Effect Of Postconditioning Research Articles

Featured Article: Pharmacological postconditioning with delta opioid attenuates myocardial reperfusion injury in isolated porcine hearts.

Ischemic preconditioning has been utilized to protect the heart from ischemia prior to ischemia onset, whereas postconditioning is employed to minimize the consequences of ischemia at the onset of reperfusion. The underlying mechanisms and pathways of ischemic pre- and postconditioning continue to be investigated as therapeutic targets. We evaluated the administration of a delta opioid agonist or cariporide on various parameters associated with myocardial reperfusion injury upon reperfusion of isolated porcine hearts. The hearts were reperfused invitro with a Krebs buffer containing either: (1) 1 µM Deltorphin D (delta opioid specific agonist, n = 6); (2) 3 µM cariporide (sodium-hydrogen exchange inhibitor, n = 4); or (3) no treatment (control, n = 6). Subsequently, postischemic hemodynamic performance, arrhythmia burden, relative tissue perfusion, and development of necrosis were assessed over a 2 h reperfusion period. Postconditioning with Deltorphin D significantly improved diastolic relaxation (Tau, P < 0.05 versus controls) and decreased the incidence of ventricular arrhythmias during early reperfusion. Additionally, these treated hearts demonstrated increased tissue perfusion after 2 h ( P < 0.05 versus controls), suggesting improved microvascular function. Delta opioid agonists elicited the potential to attenuate reperfusion injury, suggesting a postconditioning effect of these agents. We hypothesize that the induced benefits of delta opioids, in part, are associated with decreased calcium influx on reperfusion, independent of sodium-hydrogen exchange inhibition. Such agents may have a potential role in minimizing reperfusion injury associated with coronary stenting, bypass surgery, myocardial infarction, cardiac transplantation, or with the utilization of heart preservation systems. Impact statement In this study, we found that postconditioning with Deltorphin D significantly improved diastolic relaxation and decreased the incidence of ventricular arrhythmias during early reperfusion. Furthermore, these treated hearts demonstrated increased tissue perfusion after 2 h, suggesting improved microvascular function. Delta opioid agonists attenuated reperfusion injury, suggestive of a postconditioning effect. Such agents may have a potential role in minimizing reperfusion injury associated with coronary stenting, bypass surgery, myocardial infarction, cardiac transplantation, or with the utilization of heart preservation systems.

Trigger and Signal Mechanisms and the End Effector of the Cardioprotective Effect of Remote Postconditioning of the Heart

High molecular weight peptide(s) operate as the trigger for remote postconditioning (RPC) of the heart. Nitric oxide and adenosine function as mediators between peptide and intracellular structures. The autonomic nervous system does not have a role in RPC. The signal mechanism of RPC involves protein kinase C, PI3 kinase, Akt kinase, and aldehyde dehydrogenase. The hypothetical end effector of RPC is the BKCa channel

Troxerutin Preconditioning and Ischemic Postconditioning Modulate Inflammatory Response after Myocardial Ischemia/Reperfusion Injury in Rat Model.

Protective effects of ischemic postconditioning in myocardial ischemia/reperfusion (I/R) injury have been ever demonstrated, but the exact mechanisms remain unclear. Because of their multiplex activities, using natural pharmaceuticals seems to be clinically interesting. The aim of present study was to investigate the effects of troxerutin preconditioning and ischemic postconditioning on inflammatory responses after myocardial I/R injury in a rat model. Twenty-four Wistar rats were divided into four groups as the control, troxerutin receiving (TXR), postconditioning receiving (PostC), and combined therapy (TXR + PostC). Rats' isolated hearts underwent 30-min LAD regional ischemia followed by 45-min reperfusion. Troxerutin was orally administered for a month before I/R. Ischemic PostC was applied by alternative three cycles of 30-s R/I at the onset of reperfusion. The coronary effluent and ischemic left ventricular samples were used to determine the activities of creatine kinase (CK), intercellular adhesion molecule-1 (ICAM-1), interlukin-1beta (IL-1β), tumor-necrosis factor (TNF-α), and also histopathological studies. Pretreatment of rats with troxerutin significantly reduced myocardial inflammatory cytokines TNF-α and IL-1β levels and ICAM-1 activity after I/R insult compared to those of control I/R hearts (P < 0.05). Application of PostC showed similar impacts on those parameters. In fact, anti-inflammatory mechanisms of both treatments were associated with their protective effects against myocardial damages causing from I/R injury. Pretreatment with troxerutin as well as postconditioning can induce cardioprotection through prevention of the cell-cell interaction and release of inflammatory mediators, minimizing I/R pathological changes in myocardial cells. These two treatments may share same mechanisms in their actions since they showed no significant additive effects.

Cardioprotrective effect of remote postconditioning: Mechanisms and possibilities of clinical application

Experimental data indicate that postconditioning at a distance is an effective method for cardiac protection against reperfusion injury. Remote postconditioning prevents reperfusion necrosis and apoptosis of cardiomyocytes, decreases a probability of postinfarction remodeling of the heart. Cardioprotective effect of remote postconditioning depends on the release of tissue factor(s) increasing cardiac tolerance to long-term ischemia-reperfusion after transient ischemia. Clinical investigations show that postconditioning at a distance is an effective method for the prevention of reperfusion injury of the heart during coronary artery bypass surgery.

Kidney ischemia and reperfunsion syndrome: effect of lidocaine and local postconditioning.

to evaluate the effects of blocking the regulation of vascular tone on the ischemia and reperfusion syndrome in rats through the use of lidocaine in the postconditioning technique. we randomized 35 rats into seven groups of five animals: Group 1- Control; Group 2- Ischemia and Reperfusion; Group 3- Ischemia, Reperfusion and Saline; Group 4- Ischemic Postconditioning; Group 5- Ischemic Postconditioning and Saline; Group 6- Lidocaine; Group 7- Ischemic Postconditioning and Lidocaine. Except for the control group, all the others were submitted to renal ischemia for 30 minutes. In postconditioning groups, we performed ischemia and reperfusion cycles of five minutes each, applied right after the main ischemia. In saline and lidocaine groups, we instilled the substances at a rate of two drops per minute. To compare the groups, we measured serum levels of urea and creatinine and also held renal histopathology. The postconditioning and postconditioning + lidocaine groups showed a decrease in urea and creatinine values. The lidocaine group showed only a reduction in creatinine values. In histopathology, only the groups submitted to ischemic postconditioning had decreased degree of tubular necrosis. Lidocaine did not block the effects of postconditioning on renal ischemia reperfusion syndrome, and conferred better glomerular protection when applied in conjunction with ischemic postconditioning. avaliar os efeitos do bloqueio da regulação do tônus vascular por meio do uso da lidocaína na técnica de pós-condicionamento isquêmico na síndrome de isquemia e reperfusão renal em ratos. trinta e cinco ratos foram randomizados em sete grupos de cinco animais: Grupo 1- Controle; Grupo 2- Isquemia e Reperfusão; Grupo 3- Isquemia, Reperfusão e Solução Salina; Grupo 4- Pós-condicionamento Isquêmico; Grupo 5- Pós-condicionamento Isquêmico e Solução Salina; Grupo 6- Lidocaína; Grupo 7- Pós-condicionamento Isquêmico e lidocaína. Com exceção do grupo controle, todos os demais foram submetidos à isquemia renal de 30 minutos. Nos grupos de pós-condicionamento, foi realizado o ciclo de isquemia e reperfusão de cinco minutos cada, aplicado logo após a isquemia principal. Nos grupos salina e lidocaína foram instiladas as substâncias numa taxa de duas gotas por minuto. Para comparar os grupos, foram dosados os níveis séricos de ureia e creatinina e análise histopatológica renal. os grupos pós-condicionamento e pós-condicionamento + lidocaína apresentaram uma redução nos valores de ureia e creatinina. O grupo lidocaína apresentou apenas uma redução nos valores de creatinina. Na análise histopatológica, apenas os grupos submetidos ao pós-condicionamento isquêmico apresentaram redução do grau de necrose tubular. a lidocaína não bloqueou os efeitos do pós-condicionamento na síndrome de isquemia e reperfusão renal, mas conferiu melhor na proteção glomerular quando aplicada em conjunto com o pós-condicionamento isquêmico.

Exposure to cigarette smoke abrogates the beneficial effect of ischemic postconditioning.

Cigarette smoking is one of the risk factors for coronary artery disease. Although conditioning decreases infarct size in hearts from healthy animals, comorbidities may render it ineffective. We investigated the effects of cigarette smoke (CS) exposure on intracellular myocardial signaling, infarct size after ischemia-reperfusion, and the potential interference with ischemic conditioning. Exposure of mice to CS increased blood pressure, caused cardiac hypertrophy, and upregulated the nitric oxide synthatse (NOS)/soluble guanylate cyclase (sGC)/cGMP pathway. To test the effect of CS exposure on the endogenous cardioprotective mechanisms, mice were subjected to regional myocardial ischemia and reperfusion with no further intervention or application of preconditioning (PreC) or postconditioning (PostC). Exposure to CS did not increase the infarction compared with the room air (RA)-exposed group. PreC was beneficial for both CS and RA vs. nonconditioned animals. PostC was effective only in RA animals, while the infarct size-limiting effect was not preserved in the CS group. Differences in oxidative stress markers, Akt, and endothelial NOS phosphorylation and cGMP levels were observed between RA and CS groups subjected to PostC. In conclusion, exposure to CS does not per se increase infarct size. The beneficial effect of ischemic PreC is preserved in mice exposed to CS, as it does not affect the cardioprotective signaling; in contrast, PostC fails to protect CS-exposed mice due to impaired activation of the Akt/eNOS/cGMP axis that occurs in parallel to enhanced oxidative stress.

Adenosine triphosphate postconditioning is associated with better preserved global and regional cardiac function during myocardial ischemia and reperfusion: a speckle tracking imaging-based echocardiologic study.

Effects of ischemic postconditioning (IPostC) and adenosine triphosphate (ATP)-mediated pharmacologic postconditioning (ATP-PPostC) on cardiac function were evaluated by speckle tracking imaging (STI)-based echocardiography. A myocardial I/R model was induced in rabbits by reversible ligation of the left ventricular branch of coronary artery. Rabbits were randomized into three groups: ischemia and reperfusion (IR) (no further intervention), IPostC, and ATP-PPostC groups. Cardiac function was evaluated by conventional and STI-based echocardiography. Myocardial necrosis, apoptosis, and myocardial mRNAs of apoptosis-related proteins (Bcl-2 and Bax) were evaluated. Speckle tracking imaging (STI)-based echocardiography revealed that IPostC and ATP-PPostC were associated with better preserved global and regional cardiac function, as indicated by significantly increased GLSrsys, GLSrd, GLSsys, SrLsys, SrLd, and SLsys in both groups (all P<.5). Subsequent pathologic studies indicate that the percentage of necrotic myocardium and permillage of apoptotic cells were significantly lower in the IPostC and ATP-PPostC groups than in the IR group (all P<.05). Moreover, both IPostC and ATP-PPostC were associated with increased Bcl-2 mRNA levels and reduced Bax mRNA levels. IPostC and ATP-PPostC may exert cardioprotective functions by better preservation of cardiac function during the I/R process and at least partly via attenuation of myocardial apoptosis.

Neuroprotective and nephroprotective effects of remote postconditioning: Prospects for clinical use

The results of experimental and clinical studies strongly suggest that remote ischemic preconditioning (RIP) has no neuroprotective effect during cardiac surgery performed under extracorporeal circulation. Remote preconditioning (RP) has no neuroprotective effect in hemorrhagic stroke. A randomized multicenter study is needed to evaluate the efficiency RIP in patients with ischemic stroke. RP reduces the severity of ischemia/reperfusion kidney injury during transplantation. RIP has been established to prevent contrast-induced nephropathy. There is a need for a multicenter trial to evaluate the efficiency of RIP in patients with abdominal aortic aneurysm repair. Analysis of the presented data indicates that RIP fails to prevent cardiorenal syndrome in infants and children during cardiac surgery. The data available in the literature on the capacity of RIP to provide nephroprotective effect in patients after coronary artery bypass surgery are discordant and indicative of the advisability of a multicenter study.

Protective effect and mechanism of ischemic postconditioning in rats underwent myocardial ischemia/ reperfusion injury

This study is designed to observe the effect of ischemic postconditioning in rats underwent acute myocardial ischemia/reperfusion injury and to investigate the related mechanism. A total of 30 SD rats were randomly divided into sham operation group (control group, n=10), ischemia/reperfusion group (IR group, n=10) and ischemic postconditioning group (PC group, n=10) based on random number table. Rats in IR group underwent 30 minutes myocardial ischemia by occlusion of the proximal portion of left anterior descending (LAD) coronary artery followed by 2 hours reperfusion. In control group, there was no IR intervention. In PC group, at the start of reperfusion, three cycles of 30 seconds reperfusion and 30 seconds LAD reocclusion preceded the 2 hours of reperfusion. The hemodynamic values were measured via a cannula inserted into the right common carotid artery.The area at risk was assessed by Evans blue staining and the infarct size as measured by TTC staining.Western blot and Real time PCR were respectively used to assess the expression of predicted target gene Bim and microRNA-214(miR-214) in the area at risk at the end of 2 hours reperfusion. (1) The hemodynamic monitoring in different groups: the left ventricular systolic pressure (LVSP), ±dp/dtmax, and heart rate of IR group and PC group were lower than those of control group, but left ventricular end-diastolic pressure (LVEDP) was higher than that of control group (all P<0.05). The LVSP and ±dp/dtmax of PC group were higher than those of IR group, and LVEDP was lower than that of IR group (all P<0.05). (2) Myocardial ischemia area and infarction range in different groups: there was no statistically difference in the proportion of area at risk (AAR) in left ventricle (LV) (AAR/LV) between PC group and IP group ((27.00 + 7.55) % vs. (26.67 + 11.68) %, P>0.05). The proportion of infarct size in the area at risk(IS/AAR) of PC group was lower than that of IR group((30.67±3.51)% vs. (48.67±4.62)%, P<0.05). (3) The expression of Bim protein in rats ischemic myocardial tissue in different groups: the expression of Bim protein in ischemic myocardial tissue of IR group was higher than that of control group (2.34±0.15 vs. 0.75±0.05, P<0.05), and that of PC group was lower than IR group (1.25±0.14 vs. 2.34±0.15, P<0.05). (4) The expression of of miR-214 in rats ischemic myocardial tissue in different groups: the expression of miR-214 of IR group was lower than that of control group(0.20±0.04 vs. 1.00, P<0.01), and that of PC group was higer than that of IR group (0.85±0.20 vs. 0.20±0.04, P<0.01). There was no statistically difference between PC group and control group (P>0.05). Postconditioning could significantly decrease the ischemia/reperfusion injury by reducing the infarct size and improve cardiac function in this in vivo rat model. The expression of Bim in postconditioning group is significantly depressed, which may play an important role in the protection process of postconditioning, and the downregulation of Bim might be mediated with the increase of miR-214 expression.

The Design and Rationale of a Clinical Trial Evaluating Limb Postconditioning in Young Patients with Intracranial Arterial Stenosis

To examine the effectiveness of bilateral arm remote ischemic postconditioning (RIPC) on the rehabilitation of nerve function and collateral circulation in patients with symptomatic intracranial atherosclerotic stenosis (sICAS). Open, controlled, prospective trial (EPIC-sICAS trial) in Xi'an, Shaanxi, China. Up to 100 sICAS patients (age: 18-45 years, gender balance) who fulfill the inclusion and exclusion criteria will be enrolled and randomized to intervention group and control group (n ~ 50/group). The intervention group will undergo ischemia and reperfusion on both arms twice a day for 6 months. Mean changes in collateral circulation from baseline to the end of the 6-month RIPC treatment period, measured by dynamic contrast-enhanced magnetic resonance imaging, will be the primary outcome. Clinical symptoms, serum levels of vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) will be compared as secondary outcome. A safety evaluation and preliminary experiment of the EPIC-sICAS trial were completed in November 2014 and March 2015, respectively. Overall and regional brain hemodynamics remained stable throughout RIPC. Activities of daily living score and serum VEGF and bFGF levels were significantly higher (P < .05) in the intervention group. Repetitive bilateral arm RIPC appears to have protective effects in the brain related to angiogenesis promotion and neuroprotection in the acute phase of sICAS. Assessment of the role of RIPC in collateral circulation requires imaging tests and longer follow-up, as planned in the EPIC-sICAS trial.

Involvement of Protein Kinase C-δ in the Realization of Cardioprotective Effect of Ischemic Postconditioning.

Experiments on isolated perfused rat heart modeled 45-min global ischemia followed by 30-min reperfusion. Ischemic postconditioning was modeled by 3 cycles of reperfusion (30 sec) and ischemia (30 sec). Cardiomyocyte necrosis was assessed by the level of creatine phosphokinase in the perfusate. Postconditioning reduced the release of creatine phosphokinase from the heart by 30%. The cardioprotective effect of ischemic postconditioning was eliminated after inhibition of protein kinase C with cheleritrin or after blockade of δ-isoform of protein kinase C with rottlerin. These findings attest to participation of protein kinase C-δ in the realization of the cardioprotective effect of postconditioning.

Discrepancy in calcium release from the sarcoplasmic reticulum and intracellular acidic stores for the protection of the heart against ischemia/reperfusion injury

We and others have demonstrated a protective effect of pacing postconditioning (PPC) against ischemia/reperfusion (I/R) injury. However, the mechanisms underlying this protection are not completely clear. In the present study, we evaluated the effects of calcium release from the sarcoplasmic reticulum (SR) and the novel intracellular acidic stores (AS). Isolated rat hearts (n = 6 per group) were subjected to coronary occlusion followed by reperfusion using a modified Langendorff system. Cardiac hemodynamics and contractility were assessed using a data acquisition program, and cardiac injury was evaluated by creatine kinase (CK) and lactate dehydrogenase (LDH) levels. Hearts were subjected to 30min of regional ischemia, produced by ligation of the left anterior descending (LAD) coronary artery, followed by 30min of reperfusion. The hearts were also subjected to PPC (3cycles of 30s of left ventricle (LV) pacing alternated with 30s of right atrium (RA) pacing) and/or were treated during reperfusion with agonists or antagonists of release of calcium from SR or AS. PPC significantly (P < 0.05) normalized LV, contractility, and coronary vascular dynamics and significantly (P < 0.001) decreased heart enzyme levels compared to the control treatments. The blockade of SR calcium release resulted in a significant (P < 0.01) recovery in LV function and contractility and a significant reduction in CK and LDH levels (P < 0.01) when applied alone or in combination with PPC. Interestingly, the release of calcium from AS alone or in combination with PPC significantly improved LV function and contractility (P < 0.05) and significantly decreased the CK and LDH levels (P < 0.01) compared to the control treatments. An additive effect was produced when agonism of calcium release from AS or blockade of calcium release from the SR was combined with PPC. Calcium release from AS and blockade of calcium release from the SR protect the heart against I/R. Combining calcium release from acidic stores or blockade of calcium release from the SR with PPC produced a synergistic protective effect.

PS155 Effects of Ischemic Postconditioning on Sizes of Myocardial Infarction Induced by Ischemia/Reperfusion and Toll-R4 Expression in Rats

A significant proportion of patients with knee osteoarthritis have articular degeneration that is limited to the medial and patellofemoral compartments. The objective of this study was to compare clinical outcomes of unlinked bicompartmental knee arthroplasty (BCA) and total knee arthroplasty (TKA) at 5 years in this subset of patients.48 patients were randomised into two groups: unlinked, modular bicompartmental arthroplasty and total knee arthroplasty. Data on demographics and clinical outcomes were collected (Bartlett Knee Score, Oxford Knee Score, Knee Society Score). Data on intra-operative blood loss in both groups were also recorded.Out of the 48 patients, 26 underwent BCA and 22 had TKA. Both groups shared similar demographic profiles. At five years post surgery, there was significant improvement across all functional scores in both groups. However, there was no significant difference in outcome scores in the BCA group compared to the TKA group. The drop in serum haemoglobin levels postoperatively was 1.55 and 2.30 g/dl for the BCA and TKA groups respectively (p < .001). The total amount of blood loss was 397 and 647 ml respectively (p = .001).Unlinked, modular BCA results in similar clinical and functional scores as TKA for medial and patellofemoral arthritis in the mid-term. Intra-operative blood loss was significantly lower in the BCA group compared to the TKA group. BCA is a viable option for a select group of young and active patients with the advantage of reduced intra-operative blood loss and equivalent functional outcomes as TKA.

Pre- and postconditioning effects of metformin in rat donor livers

Background: Pre- or reconditioning of donor livers can improve organ quality prior to transplantation. The aim of this study was to investigate whether metformin as pre- or reconditioning agent is able to reduce preservation injury in rat donor livers and improve hepatobiliary function during ex situ normothermic machine perfusion (NMP). Methods: To study the preconditioning effects of metformin, metformin was administered via oral gavage 12 and 2 hours before the hepatectomy. To assess the reconditioning effects of metformin, in 2 other groups, metformin was added to the NMP perfusion fluid in two different concentrations (30 and 300 mg/L). In the reference group, no pre- or reconditioning was carried out. In all groups, rat donor livers were preserved for 4 hours in preservation fluid on melting ice. Thereafter, NMP was performed for viability assessment. Results: Preconditioning improved ATP production and hepatobiliary function (assessed by total bile production, biliary bilirubin and bicarbonate) and significantly lowered levels of lactate and glucose during NMP. On the other hand, metformin preconditioning did not reduce markers for hepatobiliary injury such as AST, ALT, LDH, caspase-3 activity, TBARS or biliary gamma-GT and LDH. Reconditioning with metformin did not improve hepatobiliary function or reduce injury markers during NMP. Conclusion: Preconditioning of rat donor livers with metformin improves hepatobiliary function but does not reduce preservation injury as assessed during 3 hours of NMP. Reconditioning with metformin showed no beneficial effects.

Postconditioning the Heart: Analysis of Experimental and Clinical Data

Experimental atherosclerosis and hypercholesterolemia may reduce or eliminate the infarct-limiting and anti-apoptotic effect of postconditioning (PC). Experiments in rats and mice indicate that the PC may be quite effective in patients with diabetes type 2 or metabolic syndrome. Experimental data suggest that hypertension or the past myocardial infarction is not an obstacle for the implementation of cardioprotective effect of PC. It was established that that aging does not preclude the implementation of PC cardioprotective effect. Inotropic effect of IP can simulate on isolated human atrial trabeculae. The clinical observations suggest that the PC in patients with tetralogy of Fallot and patients with operations on the valves improves the outcome of cardiac surgery. It was established that PC in these patients reduces the intensity of reperfusion necrosis of cardiomyocytes, improves the pumping function of the heart, reduces the inotropic support, shorten the extubation time.

CTGF/CCN2 Postconditioning Increases Tolerance of Murine Hearts towards Ischemia-Reperfusion Injury.

Background and PurposePrevious studies of ischemia-reperfusion injury (IRI) in hearts from mice with cardiac-restricted overexpression of CCN2 have shown that CCN2 increases tolerance towards IRI. The objectives of this study were to investigate to what extent post-ischemic administration of recombinant human CCN2 (rhCCN2) would limit infarct size and improve functional recovery and what signaling pathways are involved.Experimental ApproachIsolated mice hearts were perfused ad modum Langendorff, subjected to no-flow, global ischemia, and subsequently, exposed to mammalian cell derived, full-length (38-40kDa) rhCCN2 (250 nM) or vehicle during the first 15 min of a 60 min reperfusion period.Key ResultsPost-ischemic administration of rhCCN2 resulted in attenuation of infarct size from 58 ± 4% to 34 ± 2% (p < 0.001) which was abrogated by concomitant administration of the PI3 kinase inhibitor LY294002 (45 ± 3% vs. 50 ± 3%, ns). In congruence with reduction of infarct size rhCCN2 also improved recovery of left ventricular developed pressure (p < 0.05). Western blot analyses of extracts of ex vivo-perfused murine hearts also revealed that rhCCN2 evoked concentration-dependent increase of cardiac phospho-GSK3β (serine-9) contents.Conclusions and ImplicationsWe demonstrate that post-ischemic administration of rhCCN2 increases the tolerance of ex vivo-perfused murine hearts to IRI. Mechanistically, this postconditioning effect of rhCCN2 appeared to be mediated by activation of the reperfusion injury salvage kinase pathway as demonstrated by sensitivity to PI3 kinase inhibition and increased CCN2-induced phosphorylation of GSK3β (Ser-9). Thus, the rationale for testing rhCCN2-mediated post-ischemic conditioning of the heart in more complex models is established.

Anti-inflammatory and metabolic effects of remote ischemic preconditioning and postconditioning on the contractile performance of the diaphragm in endotoxemic rats

Background Respiratory failure is a major cause of mortality during septic shock and is due in part to the decreased ventilatory muscles contraction. These muscles depend mainly on fatty acid oxidation as an important source of ATP. We investigated the effects of remote ischemic preconditioning and postconditioning (RpostC) on the contractile functions of the diaphragm in relation to metabolic functions during systemic inflammation in lipopolysaccharide (LPS)-induced endotoxemia model. Materials and methods A total of 24 adult male albino rats were divided equally into four groups: (i) the control group (group 1); (ii) LPS group (group 2), in which rats were treated with a single intraperitoneal injection of LPS (0.8 mg/kg intraperitoneal single dose); (iii) preconditioned group (group 3), in which remote ischemic preconditioning was induced with three ischemia/reperfusion cycles of the right hind limbs just before LPS injection; and (iv) postconditioned group (group 4), in which remote ischemic postconditioning was induced as in group 3 just after LPS injection. The animals were killed 5 days after the treatment. Among all groups, the contractility of the diaphragm was examined and the gene expressions of the carnitine palmitoyl transferase 1β (CPT-10β), the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and the nuclear factor erythroid 2-related factor 2 ( Nrf2) - the master of antioxidant response element - by real-time reverse transcription-PCR in the rat diaphragm tissue were determined; in addition, the serum levels of inflammatory markers, tumor necrosis factor α (TNFα) and interleukin-6, and lipids were measured. Results Both types of remote ischemic, preconditioning and postconditioning, significantly improved the contractile performance of the diaphragm ( P Conclusion Our results showed that the improvement of contractile performance of the diaphragm during sepsis was related to the improvement in the expression of nuclear hormone receptors involved in fat oxidation and modulation in oxidative stress and its consequences on inflammatory response. On the basis of these findings, we can suggest that early rational postconditioning interventions may be one of the promising strategies in the management of sepsis.

Effects of Renal Ischemic Postconditioning on Myocardial Ultrastructural Organization and Myocardial Expression of Bcl-2/Bax in Rabbits.

We investigated the cardioprotective effect of renal ischemic postconditioning (RI-PostC) and its mechanisms in a rabbit model. Rabbits underwent 60 min of left anterior descending coronary artery occlusion (LADO) and 6 h of reperfusion. The ischemia-reperfusion (IR) group underwent LADO and reperfusion only. In the RI-PostC group, the left renal artery underwent 3 cycles of occlusion for 30 seconds and release for 30 seconds, before the coronary artery was reperfused. In the RI-PostC + GF109203X group, the rabbits received 0.05 mg/kg GF109203X (protein kinase C inhibitor) intravenously for 10 min followed by RI-PostC. Light microscopy and electron microscopy demonstrated that the RI-PostC group showed less pronounced changes, a smaller infarct region, and less apoptosis than the other two groups. Bcl-2 and Bax protein expression did not differ between the IR and RI-PostC + GF109203X groups. However, in the RI-PostC group, Bcl-2 protein expression was significantly higher and Bax protein expression was significantly lower than in the other two groups (P < 0.05). Changes in heart rate and mean arterial pressure were also smaller in the RI-PostC group than in the other two groups. These results indicate that RI-PostC can ameliorate myocardial ischemia-reperfusion injury and increase the Bcl-2/Bax ratio through a mechanism involving protein kinase C.

Exogenous Hydrogen Sulfide Postconditioning Protects Isolated Rat Hearts From Ischemia/Reperfusion Injury Through Sirt1/PGC-1α Signaling Pathway.

Sirt1 is a highly conserved nicotinamide adenine dinucleotide (NAD(+)) dependent histone deacetylase which plays an important role in heart diseases. Studies performed with Sirt1 activators indicated that it protects cells from ischemia/ reperfusion (I/R) injury. The protective effects of H2S against I/R injury also have been recognized. Hence, the present study was designed to explore whether Sirt1/PGC-1α participates in the protection of exogenous H2S postconditioning against I/R injury in isolated rat hearts. Isolated rat hearts were subjected to 30 minutes of global ischemia followed by 60 minutes of reperfusion after 20 minutes of equilibrium. During this procedure, the hearts were exposed to NaHS (10 μmol/L) treatment in the absence or presence of the selective Sirt1 inhibitor EX-527 (10 μmol/L). NaHS exerted a protective effect on isolated rat hearts subjected to I/R, as shown by the improved expression of Sirt1/PGC-1α associated with restoration of Sirt1 nuclear localization, cardiac function, decreased myocardial infarct size, decreased myocardial enzyme release, and several biochemical parameters, including up-regulation of the ATP and SOD levels, and down-regulation of the MDA level. However, treatment with EX-527 could partially prevent the above effects of NaHS postconditioning. These results indicate that H2S confers protective effects against I/R injury through the activation of Sirt1/PGC1α.

Nitric oxide signaling in the ischemic postconditioning of human heart muscle (RCD code: III)

Background: Ischemic heart conditioning is well documented to trigger the intrinsic protective mechanisms of resistance against ischemia/reperfusion (I/R) injury. Previous studies on animal model have suggested that the nitric oxide (NO) mediates the beneficial effect of ischemic postconditioning (POC). We tested the hypothesis that POC provide cardioprotection in the NO-dependent mechanism in the human myocardium. Methods: Human atrial trabeculae were subjected to simulated I/R injury. To achieve POC triple brief hypoxia periods were followed by the lethal hypoxia. Non-selective inhibitor of NO synthase: NG-monomethyl-L-arginine (L-NMMA) was used at the time of re-oxygenation in the POC protocol. Contractility of the myocardium was assessed as the maximal force of a contraction (Amax), the rate of rise of the force of a contraction (Slope L) and cardiac muscle relaxation – as the rate of decay of the force of a contraction (Slope T). Results: Co-application of L-NMMA with POC resulted in the decrease of Amax, Slope L and Slope T during re-oxygenation period as compared to POC only. Conclusions: At re-oxygenation period, the blockade of NO synthesis has deleterious effect on systolic and diastolic function of human myocardium, as well as attenuates the beneficial effect of ischemic.