Remote ischemic preconditioning-induced late cardioprotection: possible role of melatonin-mitoKATP-H2S signaling pathway

Purpose: Remote ischemic preconditioning (RIPC) confers cardioprotection against ischemia reperfusion (IR) injury. However, the precise mechanisms involved in RIPC-induced cardioprotection are not fully explored. The present study was aimed to identify the role of melatonin in RIPC-induced late cardioprotective effects in rats and to explore the role of H2 S, TNF-α and mitoKATP in melatoninmediated effects in RIPC. Methods: Wistar rats were subjected to RIPC in which hind limb was subjected to four alternate cycles of ischemia and reperfusion of 5 min duration by using a neonatal blood pressure cuff. After 24 h of RIPC or ramelteon-induced pharmacological preconditioning, hearts were isolated and subjected to IR injury on the Langendorff apparatus. Results: RIPC and ramelteon preconditioning protected the hearts from IR injury and it was assessed by a decrease in LDH-1, cTnT and increase in left ventricular developed pressure (LVDP). RIPC increased the melatonin levels (in plasma), H2 S (in heart) and decreased TNF-α levels. The effects of RIPC were abolished in the presence of melatonin receptor blocker (luzindole), ganglionic blocker (hexamethonium) and mitochondrial KATP blocker (5-hydroxydecanoic acid). Conclusion: RIPC produce delayed cardioprotection against IR injury through the activation of neuronal pathway, which may increase the plasma melatonin levels to activate the cardioprotective signaling pathway involving the opening of mitochondrial KATP channels, decrease in TNF-α production and increase in H2 S levels. Ramelteon-induced pharmacological preconditioning may also activate the cardioprotective signaling pathway involving the opening of mitochondrial KATP channels, decrease in TNF-α production and increase in H2 S levels.

Role of caveolin-eNOS platform and mitochondrial ATP-sensitive potassium channel in abrogated cardioprotective effect of ischemic preconditioning in postmenopausal women

Abstract Caveolin, the protein of the caveolar membrane, interacts and binds with endothelial nitric oxide synthase (eNOS), forming a caveolin-eNOS complex leading to suppression of the eNOS activity. Caveolin, therefore, maintains eNOS in the inactivated state leading to reduced nitric oxide (NO) production. Ischemic preconditioning disrupts the caveolin-eNOS complex leading to activation of the eNOS and thus results in cardioprotection. During ischemic preconditioning, NO produces cardioprotection by the opening of the KATP channel, and the caveolin forms a suitable signalling platform facilitating the interaction of NO with the KATP channel. Estrogen deficiency has been reported to upregulate caveolin-1 expression. The article aims to review the various mechanisms that placed the women at the risk of coronary artery diseases after postmenopausal estrogen deficiency and their role in the cardioprotective effect of ischemic preconditioning.

The influence of ischemic preconditioning on neuromuscular performance / Influencia del preacondicionamiento isquémico en el desempeño neuromuscular / Influência do pré-condicionamento isquêmico no desempenho neuromuscular

ABSTRACT Introduction: Ischemic preconditioning (IPC) has been described in the literature as a resource capable of improving physical performance. Objective: The purpose of this randomized double-blind study was to evaluate the influence of IPC on the neuromuscular performance of trained individuals. Methods: Twenty-four (24) resistance training participants (6 of them women) with a mean age of 25.8 ± 4.6 years were selected and divided into two groups: the upper limb group (ULG) composed of 12 individuals (4 women) and the lower limb group (LLG) composed of 12 individuals (2 women). The maximum repetitions test was applied in the bench press for the ULG and in the 45° leg press for the LLG, with 50% of the one-repetition maximum under control, placebo and IPC conditions, at a random interval of 72 hours between tests. The IPC was applied four hours before the tests by means of an analog sphygmomanometer cuff inflated to 220 mmHg on the arm for the ULG and on the thigh for LLG, with three cycles of five minutes each of ischemia and reperfusion, alternating between the right and left sides. For the placebo, the cuff was inflated to 40 mmHg without causing ischemia. The significance level for the Wilcoxon test was p <0.017, due to the Bonferroni correction. The effect size (ES) was also analyzed. Results: With IPC, the ULG performed 34.8 ± 4.8 repetitions, representing an improvement of 11.29% (IPC vs. control, ES = 0.68 and p = 0.002) and the LLG performed 40.5 ± 15.7 repetitions, representing an improvement of 37.47% (IPC vs. control, ES = 0.84 and p = 0.002). No significant improvements were observed for the placebo in either group. Conclusion: Our data showed that IPC positively influenced neuromuscular performance of both the upper and lower limbs. Level of evidence II; Therapeutic studies investigating the results of treatment (Prospectived comparative studye).

RESUMEN Introducción: El preacondicionamiento isquémico (PCI) ha sido descrito en la literatura como un recurso capaz de mejorar el desempeño físico. Objetivo: El objetivo de este estudio aleatorio doble ciego fue evaluar la influencia del PCI en el desempeño neuromuscular de individuos entrenados. Métodos: Fueron seleccionados 24 individuos (6 mujeres) con promedio de edad de 25,8 ± 4,6 años, practicantes de entrenamiento resistido, divididos en dos grupos, siendo un grupo de miembros superiores (GMS) compuesto por 12 individuos (4 mujeres) y grupo de miembros inferiores (GMI) compuesto por 12 individuos (2 mujeres). El test de repeticiones máximas fue aplicado en el ejercicio de supino para el GMS y en el leg press 45° para el GMI con 50% de una repetición máxima, en las condiciones de control, placebo y PCI, de forma aleatoria con intervalo de 72 horas entre los tests. El PCI fue aplicado cuatro horas antes de los tests mediante un manguito de esfigmomanómetro analógico inflado a 220 mmHg en el brazo para el GMS y en el muslo para el GMI, siendo tres ciclos de cinco minutos de isquemia y cinco minutos de reperfusión, alternando los lados derecho e izquierdo. Para el placebo, el manguito quedó en 40 mmHg, sin provocar isquemia. El nivel de significancia del test de Wilcoxon fue p <0,017, debido a la corrección de Bonferroni. El tamaño del efecto (TE) también fue analizado. Resultados: Con el PCI, el GMS realizó 34,8 ± 4,8 repeticiones, representando mejora de 11,29% (PCI vs control, TE = 0,68 y p = 0,002) y el GMI realizó 40,5 ± 15,7 repeticiones, representando mejora de 37,47% (PCI vs control, TE = 0,84 y p = 0,002). Con el placebo, ambos grupos no mostraron mejora. Conclusión: Nuestros datos mostraron que el PCI influenció positivamente el desempeño neuromuscular tanto de miembros superiores como inferiores. Nivel de evidencia II; Estudios terapéuticos: investigación de los resultados del tratamiento (estudio comparativo prospectivo).

RESUMO Introdução: O pré-condicionamento isquêmico (PCI) tem sido descrito na literatura como um recurso capaz de melhorar o desempenho físico. Objetivo: O objetivo deste estudo randomizado duplo cego foi avaliar a influência do PCI no desempenho neuromuscular de indivíduos treinados. Métodos: Foram selecionados 24 indivíduos (6 mulheres) com média de idade de 25,8 ± 4,6 anos, praticantes de treinamento resistido, divididos em dois grupos, sendo um grupo de membros superiores (GMS), composto por 12 indivíduos (4 mulheres) e grupo de membros inferiores (GMI), composto por 12 indivíduos (2 mulheres). O teste de repetições máximas foi aplicado no exercício de supino para o GMS e no leg press 45° para o GMI com 50% de uma repetição máxima, nas condições de controle, placebo e PCI, de forma aleatória com intervalo de 72 horas entre os testes. O PCI foi aplicado quatro horas antes dos testes por meio de um manguito de esfigmomanômetro analógico inflado a 220 mmHg no braço para o GMS e na coxa para o GMI, sendo três ciclos de cinco minutos de isquemia e cinco minutos de reperfusão, alternando os lados direito e esquerdo. Para o placebo, o manguito ficou em 40 mmHg, sem provocar isquemia. O nível de significância do teste de Wilcoxon foi de p < 0,017, devido à correção de Bonferroni. O tamanho do efeito (TE) também foi analisado. Resultados: Com o PCI, o GMS realizou 34,8 ± 4,8 repetições, representando melhora de 11,29% (PCI vs. controle, TE = 0,68 e p = 0,002) e o GMI realizou 40,5 ± 15,7 repetições, representando melhora de 37,47% (PCI vs. controle, TE = 0,84 e p = 0,002). Com o placebo, ambos os grupos não apresentaram melhora. Conclusão: Nossos dados mostraram que o PCI influenciou positivamente o desempenho neuromuscular tanto de membros superiores quanto inferiores. Nível de evidência II; Estudos terapêuticos-Investigação dos resultados do tratamento (Estudo prospectivo comparativo).

Comparison of remote and local postconditioning against hepatic ischemic-reperfusion injury in rats

ABSTRACT Purpose: The aim of this study is to compare the hepatic protective effect of both remote and local postconditioning (POS). Methods: Twenty-eight Wistar rats were assigned into four groups: sham group(SHAM), ischemia-reperfusion group (IR), local ischemic POS group (lPOS) and remote ischemic POS group (rPOS). Animals were subjected to liver ischemia for 30 min. Local ischemic POS group consisted of four cycles of 5 min liver ischemia, followed by 5 min reperfusion (40 min). Remote ischemic POS group consisted of four cycles of 5 min hind limb ischemia, followed by 5 min hind limb perfusion after the main liver ischemia period. After 190 minutes median and left liver lobes were harvested for biochemical and histopathology analysis. Results: All the conditioning techniques were able to increase the level of bothglutathione reductase and peroxidase, showing higher values in the rPOS group when compared to the lPOS. Also, thiobarbituric acid reactive substances were higher in all intervention groups when compared to SHAM, but rPOS had the lower rates of increase, showing the best result. The histopathology analysis showed that all groups had worst injury levels than SHAM, but rPOS had lower degrees of damage when compared to the lPOS, although it was not statistically significant. Conclusion: Remote postconditioning is a promising technique to reduce liver ischemia-reperfusion injury, once it increased antioxidants substances and reduced the damage.

Irisin and troponin I expression in dialysis patients submitted to remote ischemic preconditioning: a pilot study / Expressão de irisina e troponina I em pacientes em diálise submetidos a pré-condicionamento isquêmico remoto: um estudo piloto

ABSTRACT Background: Renal replacement therapy continues to be related to high hospitalization rates and poor quality of life. All-cause morbidity and mortality in renal replacement therapy in greater than 20% per year, being 44 times greater when diabetes is present, and over 10 times that of the general population. Regardless of treatment, the 5-year survival is 40%, surpassing many types of cancers. Irisin is a hormone that converts white adipose tissue into beige adipose tissue, aggregating positive effects like fat mass control, glucose tolerance, insulin resistance, prevention of muscle loss, and reduction in systemic inflammation. Objectives: To determine the serum levels of troponin I in hemodialysis patients submitted to remote ischemic preconditioning (RIPC) associated with irisin expression. Methods: This was a prospective, randomized, double-blind clinical trial with patients with chronic kidney disease submitted to hemodialysis for a 6-month period. Troponin I, IL-6, urea, TNF-α, and creatinine levels were determined from blood samples. The expressions of irisin, thioredoxin, Nf-kb, GPX4, selenoprotein and GADPH were also evaluated by RT-PCR. Results: Samples from 14 hypertensive patients were analyzed, 9 (64.3%) of whom were type 2 diabetics, aged 44-64 years, and 50% of each sex. The difference between pre- and post-intervention levels of troponin I was not significant. No differences were verified between the RIPC and control groups, except for IL-6, although a significant correlation was observed between irisin and troponin I. Conclusion: Remote ischemic preconditioning did not modify irisin or troponin I expression, independent of the time of collection.

RESUMO Introdução: A terapia de substituição renal continua associada a altas taxas de hospitalização e baixa qualidade de vida. A morbimortalidade por todas as causas na terapia de substituição renal é superior a 20% ao ano, sendo 44 vezes maior quando a diabetes está presente e mais de 10 vezes a da população em geral. Independentemente do tratamento, a sobrevida em 5 anos é de 40%, superando muitos tipos de câncer. A irisina é um hormônio que converte tecido adiposo branco em tecido adiposo bege, agregando efeitos positivos como o controle de massa gorda, tolerância à glicose, resistência à insulina, prevenção de perda muscular e redução da inflamação sistêmica. Objetivos: Determinar os níveis séricos de troponina I em pacientes em hemodiálise submetidos ao pré-condicionamento isquêmico remoto (PCIR) associado à expressão da irisina. Métodos: Estudo clínico prospectivo, randomizado, duplo-cego, com pacientes com doença renal crônica submetidos à hemodiálise por um período de 6 meses. Os níveis de troponina I, IL-6, uréia, TNF-α e creatinina foram determinados a partir de amostras de sangue. As expressões de irisina, tioredoxina, Nf-kb, GPX4, selenoproteína e GADPH foram também avaliadas por RT-PCR. Resultados: Foram analisadas amostras de 14 pacientes hipertensos, 9 (64,3%) dos quais eram diabéticos tipo 2, com idades entre 44 e 64 anos e 50% de cada gênero. A diferença entre os níveis pré e pós-intervenção de troponina I não foi significativa. Não houve diferenças entre os grupos PCIR e controle, exceto pela IL-6, embora tenha sido observada correlação significativa entre irisina e troponina I. Conclusão: O pré-condicionamento isquêmico remoto não modificou a expressão de irisina ou troponina I, independentemente do tempo de coleta.

Effects of bradykinin preconditioning in an experimental intestinal ischemia reperfusion model on rats

Abstract Purpose To investigate the effects of bradykinin on reperfusion injury in an experimental intestinal ischemia reperfusion model. Methods We used 32 Wistar-Albino rats. We composed 4 groups each containing 8 rats. Rats in sham group were sacrified at 100 minutes observation after laparotomy. Thirty minutes reperfusion was performed following 50 minutes ischaemia in control group after observing 20 minutes. Ischaemic preconditioning was performed in one group of the study. We performed the other study group pharmacologic preconditioning by infusional administration of 10 μg/kg/minute bradykinin intravenously. We sacrified all of the rats by taking blood samples to evaluate the lactate and lactate dehydrogenase (LDH) after resection of jejunum for detecting tissue myeloperoxidase (MPO) activity. Results Lactate and LDH levels were significantly higher in control and study groups than the sham group (P<0.001). There is no difference between the study groups statistically. (P>0.05). The results were the same for MPO levels. Although definitive cell damage was determinated in the control group by hystopatological evaluation, the damage in the study groups observed was lower in different levels. However, there was no significant difference between the study groups statistically (P>0.05). Conclusion Either ischeamic preconditioning or pharmacologic preconditioning made by bradykinin reduced the ischemia reperfusion injury at jejunum.

Effect of preconditioning and postoperative hyperbaric oxygen therapy on colonic anastomosis healing with and without ischemia in rats

Abstract Purpose To investigate the effect of hyperbaric oxygen therapy on colonic anastomosis healing with and without ischemia in rats. Methods Forty female rats underwent segmental resection of 1 cm of the left colon followed by end-to-end anastomosis. They were randomly assigned to four groups (n=10 each), a sham group; two groups were submitted to Hyperbaric Oxygen therapy (HBOT) with and without induced ischemia and the induced ischemia group without HBOT. The HBOT protocol evaluated was 100% O2 at 2.4 Atmosphere absolute pressure (ATA) for 60 minutes, two sessions before as a preconditioning protocol and three sessions after the operation. Clinical course and mortality were monitored during all experiment and on the day of euthanasia on the fourth day after laparotomy. Macroscopic appearance of the abdominal cavity were assessed and samples for breaking strength of the anastomosis and histopathological parameters were collected. Results There was no statistically significant difference in mortality or anastomosis leak between the four experimental groups. Anastomosis breaking strength was similar across groups. Conclusion The HBOT protocol tested herein at 2.4 ATA did not affect histopathological and biomechanical parameters of colonic anastomotic healing, neither the clinical outcomes death and anastomosis leak on the fourth day after laparotomy.

Remote ischemic conditioning enhances heart and brain antioxidant defense / Condicionamento isquêmico remoto melhora a defesa antioxidante do coração e do cérebro

Abstract Background Ischemia-reperfusion injury contributes to morbidity after revascularization procedures. Along with early reperfusion, tissue conditioning by alternating intervals of brief ischemia-reperfusion episodes is considered the best approach to limit tissue damage. Remote ischemic conditioning is conducted remotely, in tissues other than those under ischemia. Despite this, remote ischemic conditioning protection mechanisms are poorly understood, which can lead to misapplication. Objectives To assess whether remote ischemic conditioning works in the heart and brain through enhancement of cells' antioxidant defenses and whether the response is sustained or temporary. Methods Twenty-one male Wistar rats were assigned to three groups (n = 7): SHAM: same procedure as the other groups, but no remote ischemic conditioning was carried out. RIC 10: heart and brain were harvested 10 minutes after the remote ischemic conditioning protocol. RIC 60: heart and brain were harvested 60 minutes after the remote ischemic conditioning protocol. The remote ischemic conditioning protocol consisted of 3 cycles of 5 min left hindlimb ischemia followed by 5 min left hindlimb perfusion, lasting 30 min in total. Heart and brain samples were used to measure the tissue antioxidant capacity. Results Remote ischemic conditioning increased heart and brain antioxidant capacity after 10 minutes (0.746 ± 0.160/0.801 ± 0.227 mM/L) when compared to SHAM (0.523 ± 0.078/0.404 ± 0.124 mM/L). No enhancement of heart or brain antioxidant capacity was detected 60 minutes after remote ischemic conditioning (0.551 ± 0.073/0.455 ± 0.107 mM/L). Conclusions Remote ischemic conditioning temporarily enhances heart and brain antioxidant defenses in male Wistar rats.

Resumo Contexto A lesão de isquemia e reperfusão contribui para a morbidade após procedimentos de revascularização. Juntamente com a reperfusão precoce, o condicionamento tecidual através de breves episódios de isquemia e reperfusão é considerado a melhor abordagem para limitar o dano tecidual. Apesar disso, os mecanismos do condicionamento isquêmico remoto são pouco compreendidos, o que pode levar a uma aplicação incorreta. Objetivos Avaliar se o condicionamento isquêmico remoto funciona no coração e no cérebro através do aprimoramento da defesa antioxidante das células e se é uma resposta sustentada ou temporária. Métodos Vinte e um ratos Wistar foram divididos em três grupos (n = 7): SHAM, no qual não foi realizado condicionamento isquêmico; RIC 10, no qual 10 minutos após o protocolo de condicionamento isquêmico, foi realizada a coleta dos órgãos; e RIC 60, no qual 60 minutos após o protocolo de condicionamento isquêmico, foi realizada a coleta dos órgãos. O protocolo de condicionamento isquêmico remoto consistiu em três ciclos de 5 minutos de isquemia, seguidos de 5 minutos de perfusão no membro posterior esquerdo, com duração total de 30 minutos. Amostras foram usadas para medir a capacidade antioxidante do tecido. Resultados O condicionamento isquêmico remoto aumentou a capacidade antioxidante do coração e do cérebro após 10 minutos (0,746 ± 0,160/0,801 ± 0,227 mM/L) quando comparado ao SHAM (0,523 ± 0,078/0,404 ± 0,124 mM/L) . Sessenta minutos após o condicionamento isquêmico remoto, não foi detectado aumento da capacidade antioxidante do coração ou do cérebro (0,551 ± 0,073/0,455 ± 0,107 mM/L). Conclusões O condicionamento isquêmico remoto melhora temporariamente as defesas antioxidantes do coração e do cérebro em ratos Wistar.

Remote ischemic conditioning protects against testicular ischemia∕reperfusion injury in rats

Abstract Purpose To evaluate the effect of remote ischemic conditioning associated to N-acetylcysteine (NAC) on testicular ischemia∕reperfusion (I∕R) injury in rats. Methods Twenty-five adult male Wistar rats were randomly distributed into five experimental groups (n=5), as follows: Sham, I∕R, Perconditioning (PER), NAC and PER+NAC. Two-hour ischemia was induced by rotating the left testis 720° to clockwise direction, followed by 4 hours of reperfusion. Perconditioning was performed by three I/R cycles of 10 min each on the left limb, 30 min before reperfusion. N-acetylcysteine (150 mg∕kg) was administered 30 min before reperfusion. Results Statistical differences were observed in MDA levels between I/R group with all groups (p<0.01), in addition there was statistical difference between PER and Sham, and PER+ NAC groups (p<0.05) in plasma. Conclusions The protective effect of perconditioning isolated in the reduction of lipid peroxidation related to oxidative stress was demonstrated. However, when Perconditioning was associated with NAC, there was no protective effect against testicular injury of ischemia and reperfusion.

Isoflurane preconditioning inhibits caspase-11-related noncanonical pyroptosis pathway to alleviate hepatic ischemia-reperfusion injury in mice / 南方医科大学学报

OBJECTIVE@#To study the protective effect of isoflurane preconditioning on hepatic ischemia-reperfusion (I/R) injury mediated by the noncanonical pyroptosis pathway.@*METHODS@#Thirty C57BL/6 mice were randomly divided into sham-operated group, isoflurane group and I/R group, and in the latter two groups, hepatic I/R injury was induced by clamping the portal vein for 30 min. In isoflurane group, the mice were pretreated with 1.4% isoflurane 30 min before the surgery. The protective effect of isoflurane preconditioning against hepatic I/R injury was evaluated by assessing the pathological score of HE staining of the liver tissue and serum ALT and AST levels. Serum IL-1β and IL-18 levels and the protein expression of GSDMS were detected by ELISA and Western blotting to evaluate the inhibitory effect of isoflurane preconditioning on pyroptosis. Western blotting and immunofluroescence were used to detect the protein expression of caspase-11 in the liver tissues to evaluate the inhibitory effect of isoflurane preconditioning on noncanonical pyroptosis pathway.@*RESULTS@#The Suzuki's score of the liver tissue was significantly higher in I/R group than in the sham group ( < 0.05), while the score in the isoflurane group was significantly lower than that in the I/R group ( < 0.05). Serum ALT and AST levels significantly increased in the sham group ( < 0.05), and were significantly lower in isoflurane group than in I/R group ( < 0.05). The serum levels of IL-1β and IL-18 were significantly higher in I/R group than in sham group ( < 0.05), and were significantly lower in isoflurane group than in I/R group ( < 0.05). The expression of GSDMD in the I/R group was significantly higher than that in sham group, and was significantly lower in isoflurane group than in I/R group ( < 0.05). The hepatic expression of caspase-11 was significantly higher in I/R group than in sham group ( < 0.05), and was significantly lower in isoflurane group than in I/R group ( < 0.05).@*CONCLUSIONS@#Isoflurane preconditioning has protective effect against hepatic I/R injury, which is related to the inhibition of the noncanonical pyroptosis pathway.

Protección renal y hepática por condicionamiento isquémico a distancia en la revascularización miocárdica quirúrgica / Renal and hepatic protection due to remote ischemic conditioning in coronary artery bypass grafting

RESUMEN Introducción: Breves períodos de isquemia a distancia pueden limitar el daño miocárdico producido por la isquemia/reperfusión. Objetivos: Identificar el efecto del condicionamiento isquémico a distancia con fines de protección renal y hepática, relacionado al comportamiento postoperatorio de los niveles de creatinina y transaminasas glutámico-purúvica y glutámico-oxalacética en la revascularización miocárdica quirúrgica. Método: Se realizó un estudio cuasiexperimental, explicativo, comparativo con control histórico, en dos grupos de 247 pacientes cada uno, propuestos para revascularización miocárdica quirúrgica. Se colocó un torniquete en el brazo derecho, en el grupo estudio, alternando 3 insuflaciones (con una presión de 200 mmHg) con 3 desinsuflaciones, durante cinco minutos cada una. Este procedimiento se realizó previo, durante y después de la mayor isquemia inducida, provocada por el pinzamiento de la arteria coronaria. Resultados: Se logró una disminución significativa en los valores de creatinina (p<0,001), transaminasa glutámico-purúvica (p<0,001) y transaminasa glutámico-oxalacética (p<0,05). Conclusiones: El condicionamiento isquémico a distancia es una importante herramienta a tener en cuenta para la protección renal y hepática en la revascularización miocárdica quirúrgica.

ABSTRACT Introduction: Short periods of distant ischemia can limit myocardial damage caused by ischemia/reperfusion. Objective: To identify the effect of remote ischemic preconditioning in relation to the postoperative behavior of creatinine, glutamic transaminase, puruvic and oxalacetic levels. Method: A quasi-experimental, explanatory, comparative study with historical control was carried out in two groups of 247 patients each; all candidates for coronary artery bypass grafting. A blood-pressure cuff was placed on the right arm in the study group alternating three inflations with three deflations of five minutes at 200 mmHg. This procedure was performed prior to during and after the major ischemic episode caused by the coronary artery impingement. Results: A significant decrease in the values ​​of creatinine, puruvic glutamic transaminase and glutamic oxalacetic transaminase was achieved. Conclusions: Remote ischemic conditioning is an important tool to take into account for renal and hepatic protection in coronary artery bypass grafting.

Protección miocárdica por condicionamiento isquémico a distancia en la revascularización coronaria / Myocardial protection by ischemic remote conditioning in coronary revascularization

Introducción: Una serie de breves períodos de isquemias a distancia, previo al evento isquémico mayor, pueden limitar el daño miocárdico producido por la isquemia/reperfusión. Objetivo: Evaluar la utilidad del condicionamiento isquémico a distancia, en pacientes programados para procedimientos quirúrgicos de revascularización coronaria. Métodos: Se realizó un estudio cuasiexperimental, explicativo, comparativo con control histórico, en dos grupos de 247 pacientes, propuestos para revascularización coronaria. Se colocó un torniquete en el brazo derecho, en el grupo estudio, alternando 3 insuflaciones con 3 desinsuflaciones con una presión de 200 mmHg, manteniéndola 5 min cada una. Este proceder se realizó previo, durante y después del evento isquémico mayor, provocado por el pinzamiento de la arteria coronaria. Resultados: Se logró una disminución significativa de los parámetros enzimáticos. No se encontraron diferencias significativas (p>0,05) según un conjunto de variables que representan el estado inicial de los pacientes(AU)

Introduction: A series of short periods of distant ischemia, prior to the major ischemic event, can limit the myocardial damage produced by ischemia or reperfusion. Objective: To evaluate the usefulness of remote ischemic conditioning in patients scheduled for surgical procedures of coronary revascularization. Methods: A quasi-experimental, explanatory, comparative study with historical control was conducted in two groups of 247 patients proposed for coronary revascularization. A tourniquet was placed in the right arm in the study group, alternating 3 insufflations with 3 dessufflations with a pressure of 200 mmHg, keeping each for 5 minutes. This procedure was performed before, during and after the major ischemic event, caused by the impingement of the coronary artery. Results: A significant decrease in enzymatic parameters was achieved. No significant differences were found (p>0.05) according to a set of variables that represent the initial state of the patients(AU)

Splenic ischemic preconditioning attenuates oxidative stress induced by hepatic ischemia-reperfusion in rats

Abstract Purpose: To evaluate the effects of splenic ischemic preconditioning (sIPC) on oxidative stress induced by hepatic ischemia-reperfusion in rats. Methods: Fifteen male Wistar rats were equally divided into 3 groups: SHAM, IRI and sIPC. Animals from IRI group were subjected to 45 minutes of partial liver ischemia (70%). In the sIPC group, splenic artery was clamped in 2 cycles of 5 min of ischemia and 5 min of reperfusion (20 min total) prior to hepatic ischemia. SHAM group underwent the same surgical procedures as in the remaining groups, but no liver ischemia or sIPC were induced. After 1h, hepatic and splenic tissue samples were harvested for TBARS, CAT, GPx and GSH-Rd measurement. Results: sIPC treatment significantly decreased both hepatic and splenic levels of TBARS when compared to IRI group (p<0.01). Furthermore, the hepatic and splenic activities of CAT, GPx and GSH- Rd were significantly higher in sIPC group than in IRI group. Conclusion: sIPC was able to attenuate hepatic and splenic IRI-induced oxidative stress.

Effect of sevoflurane pretreatment in relieving liver ischemia/reperfusion-induced pulmonary and hepatic injury

Abstract Purpose To investigate the effect of sevoflurane preconditioning on ischemia/reperfusion (I/R)-induced pulmonary/hepatic injury Methods Fifty-one Wistar rats were randomly grouped into sham, I/R, and sevoflurane groups. After reperfusion, the structural change of the lung was measured by Smith score, the wet and dry weights (W/D) were determined, malondialdehyde (MDA) myeloperoxidase (MPO) content was determined colorimetrically and by fluorescence, respectively, and matrix metalloprotein-9 (MMP-9) mRNA was quantified by RT-PCR. Biopsy and morphological analyses were performed on liver tissue, activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined, and tumor necrosis factor-alpha (TNF-α) level was determined. Results The sham group showed no changes in tissue structure. Structural lesions in the sevoflurane and I/R groups were mild and severe, respectively. Smith score, W/D, MDA, MPO, and MMP mRNA showed the same trend, and were increased in the I/R group and recovered in the sevoflurane group, compared with the sham group (both P<0.05). AST and ALT were significantly increased compared to the sham group (AST: 655±52.06 vs . 29±9.30 U/L; ALT: 693±75.56 vs . 37±6.71 U/L; P<0.05). In the sevoflurane group, AST and ALT levels were significantly decreased (464±47.71 and 516±78.84 U/L; P<0.001). TNF-α presented similar results. Conclusion The protection of lung and liver by sevoflurane may be mediated by inhibited leukocyte recruitment and MMP-9 secretion.

The role of ischemic preconditioning in the expression of apoptosis-related genes in a rat model of intestinal ischemia-reperfusion injury

Abstract Purpose: To analyze the effects of ischemic preconditioning (IPC) in the expression of apoptosis-related genes in rat small intestine subjected to ischemia and reperfusion. Methods: Thirty anesthetized rats underwent laparotomy and were drive into five groups: control (CG); ischemia (IG); ischemia and reperfusion (IRG); IPC and ischemia (IG+IPC); IPC and ischemia and reperfusion (I/RG+IPC). Intestinal ischemia was performed by clamping the superior mesenteric artery for 60 minutes, whereas reperfusion lasted for 120 minutes. IPC was carried out by one cycle of 5 minutes of ischemia followed by 10 minutes of reperfusion prior to the prolonged 60-minutes-ischemia and 120-minutes-reperfusion. Thereafter, the rats were euthanized and samples of small intestine were processed for histology and gene expression. Results: Histology of myenteric plexus showed a higher presence of neurons presenting pyknotic nuclei and condensed chromatin in the IG and IRG. IG+IPC and I/RG+IPC groups exhibited neurons with preserved volume and nuclei, along with significant up-regulation of the anti-apoptotic protein Bcl2l1 and down-regulation of pro-apoptotic genes. Moreover, Bax/Bcl2 ratio was lower in the groups subjected to IPC, indicating a protective effect of IPC against apoptosis. Conclusion: Ischemic preconditioning protect rat small intestine against ischemia/reperfusion injury, reducing morphologic lesions and apoptosis.

The role of ischemic preconditioning in gene expression related to inflammation in a rat model of intestinal ischemia-reperfusion injury

Abstract Purpose: To investigate the gene expression related to inflammation on mice subjected to intestinal ischemia and reperfusion (I/R) and treated with ischemic preconditioning (IPC). Methods: Thirty rats (EPM-Wistar), distributed in five groups of six animals each, were underwent anesthesia and laparotomy. The ischemia time was standardized in 60 minutes and the reperfusion time 120 minutes. IPC was standardized in 5 minutes of ischemia followed by 10 minutes of reperfusion accomplished before I/R. The control group was submitted only to anesthesia and laparotomy. The other groups were submitted to ischemia, I/R, ischemia + IPC and I/R + IPC. It was collected a small intestine sample to analyses by Quantitative Polymerase Chain Reaction in real Time (RT-qPCR) and histological analyses. It was studied 27 genes. Results: The groups that received IPC presented downregulation of genes, observed in of genes in IPC+ischemia group and IPC+I/R group. Data analysis by clusters showed upregulation in I/R group, however in IPC groups occurred downregulation of genes related to inflammation. Conclusion: The ischemia/reperfusion promoted upregulation of genes related to inflammation, while ischemic preconditioning promoted downregulation of these genes.

Topical hepatic hypothermia associated with ischemic preconditioning. Histopathological and biochemical analysis of ischemia reperfusion damage in a 24 hour model

Abstract Purpose: To develop a new 24 hour extended liver ischemia and reperfusion (LIR) model analyzing the late biochemical and histopathological results of the isolated and combined application of recognized hepatoprotective mechanisms. In addition, we used a new stratification with zoning to classify the histological lesion. Methods: A modified animal model of severe hepatic damage produced through 90 minutes of segmental ischemia (70% of the organ) and posterior observation for 24 hours of reperfusion, submitted to ischemic preconditioning (IPC) and topical hypothermia (TH) at 26ºC, in isolation or in combination, during the procedure. Data from intraoperative biometric parameters, besides of late biochemical markers and histopathological findings, both at 24 hours evolution time, were compared with control (C) and normothermic ischemia (NI) groups. Results: All groups were homogeneous with respect to intraoperative physiological parameters. There were no losses once the model was stablished. Animals subjected to NI and IPC had worse biochemical (gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and total bilirubin) and histopathological scores (modified Suzuki score) compared to those of control groups and groups with isolated or associated TH (p < 0.05). Conclusion: The new extended model demonstrates liver ischemia and reperfusion at 24 hour of evolution and, in this extreme scenario, only the groups subjected to topical hypothermia, combined with ischemic preconditioning or alone, had better outcomes than those subjected to only ischemic preconditioning and normothermic ischemia, reaching similar biochemical and histopathological scores to those of the control group.

Liver ischemia and reperfusion injury. Pathophysiology and new horizons in preconditioning and therapy

Abstract It is well known that during hepatic operative procedures, it is often critical that the irrigation is interrupted to avoid possible bleeding, blood transfusions, variable intensities, and their short and long-term consequences. It was believed in the past that the flow interruption should not exceed 20 minutes, which limited the use of this maneuver. However, it has been postulated that ischemia could be maintained for more than 60 minutes in healthy livers. The present paper review includes: 1) A brief introduction to justify the rationale of the review design; 2) Aspects of the pathophysiology of the three stages of the liver ischemia-reperfusion injury; 3) The innate and acquired immunity; 4) Oxidative stress; 5) Apoptosis and autophagy, Some essential biomarkers (Tumor Necrosis Factor-α, nitric oxide, metalloproteinases); and, finally; 6) Preventive ("cheating") strategies, non-pharmacological and pharmacological options to treat the liver IR injury.

Is the early or delayed remote ischemic preconditioning the more effective from a microcirculatory and histological point of view in a rat model of partial liver ischemia-reperfusion?

Abstract Purpose: To compare early- and late-effect remote ischemic preconditioning (RIPC) by analysing the microcirculatory, hemodynamic and histological changes in partial liver ischemia-reperfusion of rats. Methods: 60-minute partial liver ischemia followed by 120-minute reperfusion was performed without (Control group, n=7) or with preconditioning. In RIPC groups a tourniquet was applied around the left thigh using 3 cycles of 10-minute ischemia/10-minute reperfusion, one (RIPC-1, n=7) or twenty-four hours (RIPC-24, n=7) before I/R. Hemodynamic and microcirculatory measurements were performed before and after ischemia and in 30th, 60th and 120th minute of reperfusion and histological examination at the end of reperfusion. Results: Blood pressure decreased in all groups followed by biphasic changes in Control group. In RIPC groups R120 values returned almost to normal. Heart rate increased in Control and RIPC-1 groups at R120, while RIPC-24 did not show significant changes. Microcirculation of non-ischemic liver stayed constant in Control and showed significant changes in RIPC-24 group, while in ischemic liver elevated by R120 in all groups. RIPC didn't reduce histological alterations. Conclusion: Considering the survival and the results, both remote ischemic preconditioning protocols had beneficial effect in hepatic ischemia-reperfusion, however the histopathological findings were controversial.

Effects of remote ischemic preconditioning and topical hypothermia in renal ischemia-reperfusion injury in rats

Abstract Purpose: To evaluate whether combining hypothermia and remote ischemic preconditioning (RIPC) results in protection from ischemia-reperfusion (IR). Methods: Thirty-two Wistar rats underwent right nephrectomy and were randomly assigned to four experimental protocols on the left kidney: warm ischemia (group 1), cold ischemia (group 2), RIPC followed by warm ischemia (group 3), and RIPC followed by cold ischemia (group 4). After 240 minutes of reperfusion, histological changes in the left kidney, as well as lipid peroxidation and antioxidant enzyme activity, were analyzed. The right kidney was used as the control. Serum creatinine was collected before and after the procedures. Results: RIPC combined with hypothermia during IR experiments revealed no differences on interventional groups regarding histological changes (p=0.722). Oxidative stress showed no significant variations among the groups. Lower serum creatinine at the end of the procedure was seen in animals exposed to hypothermia (p<0.001). Conclusions: Combination of RIPC and local hypothermia provides no renal protection in IR injury. Hypothermia preserves renal function during ischemic events. Furthermore, RIPC followed by warm IR did not show benefits compared to warm IR alone or controls in our experimental protocol.