Ischemic Preconditioning Research Articles

Ischemic Preconditioning, But Not Priming Exercise, Improves Exercise Performance in Trained Rock Climbers.

MacDougall, KB, McClean, ZJ, MacIntosh, BR, Fletcher, JR, and Aboodarda, SJ. Ischemic preconditioning, but not priming exercise, improves exercise performance in trained rock climbers. J Strength Cond Res 37(11): 2149-2157, 2023-To assess the effects of ischemic preconditioning (IPC) and priming exercise on exercise tolerance and performance fatigability in a rock climbing-specific task, 12 rock climbers completed familiarization and baseline tests, and constant-load hangboarding tests (including 7 seconds on and 3 seconds off at an intensity estimated to be sustained for approximately 5 minutes) under 3 conditions: (a) standardized warm-up (CON), (b) IPC, or (c) a priming warm-up (PRIME). Neuromuscular responses were assessed using the interpolated twitch technique, including maximum isometric voluntary contraction (MVC) of the finger flexors and median nerve stimulation, at baseline and after the performance trial. Muscle oxygenation was measured continuously using near-infrared spectroscopy (NIRS) across exercise. Time to task failure (T lim ) for IPC (316.4 ± 83.1 seconds) was significantly greater than CON (263.6 ± 69.2 seconds) ( p = 0.028), whereas there was no difference between CON and PRIME (258.9 ± 101.8 seconds). At task failure, there were no differences in MVC, single twitch force, or voluntary activation across conditions; however, recovery of MVC and single twitch force after the performance trial was delayed for IPC and PRIME compared with CON ( p < 0.05). Despite differences in T lim , there were no differences in any of the NIRS variables assessed. Overall, despite exercise tolerance being improved by an average of 20.0% after IPC, there were no differences in neuromuscular responses at task failure, which is in line with the notion of a critical threshold of peripheral fatigue. These results indicate that IPC may be a promising precompetition strategy for rock climbers, although further research is warranted to elucidate its mechanism of action.

Effects of remote ischemic preconditioning on coronary blood flow and microcirculation

This study aimed to determine the effect of short-term remote ischemic preconditioning (RIPC) on coronary blood flow and microcirculation function using the quantitative flow ratio (QFR) and index of microcirculatory resistance (IMR). We randomly divided 129 patients undergoing coronary angiography (CAG) into RIPC and control groups. Following the first CAG, we randomly divided the patients further into the unilateral upper limb and lower limb groups for four cycles of ischemia/reperfusion circulation; subsequently, we performed the second CAG. During each CAG, contrast-flow QFR (cQFR), fixed-flow QFR (fQFR), and IMR (in patients with cardiac syndrome X) were calculated and compared. We measured 253 coronary arteries in 129 patients. Compared to the control group, the average cQFR of the RIPC group increased significantly after RIPC. Additionally, 23 patients with cardiac syndrome X (IMR > 30) were included in this study. Compared to the control group, IMR and the difference between cQFR and fQFR (cQFR-fQFR) both decreased significantly after receiving RIPC. The application of RIPC can increase coronary blood flow and improve coronary microcirculation function.

Mitochondrial pannexin1 controls cardiac sensitivity to ischaemia/reperfusion injury.

No effective therapy is available in clinics to protect the heart from ischaemia/reperfusion (I/R) injury. Endothelial cells are activated after I/R, which may drive the inflammatory response by releasing ATP through pannexin1 (Panx1) channels. Here, we investigated the role of Panx1 in cardiac I/R. Panx1 was found in cardiac endothelial cells, neutrophils, and cardiomyocytes. After in vivo I/R, serum Troponin-I, and infarct size were less pronounced in Panx1-/- mice, but leukocyte infiltration in the infarct area was similar between Panx1-/- and wild-type mice. Serum Troponin-I and infarct size were not different between mice with neutrophil-specific deletion of Panx1 and Panx1fl/fl mice, suggesting that cardioprotection by Panx1 deletion rather involved cardiomyocytes than the inflammatory response. Physiological cardiac function in wild-type and Panx1-/- hearts was similar. The time to onset of contracture and time to maximal contracture were delayed in Panx1-/- hearts, suggesting reduced sensitivity of these hearts to ischaemic injury. Moreover, Panx1-/- hearts showed better recovery of left ventricle developed pressure, cardiac contractility, and relaxation after I/R. Ischaemic preconditioning failed to confer further protection in Panx1-/- hearts. Panx1 was found in subsarcolemmal mitochondria (SSM). SSM in WT or Panx1-/- hearts showed no differences in morphology. The function of the mitochondrial permeability transition pore and production of reactive oxygen species in SSM was not affected, but mitochondrial respiration was reduced in Panx1-/- SSM. Finally, Panx1-/- cardiomyocytes had a decreased mitochondrial membrane potential and an increased mitochondrial ATP content. Panx1-/- mice display decreased sensitivity to cardiac I/R injury, resulting in smaller infarcts and improved recovery of left ventricular function. This cardioprotective effect of Panx1 deletion seems to involve cardiac mitochondria rather than a reduced inflammatory response. Thus, Panx1 may represent a new target for controlling cardiac reperfusion damage.

Abstract P3178: Gja1-20k Is Downstream Of Drp1 And Can Rescue Drp1 Suppression In Mouse Heart

Dynamin-Related Protein 1 (DRP1) is a major mediator of mitochondrial fission and its mutation results with hyper-fused mitochondria and, in mice, a dilated cardiomyopathy. GJA1-20k is the most abundant N-terminus truncated isoform of Connexin 43 (Cx43) formed by internal translation and was originally identified as a trafficking subunit of Cx43. It has been recently identified that GJA1-20k is located on the mitochondrial membrane and plays a role in mediating ischemia preconditioning by promoting a protective mitochondrial fission. Interestingly, GJA1-20k mediated fission occurs even under DRP1 inhibition in vitro. Here, we hypothesize that GJA1-20k is downstream of DRP1 and that exogenous GJA1-20k administration rescues hyper-fusion of mitochondria in DRP1-suppressed mouse hearts. Using an AAV9-mediated DRP1 dominant negative mutant (Drp1-K38A) to suppress DRP1, we confirmed that the Drp1-K38A mouse hearts have an increase in cardiac mitochondrial size (158.9 ± 3.7% of control) and decrease in cardiac function (ejection fraction is 43.1 ± 1.5% versus 64.0 ± 4.1% in control animals), as assayed by electron microscopy and in vivo echocardiography, respectively. However, the administration of exogenous GJA1-20k via AAV9 transduction normalizes mitochondrial size (net 14.1 ± 3.3% decrease from control group) and rescues cardiac function (ejection fraction 61.6 ± 2.7%), suggesting that the progression to the cardiomyopathy is prevented by GJA1-20k administration. In summary, GJA1-20k functions downstream of DRP1 and can rescue the effect DRP1 suppression on mitochondrial size and cardiac function.

Remote Ischaemic Preconditioning Accelerates Brain to Blood Glutamate Efflux via EAATs-mediated Transport

Remote ischaemic conditioning (RIC) becomes an attractive strategy for the endogenous stimulation of mechanisms protecting neurons against ischaemia. Although the processes underlying the RIC are not clearly understood, the homeostasis of glutamate seems to play an important role. The present study is focused on the investigation of the brain to blood efflux of glutamate in a condition mimicking ischaemia-mediated excitotoxicity and remote ischaemic preconditioning (RIPC). The animals were pre-treated with a hind-limb tourniquet one hour before the intraventricular administration of glutamate and its release was monitored as the concentration of glutamate/glutathione in blood and liquor for up to 1 h. The transport mediated by excitatory amino acid transporters (EAATs) was verified by their inhibition with Evans Blue intraventricular co-administration. RIPC mediated the efflux of glutamate exceeding from CSF to blood in the very early stage of intoxication. As a consequence, the blood level of glutamate rose in a moment. EAATs inhibition confirmed the active role of glutamate transporters in this process. In the blood, elevated levels of glutamate served as a relevant source of antioxidant glutathione for circulating cells in RIPC-treated individuals. All of those RIPC-mediated recoveries in processes of glutamate homeostasis reflect the improvement of oxidative stress, suggesting glutamate-accelerated detoxication to be one of the key mechanisms of RIPC-mediated neuroprotection.

P55γ degrades RIP3 via MG53 to suppress ischaemia-induced myocardial necroptosis and mediates cardioprotection of preconditioning.

Regulated necrosis (necroptosis) and apoptosis are important biological features of myocardial infarction, ischaemia-reperfusion (I/R) injury, and heart failure. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Ischaemic preconditioning (IPC) is the most powerful intrinsic cardioprotection against myocardial I/R injury. In this study, we aimed to determine whether IPC suppresses I/R-induced necroptosis and the underlying molecular mechanisms. We generated p55γ transgenic and knockout mice and used ligation of left anterior descending coronary artery to produce an in vivo I/R model. The effects of p55γ and its downstream molecules were subsequently identified using mass spectroscopy and co-immunoprecipitation and pulldown assays. We found that p55γ expression was down-regulated in failing human myocardium caused by coronary heart disease as well as in I/R mouse hearts. Cardiac-specific p55γ overexpression ameliorated the I/R-induced necroptosis. In striking contrast, p55γ deficiency (p55γ-/-) and cardiac-specific deletion of p55γ (p55γc-KO) worsened I/R-induced injury. IPC up-regulated p55γ expression in vitro and in vivo. Using reporter and chromatin immunoprecipitation assays, we found that Hif1α transcriptionally regulated p55γ expression and mediated the cardioprotection of IPC. IPC-mediated suppression of necroptosis was attenuated in p55γ-/- and p55γc-KO hearts. Mechanistically, p55γ overexpression decreased the protein levels of RIP3 rather than the mRNA levels, while p55γ deficiency increased the protein abundance of RIP3. IPC attenuated the I/R-induced up-regulation of RIP3, which was abolished in p55γ-deficient mice. Up-regulation of RIP3 attenuated the p55γ- or IPC-induced inhibition of necroptosis in vivo. Importantly, p55γ directly bound and degraded RIP3 in a ubiquitin-dependent manner. We identified MG53 as the E3 ligase that mediated the p55γ-induced degradation of RIP3. In addition, we also found that p55γ activated the RISK pathway during IPC. Our findings reveal that activation of the MG53-RIP3 signal pathway by p55γ protects the heart against I/R-induced necroptosis and underlies IPC-induced cardioprotection.

Cardioprotective and anti-anginal efficacy of Nicorandil: A Comprehensive Review.

Angina pectoris remains a significant burden despite advances in medical therapy and coronary revascularization. Many patients (up to 30%) with angina have normal coronary arteries, with coronary microvascular disease (CMD) and/or coronary artery vasospasm (CAVS) being major drivers of the myocardial demand-supply mismatch. Even among patients revascularized for symptomatic epicardial coronary stenosis, recurrent angina remains highly prevalent. Medical therapy for angina currently centers around two disparate goals, viz secondary prevention of hard clinical outcomes and symptom control. Vasodilators such as nitrates have been first-line anti-anginal agents for decades, along with beta-blockers and calcium channel blockers. However, efficacy in terms of symptoms control is heterogenous, depending on underlying mechanism(s) of angina in an individual patient, often necessitating multiple agents. Nicorandil (NCO) is an anti-anginal first discovered in the late 1970s with a uniquely dual mechanism of action. Like a typical nitrate, it mediates medium-large vessel vasodilation via nitric oxide. Additionally, NCO has ATP-dependent potassium channel-agonist activity (KATP), mediating microvascular dilatation. Hence, it has proven effective in both CAVS and CMD, typically challenging patient populations. Moreover, emerging evidence suggests cardiomyocyte protection against ischemia via ischemic preconditioning (IPC) may be mediated via KATP-agonism. Finally, there is now fairly firm evidence in favor of NCO in terms of hard event reduction among patients with stable coronary artery disease (CAD), following myocardial infarction, and perhaps even among patients with congestive heart failure (CHF). This review aims to summarize the mechanism of action of NCO, its efficacy as an anti-anginal, and current evidence behind its impact on hard outcomes. Finally, we review other cardiac and emerging non-cardiac indications for NCO use.Keywords: angina, stable ischemic heart disease, anti-anginal, efficacy, cardioprotective.

Remote ischemic preconditioning does not provoke metabolomic alterations in patients undergoing major vascular surgery: A randomized controlled trial

Remote ischemic preconditioning does not provoke metabolomic alterations in patients undergoing major vascular surgery: A randomized controlled trial

Mitochondrial modulation of amplified preconditioning influences of remote ischemia plus erythropoietin against skeletal muscle ischemia/reperfusion injury in rats

AimsSkeletal muscle ischemia and reperfusion (S-I/R) injury is relieved by interventions like remote ischemic preconditioning (RIPC). Here, we tested the hypothesis that simultaneous exposure to a minimal dose of erythropoietin (EPO) boosts the protection conferred by RIPC against S-I/R injury and concomitant mitochondrial oxidative and apoptotic defects. Main methodsS-I/R injury was induced in rats by 3-h right hindlimb ischemia followed by 3-h of reperfusion, whereas RIPC involved 3 brief consecutive I/R cycles of the contralateral hindlimb. Key findingsS-I/R injury caused (i) rises in serum lactate dehydrogenase and creatine kinase and falls in serum pyruvate, (ii) structural deformities like sarcoplasm vacuolations, segmental necrosis, and inflammatory cells infiltration, and (iii) decreased amplitude and increased duration of electromyography action potentials. These defects were partially ameliorated by RIPC and dose-dependently by EPO (500 or 5000 IU/kg). Further, greater repairs of S-I/R-evoked damages were seen after prior exposure to the combined RIPC/EPO-500 intervention. The latter also caused more effective (i) preservation of mitochondrial number (confocal microscopy assessed Mitotracker red staining) and function (citrate synthase activity), (ii) suppression of mitochondrial DNA damage and indices of oxidative stress and apoptosis (succinate dehydrogenase, myeloperoxidase, cardiolipin, and cytochrome c), (iii) preventing calcium and nitric oxide metabolites (NOx) accumulation and glycogen consumption, and (iv) upregulating EPO receptors (EPO-R) gene expression. Significancedual RIPC/EPO conditioning exceptionally mends structural, functional, and neuronal deficits caused by I/R injury and interrelated mitochondrial oxidative and apoptotic damage. Clinically, the utilization of relatively low EPO doses could minimize the hormone-related adverse effects.

Ischemic preconditioning attenuates endoplasmic reticulum stress-dependent apoptosis of hepatocytes by regulating autophagy in hepatic ischemia-reperfusion injury

Hepatic ischemia–reperfusion injury (HIRI) usually occurs during subtotal hepatectomy and severely damages liver function during the perioperative period. Endoplasmic reticulum stress (ERS) dependent apoptosis has been suggested to play a crucial role in HIRI progression. The present study focused on the regulatory effect of autophagy activation induced by ischemic preconditioning (IPC) on ERS-dependent apoptosis of hepatocytes in HIRI. A HIRI mouse model and oxygen-glucose deprivation/reperfusion (OGD/R) AML-12 hepatocyte cell lines were constructed to evaluate the protective effect of IPC in vivo and in vitro. The protein levels of p-eIF2α, CHOP, and cleaved caspase-12 were used to evaluate the ERS-dependent apoptosis, whereas LC3-II and p62 were considered as the autophagy activation markers. The beneficial molecular chaperones GRP78, HSP60, and HSP70 were also tested to evaluate autophagy. HIRI significantly increased ERS-dependent apoptosis markers and the number of apoptotic cells and damaged liver function. The ERS inhibitor salubrinal significantly alleviated liver injury in HIRI and OGD/R hepatocytes. Furthermore, both remote IPC and direct IPC significantly alleviated liver injury and inflammatory cell infiltration. IPC also upregulated LC3-II, downregulated p62 expression, and increased the mRNA levels of GRP78, HSP60, and HSP70 in HIRI mice and OGD/R hepatocytes, indicating the activation of autophagy by IPC. The autophagy inhibitor 3-methyladenine significantly attenuated the protective effects of IPC on ERS-dependent apoptosis and liver function, whereas the autophagy activator rapamycin mimicked the protective effects of IPC on ERS-dependent apoptosis in vivo and in vitro, suggesting a regulatory role of autophagy in ERS-dependent apoptosis. These results demonstrated that IPC could induce moderate autophagy and upregulate a few molecular chaperones to strengthen endogenous defense mechanisms, which is beneficial for alleviating ERS-dependent apoptosis and protecting hepatocytes from HIRI.

Effects of RIPC on the Metabolomical Profile during Lower Limb Digital Subtraction Angiography: A Randomized Controlled Trial.

Remote ischemic preconditioning (RIPC) has demonstrated protective effects in patients with lower extremity arterial disease (LEAD) undergoing digital subtraction angiography (DSA) and/or percutaneous transluminal angioplasty (PTA). This study aimed to investigate the impact of RIPC on the metabolomical profile of LEAD patients undergoing these procedures and to elucidate its potential underlying mechanisms. A total of 100 LEAD patients were enrolled and randomly assigned to either the RIPC group (n = 46) or the sham group (n = 54). Blood samples were drawn before and 24 h after intervention. Targeted metabolomics analysis was performed using the AbsoluteIDQ p180 Kit, and changes in metabolite concentrations were compared between the groups. The RIPC group demonstrated significantly different dynamics in nine metabolites compared to the sham group, which generally showed a decrease in metabolite concentrations. The impacted metabolites included glutamate, taurine, the arginine-dimethyl-amide-to-arginine ratio, lysoPC a C24:0, lysoPC a C28:0, lysoPC a C26:1, PC aa C38:1, PC ae C30:2, and PC ae C44:3. RIPC exhibited a 'stabilization' effect, maintaining metabolite levels amidst ischemia-reperfusion injuries, suggesting its role in enhancing metabolic control. This may improve outcomes for LEAD patients. However, additional studies are needed to definitively establish causal relationships among these metabolic changes.

Effect of Remote Ischemic Preconditioning on Patient Survival and End Organ Injury During Elective Open Abdominal Aortic Surgery Repair: A Randomized Controlled Trial

Effect of Remote Ischemic Preconditioning on Patient Survival and End Organ Injury During Elective Open Abdominal Aortic Surgery Repair: A Randomized Controlled Trial

건강한 대상자에게 허혈성 전처치와 햄스트링 스트레칭, 복합적용이 운동능력에 미치는 즉각적인 효과비교

Purpose: This study aimed to examine the effects of ischemic preconditioning (IPC), hamstring stretching, and complex approach on exercise ability and to identify the impact on the ability to recover after exercise. Methods: A total of 20 healthy adult males were included in this study. All subjects performed different interventions before exercise (nothing applied [CON], IPC, hamstring stretching, and IPC + hamstring stretching [Complex]), followed by cycling exercise, with a 5-min rest after exercise. Heart rate (HR), rate of perceived exertion (RPE), and oxygen saturation (Spo2) were measured during exercise and 5 min after exercise. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) was measured before exercise, immediately after exercise, and 5 min after exercise. Data analysis was performed using one-way repeated measures analysis of variance. Results: Exercise time was significantly different between Complex and CON and IPC conditions. RPE measured during exercise was significantly different between Complex and CON and IPC conditions. A significant difference in HR measured during exercise was observed between Complex and CON conditions. However, no significant difference in SBP, DBP, HR, Spo2, and RPE measured 5 min after exercise was observed between the conditions. Conclusion: Applying IPC and hamstring stretching together before exercise can be a particularly effective method for improving aerobic exercise capacity.

Effect of Ischemic Preconditioning (IPC) on Recovery of Exercise Performance Following a Bout of Exercise to Volitional Exhaustion

The purpose of the present study was to investigate the effect of ischemic preconditioning (IPC) on the recovery of exercise performance following maximal, incremental exercise. A total of 13 healthy males volunteered to participate, undertaking three experimental trials involving a constant work-rate bout of severe intensity exercise undertaken to the limit of tolerance that was preceded by a 40-min recovery period consequent to a maximal, incremental exercise test. During the recovery period, participants underwent IPC at 220 mmHg, sham IPC (SHAM; 20 mmHg), and passive rest (CON). Exercise tolerance time was higher following IPC as compared to SHAM and CON {199 ± 36 (CON) vs. 203 ± 35 (SHAM) vs. 219 ± 34 (IPC), p = 0.03}. This effect was accompanied by a tendency toward an augmented increase in blood lactate from rest to exercise in IPC compared to SHAM and CON (p = 0.08). There was no effect of IPC on oxygen uptake kinetics or muscle oxygenation as indicated via near-infrared spectroscopy. IPC may therefore have the capacity to augment recovery from prior maximal exercise, but this does not appear to be due to enhancements to oxygen uptake kinetics or muscle oxygenation.

How does remote ischemic preconditioning (RIPC) compare with no RIPC for adults undergoing major vascular surgery?

How does remote ischemic preconditioning (RIPC) compare with no RIPC for adults undergoing major vascular surgery?

ASO Visual Abstract: Prospective Evaluation of a Universally Applied Laparoscopic Gastric Ischemic Preconditioning Protocol Prior to Esophagectomy with Comparison to Historical Controls.

ASO Visual Abstract: Prospective Evaluation of a Universally Applied Laparoscopic Gastric Ischemic Preconditioning Protocol Prior to Esophagectomy with Comparison to Historical Controls.

Quantitative assessment of gastric ischemic preconditioning on conduit perfusion in esophagectomy: propensity score weighting study.

Gastric ischemic preconditioning prior to esophagectomy has been studied as a method to improve gastric conduit perfusion and reduce anastomotic complications, without conclusive results. The aim of this study is to evaluate the feasibility and safety of gastric ischemic preconditioning in terms of post-operative outcomes and quantitative gastric conduit perfusion. Patients who underwent an esophagectomy with gastric conduit reconstruction between January 2015 and October 2022 at a single high-volume academic center were reviewed. Patient characteristics, surgical approach, post-operative outcomes, and indocyanine green fluorescence angiography data (ingress index for arterial inflow and ingress time for venous outflow, and the distance from the last gastroepiploic branch to the perfusion assessment point) were analyzed. Two propensity score weighting methods were used to investigate whether gastric ischemic preconditioning reduces anastomotic leaks. Multiple linear regression analysis was used to evaluate the conduit perfusion quantitatively. There were 594 esophagectomies with gastric conduit performed, with 41 having a gastric ischemic preconditioning. Among 544 with cervical anastomoses, leaks were seen in 2/30 (6.7%) in the ischemic preconditioning group and 114/514 (22.2%) in the control group (p = 0.041). Gastric ischemic preconditioning significantly reduced anastomotic leaks on both weighting methods (p = 0.037 and 0.047, respectively). Ingress index and time of the gastric conduit with ischemic preconditioning were significantly better than those without preconditioning (p = 0.013 and 0.025, respectively) after removing the effect of the distance from the last gastroepiploic branch to the perfusion assessment point. Gastric ischemic preconditioning results in a statistically significant improvement in conduit perfusion and reduction in post-operative anastomotic leaks.

Kir1.1 and SUR1 are not implicated as subunits of an adenosine triphosphate-sensitive potassium channel involved in diazoxide cardioprotection

ObjectiveThe adenosine triphosphate-sensitive potassium channel opener diazoxide mimics ischemic preconditioning and is cardioprotective. Clarification of diazoxide's site and mechanism of action could lead to targeted pharmacologic therapies for patients undergoing cardiac surgery. Several mitochondrial candidate proteins have been investigated as potential adenosine triphosphate-sensitive potassium channel components. Renal outer medullary potassium (Kir1.1) and sulfonylurea sensitive regulatory subunit 1 have been suggested as subunits of a mitochondrial adenosine triphosphate-sensitive potassium channel. We hypothesized that pharmacologic blockade or genetic deletion (knockout) of renal outer medullary potassium and sensitive regulatory subunit 1 would result in loss of diazoxide cardioprotection in models of global ischemia with cardioplegia. MethodsMyocyte volume and contractility were compared after Tyrode's physiologic solution (20 minutes), stress (hyperkalemic cardioplegia ± diazoxide, ± VU591 (Kir1.1 inhibitor), N = 9 to 23 each, 20 min), and Tyrode's (20 minutes). Isolated mouse (wild-type, sensitive regulatory subunit 1 [−/−], and cardiac knockout renal outer medullary potassium) hearts were given cardioplegia ± diazoxide (N = 9-16 each) before global ischemia (90 minutes) and 30 minutes reperfusion. Left ventricular pressures were compared before and after ischemia. ResultsStress (cardioplegia) was associated with reduced myocyte contractility that was prevented by diazoxide. Isolated myocytes were not responsive to diazoxide in the presence of VU591. In isolated hearts, diazoxide improved left ventricular function after prolonged ischemia compared with cardioplegia alone in wild-type and knockout (sensitive regulatory subunit 1 [−/−] and cardiac knockout renal outer medullary potassium) mice. ConclusionsIsolated myocyte and heart models may measure independent and separate actions of diazoxide. By definitive genetic deletion, these data indicate that sensitive regulatory subunit 1 and renal outer medullary potassium are not implicated in cardioprotection by diazoxide.

#6635 ARNT AND ALK3 MEDIATE RENO PROTECTION AFTER ISCHEMIC PRECONDITIONING

Abstract Background and Aims Ischemia and following hypoxia are a common cause of acute kidney injury (AKI). Strategies for prevention and treatment of AKI are limited. In several animal models, ischemic preconditioning (IPC) has been established as an effective intervention to prevent ischemic organ injury. An IPC protocol of ischemia and reperfusion mediates organ protection for a few hours. This first phase of organ protection is followed by a second, protective phase occurring after 24–48 h. The second phase, named second window of protection (SWOP), persists for 3–4 d. Mechanisms and transcriptional mediators during SWOP are mostly unknown. The aim of the underlying study was to investigate effectors and target genes during SWOP and to identify a potential pharmacological therapeutic target. Method 6–8-week-old C57BL/6 mice were undergoing an IPC intervention; five minutes of renal sinistra artery ischemia was followed by five minutes of reperfusion. This cycle was performed five times. Mice were sacrificed 2, 4, 8, 12, 25, 48, 72 h after IPC. Two additional groups of mice were pharmacologically preconditioned for 48 h with low dose FK506 and small molecule GPI1046. Analysis of murine kidneys were performed by SDS-Page and Western blot. Results The first phase after IPC (2–4 h) was characterized by an increasing expression of hypoxia inducible factor-1α (HIF1α); 48 h after intervention a significant increase of expression of aryl hydrocarbon receptor nuclear translocator (ARNT) and consecutive activin receptor-like kinase 3 (ALK3) was observed. Comparable induction of ARNT and ALK3 expression was obtained by pharmacological preconditioning with FK506 or GPI1046. Conclusion Affected by hypoxia, HIF1α activates transcriptional upregulation of ARNT 48 h after IPC. The increasing expression of ARNT, follows an increased ARNT homodimerization. ARNT homodimer binds to the palindromic E-box 5′-CACGTG-3′ of the proximal ALK3 promoter. By this it induces the expression of the renoprotective ALK3 during SWOP. The organ-protective effects of constitutively expressed ARNT during SWOP can be mimicked pharmacologically by administration of FK506 or GPI1046 and may be used as a future therapeutic target.

#6287 EFFECT OF REMOTE ISCHEMIC PRECONDITIONING ON NUTRITIONAL STATUS, COGNITIVE FUNCTION, AND BONE IN HEMODIALYSIS PATIENTS: A RANDOMIZED CONTROLLED TRIAL

Abstract Background and Aims Remote ischemic preconditioning (RIPC) is a process in which a brief period of ischemia is induced in one part of the body to protect another part from damage due to subsequent periods of more severe ischemia. Hemodialysis sessions are considered an ischemic process because it involves reducing blood flow to certain parts of the body, which can lead to tissue damage .Malnutrition, deterioration of cognitive function, bone disorders, cardiovascular disease, and hemodynamic instability can result from ischemia induced by hemodialysis sessions. These adverse effects increase mortality in HD patients. RIPC has been studied as a potential therapeutic strategy to reduce the risk of cardiovascular events in hemodialysis patients; however, the effect of RIPC on cognitive function, nutritional status, and bone disorder among hemodialysis patients has not been enough studied. Aim: to assess the effect of remote ischemic preconditioning on nutritional status, bone disorders, and cognitive function in hemodialysis patients at the urology and nephrology center, Mansoura University. Method Fifty patients who received regular hemodialysis for more than one year in our dialysis unit were included. The patients were randomized (single-blind) into two groups a control group (20 patients) and an intervention group (30 patients). Before each HD session, sphygmomanometer cuffs was placed around the non-vascular access arm. Three cycles of ischemia for five minutes were performed followed by reperfusion for five minutes. Ischemia was induced by inflating the sphygmomanometer cuffs to 200 mmHg. This maneuver was done before each HD session for 12 weeks. The Montreal Cognitive Assessment (MOCA) was used to assess cognitive function. The nutritional state was assessed by anthropometric measurement (body weight, BMI), laboratory (serum albumin and serum cholesterol), and Subjective Global Assessment Form (SGA). Serum calcium (s.Ca) and serum phosphorus (s.po), serum alkaline phosphate (s. ALP) and intact parathyroid hormone (iPTH) were used as indices for bone profile. Results The intervention group include 30 patient with mean age (36+/-10), 19 male (63.3%) and 11 females (36.7%). The control group include 20 patient with mean age (46+/-9), 12 male (60%) and eight female (40%). None of these patients’ demographic data (age, sex, original kidney disease, and duration of dialysis) were significantly different between the study groups (P&amp;gt;0.05). MOCA test score at baseline was (24.5 +/-2.6) at intervention group and (24.4+/-3.2) at control group, and after 12 weeks intervention was (24.8 +/-2.2) at intervention group and (24.4+/-2.8) at control group. there were no statistical significance regarding cognitive function between the two group over time (p = 0.4). NO significant Statistical changes in anthropometric measurements (Body weight (p = 0.3) and BMI (P = 0.6) were found between the two groups. Additionally, no significant changes (serum albumin and cholesterol) were detected. SGA score at baseline was at intervention group (1.2+/-0.4) and control group (1.1 +/- 0.3), and after 12 week was at the intervention group (1.4 +/-0.5) and control group (1.6 +/-0.5). SGA showed no statistical significance between the two groups over time (p = 0.2). No significant statistical changes regarding bone profile (s.ca (p = 0.5), s.PO (p = 0.2), s.ALP (p = 0.7) and iPTH (p = 0.5)). Conclusion Although some studies showed a beneficial effect of RIBC on reduction of cardiovascular risk, our study found no significant effect on cognitive function, nutritional status, and bone disorders among hemodialysis patients.