC 0.97  0.20 0.86  0.15 0.54  0.04a,c 0.82  0.18g
TOA 39.75  15.14 43.05  16.41 119.26  56.67a,d 47.65  23.38h
OSI 4217.76  1700.31 5134.76  2010.80 22,261.37  11,129.96a,c 5927.13  3172.20g
Renal PON-1 10.74  1.26 10.85  1.77 6.87  0.84a,c 9.10  2.00h
TAC 1.89  0.30 1.83  0.33 0.93  0.10a,c 1.70  0.28g
TOA 34.59  13.17 37.45  14.28 103.76  49.30a,d 46.85  22.99h
OSI 1881.08  832.86 2201.16  5763.40 11,441.93  5763.40a,c 2789.62  1265.87g
Lung PON-1 7.03  0.83 6.96  1.00 4.77  0.52a,c 6.05  0.68b,e,g
TAC 0.95  0.23 0.88  0.19 0.50  0.05a,c 0.81  0.16g
TOA 15.04  5.73 16.28  6.21 45.11  21.43a,d 18.93  9.29h
OSI 1639.35  662.70 1945.74  898.05 9071.71  4443.20a,c 2347.68  972.75g

Groups are as follows; S Sham, Dex dexmedetomidine, IR ischemia reperfusion, PON-1(U/L) paraoxanase, TAC(mmol Trolox Equiv./L) total antioxidant capacity,
TOA(mmol H2O2 Equiv./L) total oxidant activity, OSI(Arbitrary Unite) oxidative stress index, SD standard deviation.
a
Compared with S group (p  0.001).
b
Compared with S group (p < 0.05).
c
Compared with Dex group (p  0.001).
d
Compared with Dex group (p < 0.01).
e
Compared with Dex group (p < 0.05).
f
Compared with IR group (p < 0.05).
g
Compared with IR group (p  0.001).
h
Compared with IR group (p < 0.01).

When dexmedetomidine was applied TAC and PON-1 values was a positive correlation between TOA (p 0.018, rho 0.722) and
increased signicantly, compared to the IR group (Table 1). OSI (p 0.006, rho 0.798) levels.

3.3. Comparison of histological ndings

The general structure and properties of the liver, kidney, and
lung tissue in the sham group seemed normal. According to the
histopathological evaluation, when the IR and sham groups were
compared, the histopathological evaluations scores of the liver
tissues were signicantly higher (p  0.001). There was clear
hemorrhage, extended sinusoids, hepatocyte congestion, and areas
of focal necrosis in the liver tissue of the IR group. When the
IR Dex group and IR group were compared, there was
a substantial recovery in the histopathological changes in the liver
tissue (p  0.001) (Fig. 1). Nevertheless, there were no drastic
differences in terms of the kidney and lung tissues between the
sham group and the IR group or between the IR group and the
IR Dex group (Table 2). When the correlations between the
histopathological evaluation scores in the liver tissues and serum
biochemical parameters were analyzed, it was observed that in the
IR group, there was a negative correlation between histopatho-
logical changes and TOA (p 0.018, rho 0.724) and OSI
(p 0.037, rho 0.663) levels, while in the IR Dex group, there
4. Discussion
The present study showed that dexmedetomidine has a protec-
tive effect in IR related hepatic injury.
Hepatic IR injury is a complex process accompanied by intra-
cellular signaling pathways, mediators, cells, and pathophysiolog-
ical alterations.18 In particular, the damage is mediated by ROS in
the early stage of hepatic IR injury.19 Massive and abrupt release of
ROS after reperfusion followed by endothelial dysfunction or
neutrophil inltration triggers the oxidative damage.20 Moreover, it
is known that the IR damage affects not only the liver, but also other
remote organs, especially the lung and kidneys, and causes
a systematic response in the organism.1,4
A number of chemicals and drugs, including oxygen radical
scavengers, have been successfully used to reduce hepatic IR injury
in animal models, but few of them are currently used clinically
because of severe adverse side effects.5 In addition, these chemicals
and drugs may not be available at the time of the operation.
Therefore, the effects of anesthetic or sedative agents that can

Fig. 1. Histopathological changes in liver tissue A) Normal liver tissue (H&E stain, 200) was shown in sham group; B) Cytoplasmic hypereosinophilic changes, nuclear pyknosis,
necrosis, edema, moderate vascular congestion (H&E stain, 200) were shown in IR group; C) In IR Dex group, liver tissue seemingly normal other than to mild sinusoidal
dilatation (H&E stain, 200).
 ORIGINAL RESEARCH
A. Tfek et al. / International Journal of Surgery 11 (2013) 96e100
Table 2
The histopathological scores of the hepatic, renal and lung tissues.
Group Hepatic (mean  SD) Renal (mean  SD) Lung (mean  SD)
S 0 0 0
Dex 0 0 0 tions of the antiapoptotic proteins, and prevents cell death in
IR 1.6  0.7a 0.4  0.5 0.5  0.7
IR Dex 0.3  0.4b 0.1  0.3 0.2  0.4
Groups are as follows; S Sham, Dex dexmedetomidine, IR ischemia
reperfusion, SD standard deviation, NS Not signicant.
a
Different from S group (p  0.001).
b
Different from IR group (p  0.001).
already be used in anesthesia become an important issue for the
reduction of IR injury.5,21,22
4.1. Total antioxidant status and PON-1 level
PON-1 is a high-density lipoprotein (HDL) associated enzyme
with antioxidant effects, and PON-1 levels can be used in moni-
toring the antioxidant defense system.23 Decreased TAC and PON-1
activity in the rats with hepatic IR may be secondary to depleted
antioxidant stores against increased oxidative stress.24 Further-
more, OSI measurements provide a sensitive, novel index of
oxidative stress, and can reect both oxidative and antioxidative
parameters.25 The decrease in TAC and PON-1 levels and increase in
TOA and OSI levels were reported in hepatic IR damage.26,27 In
a recent study, the effects of dexmedetomidine on hepatic IR were
analyzed biochemically, and it was shown that dexmedetomidine
decreased lipid peroxidation and the erythrocyte deformability
index after hepatic IR.28 In the present study, dexmedetomidine
was administered before induction of ischemia, and resulted in
decreased TOA and OSI levels with an increase of TAC levels and
PON-1 activity in serum, liver, and remote organs. The oxidante
antioxidant balance shifted toward the antioxidant status in rats
with hepatic IR pretreated with dexmedetomidine.
4.2. Histopathological changes
After the hepatic IR damage, the following changes were
observed; inltration of leukocytes into interstitial and alveolar
spaces, edema and partial destruction in lung tissue; leukocyte
inltration, proximal tubule necrosis, loss of brush borders from
proximal tubules and tubular dilatation in the kidney tissue.29,30
Moreover, IR affects not only the liver but also remote organs
such as the lungs and the kidneys.1,4 In our study, focal hemorrhage
and necrosis, sinusoidal dilatation and hepatocyte congestion were
observed in the liver in relation to the hepatic IR damage; however,
no signicant histopathological changes were observed in the
kidney tissue after the hepatic IR damage. The reason for this might
be that ischemia period in our study was limited to 30 min. In the
dexmedetomidine-induced group, histopathological changes
resulting from the hepatic IR damage were signicantly lower than
in the IR group. In the experimental IR damage studies, different
tissues and doses of dexmedetomidine were used. A previous study
showed that the administration of dexmedetomidine after the IR
period may produce no benecial effect. However, when dexme-
detomidine was used preoperatively, it was proved to be more
effective against IR damage.7 Therefore, we used dexmedetomidine
before surgery.
4.3. Potential mechanism of protection
TThe anti-inammatory effects of dexmedetomidine might be
responsible for the prevention of IR injury.31 Dexmedetomidine can
inhibit lipid peroxidation in cell membranes after IR injury of various
99
tissues.5,6,21,32e34 Previous studies have demonstrated that dexme-
detomidine minimizes IR injury in the central nervous system and
has neuroprotective effects.31,32,34,35 It has also been reported that
dexmedetomidine alters gene expression, increases the concentra-
experimental IR models.32,36 Furthermore, it has been reported that
dexmedetomidine has a cardioprotective effect that is mediated by
alpha-2 adrenergic stimulation in the myocardial ischemia.37,38
4.4. Limitations of the study
The damage related to I/R manifest upto 6 h following reper-
fusion. Although observation of 30 min post-reperfusion showed
signicant changes, 2e6 h post-reperfusion analysis would yield
better results.
5. Conclusion
The results of this study clearly demonstrate that oxidative
stress parameters are signicantly altered in experimental hepatic
IR injury in the rats. Dexmedetomidine was found to be a protective
agent against the oxidative alterations in hepatic IR injury on the
liver and remote organs, when given before induction of ischemia.
Moreover, dexmedetomidine protected against the harmful effects
of IR in terms of the histopathological changes in the liver. There-
fore, dexmedetomidine may be used as an adjuvant anesthetic
agent before surgery for patients with potential hepatic IR injury.
Ethical approval
The study protocol was approved (2010e40) by the Committee
of Experimental Animals of Dicle University.
Financial closure
The authors declared that there was no nancial closure.
Author contribution
AT, OT, IA, UA; Study design, data collection, analyses and
writing.
OE, T, AG, ZBY; Data collection, Statistical analysis.
Conict of interest
The authors declared that there was no conict of interest.
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