Ischemic Preconditioning Group Research Articles

Remote ischemic preconditioning of spleen decreases hepatic ischemia reperfusion injury in rats

Objective To investigate the effect and mechanism of remote ischemic preconditioning on hepatic ischemia-reperfusion injury.Methods Thirty six SD rats were divided into three group randomly:Sham-operated group (Sham group),ischemia-reperfusion group (IR group:produced by total inflow occlusion for 15 min),and remote ischemic preconditioning group [remote ischemic preconditioning (RIPC) group:induced with 15 min ischemia of spleen before hepatic ischemia].Serum aminotransferases [alanine aminotransferase (ALT),aspartate aminotransferase (AST)] and tumor necrosis factor (TNF)-α,P-selectin in liver were measured after reperfusion for 2 h.Results Compared with the Sham group,the level of ALT,AST and the pathological injury scores were significantly increased in the IR [(466.75 ± 89.45),(782.25 ±87.71) U/L and RIPC (231.87 ±50.80),(326.75 ± 19.12) U/L] groups.TNF-α and p-selectin expression were high when IR only as well.These variables were significant decreased in RIPC group.Conclusion Remote ischemic preconditioning of spleen decreases the reperfusion injury during hepatic ischemia which may be caused by the decrease of pro-inflammatory and activity of neutophils. Key words: Remote ischemic preconditioning; Ischemia-reperfusion injury ; Liver; Spleen

Abstract 196: Remote Ischemic Pre-Conditioning Improves Microcirculation following Severe Hemorrhagic Shock in a Rat Model

Introduction: The microcirculatory flow is a major determinant of tissue oxygen delivery. A significantly reduced microcirculatory flow has been described during and following hemorrhagic shock. We investigated whether remote ischemic pre-conditioning (RIPC) would improve microcirculation following severe hemorrhagic shock. Hypothesis: RIPC improves sublingual microcirculation following hemorrhagic shock. Methods: Fourteen male Sprague-Dawley rats were randomized into two groups: 1) Remote ischemic pre-conditioning (RIPC) group, 2) Control group. RIPC was performed by four cycles of 5 mins of limb ischemia followed by reperfusion for 5 mins. Hemorrhagic shock was induced by reduction of total blood volume by 50% over an interval of 1 hour, 30 mins after bleeding, reinfusion was initiated with the shed blood over the ensuing 30 mins. Sublingual microcirculation was measured by a sidestream dark-field imaging device at baseline, 1 hour after bleeding, 30 mins after shock, 30 mins after reinfusion and at hourly intervals thereafter for a total of 120 mins. Results: The sublingual microvascular flow index (MFI) and perfused vessel density (PVD) were significantly reduced during hemorrhage (P<0.001) when compared with the baseline values. The MFI and PVD were significantly greater after reinfusion in the RIPC group than that in the Control group (P<0.001)(Table). Conclusions: RIPC improved sublingual microcirculation following severe hemorrhagic shock.

Ischemic preconditioning produces more powerful anti-inflammatory and cardioprotective effects than limb remote ischemic postconditioning in rats with myocardial ischemia-reperfusion injury

Background Both ischemic preconditioning (IPC) and limb remote ischemic postconditioning (LRIPOC) have been shown to possess significantly different cardioprotective effects against the myocardial ischemia reperfusion injury (IRI), but no study has compared the anti-inflammatory effects of IPC and LRIPOC during myocardial IRI process. We hypothesized that IPC and LRIPOC would produce different anti-inflammatory effects in an in vivo rat model with myocardial IRI. Methods Eighty rats were randomly allocated into four equal groups: sham group, IRI group, IPC group and LRIPOC group. In 10 rats randomly selected from each group, serum levels of TNF-α, HMGB1, ICAM1, IL-1, IL-6 and IL-10 were assessed, and infarct size was determined. In another 10 rats of each group, myocardial levels of TNF-α, HMGB1, ICAM1, IL-1, IL-6 and IL-10 in both ischemic and non-ischemic regions were measured. Results The infarct size was significantly lower in IPC and LRIPOC groups than in IRI group. The serum and myocardial levels of pro-inflammatory cytokines including TNF-α, HMGB1, ICAM1, IL-1 and IL-6 during reperfusion were significantly reduced in IPC and LRIPOC groups compared to IRI group. As compared to the IPC group, infarct size, serum level of TNF-α at 60 minutes of reperfusion, serum levels of HMGB1 and ICAM1 at 120 minutes of reperfusion, myocardial levels of TNF-α, ICAM1, IL-1 and IL-6 in the ischemic region, myocardial levels of ICAM1, IL-1 and IL-6 in the non-ischemic region were significantly increased in the LRIPOC group. Conclusions In the rats with myocardial IRI, IPC produces more powerful inhibitory effects on local myocardial and systemic inflammatory responses than LRIPOC. This may be partly attributed to more potent cardioprotection produced by IPC.

Comparison of the flap survival with ischemic preconditioning on different pedicles under varied ischemic intervals in a rat bilateral pedicled flap model

The study was undertaken to search whether pedicle selection for ischemic preconditioning (IP) and duration of global ischemia applied after IP influenced efficacy of IP on flap viability in epigastric adipocutaneous island flap with bilateral pedicles in rat model. In total, 159 rats were divided into one control and three (primary, secondary, or bilateral pedicle) IP treatment groups. IP was performed on different pedicles by three cycles of 10 minutes of pedicle clamping and 10 minutes of release. After IP procedure secondary pedicle was ligated in all groups, and flaps were exposed to 0, 1, 2, 4, or 6 hours of global ischemia by clamping primary pedicle. In control groups, after the perfusion of bipedicled flaps for 1 hour, left pedicle was ligated and flaps were exposed to global ischemia as in IP groups. On day 5 post-surgery, tissue samples and topographic measurements were taken. No significant differences in semi-quantitative scorings of polymorphonuclear leukocytes infiltration, chronic inflammation, interstitial edema, neovascularization, VEGF, and CD105 expression levels among groups were found (P > 0.05). Percentages of necrosis were consistently smaller in IP groups compared to controls for the same duration of global ischemia, with exception of the no-ischemia. Area of necrosis was significantly smaller in primary IP group versus secondary IP group in the absence of global ischemia (P < 0.01). In the presence of global ischemia, both primary and secondary pedicle IP groups had significantly smaller percentage of necrosis than controls (P < 0.05) and there was no significant difference between primary and secondary IP groups (P > 0.05). Thus, IP performed on different pedicles may ameliorate flap survival in a comparable fashion, depending on the duration of global ischemia. Secondary pedicle IP was as effective as primary pedicle IP and may be feasible in free flap transfers.

Effects of ischemic preconditioning on myocardium Caspase-3, SOCS-1, SOCS-3, TNF-α and IL-6 mRNA expression levels in myocardium IR rats

The aim of this study was to characterise the effects of ischemic preconditioning (IP) on heart function parameters (ΔST and ΔT), activities of serum creatine kinase (CK), lactate dehydrogenase (LDH), and levels of serum nitric oxide (NO), malondialdehyde (MDA), and myocardium Caspase-3 mRNA, SOCS-1, SOCS-3, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) expression levels and Apoptosis index in myocardium IR rats. Results showed that ΔST and ΔST values in IP group were markedly lower than those in IR group. Compared with IR group, IP significantly (p < 0.01) decreased serum CK (0.83 ± 0.09 vs 1.36 ± 0.15), LDH (5613 ± 462 vs 7106 ± 492) activities and MDA (11.32 ± 1.05 vs 15.49 ± 1.26) level, increased the serum NO (86.39 ± 7.03 vs 53.77 ± 4.27) level in IR group. The IP induced a significant decreased in myocardium Caspase-3 mRNA (0.303 ± 0.021 vs 0.515 ± 0.022) gene expression (p < 0.01) compared to IR model group. The IP induced a significant decreased in myocardium SOCS-1 (0.241 ± 0.031 vs 0.596 ± 0.036), SOCS-3 (0.258 ± 0.031 vs 0.713 ± 0.057), TNF-α (0.137 ± 0.011 vs 0.427 ± 0.035) and IL-6 (0.314 ± 0.021 vs 0.719 ± 0.064) mRNA gene expression (p < 0.01) compared to IR model group. We conclude that IP is effective in the therapy of heart disease. These findings may have implications for the clinical development of preconditioning-based therapies for ischemic heart disease.

Ischemic preconditioning versus intermittent clamping of portal triad in liver resection: A meta‐analysis of randomized controlled trials

To compare the clinical outcome of patients undergoing liver resection under ischemic preconditioning (IP) versus intermittent clamping (IC). A systematic published work search was conducted to detect randomized controlled trials (RCT) comparing IP and intermittent clamping of the portal triad. A meta-analysis was conducted to estimate postoperative morbidity and mortality, blood loss, transfusion requirement, and liver injury based on the levels of bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Meta-analysis was performed using either the fixed-effects model or random-effects model. Five RCT published between 2006 and 2012 containing a total of 403 patients were eligible for final analysis. Meta-analysis of operative time showed it was lower in the IP group than the IC group with weighted mean difference (WMD) of -18.23 (95% confidence interval (CI), -28.58 to -7.87; P = 0.0006). Meta-analysis of ALT levels indicated lower levels in the IP group on postoperative days 3 and 7 (WMD on day 3: -45.27, 95% CI, -49.92 to -40.62; P < 0.00001; I(2) = 0%; WMD on day 7: -24.33, 95% CI, -28.04 to -20.62; P < 0.00001; I(2) = 0%). Meta-analyses revealed no significant difference in blood loss, transfusion requirement, mortality, morbidity, ischemic duration, hospital stay, AST and bilirubin levels on postoperative days 1, 3 and 7, and ALT levels on postoperative day 1 between IP and IC groups. On currently available evidence, IP does not offer a satisfying benefit to patients undergoing hepatic resection. However, they have lower operative time and less liver injury after liver resections.

Remote ischemic preconditioning is feasible in ad hoc percutaneous coronary interventions

Purpose: Percutaneous coronary intervention (PCI)-induced troponin cTnI release is associated with a worst prognosis. Recently, 3 cycles of 5-minute ischemia followed by 5-minute reperfusion of the upper extremities were shown to reduce troponin release in elective PCI. However, this ischemic preconditioning (IPC) protocol requires 30 minutes and is of limited use in the context of ad hoc PCI. Since experimental evidence suggests that IPC is a graded than an all-or-nothing phenomenon, and even a short, single IPC cycle may have protective effects in the myocardium, we hypothesized that patients undergoing ad hoc PCI would have reduced peri-procedural troponin release if subjected to a single, remote IPC cycle, between diagnostic catheterization and coronary intervention. Methods: Subjects were randomized to receive remote IPC (induced by one single 5-minute inflation of a blood pressure cuff to 200 mm Hg around the upper arm, followed by 1 minute of reperfusion) or control (an uninflated cuff around the arm) in the catheter laboratory. The primary outcome was the difference between post-procedural cTnI (at 24 hours after PCI) and pre-procedural cTnI. Results: Ninety-three patients were included in the study (46 control group, 47 remote IPC group). Peri-procedural troponin release was significantly higher in the control group compared to the remote IPC group (0.49±0.42 vs. 0.10±0.19, p<0.001). No significant difference in ECG ST-segment deviation or ischemic discomfort was observed. Conclusion: One cycle of remote IPC attenuates procedure-related cTnI release, thus IPC may be feasible without introducing any delays in the catheter laboratory.

Effects of the Ischemic Preconditioning on Anastomotic Healing in Laparoscopic Colon Operations

Previous experimental studies have repeatedly demonstrated the potential protective effect of remote ischemic preconditioning (IPC) on colon anastomosis. The purpose of this experimental study was to investigate the possible positive effects of IPC by interval insufflations in laparoscopic colon operations. Thirty Wistar-albino rats were randomized into 3 groups. Colonic transsection and anastomosis were performed in the control group. In the laparoscopic colon operation without IPC group, the intra-abdominal pressure was raised to 14 mm Hg for 60 minutes, and then laparotomy and colonic anastomosis were performed. In the IPC group, the intra-abdominal pressure was raised to 14 mm Hg for 5 minutes, followed by desufflation. Laparotomy and colonic anastomosis were performed exactly as in the non-IPC group. On the seventh postoperative day, all animals were killed, and blood and tissue samples were obtained. Anastomotic healing and inflammatory responses were determined by histopathologic examination and by measuring the anastomotic bursting pressure, tissue hydroxyproline level, and tissue and serum nitric oxide, malondialdehyde (MDA), and catalase activity levels. Differences with P-values of <0.05 were considered to be statistically significant. Although the best anastomotic healing was detected in the control group, anastomotic healing was better in the IPC group than that in the non-IPC group. In terms of anastomotic bursting pressure, plasma MDA, serum catalase activity, and tissue nitric oxide levels, the IPC group was superior to the non-IPC group. No significant differences were found between the control and IPC groups, except in the plasma MDA levels. Use of IPC with colon anastomosis had positive effects on wound healing and may serve as a safe method to reduce the adverse effects of ischemia and wound healing in laparoscopic colon operations.

Role of stress in myocardial protection of ischemic preconditioning

To determine the role of stress in myocardial protection of ischemic preconditioning (IPC). Thirty rabbits were randomly divided into an IPC group, an etomidate (Etom) group, an ischemic/reperfusion (IR) group, a methylprednisolone (MP) group and a sham group. The ratio of infarction size versus risk area (infarct/risk) was calculated. The elevations of the serum creatine kinase (CK) activity and cardiac troponin I (cTnI) concentrations as well as the serum cortisol concentrations were measured. The percentages of infarct/risk in the IPC group, the MP group, the IR group, and the Etom group were (5.86±2.81)%, (11.28±3.62)%, (26.79±4.53)%, and (18.19±3.72)%, respectively. The elevations of the serum CK activity in the IPC group, the MP group, the IR group, and the Etom group were (255±89), (314±160), (855±371), and (768±404) U/L, respectively. The elevations of serum cTnI concentrations in the IPC group, the MP group, the IR group, and the Etom group were (3.6±0.6),(6.1±2.2), (8.1±3.6), and (6.4±1.6) μg/L, respectively. Those indicators among the groups were significantly different (P<0.05). Cortisol reaction was markedly diminished in the Etom group. A blunted cortisol reaction can markedly reduce the benefit of IPC while methylprednisolone shows cardioprotective effects, suggesting that stress might be involved in the myocardial protection of IPC.

Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial

Remote ischaemic preconditioning has been associated with reduced risk of myocardial injury after coronary artery bypass graft (CABG) surgery. We investigated the safety and efficacy of this procedure. Eligible patients were those scheduled to undergo elective isolated first-time CABG surgery under cold crystalloid cardioplegia and cardiopulmonary bypass at the West-German Heart Centre, Essen, Germany, between April, 2008, and October, 2012. Patients were prospectively randomised to receive remote ischaemic preconditioning (three cycles of 5 min ischaemia and 5 min reperfusion in the left upper arm after induction of anaesthesia) or no ischaemic preconditioning (control). The primary endpoint was myocardial injury, as reflected by the geometric mean area under the curve (AUC) for perioperative concentrations of cardiac troponin I (cTnI) in serum in the first 72 h after CABG. Mortality was the main safety endpoint. Analysis was done in intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT01406678. 329 patients were enrolled. Baseline characteristics and perioperative data did not differ between groups. cTnI AUC was 266 ng/mL over 72 h (95% CI 237-298) in the remote ischaemic preconditioning group and 321 ng/mL (287-360) in the control group. In the intention-to-treat population, the ratio of remote ischaemic preconditioning to control for cTnI AUC was 0·83 (95% CI 0·70-0·97, p=0·022). cTnI release remained lower in the per-protocol analysis (0·79, 0·66-0·94, p=0·001). All-cause mortality was assessed over 1·54 (SD 1·22) years and was lower with remote ischaemic preconditioning than without (ratio 0·27, 95% CI 0·08-0·98, p=0·046). Remote ischaemic preconditioning provided perioperative myocardial protection and improved the prognosis of patients undergoing elective CABG surgery. German Research Foundation.

Role of silent information regulator 1 in ischemic preconditioning-induced alleviation of myocardial ischemia-reperfusion injury

Objective To evaluate the role of silent information regulator 1 (SIRT1) in ischemic preconditioning (IPC)-induced alleviation of myocardial ischemia-reperfusion (I/R) injury in rats.Methods Forty-eight male Sprague-Dawley rats,aged 12 weeks,weighing 200-250 g,were randomly divided into 4 groups (n =12 each):sham operation group (S group),I/R group,IPC group and IPC + SIRT1 inhibitor ex527 group (IPC + ex527 group).Myocardial I/R was induced by 30 min occlusion of left anterior descending branch of coronary artery followed by 120 min reperfusion.IPC was induced by 3 episodes of 5 min occlusion of left anterior descending branch at 5 min intervals before myocardial ischemia.SIRT1 inhibitor ex527 1 μg/kg was injected intravenously 15 min before myocardial ischemia and at 1 min before reperfusion.Blood samples were collected before myocardial ischemia and at 120 min of reperfusion for measurement of serum TNF-α and IL-6 concentrations by ELISA.The rats were then sacrificed and myocardial specimens were obtained for determination of myocardial lactic dehydrogenase (LDH) and creatine kinase MB (CK-MB) activities,SIRT1 expression and acetylation of NF-κB p65.Results Compared with S group,the serum TNF-α and IL-6 concentrations at 120 min of reperfusion,and myocardial LDH and CK-MB activities and acetylation of NF-κB p65 were significantly increased,and SIRT1 expression was down-regulated in I/R and IPC + ex527 groups (P ＜ 0.05).Compared with I/R group,the serum TNF-α and IL6 concentrations at 120 min of reperfusion,and myocardial LDH and CK-MB activities and acetylation of NF-κB p65 were significantly decreased,SIRT1 expression was up-upregulated in group IPC (P ＜ 0.05),and no significant change was found in the parameters mentioned above in group IPC + ex527 (P ＞ 0.05).Compared with IPC group,the serum TNF-α and IL-6 concentrations at 120 min of reperfusion,and myocardial LDH and CK-MB activities and acetylation of NF-κB p65 were significantly increased,and SIRT1 expression was down-regulated in group IPC + ex527 (P ＜ 0.05).Conclusion SIRT1 is involved in IPC-induced alleviation of myocardial I/R injury in rats. Key words: Sirtuins ; NF-kappa B ; Ischemic preconditioning, myocardial; Myocardial reperfusion injury

The Protective Effect of Ischemic Preconditioning Against Hepatic Ischemic-Reperfusion Injury Under Isoflurane Anesthesia in Rats

PurposeApoptosis is a central mechanism of ischemic-reperfusion injury (IRI) to the liver. Among the methods to reduce IRI, ischemic preconditioning (IP) has been shown to confer protection. Therefore, the aim of this study was to determine if IP conferred protection against hepatic IRI under isoflurane anesthesia in rats and to investigate underlying protective mechanisms. Materials and MethodsTwenty-three rats weighing 270 to 300 grams were randomly divided into three groups: (1) the sham operated group (n = 5); (2) the non-IP group (n = 9; 45 minutes of hepatic ischemia followed by 2 hours of reperfusion); and (3) the IP group (n = 9); IP induced by 10 minutes of hepatic ischemia followed by 15 minutes of reperfusion before 45 minutes of prolonged hepatic ischemia). Anesthesia was maintained with isoflurane (1.5%). We compared the degrees of hepatic injury and expressions of B cell lymphoma 2 (Bcl-2) and caspase 3 and 8 mRNAs. ResultsThe IP group showed significantly lower levels of aspartate transaminase and alanine transaminase as well as reduced histological grades of hepatocyte injury compared with the non-IP group at 2 hours after reperfusion. At the corresponding time, the Bcl-2 mRNA level was 2-fold higher in the IP group. Caspase 3 mRNA levels were highest in the non-IP group significantly compared with the sham cohort. Similarly, caspase 8 mRNA levels were highest in the Non_IP group albeit not significancely. ConclusionIP protected against hepatic IRI under isoflurane anesthesia in rats. The mechanism of protection appeared to involve upregulation of Bcl-2 expression resulting in inhibited apoptosis.

Remote Ischemic Preconditioning Improves Outcome at 6 Years After Elective Percutaneous Coronary Intervention

Postprocedural myocardial infarction (type 4a) has been shown to be an adverse prognostic indicator after elective percutaneous coronary intervention (PCI). The Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) study demonstrated that remote ischemic preconditioning reduced procedural symptoms, ECG ST-segment deviation, and cardiac troponin I release after elective PCI and reduced the major adverse cardiac and cerebral event (MACCE) rate at 6 months. We were interested to confirm if this early benefit in MACCE rate in the remote ischemic preconditioning group was sustained long-term. Patients were telephoned by researchers blinded to the randomization details. MACCE, defined as all-cause mortality, nonfatal myocardial infarction, transient ischemic attack or stroke, and heart failure requiring hospital admission, were adjudicated by case note and national database review. One hundred ninety-two (89.3%) of the 225 patients with elective PCI randomized in the original study were available for long-term follow-up (mean time to event or last follow-up: 1579.7±603.6 days). There were a total of 59 (30.7%) MACCEs. Patients with an MACCE had a higher mean cardiac troponin I after PCI (±SD): 2.07±6.99 versus 0.91±2.07 ng/mL (P=0.05). The MACCE rate at 6 years remained lower in the remote ischemic preconditioning group (hazard ratio, 0.58; 95% confidence interval, 0.35-0.97; P=0.039; absolute risk reduction=0.13 and number needed to treat=8 to prevent the MACCE at 6 years). Remote ischemic preconditioning reduces the incidence of postprocedural cardiac troponin I after elective PCI and confers an MACCE-free survival benefit at both short- and long-term follow-up. URL: http://www.ukcrn.org.uk. Unique identifier: UKCRN 4074.

Effect of remote ischemic perconditioning on systemic inflammatory response in patients undergoing cardiac valve replacement with cardiopulmonary bypass

Objective To evaluate the effect of remote ischemic perconditioning on systemic inflammatory response in the patients undergoing cardiac valve replacement with cardiopulmonary bypass (CPB).Methods Forty adult patients undergoing cardiac valve replacement under CPB were randomly divided into 2 groups (n =20 each):control group (group C) and remote ischemic preconditioning group (group R).Anesthesia was induced with iv injection of midazolam,fentanyl,vecuronium.The patients were mechanically ventilated after endotracheal intubation.Anesthesia was maintained with iv injection of midazolam,fentanyl,vecuronium and inhalation of sevoflurane.Three cycles of 5-min ischemia and 5-rmin reperfusion were performed on the fight lower extremity immediately after aortic occlusion by means of a tourniquet in group R.A tourniquet was only placed under the right lower extremity in group C.Before CPB and at 0,6 and 24 h after termination of CPB (T1-4),blood samples were obtained from the right internal jugular vein for determination of levels of serum intercellular adhesion molecule-1 (ICAM-1),IL-6 and TNF-α.Results The levels of serum ICAM-1,IL-6 and TNF-α were significantly lower in group R than in group C (P ＜ 0.05).Compared with the baseline value at T1,the levels of serum ICAM-1,IL-6 and TNF-α were significantly increased at T2 and T3 in both groups,serum ICAM-1 and IL-6 levels were increased at T4 in group C,while serum IL-6 level was increased at T4 in group R (P ＜ 0.05).The levels of serum ICAM-1,IL-6 and TNF-α were significantly decreased at T3 and T4 than at T2 in both group (P ＜ 0.05).The levels of serum ICAM-1,IL-6 and TNF-α were significantly lower at T4 than at T3 in both groups (P ＜ 0.05).Conclusion Remote ischemic perconditioning can alleviate the systemic inflammatory response in patients undergoing cardiac valve replacement with CPB. Key words: Extracorporeal circulation; Systemic inflammatory response syndrome; Remote ischemic perconditioning

Physical rehabilitation based on the phenomenon of ischemic preconditioning in patients with ischemic heart disease

Ischemic preconditioning (IP) triggers mechanisms that are cardioprotective during non‐fatal ischemia. Exercise programs are frequently prescribed for patients with ischemic heart disease (IHD). Here we report a strategy for physical rehabilitation of IHD patients based on presumed IP. Patients with stable IHD (age 38–65 y; ejection fraction &gt;;40%), incomplete revascularization after transcutaneous coronary angioplasty, and positive results of a diagnostic exercise stress test were studied. The IP group (53.9±6.2 y; n=11) performed treadmill exercise for 10 days at 70–80% of diagnostic intensity, with duration determined by the time to ST depression and/or appearance of anginal symptoms. The control (C) group (56.1±4.8 y, n=10) performed standard exercise training for 10 days at 50–60% of diagnostic intensity for 30 min. Monitored safety indices: ECG, BP, heart rate, and myocardial injury markers. Post‐training, for the IP group compared to the C group, diagnostic exercise duration increased by 17.5±3.6% vs 4.1±1.2% (p &lt;0.05); MET by 9.3±2.6% vs 2.4±1.1% (p &lt;0.05); double product by 6.5±2.9% vs 2.1±1.0% (p=0.021); maximum ST depression decreased by 46.3±6.8% in the IP group vs 9.8±1.6% in the C group (p &lt;0.001). Safety indices were within reference ranges in both groups. Thus, exercise‐induced IP effectively improves exercise tolerance in IHD patients.

Protective effect of endothelial progenitor cells mediated by ischemic preconditioning on renal ischemic injury induced by nephron sparing surgery

Objective To investigate the role of endothelial progenitor cells (EPCs) mediated by ischemic preconditioning (IPC) in renal ischemic injury in a nephron sparing surgery (NSS) rat model.Methods Ninety male Sprague-Dawley rats were randomly divided into three groups after right-side kidney nephrectomy.In sham-operated rats,lumbotomy without vascular clamping was performed; In NSS rats,renal blood vesses were clamped for 40 min and lower pole partial nephrectomy (PN) was performed; In NSS + IPC rats,besides pre-treatment with 15-min ischemia and 10-min reperfusion,the rest procedures were the same as those in NSS rats.At 1,3,6,12,24 h,and 3 days after reperfusion,the circulating pool and kidneys were harvested.The severity of renal injury,the home of EPCs,proliferation of endothelial cells as well as vascular growth factor expression was examined.Results Pretreated rats exhibited significant improvements in renal function and morphology.The histological score was significantly decreased in IPC group as compared with NSS group [(1.80 ± 0.45) vs.(3.00 ± 0.71),P ＜ 0.05].The number of EPCs in the kidneys was increased at 12 h after reperfusion in IPC group as compared with NSS groups [(5.75 ± 0.71) ％ vs.(2.92 ± 0.71) ％,P ＜ 0.05].Proliferation of EPCs in peritubular capillaries was markedly increased in the kidneys treated with IPC.In addition,the expression of vascular endothelial growth factor,and stromal cell-derived factor-1α in the kidneys of pretreated rats was increased as compared with that in rats subjected to ischemic injury (P ＜ 0.05).Conclusion IPC may attenuate renal ischemic injury induced by NSS; EPCs play an important role in renal protection,which involves promotion of endothelial cell proliferation through release of several angiogenic factors. Key words: Ischemic preconditioning; Endothelial progenitor cells; Nephron sparing surgery

Ischemic preconditioning attenuates remote pulmonary inflammatory infiltration of diabetic rats with an intestinal and hepatic ischemia-reperfusion injury

To assess ischemic preconditioning (IPC) effects in pulmonary lesion in intestinal and hepatic ischemia-reperfusion (IR) injury models using diabetic rats. Diabetes (DM) was induced in 28 male Wistar rats by alloxan (42 mg/kg, IV). After 28 days, severe DM rats were submitted to intestinal or hepatic IR injury with or without IPC. Intestinal IR (30 min of mesenteric artery occlusion and 30 min of reperfusion; n=6) and IPC groups (10 min ischemia, 10 min reperfusion, followed by intestinal IR; n=6), and Hepatic IR (30 min of hepatic pedicle occlusion and 30 min of reperfusion; n=5) and IPC groups (10 min ischemia, 10 min reperfusion, followed by hepatic IR; n=5), were compared to DM rats group (n=6). Plasmatic lactate, glycemia were measured before and after IR injury. Histomorphology of lung was performed counting inflammatory cells. Data was expressed in mean± SE. P<0.05. Glycemia and lactate were similar among groups. IPC did not interfere in these parameters. On histological evaluation, IR increased inflammatory cells infiltration in pulmonary parenchyma compared to control in both IR injury models. IPC attenuated inflammatory infiltration in lungs. Ischemic preconditioning protects against remote ischemia-reperfusion injury in lung on intestinal or hepatic ischemia-reperfusion model with acute diabetes.

Role of beclin 1-dependent autophagy in cardioprotection of ischemic preconditioning

Emerging evidence indicates that ischemic preconditioning (IPC) induces autophagy which attenuates myocardial ischemia/reperfusion (I/R) injury. However, the precise mechanisms remain complex and unclear. The present study was to investigate which autophagy pathway was involved in the cardioprotection induced by IPC, so that we can acquire an attractive treatment way for ischemic heart disease. Adult male Sprague-Dawley (SD) rats were randomly divided into sham group, I/R group and IPC group. IPC was induced with three cycles of 5 min regional ischemia alternating with 5 min reperfusion in a heart I/R model. Samples were taken from the center of the infracted heart and examined by using the electron microscopy, the terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) method, Western blotting and co-immunoprecipitation (Co-IP). A large number of autophagic vacuoles were observed in the cardiomyocytes of IPC group as compared with I/R group. LC3-II formation, an autophagy marker, was up-regulated in IPC group as compared with I/R group (P<0.05). Moreover, the interaction between Beclin 1 and Bcl-2 was significantly increased in IPC group as compared with I/R group (P<0.01). It was also found that IPC decreased I/R-induced apoptosis (P<0.01). These results suggest that IPC inhibits Beclin 1-dependent excessive autophagy in reperfusion phase and cooperates with anti-apoptosis pathway to diminish the cell death induced by the myocardial I/R injury.

Ischemic Preconditioning Increases Endothelial Progenitor Cell Number to Attenuate Partial Nephrectomy-Induced Ischemia/Reperfusion Injury

ObjectivesThe objective of this study was to investigate the role of endothelial progenitor cells (EPCs) in the modulation of ischemia-reperfusion injury (IRI) in a partial nephrectomy (PN) rat model using early-phase ischemic preconditioning (IPC).Materials and MethodsNinety male Sprague-Dawley rats were randomly divided into three groups following right-side nephrectomy: Sham-operated rats (surgery without vascular clamping); PN rats (renal blood vessels were clamped for 40 min and PN was performed); and IPC rats (pretreated with 15 min ischemia and 10 min reperfusion). At 1, 3, 6, 12, 24 h, and 3 days after reperfusion, the pool of circulating EPCs and kidneys were harvested. The extent of renal injury was assessed, along with EPC number, cell proliferation, angiogenesis, and vascular growth factor expression.ResultsPretreated rats exhibited significant improvements in renal function and morphology. EPC numbers in the kidneys were increased at 12 h following reperfusion in the IPC group as compared to the PN or Sham groups. Cell proliferation (including endothelial and tubular epithelial cells) and angiogenesis in peritubular capillaries were markedly increased in kidneys treated with IPC. In addition, vascular endothelial growth factor-A (VEGF-A) and stromal cell-derived factor-1α (SDF-1α) expression in the kidneys of pretreated rats was increased compared to rats subjected to PN.ConclusionsOur investigation suggested that: (1) the early phase of IPC may attenuate renal IRI induced by PN; (2) EPCs play an important role in renal protection, involving promotion of cell proliferation and angiogenesis through release of several angiogenic factors.

Assessment of effects of IR and IPC on activities of cytochrome P450 isozymes in rats by a five-drug cocktail approach

Background and objective: To evaluate the effects of ischemia and reperfusion (IR) and ischemic preconditioning (IPC) on the metabolic activities of cytochrome P450 (CYP) isozymes in rats by a five-drug cocktail approach.Methods: Cocktail approach was used to evaluate the influence of IR and IPC on the activities of CYP1A2, CYP2C9, CYP2E1, CYP2D6 and CYP3A4, which were reflected by the changes of pharmacokinetic parameters of five specific probe drugs: caffeine, chlorzoxazone, tolbutamide, metoprolol and midazolam, respectively. Rats were randomly divided into IR, IPC and sham groups, and then injected the mixture of five probe drugs. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by a HPLC method with UV detection. The pharmacokinetic parameters were calculated by the software of DAS 2.0.Results: The parameters including t1/2β, CLs, AUC, MRT and K10 exhibited a similar tendency for both IR and IPC groups. Compared with sham group, CLs and K10 of five probe drugs were significantly lower (p < 0.05), AUC and t1/2β of five or some probe drugs were significantly increased in IR and IPC groups (p < 0.05). Compared with IPC group, CLs of five probe drugs were decreased and AUC were significantly increased in the IR group (p < 0.05).Conclusion: IR can variably decrease the activities of CYP isozymes in rats and this decrease can be attenuated by IPC.