El postacondicionamiento del miocardio con remifentanil en el corazón aislado y perfundido de rata / Myocardial postconditioning with remifentanyl in the isolated perfused rat heart

Resumen: La isquemia miocárdica perioperatoria es un evento observado durante la cirugía en pacientes de alto riesgo y aumenta significativamente la morbimortalidad postoperatoria. El corazón puede tolerar los efectos de la lesión aguda por la isquemia-reperfusión (I/R) si se aplican varios ciclos cortos de I/R previos a la isquemia miocárdica sostenida. Esta estrategia cardioprotectora puede ser usada previamente (preacondicionamiento isquémico) o posteriormente (postacondicionamiento isquémico) al período de isquemia sostenida letal. El condicionamiento farmacológico consiste en el uso de fármacos para obtener efectos cardioprotectores similares al condicionamiento isquémico. Los opioides se han utilizado en el condicionamiento farmacológico, en particular el remifentanil es el más extensamente estudiado en la cardioprotección. Estudios previos demuestran que protege contra el daño por la I/R aplicándolo pre, trans y postreperfusión tanto en estudios experimentales como en la práctica clínica. En este trabajo se estudia el postacondicionamiento inducido con remifentanil en el modelo de Langendorff de corazón aislado y perfundido de rata. Este modelo permite reproducir la isquemia miocárdica en el corazón aislado de un animal anestesiado. Las variables registradas fueron: presión intraventricular izquierda (PVI), frecuencia cardíaca (FC) y actividad contráctil del corazón expresada como el trabajo cardíaco (TC = PVI × FC). La isquemia se produjo al suspender la perfusión de la solución Krebs-Henseleit durante 30 minutos, posteriormente se estableció la reperfusión durante dos horas, observándose la respuesta del corazón aislado en las diferentes condiciones. En los corazones control con I/R, el TC disminuyó un 40%. Por otro lado, el remifentanil recuperó los niveles basales de TC del control sin I/R, demostrando su efecto cardioprotector.

Abstract: Perioperative myocardial ischemia can occur during surgery in high-risk patients, which could increase postoperative morbidity and mortality. The heart can tolerate the effects of acute ischemia-reperfusion (I/R) injury if several short cycles of I/R are applied prior to sustained myocardial ischemia. This strategy is used before (ischemic preconditioning) or after (ischemic postconditioning) sustained lethal ischemia. In pharmacological conditioning, drugs are used to obtain cardioprotective effects like ischemic preconditioning. Opioids have been used in pharmacological conditioning. Remifentanyl is the most extensively studied opioid in cardioprotection. Previous studies show that remifentanyl protects against I/R damage by applying it pre, trans and post-reperfusion in experimental studies and in clinical practice. In this work we studied the postconditioning induced with remifentanyl in the Langendorff model of isolated and perfused rat heart. This model reproduces myocardial ischemia in the heart isolated from an anesthetized animal. The variables recorded were left intraventricular pressure (LVP), heart rate (HR), and heart contractile activity expressed as cardiac work (TC = LVP × HR). Ischemia occurred when the perfusion was stopped for 30 minutes. Later, reperfusion was restored for two hours, observing the response of the isolated heart under the different conditions. In control hearts with I/R, the TC decreased by 40%. On the other hand, remifentanyl recovered the basal levels of TC control without I/R. Further studies are needed to evaluate the effectiveness of remifentanyl postconditioning in daily clinical practice.

Pre- and Post-Conditioning of the Heart: An Overview of Cardioprotective Signaling Pathways.

Since the discovery of ischemic pre- and post-conditioning, more than 30 years ago, the knowledge about the mechanisms and signaling pathways involved in these processes has significantly increased. In clinical practice, on the other hand, such advancement has yet to be seen. This article provides an overview of ischemic pre-, post-, remote, and pharmacological conditioning related to the heart. In addition, we reviewed the cardioprotective signaling pathways and therapeutic agents involved in the above-mentioned processes, aiming to provide a comprehensive evaluation of the advancements in the field. The advancements made over the last decades cannot be ignored and with the exponential growth in techniques and applications. The future of pre- and post-conditioning is promising.

Sulforaphane protects from myocardial ischemia-reperfusion damage through the balanced activation of Nrf2/AhR.

The activation of the transcription factor Nrf2 and the consequent increment in the antioxidant response might be a powerful strategy to contend against reperfusion damage. In this study we compared the effectiveness between sulforaphane (SFN), a well known activator of Nrf2 and the mechanical maneuver of post-conditioning (PostC) to confer cardioprotection in an in vivo cardiac ischemia-reperfusion model. We also evaluated if additional mechanisms, besides Nrf2 activation contribute to cardioprotection. Our results showed that SFN exerts an enhanced protective response as compared to PostC. Bot, strategies preserved cardiac function, decreased infarct size, oxidative stress and inflammation, through common protective pathways; however, the aryl hydrocarbon receptor (AhR) also participated in the protection conferred by SFN. Our data suggest that SFN-mediated cardioprotection involves transient Nrf2 activation, followed by phase I enzymes upregulation at the end of reperfusion, as a long-term protection mechanism.

Remote post-conditioning and allopurinol reduce ischemia-reperfusion injury in an infra-renal ischemia model.

BACKGROUND:: The aim of this study was to evaluate the effects of the antioxidant allopurinol and ischemic post-conditioning on the deleterious effects of ischemia followed by reperfusion (I/R) in a standardized model of ischemia involving infra-renal aortic occlusion in rats. METHODS:: The animals were randomly divided into five groups: (A) animals not subjected to ischemia; (B) animals subjected to 2 h of ischemia and reperfusion only once; (C) animals given an allopurinol dose by gavage, then subjected to 2 h of ischemia and reperfusion only once; (D) animals subjected to 2 h of ischemia and post-conditioning and (E) animals that received allopurinol, then subjected to 2 h of ischemia and post-conditioning. The blood samples and small intestine segments were harvested for analysis after 3 days. RESULTS:: The protective effects of the use of allopurinol and ischemic post-conditioning were observed by measuring aspartate aminotransferase, alanine aminotransferase and lactate levels. The benefits of post-conditioning were evident from the total antioxidant capacity and creatinine levels, but these could not ascertain any positive effects of allopurinol. The histological analysis of mesentery revealed that both methods were effective in minimizing the harmful effects of the ischemia and reperfusion process. CONCLUSION:: Individual protocols significantly reduced I/R systemic injuries, but no additional protection was observed when the two strategies were combined.

Survival kinase-dependent pathways contribute to gender difference in the response to myocardial ischemia-reperfusion and ischemic post-conditioning.

The response to ischemia/reperfusion and the effects of ischemic post-conditioning (IPC) are sex-dependent, but the mechanisms have not been clarified. Male (M) and female (F) rat hearts isolated and perfused using the Langendorff technique were subject to 30 min of global ischemia (GI) and 60 min reperfusion (R). In IPC hearts, three cycles of 30-sec GI/30-sec R were applied at the beginning of R. Infarct size and myocardial function were assessed. Superoxide production, antioxidant systems, and expressions of phosphorylated forms of serine/threonine kinase (Akt), glycogen synthase kinase 3ß (GSK-3ß), protein kinase C ε (PKCε), endothelial nitric oxide synthase (eNOS), and apoptosis were measured. In the basal state, superoxide production and apoptosis were lower, and antioxidant systems and phospho-kinase expressions were higher in F rather than in M hearts. After ischemia-reperfusion, infarct size was less in F hearts, and post-ischemic recovery of myocardial function was higher in F rather than in M hearts. Superoxide production, phospho-kinase activity, phospho-eNOS, and apoptosis increased in both sexes while antioxidants decreased in both sexes. After IPC, infarct size, superoxide production, and apoptosis decreased and phospho-eNOS increased in F and M hearts but phospho-kinase expressions and post-ischemic recovery of myocardial function improved only in M hearts. These results show that Akt/GSK-3ß/PKCε/eNOS-dependent pathways-mediated superoxide production and apoptosis appear as important factors involved in the observed gender differences.

Myocardial ischemic post-conditioning protects the lung against myocardial ischemia/reperfusion-induced damage by activating GSK-3

Purpose: To investigate whether modulating GSK-3 could attenuate myocardial ischemia reperfusion injury (MIRI) induced acute lung injury (ALI) and analyze the underlying mechanism. Methods: Male SD rats were subjected to MIRI with or without myocardial ischemic post-conditioning in the presence or absence of GSK-3 inhibitor. GSK-3 inhibitor was injected peritoneally 10min before MIRI. Lung W/D weight ratio, MPO, PMNs, histopathological changes, TUNEL, Bax, Bcl-2, IL-6, IL-8, IL-10, GSK-3, and caspase-3 were evaluated in the lung tissues of all rats. Results: After MIRI, lung injury was significantly increased manifested as significant morphological changes and increased leukocytes in the interstitial capillaries, Lung W/D ratio, MPO, and PMN in BALF, which was associated with enhanced inflammation evidenced by increased expressions of IL-6, IL-8 and reduced expression of IL-10. MIRI significantly increased cell apoptosis in the lung as increased levels of apoptotosis, Bax, cleaved caspase-3, and reduced expression of Bcl-2 was observed, which was concomitant with reduced p-GSK-3. All these changes were reversed/prevented by ischemic post-conditioning, while these beneficial effects of ischemic post-conditioning were abolished by GSK-3 inhibition. Conclusion: Myocardial ischemia reperfusion injury induces acute lung injury by induction of inflammation and cell apoptosis. Ischemic post-conditioning protects the lung from ALI following MIRI by increasing p-GSK-3.(AU)

Myocardial ischemic post-conditioning protects the lung against myocardial ischemia/reperfusion-induced damage by activating GSK-3

Abstract Purpose: To investigate whether modulating GSK-3β could attenuate myocardial ischemia reperfusion injury (MIRI) induced acute lung injury (ALI) and analyze the underlying mechanism. Methods: Male SD rats were subjected to MIRI with or without myocardial ischemic post-conditioning in the presence or absence of GSK-3β inhibitor. GSK-3β inhibitor was injected peritoneally 10min before MIRI. Lung W/D weight ratio, MPO, PMNs, histopathological changes, TUNEL, Bax, Bcl-2, IL-6, IL-8, IL-10, GSK-3β, and caspase-3 were evaluated in the lung tissues of all rats. Results: After MIRI, lung injury was significantly increased manifested as significant morphological changes and increased leukocytes in the interstitial capillaries, Lung W/D ratio, MPO, and PMN in BALF, which was associated with enhanced inflammation evidenced by increased expressions of IL-6, IL-8 and reduced expression of IL-10. MIRI significantly increased cell apoptosis in the lung as increased levels of apoptotosis, Bax, cleaved caspase-3, and reduced expression of Bcl-2 was observed, which was concomitant with reduced p-GSK-3β. All these changes were reversed/prevented by ischemic post-conditioning, while these beneficial effects of ischemic post-conditioning were abolished by GSK-3β inhibition. Conclusion: Myocardial ischemia reperfusion injury induces acute lung injury by induction of inflammation and cell apoptosis. Ischemic post-conditioning protects the lung from ALI following MIRI by increasing p-GSK-3β.

Different protocols of postconditioning does not attenuate mesenteric ischemia-reperfusion injury after short-term reperfusion / Diferentes protocolos de pós-condicionamento não atenua a lesão de isquemia e reperfusão mesentérica após curto período de reperfusão

ABSTRACT Background: Mesenteric ischemia is a challenging diagnosis. Delay in diagnosis can lead to extent bowel necrosis and poor outcomes. Ischemia and reperfusion syndrome plays an important role in this scenario. Aim: To access effects of different post-conditioning cycles on mesenteric ischemia-reperfusion syndrome. Method: Twenty-five rats were assigned into five groups: Sham, used to establish normal parameters; control group, submitted to mesenteric ischemia for 30 min; in groups GP3, GP1 and GP30, ischemia was followed by post-conditioning protocol, which consisted of 1 cycle of 3 min (GP3), 3 cycles of 1 min (GP1) or 6 cycles of 30 s (GP30), respectively. Ileum samples were harvested after one hour of reperfusion. Intestinal mucosal injury was evaluated through histopathological analysis. Results: The average of mesenteric injury degree was 0 in the sham group, 3.6 in the control group, 3.4 in GP3, 3.2 in GP1, and 3.0 in GP30; villous length average was 161.59 in sham group, 136.27 in control group, 135.89 in GP3, 129.46 in GP1, and 135.18 in GP30. Was found significant difference between sham and other groups (p<0.05); however, there was no difference among post-conditioning groups. Conclusion: Post-conditioning adopted protocols were not able to protect intestinal mucosa integrity after mesenteric ischemia and short term reperfusion.

RESUMO Racional: O desfecho satisfatório na abordagem cirúrgica da obesidade deve contemplar, além da perda de peso, alteração significativa nas comorbidades preexistentes e na qualidade de vida dos pacientes. Objetivo: Avaliar a qualidade de vida no pós-operatório tardio de pacientes submetidos à cirurgia de gastrectomia vertical por videolaparoscopia. Métodos: Foi aplicado o questionário "Bariatric Analysis and Reporting Outcome System" (BAROS) em pacientes submetidos à gastrectomia vertical por videolaparoscopia. Resultados: Foram avaliados 47 pacientes, entre 21 e 60 anos de idade. O IMC médio antes da operação era 43,06±5,87 kg/m². A média percentual de redução do excesso de peso após foi de 85,46±23,6%. A pontuação obtida pelos pacientes no questionário sobre a melhora na qualidade de vida evidenciou resultado excelente (36,17%), ótimo (40,43%), bom (21,28%) e razoável (2,13%). Houve melhora clínica após a operação em todas as comorbidades investigadas. Conclusão: A perda de peso foi fundamental para a melhoria na qualidade de vida e proporcionou resolução ou a melhora clínica em todas as comorbidades investigadas.

Ischemic post-conditioning attenuates the intestinal injury induced by limb ischemia/reperfusion in rats

The purpose of this study was to investigate the protective effects of ischemic post-conditioning on damage to the barrier function of the small intestine caused by limb ischemia-reperfusion injury. Male Wistar rats were randomly divided into 3 groups (N = 36 each): sham operated (group S), lower limb ischemia-reperfusion (group LIR), and post-conditioning (group PC). Each group was divided into subgroups (N = 6) according to reperfusion time: immediate (0 h; T1), 1 h (T2), 3 h (T3), 6 h (T4), 12 h (T5), and 24 h (T6). In the PC group, 3 cycles of reperfusion followed by ischemia (each lasting 30 s) were applied immediately. At all reperfusion times (T1-T6), diamine oxidase (DAO), superoxide dismutase (SOD), and myeloperoxidase (MPO) activity, malondialdehyde (MDA) intestinal tissue concentrations, plasma endotoxin concentrations, and serum DAO, tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) concentrations were measured in sacrificed rats. Chiu’s pathology scores for small intestinal mucosa were determined under a light microscope and showed that damage to the small intestinal mucosa was lower in group PC than in group LIR. In group PC, tissue DAO and SOD concentrations at T2 to T6, and IL-10 concentrations at T2 to T5 were higher than in group LIR (P < 0.05); however, tissue MPO and MDA concentrations, and serum DAO and plasma endotoxin concentrations at T2 to T6, as well as TNF-α at T2 and T4 decreased significantly (P < 0.05). These results show that ischemic post-conditioning attenuated the permeability of the small intestines after limb ischemia-reperfusion injury. The protective mechanism of ischemic post-conditioning may be related to inhibition of oxygen free radicals and inflammatory cytokines that cause organ damage.