ABSTRACT
Objective:
To evaluate the capacity of ischemic postconditioning and atorvastatin in prevent or minimize reperfusion injury in small bowel of rats subjected to ischemia and reperfusion by abdominal aorta clamping.
Methods:
41 Wistar norvegic rats were distributed into 5 groups: ischemia and reperfusion, ischemic postconditioning, postconditioning + statin, statin and Sham. After anesthesia, laparotomy and dissection of the infra-renal abdominal aorta were performed; except the Sham group, all others were subjected to aorta clamping for 70 min (ischemia) and withdrawal of clamp for 70 min (reperfusion). In the IPC and IPC + S groups, four cycles of postconditioning were performed between the phases of ischemia and reperfusion lasting 30 s each. In IPC + S and S groups, 3.4 mg/day of atorvastatin was given for seven days per gavage; 1 cm of the ileum were removed for histological study and the results were subjected to statistical treatment considering significant p < 0.05.
Results:
The average of intestinal lesion was 2 in the I/R group, 0.66 in the IPC group, 0 in the IPC + S group, 0 in the S group, and 0 in the SHAM group.
Conclusion:
The ischemic postconditioning and atorvastatin were capable of minimizing intestinal reperfusion injury, either alone or in combination.
Keywords:
Ischemia; Reperfusion; Ischemic postconditioning; Hydroxymethylglutaryl-CoA reductase inhibitors; Small intestine
RESUMO
Objetivo:
Avaliar a capacidade do pós-condicionamento isquêmico e da atorvastatina para prevenir ou minimizar a lesão de reperfusão no intestino Delgado de ratos submetidos à isquemia e reperfusão por pinçamento de aorta abdominal.
Métodos:
41 ratos noruegueses Wistar foram distribuídos em 5 grupos: isquemia e reperfusão, pós-condicionamento isquêmico, pós-condicionamento + estatina, estatina e simulacro. Depois da anestesia, procedeu-se à laparotomia e dissecação da aorta abdominal infrarrenal; exceto no grupo de simulacro, todos os demais grupos foram submetidos ao pinçamento da aorta durante 70 minutos (isquemia) e à retirada do pinçamento também durante 70 minutos (reperfusão). Nos grupos PCI e PCI + E, foram efetuados quatro ciclos de pós-condicionamento entre as fases de isquemia e de reperfusão, com duração de 30 segundos cada. Nos grupos PCI + E e E, foram administrados 3,4 mg/dia de atorvastatina durante 7 dias por gavagem; procedemos à remoção de 1 cm do íleo para o estudo histológico, e os resultados foram estatisticamente tratados. Consideramos p < 0,05 como estatisticamente significativo.
Resultados:
As médias para as lesões intestinais foram 2 no grupo I/R, 0,66 no grupo PCI, 0 no grupo PCI + E, 0 no grupo E, e 0 no grupo S.
Conclusão:
O procedimento de pós-condicionamento e atorvastatina demonstraram capacidade de minimizar a lesão de reperfusão intestinal, tanto isoladamente como em conjunto.
Palavras-chave:
Isquemia; Reperfusão; Pós-condicionamento isquêmico; Hidroximetilglutaril-CoA redutase, inibidores da; Intestino delgado
Introduction
Reperfusion is a fundamental step in the treatment of ischemia. However, clinical and experimental evidence shows that the main events leading to cell and tissue dysfunction are related to reperfusion.11 Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: new strategies for cardioprotection. Diabetes Obes Metab. 2008;10:451-9.
The ischemia and reperfusion (IR) injury is a pathophysiological event common to several diseases of daily clinical practice. The intestine may be the target of IR injury directly, as in mesenteric ischemia, or be reached at a distance, as in cases of shock or reperfusion injury in other organs, such as aortic clamping, used in aneurysm surgeries.22 Sotoudeh A, Takhtfooladi MA, Jahanshahi A, Asl AHK, Takhtfooladi HA, Khansari M. Effect of N-acetylcysteine on lung injury induced by skeletal muscle ischemia-reperfusion: histopathological study in rat model. Acta Cir Bras. 2012;27:168-71.
Increasing evidence is emerging that the gut can be affected by remote reperfusion injury, since toxic reactive oxygen species (ROS) act systemically. In surgeries with temporary aortic occlusion, intestinal vascular involvement is a frequent complication, with a multifactorial etiology, including reperfusion injury.33 Gelman S. The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology. 1995;82:1026-60.
Regardless of where ischemia occurs, when reperfusion happens, there is a systemic impairment to a greater or lesser extent. IR is associated with the production of tumor necrosis factor (TNF). Injury of the intestinal mucosa by IR allows the release of endotoxin into the portal circulation, inducing the production of TNF by liver macrophages. Increased TNF in the systemic circulation is capable of leading to inflammatory lung injury, characterized by the accumulation of neutrophils. This sequence of events was demonstrated by Caty et al.44 Caty MG, Guice KS, Oldham KT, Remick DG, Kunkel SI. Evidence for tumor necrosis factor-induced pulmonary microvascular injury after intestinal ischemia-reperfusion injury. Ann Surg. 1990;212:694-700. in a model of IR by temporary occlusion of the superior mesenteric artery in rats. After reperfusion, endotoxin levels in portal venous blood and TNF were increased in the systemic circulation. In parallel, there was accumulation of neutrophils in the lungs and increased pulmonary capillary permeability.
Some techniques for protection against reperfusion injury have already been tried and tested, and among them, ischemic postconditioning (IPC), which consists of one or more short cycles of reperfusion, followed by one or more short cycles of ischemia, immediately after the ischemic phase and before permanent reperfusion occurs. Although IPC has already demonstrated a protective effect in many organs submitted to IR as well as in distance protection,55 Santos CHM, Aydos RD, Nogueira Neto E, Miiji LNO, Cassino PC, Alves II, et al. Evaluation of pulmonary reperfusion injury in rats undergoing mesenteric ischemia and reperfusion and protective effect of postconditioning on this process. Braz J Cardiovasc Surg. 2015;30:533-7. its efficacy in the prevention of remote intestinal lesion is still very early.66 Dorsa RC, Pontes JCDV, Antoniolli ACB, Silva GVR, Benfatti RA, Santos CHM, et al. Effect of remote ischemic postconditioning in inflammatory changes of the lung parenchyma of rats submitted to ischemia and reperfusion. Braz J Cardiovasc Surg. 2015;30:353-9.
Much has been studied about the pathophysiology of reperfusion injury and some mechanisms have already been well evidenced such as the role of free radicals, vascular endothelial dysfunction, and neutrophil-mediated injury.11 Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: new strategies for cardioprotection. Diabetes Obes Metab. 2008;10:451-9. Recently, there has been an increase in interest in statins, drugs known for their anti-dyslipidemic effect, this time due to its pleiotropic effect, which is characterized by anti-inflammatory properties, immunomodulatory, antithrombogenic and endothelial function.77 Turóczi Z, Fülöp A, Czigány Z, Varga G, Rosero O, Tökés T, et al. Improvement of small intestinal microcirculation by postconditioning after lower limb ischemia. Microvasc Res. 2015;98:119-25. Recent experimental studies88 Bian B, Yu X, Wang Q, Teng T, Nie J. Atorvastatin protects myocardium against ischemia-reperfusion arrhythmia by increasing Connexin 43 expression: a rat model. Eur J Pharmacol. 2015;768:13-20. have shown promising results with the use of statins demonstrating their role in the protection against IR injury, a fact that led us to inquire about its benefits in the face of reperfusion injury, the objective of this study being to evaluate the capacity of IPC and statins in reducing intestinal injury, alone and in combination.
Considering the lack of studies on the protective effect of postconditioning on remote intestinal reperfusion injury, as well as the potential protective effect of statins, which have not yet been tested in a model similar to the one presented here, it is fundamental that such research be performed. Thus, the objective of this study is to evaluate the capacity of ischemic postconditioning and atorvastatin in prevent or minimize reperfusion injury in small bowel of rats subjected to ischemia and reperfusion by abdominal aorta clamping.
Methods
The study was approved by the Committee of Ethics in Animal Experimentation of the University Anhanguera-Uniderp. A total of 41 Wistar norvergic male rats weighing 250-300 g were collected from the Anhanguera-Uniderp University Animal Hospital. The animals were kept in cages at ambient temperature of approximately 23 °C with 12 h light cycles and received water and feed ad libitum.
The number of animals of each group was made by a sample calculation and based on previous researches of our group, following the ethical principle of using as few animals as possible for research. The animals were distributed in the following groups:
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- Ischemia and reperfusion group (I/R): Nine rats were submitted to ischemia for 70 min by aortic clamping, followed by reperfusion of 70 min. The duration of the ischemia and reperfusion phases of 70 min was defined based on previous publications that demonstrated that this time was sufficient to cause remote lesion and, consequently, allow the evaluation of the protective effect of the methods used.55 Santos CHM, Aydos RD, Nogueira Neto E, Miiji LNO, Cassino PC, Alves II, et al. Evaluation of pulmonary reperfusion injury in rats undergoing mesenteric ischemia and reperfusion and protective effect of postconditioning on this process. Braz J Cardiovasc Surg. 2015;30:533-7.,66 Dorsa RC, Pontes JCDV, Antoniolli ACB, Silva GVR, Benfatti RA, Santos CHM, et al. Effect of remote ischemic postconditioning in inflammatory changes of the lung parenchyma of rats submitted to ischemia and reperfusion. Braz J Cardiovasc Surg. 2015;30:353-9.
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- Ischemic postconditioning group (IPC): Nine rats were submitted to the ischemia procedure for 70 min by aortic clamping and reperfusion for 70 min. Between ischemia and reperfusion, four cycles of reperfusion (30 s each) were performed, interspersed with four cycles of ischemia (30 s each).
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Ischemic postconditioning + statin group (IPC + S): Nine rats received a dose of 3.4 mg/day of atorvastatin, one dose per day through the gavage method, for seven days and were submitted to the ischemia procedure for 70 min by aortic clamping and reperfusion for 70 min. Between ischemia and reperfusion, four cycles of reperfusion (30 s each) were performed, interspersed with four cycles of ischemia (30 s each).
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- Statin group (S): Nine rats received a dose of 3.4 mg/day of atorvastatin, one dose per day through the gavage method, for seven days, and then subjected to the ischemia procedure for 70 min by aortic clamping and reperfusion for 70 min.
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- SHAM group: Five rats submitted to laparotomy, dissection and isolation of infra-renal abdominal aorta artery.
The animals were anesthetized by intraperitoneal injection of a 2:1 solution of Cetamine Hydrochloride (Cetamin®, Syntec, Cotia-Brazil), 50 mg/mL, and Xilazin Hydrochloride (Xilazin®, Syntec, Cotia-Brazil), 20 mg/mL, respectively, at a dose of 0.1 mL/100 g.
After anesthesia, the rats were submitted to median longitudinal laparotomy of approximately four centimeters, exteriorization of the small intestine, identification and dissection of infra-renal abdominal aorta artery.
In all groups except SHAM, the abdominal aorta was occluded by atraumatic vascular clamp that remained for 70 min (ischemia phase). After clamp placement, the small intestine was repositioned into the abdominal cavity and the surgical wound was closed with continuous suturing of the skin with 4-0 monofilament nylon thread. After the ischemia phase, the abdominal wall was reopened by removal of the suture and in the I/R and S groups the vascular clamp was removed, initiating the reperfusion phase, lasting 70 min. In the IPC and IPC + S groups, preceding the reperfusion phase, the ischemic postconditioning was performed through four cycles of reperfusion (removal of the atraumatic vascular clamp of the abdominal aorta) with duration of 30 s each, interspersed with four cycles of ischemia (occlusion of the abdominal aorta artery by atraumatic vascular clamp), also with duration of 30 s each.
In all groups after started the reperfusion phase, the abdomen was again closed by continuous suturing of the skin with 4-0 monofilament nylon thread until the end of the experiment.
In the SHAM group, only a median longitudinal laparotomy of approximately four centimeters was performed, exteriorization of the small intestine, identification and dissection of infra-renal abdominal aorta artery.
After the reperfusion phase, all animals were resected one centimeter of the ileum, five centimeters proximal to the ileocecal valve, and the specimens were washed with saline solution and placed in 10% formaldehyde solution for histological analysis.
Euthanasia was performed by intraperitoneal administration of a lethal dose of Cetamine + Xylazine hydrochloride (0.4 mL/100 g).
Slides were prepared with the harvested material, which were stained with hematoxylin-eosin and analyzed by optical microscopy by a single observer, without prior knowledge of it on the group belonging to each rat.
The intestinal segments were classified according to the degree of tissue injury according to Chiu et al.99 Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. Intestinal mucosal lesion in low-flow states. Am J Surg Arch. 1970;101:478-83. (Table 1).
Classification of intestinal lesion degrees according to Chiu et al.99 Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. Intestinal mucosal lesion in low-flow states. Am J Surg Arch. 1970;101:478-83.
After the analysis of the data, the results were submitted to statistical treatment, using the non-parametric Kruskal-Wallis test, being considered significant p < 0.05.
Results
After the histological analysis of each slide, the mean of the degree of intestinal lesion of each animal was defined, following the method used by other researchers with a study design similar to the one used here. The means of the intestinal lesion grades were 2 in the I/R group, 0.66 in the IPC group, and 0 in the IPC + S, S and SHAM groups (Table 1 and Fig. 1). All groups had a lower degree of tissue injury when compared to the control group with a statistically significant difference (p < 0.05 between control and IPC; p = 0.0006 between control and IPC + S, S and SHAM).
Comparison of the degrees of intestinal lesion among the different groups analyzed (Kruskal-Wallis; p = 0.0006; “a” p < 0.05 in relation to the I/R group).
Discussion
Ischemia followed by reperfusion may induce apoptosis and an inflammatory response that affects tissue repair, especially the lung. As a result, many have evaluated the impact of IPC on subsequent apoptotic and inflammatory responses. In experimental IR models in rats with 30 min of ischemia and 3 h of reperfusion there was a significant decrease in tissue necrosis with PCI. There is also a decrease in ROS generation and protection of mitochondrial integrity, suggesting that the protective effect of IPC may be the result of a reduction in the inflammatory response. However, few studies have directly assessed the impact of IPC on inflammation. IPC may limit the expression of P-selectin, which is required for neutrophil bearing and its recruitment. In addition, it may reduce the accumulation of neutrophils in the affected region, decrease adhesion to ischemic vascular endothelium, and attenuate the endothelial dysfunction of the involved vessel, events that normally occur in IR.1010 Jivraj N, Liew F, Marber M. Ischaemic postconditioning: cardiac protection after the event. Anaesthesia. 2015;70:598-612.
In the present study intestinal protection was observed with IPC, demonstrating the efficacy of the method against this IR model, which may be justified by the fact that ROS, regardless of where they are produced, when reperfusion occurs are scattered throughout the organism causing the remote reperfusion injury, so much so that in the I/R group it was observed grade two intestinal lesion, that is, moderate. By acting as a moderator of ROS production, IPC causes less local and distant injury.
The study of the reperfusion injury at a distance on the intestine is a relatively new subject, therefore, lacking publications that allow us to further compare with the present results. Turóczi et al.77 Turóczi Z, Fülöp A, Czigány Z, Varga G, Rosero O, Tökés T, et al. Improvement of small intestinal microcirculation by postconditioning after lower limb ischemia. Microvasc Res. 2015;98:119-25. also performed aortic clamping ischemia and evaluated the protective effect of IPC, confirming the results presented here that this method may decrease the degree of intestinal damage. Another study that obtained similar results was that of Yang et al.,1111 Yang M, Dong JX, Li LB, Che HJ, Yong J, Song FB, et al. Local and remote postconditioning decrease intestinal injury in a rabbit ischemia/reperfusion model. Gastroenterol Res Pract. 2016;2016:2604032. in which the authors also applied infra-renal aortic clamping as a method of ischemia and obtained intestinal protection with IPC.
As seen, there are few publications aimed at evaluating the remote intestinal damage against IR, especially using IPC as a protection method. Existing publications point to a promising role in this method, similar to other IR conditions in which IPC provides tissue protection.1212 Santos CHM, Gomes OM, Pontes JCDV, Miiji LNO, Bispo MAF. Tratamento da isquemia mesentérica pelo pós-condicionamento isquêmico. Rev Bras Coloproct. 2008;28:187-92. Despite this, there are few studies that have used IPC in clinical practice, which reinforces the importance of finding a pharmacological method that presents the same or higher efficacy, in a way that is growing interest for safe drugs such as statins and that at least their pleiotropic effect could be useful in such situations.
In the present study intestinal protection was obtained with the use of atorvastatin, at the same intensity as with IPC. As there are no studies with the same design used here, i.e., aortic clamping and atorvastatin use, the comparison with the literature is also impaired. Moreover, since the use of statins for the prevention of reperfusion injury is relatively new, the best route of administration and ideal dose are items to be better clarified in future research. It has been chosen by gavage administration with the intention of simulating what is practiced in humans, that is, the absorption by the gastrointestinal tract, aiming at its clinical applicability.
Statins have been successfully tested for this purpose in several situations. Wu et al.1313 Wu K, Lei W, Tian J, Li H. Atorvastatin treatment attenuates renal injury in an experimental model of ischemia-reperfusion in rats. BMC Nephrol. 2014;15:14-8. performed renal IR in rats and demonstrated that atorvastatin decreased tissue damage compared to the control group. The same results were obtained by Cusomano et al.1414 Cusumano G, Romagnoli J, Liuzzo G, Ciavarella LP, Severino A, Copponi G, et al. N-acetylcysteine and high-dose atorvastatin reduce oxidative stress in an ischemia-reperfusion model in the rat kidney. Transplant Proc. 2015;47:2757-62. in the renal IR of rats using atorvastatin.
Statins also protect other tissues in the course of IR such as heart,1515 Kisvári G, Kovács M, Seprényi G, Végh Á. The activation of PI 3-kinase/Akt pathway is involved in the acute effects of simvastatin against ischaemia and reperfusion-induced arrhythmias in anaesthetised dogs. Eur J Pharmacol. 2015;769:185-94.
16 Han QF, Wu L, Zhou YH, Wang LH, Zhang DY, Liu T, Yao HC. Simvastatin protects the heart against ischemia reperfusion injury via inhibiting HMGB1 expression through PI3K/Akt signal pathways. Int J Cardiol. 2015;201:568-9.-1717 Kelle I, Akkoç H, Uyar E, Erdinç M, Evliyaoğlu O, Sarıbaş S, et al. The combined effect of rosuvastatin and ischemic pre- or post-conditioning on myocardial ischemia-reperfusion injury in rat heart. Eur Rev Med Pharmacol Sci. 2015;19:2468-76. nervous system1818 Fang X, Tao D, Shen J, Wang Y, Dong X, Ji X. Neuroprotective effects and dynamic expressions of MMP9 and TIMP1 associated with atorvastatin pretreatment in ischemia-reperfusion rats. Neurosci Lett. 2015;603:60-5. and liver.1919 Kocak FE, Kucuk A, Ozyigit F, Tosun M, Kocak C, Kocak A, et al. Protective effects of simvastatin administered in the experimental hepatic ischemia-reperfusion injury rat model. J Surg Res. 2015;199:393-401. In the lung, the efficacy of statins has also been demonstrated, as demonstrated by Matsuo et al.,2020 Matsuo S, Saiki Y, Adachi O, Kawamoto S, Fukushige S, Horii A, et al. Single-dose rosuvastatin ameliorates lung ischemia-reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension. J Thorac Cardiovasc Surg. 2015;149:902-9. however, with a method different from the one used here, since these authors performed IR directly on the pulmonary hilum and were therefore not a protective study of remote reperfusion injury. In addition, these authors used rosuvastatin as a protective drug and not atorvastatin as in the present study.
The mechanism of protection of statins to the situations of IR is due to its pleiotropic effect. By inhibiting the conversion of HMG-CoA to L-mevalonate, statins prevent the synthesis of isoprenoids, which are precursors of cholesterol biosynthesis, which serve as important lipid ligands for the post-translational modification of intracellular proteins, such as small GTPases, Rho, Rac and Ras. This protein isoprenylation allows adequate subcellular localization and intracellular trafficking of proteins, which control various cellular functions, and the inhibition of these pathways may determine important components of the pleiotropic effects of statins. The Rho pathway is related to oxidative stress, atherosclerosis and elevated blood pressure. Rac pathway signaling is involved in two crucial mechanisms, such as cytoskeletal remodeling and ROS synthesis.1515 Kisvári G, Kovács M, Seprényi G, Végh Á. The activation of PI 3-kinase/Akt pathway is involved in the acute effects of simvastatin against ischaemia and reperfusion-induced arrhythmias in anaesthetised dogs. Eur J Pharmacol. 2015;769:185-94.
In the development of this project we did not know that the therapeutic methods applied would achieve the results presented here, so that an association group was created (IPC + S) aiming at enhancing tissue protection. However, there was no advantage in the association, since in isolation these therapeutic methods obtained statistically similar mean tissue lesion to the SHAM group, i.e., it would not be possible to have a lower lesion than had already been achieved. Thus, it can be verified that atorvastatin has the capacity to protect the intestine in situations of reperfusion at a distance, at the same intensity as IPC, and it is possible to invest in research that confirms the best method of using these therapies in order to apply them in clinical practice.
Although the method used here is similar to that of other publications, which allowed us to make comparisons of our results, it should be emphasized as a limitation of the study that we use only histological evaluation. Future research may be done using other methods of evaluating local and remote reperfusion injury such as tissue and plasmatic malondialdehyde, which may offer greater value to the results.
In conclusion, ischemic postconditioning and atorvastatin were able to minimize intestinal reperfusion injury, either alone or in combination.
References
-
1Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: new strategies for cardioprotection. Diabetes Obes Metab. 2008;10:451-9.
-
2Sotoudeh A, Takhtfooladi MA, Jahanshahi A, Asl AHK, Takhtfooladi HA, Khansari M. Effect of N-acetylcysteine on lung injury induced by skeletal muscle ischemia-reperfusion: histopathological study in rat model. Acta Cir Bras. 2012;27:168-71.
-
3Gelman S. The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology. 1995;82:1026-60.
-
4Caty MG, Guice KS, Oldham KT, Remick DG, Kunkel SI. Evidence for tumor necrosis factor-induced pulmonary microvascular injury after intestinal ischemia-reperfusion injury. Ann Surg. 1990;212:694-700.
-
5Santos CHM, Aydos RD, Nogueira Neto E, Miiji LNO, Cassino PC, Alves II, et al. Evaluation of pulmonary reperfusion injury in rats undergoing mesenteric ischemia and reperfusion and protective effect of postconditioning on this process. Braz J Cardiovasc Surg. 2015;30:533-7.
-
6Dorsa RC, Pontes JCDV, Antoniolli ACB, Silva GVR, Benfatti RA, Santos CHM, et al. Effect of remote ischemic postconditioning in inflammatory changes of the lung parenchyma of rats submitted to ischemia and reperfusion. Braz J Cardiovasc Surg. 2015;30:353-9.
-
7Turóczi Z, Fülöp A, Czigány Z, Varga G, Rosero O, Tökés T, et al. Improvement of small intestinal microcirculation by postconditioning after lower limb ischemia. Microvasc Res. 2015;98:119-25.
-
8Bian B, Yu X, Wang Q, Teng T, Nie J. Atorvastatin protects myocardium against ischemia-reperfusion arrhythmia by increasing Connexin 43 expression: a rat model. Eur J Pharmacol. 2015;768:13-20.
-
9Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. Intestinal mucosal lesion in low-flow states. Am J Surg Arch. 1970;101:478-83.
-
10Jivraj N, Liew F, Marber M. Ischaemic postconditioning: cardiac protection after the event. Anaesthesia. 2015;70:598-612.
-
11Yang M, Dong JX, Li LB, Che HJ, Yong J, Song FB, et al. Local and remote postconditioning decrease intestinal injury in a rabbit ischemia/reperfusion model. Gastroenterol Res Pract. 2016;2016:2604032.
-
12Santos CHM, Gomes OM, Pontes JCDV, Miiji LNO, Bispo MAF. Tratamento da isquemia mesentérica pelo pós-condicionamento isquêmico. Rev Bras Coloproct. 2008;28:187-92.
-
13Wu K, Lei W, Tian J, Li H. Atorvastatin treatment attenuates renal injury in an experimental model of ischemia-reperfusion in rats. BMC Nephrol. 2014;15:14-8.
-
14Cusumano G, Romagnoli J, Liuzzo G, Ciavarella LP, Severino A, Copponi G, et al. N-acetylcysteine and high-dose atorvastatin reduce oxidative stress in an ischemia-reperfusion model in the rat kidney. Transplant Proc. 2015;47:2757-62.
-
15Kisvári G, Kovács M, Seprényi G, Végh Á. The activation of PI 3-kinase/Akt pathway is involved in the acute effects of simvastatin against ischaemia and reperfusion-induced arrhythmias in anaesthetised dogs. Eur J Pharmacol. 2015;769:185-94.
-
16Han QF, Wu L, Zhou YH, Wang LH, Zhang DY, Liu T, Yao HC. Simvastatin protects the heart against ischemia reperfusion injury via inhibiting HMGB1 expression through PI3K/Akt signal pathways. Int J Cardiol. 2015;201:568-9.
-
17Kelle I, Akkoç H, Uyar E, Erdinç M, Evliyaoğlu O, Sarıbaş S, et al. The combined effect of rosuvastatin and ischemic pre- or post-conditioning on myocardial ischemia-reperfusion injury in rat heart. Eur Rev Med Pharmacol Sci. 2015;19:2468-76.
-
18Fang X, Tao D, Shen J, Wang Y, Dong X, Ji X. Neuroprotective effects and dynamic expressions of MMP9 and TIMP1 associated with atorvastatin pretreatment in ischemia-reperfusion rats. Neurosci Lett. 2015;603:60-5.
-
19Kocak FE, Kucuk A, Ozyigit F, Tosun M, Kocak C, Kocak A, et al. Protective effects of simvastatin administered in the experimental hepatic ischemia-reperfusion injury rat model. J Surg Res. 2015;199:393-401.
-
20Matsuo S, Saiki Y, Adachi O, Kawamoto S, Fukushige S, Horii A, et al. Single-dose rosuvastatin ameliorates lung ischemia-reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension. J Thorac Cardiovasc Surg. 2015;149:902-9.
Publication Dates
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Publication in this collection
Oct-Dec 2017
History
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Received
17 June 2017 -
Accepted
13 Aug 2017