Protective Effect Of Remote Ischemic Preconditioning Research Articles

Role of Remote Ischemic Preconditioning in Hepatic Ischemic Reperfusion Injury.

The effect of remote ischemic preconditioning (RIPC) has been proposed that mediates the protective response in ischemia reperfusion injury (IRI) of various organs. In this study, we investigated the effect of RIPC in hepatic IRI, by assessing biomarker of oxidative stress and inflammatory cytokines. Moreover, we intended to demonstrate any such protective effect through nitric oxide (NO). Twenty-five rats were divided into the 5 groups: (1) Sham; (2) RIPC; (3) hepatic IRI; (4) RIPC + hepatic IRI; (5) C-PTIO, 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide, + RIPC + hepatic IRI. RIPC downregulated the level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), histologic damage, and activity of Malondialdehyde (MDA). However, there was no significant reduction in the level of tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). AST and ALT levels, and hepatic tissue morphology in the C-PTIO group showed a significant improvement compared to those of the RIPC + hepatic IRI group. The application of RIPC before hepatic ischemia downregulated the oxidative stress, not the inflammatory cytokines. Moreover, these protective effect of RIPC would be mediated through the activation of NO as well as anti-oxidant effect.

P2687Impact of cardiovascular risk factors on effectiveness of remote ischemic preconditioning in the setting of ischemia/reperfusion-injury in a langendorff heart model

Abstract Introduction Cardiovascular diseases are the most frequent cause of death in the western world. During myocardial infarction both, ischemia and reperfusion after therapeutic intervention cause myocardial damages, resulting in ischemia/reperfusion-injury (I/R-injury). Research therefore searches cardio protective interventions, aiming to reduce myocardial injury and following consequences such as heart failure. A promising method, named Remote Ischemic Preconditioning (RIPC), consists of transient local ischemia distant from the heart. Its cardio-protective effects were already proved in basic research but failed in clinical trials. Purpose The aim of the study is to examine the impact of cardiac risk factors like diabetes mellitus (DM) or age on effectiveness of RIPC in order to identify distinct groups of patients who might benefit from RIPC in the clinical setting and to reveal the effectiveness of cardioprotection delivered by plasma samples of these groups of patients. Methods RIPC (3 x 5 min arm ischemia, induced by an inflated blood pressure cuff) was performed on young and healthy volunteers and elderly patients with coronary heart disease with or without diabetes mellitus. Blood was taken before (Baseline) and 30 minutes after the intervention. The coronary system of murine hearts in a Langendorff heart model was perfused using dialysate from the human plasma obtained before and after RIPC. This was followed by 40 minutes of global ischemia. After 60 minutes of reperfusion left ventricular function was analysed. The infarct size was measured after 120 minutes reperfusion time using a TTC staining. Results Addition of dialysate of plasma obtained from healthy volunteers after RIPC to the coronary system of Langendorff perfused murine hearts significantly improved the recovery of left ventricular developed pressure (39±15.1 vs 26±8.5% of baseline levels, p=0.04) and reduced the infarct size (37.5±15.6 vs 21.2±11.4% of the ventricular volume, p=0.03) compared to baseline-dialysate treated controls. While plasma dialysate obtained from elderly patients with DM undergoing RIPC failed to show significant cardio protective effects of RIPC, murine hearts treated with plasma dialysate of elderly patients with coronary heart disease without diabetes after undergoing RIPC showed significant improvement of cardiac function (20±6.5 vs 24±7% of baseline levels, p=0.02) and infarct size (33.2±8.0 vs 11.1±2.5% of the ventricular volume, p=0.01). Conclusion The cardio-protective effect of RIPC on myocardial function and infarct size after I/R is influenced by diabetes but not by age or the presence of coronary heart disease. In consequence, RIPC might protect patients with coronary heart disease without DM but not diabetic patients from cardiac I/R injury. This important finding potentially explains why RIPC yielded promising results in various basic science experiments but failed to show cardio protective effects in clinical trials. Acknowledgement/Funding Forschungskommission of the Faculty of Medicine of the Heinrich-Heine-University Düsseldorf

The Effect of Nitric Oxide on Remote Ischemic Preconditioning in Renal Ischemia Reperfusion Injury in Rats.

Although remote ischemic preconditioning (RIPC) is an organ-protective maneuver from subsequent ischemia reperfusion injury (IRI) by application of brief ischemia and reperfusion to other organs, its mechanism remains unclear. However, it is known that RIPC reduces the heart, brain, and liver IRI, and that nitric oxide (NO) is involved in the mechanism of this effect. To identify the role of NO in the protective effect of RIPC in renal IRI, this study examined renal function, oxidative status, and histopathological changes using N-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor. Remote ischemic preconditioning was produced by 3 cycles of 5 minutes ischemia and 5 minutes reperfusion. Blood urea nitrogen, creatinine (Cr), and renal tissue malondialdehyde levels were lower, histopathological damage was less severe, and superoxide dismutase level was higher in the RIPC + IRI group than in the IRI group. The renoprotective effect was reversed by L-NAME. Obtained results suggest that RIPC before renal IRI contributes to improvement of renal function, increases antioxidative marker levels, and decreases oxidative stress marker levels and histopathological damage. Moreover, NO is likely to play an important role in this protective effect of RIPC on renal IRI.

Is there a protective effect with remote ischemic preconditioning on contrast-induced acute renal injury after coronary angiography in low-risk patients?

Introduction: Contrast-induced acute kidney injury (CIN-AKI) is a serious complication of coronary angiography. Given the weaknesses in the common protective methods used to prevent CIN-AKI, a safe and effective strategy is needed. RIPC has been shown to have a nephroprotective effect. Objectives: We aimed to determine the protective effect of RIPC on CIN-AKI after angiography or percutaneous coronary intervention (PCI) in low-risk patients. Patients and Methods: In our study, 140 low-risk patients who needed angiography or PCI, were assigned to either RIPC or control group. In each group, serum creatinine and urinary neutrophil gelatinaseassociated lipocalin (uNGAL) were measured before the procedure. Serum creatinine was measured daily for 2 days and uNGAL was measured 6 and 24 hours after the procedure. Diagnosis of AKI was, according to the Kidney Disease; Improving Global Outcomes (KDIGO) criteria (2012). Results: The mean age in the remote ischemic preconditioning (RIPC) group was 56.8 ± 11.4 years and 56.3 ± 11.8 years in the control group. We observed no significant difference regarding patient’s characteristic and renal biomarkers at baseline. There was no significant difference in the incidence of AKI (P = 0.116). The uNGAL increased by 36.2% 6-hour after the procedure in patients with AKI, while at the same time, this biomarker increased only by 4.3% in patients without AKI. Conclusion: We concluded that RIPC, with 3 cycles of 5-minute ischemia and 5-minute reperfusion, did not decrease CIN-AKI or altering renal biomarkers course in low-risk patients undergoing coronary angiography or PCI. Additionally, uNGAL, seems to be an appropriate biomarker for early diagnosis of CIN-AKI, 6 hours after contrast media exposure.

Integrative Analysis of Renal Ischemia/Reperfusion Injury and Remote Ischemic Preconditioning in Mice.

Remote ischemic preconditioning (RIPC) is a strategy to induce resistance in a target organ against the oxidative stress and injury caused by ischemia and reperfusion (IR). RIPC harnesses the body's endogenous protective capabilities through brief episodes of IR applied in organs remote from the target. Few studies have analyzed this phenomenon in the kidney. Furthermore, the window of protection representing RIPC efficacy has not been fully elucidated. Here, we performed a multiomics study to specify those associated with protective effects of RIPC against the IR injury. A total of 30 mice were divided to four groups: sham, IR only, late RIPC + IR, and early RIPC + IR. We found that IR clearly led to tubular injury, whereas both preconditioning groups exhibited attenuated injury after the insult. In addition, renal IR injury produced changes of the metabolome in kidney, serum, and urine specimens. Furthermore, distinctive mRNA and associated protein expression changes supported potential mechanisms. Our findings revealed that RIPC effectively reduces renal damage after IR and that the potential mechanisms differed between the two time windows of protection. These results may potentially be extended to humans to allow non- or minimally invasive diagnosis of renal IR injury and RIPC efficacy.

Effects of Remote Ischemic Preconditioning on Heme Oxygenase-1 Expression and Cutaneous Wound Repair.

Skin wounds may lead to scar formation and impaired functionality. Remote ischemic preconditioning (RIPC) can induce the anti-inflammatory enzyme heme oxygenase-1 (HO-1) and protect against tissue injury. We aim to improve cutaneous wound repair by RIPC treatment via induction of HO-1. RIPC was applied to HO-1-luc transgenic mice and HO-1 promoter activity and mRNA expression in skin and several other organs were determined in real-time. In parallel, RIPC was applied directly or 24h prior to excisional wounding in mice to investigate the early and late protective effects of RIPC on cutaneous wound repair, respectively. HO-1 promoter activity was significantly induced on the dorsal side and locally in the kidneys following RIPC treatment. Next, we investigated the origin of this RIPC-induced HO-1 promoter activity and demonstrated increased mRNA in the ligated muscle, heart and kidneys, but not in the skin. RIPC did not change HO-1 mRNA and protein levels in the wound 7 days after cutaneous injury. Both early and late RIPC did not accelerate wound closure nor affect collagen deposition. RIPC induces HO-1 expression in several organs, but not the skin, and did not improve excisional wound repair, suggesting that the skin is insensitive to RIPC-mediated protection.

Clinical Outcomes of Remote Ischemic Preconditioning Prior to Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials.

BackgroundMultiple randomized controlled trials of remote ischemic preconditioning (RIPC) prior to cardiac surgery have failed to demonstrate clinical benefit. The aim of this updated meta‐analysis was to evaluate the effect of RIPC on outcomes following cardiac surgery.Methods and ResultsSearches of PubMed, Cochrane, EMBASE, and Web of Science databases were performed for 1970 to December 13, 2015. Randomized controlled trials comparing RIPC with a sham procedure prior to cardiac surgery performed with cardiopulmonary bypass were assessed. All‐cause mortality, acute kidney injury (AKI), and myocardial infarction were the primary outcomes of interest. We identified 21 trials that randomized 5262 patients to RIPC or a sham procedure prior to undergoing cardiac surgery. The majority of patients were men (72.6%) and the mean or median age ranged from 42.3 to 76.3 years. Of the 9 trials that evaluated mortality, 188 deaths occurred out of a total of 4210 randomized patients, with 96 deaths occurring in 2098 patients (4.6%) randomized to RIPC and 92 deaths occurring in 2112 patients (4.4%) randomized to a sham control procedure, demonstrating no significant reduction in all‐cause mortality (risk ratio [RR], 0.987; 95% CI, 0.653–1.492, P=0.95). Twelve studies evaluated AKI in 4209 randomized patients. In these studies, AKI was observed in 516 of 2091 patients (24.7%) undergoing RIPC and in 577 of 2118 patients (27.2%) randomized to a sham procedure. RIPC did not result in a significant reduction in AKI (RR, 0.839; 95% CI, 0.703–1.001 [P=0.052]). In 6 studies consisting of 3799 randomized participants, myocardial infarction occurred in 237 of 1891 patients (12.5%) randomized to RIPC and in 282 of 1908 patients (14.8%) randomized to a sham procedure, resulting in no significant reduction in postoperative myocardial infarction (RR, 0.809; 95% CI, 0.615–1.064 [P=0.13]). A subgroup analysis was performed a priori based on previous studies suggesting that propofol may mitigate the protective benefits of RIPC. Three studies randomized patients undergoing cardiac surgery to RIPC or sham procedure in the absence of propofol anesthesia. Most of these patients were men (60.3%) and the mean or median age ranged from 57.0 to 70.6 years. In this propofol‐free subgroup of 434 randomized patients, 71 of 217 patients (32.7%) who underwent RIPC developed AKI compared with 103 of 217 patients (47.5%) treated with a sham procedure. In this cohort, RIPC resulted in a significant reduction in AKI (RR, 0.700; 95% CI, 0.527–0.930 [P=0.014]). In studies of patients who received propofol anesthesia, 445 of 1874 (23.7%) patients randomized to RIPC developed AKI compared with 474 of 1901 (24.9%) who underwent a sham procedure. The RR for AKI was 0.928 (95% CI, 0.781–1.102; P=0.39) for RIPC versus sham. There was no significant interaction between the two subgroups (P=0.098).ConclusionsRIPC does not reduce morbidity or mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. In the subgroup of studies in which propofol was not used, a reduction in AKI was seen, suggesting that propofol may interact with the protective effects of RIPC. Future studies should evaluate RIPC in the absence of propofol anesthesia.

Repeated remote ischemic preconditioning and isoflurane anesthesia in an experimental model of renal ischemia-reperfusion injury

BackgroundIn animal studies, remote ischemic preconditioning (RIPC) and anesthetic preconditioning are successful in reducing renal ischemia reperfusion injury (IRI), however the protective effect of RIPC may be improved by repeating the RIPC stimulus.MethodsSprague-Dawley rats underwent unilateral nephrectomy followed by 30 min of renal pedicle clamping. Animals were allocated into six groups: sham, control (IRI), RepISO (daily isoflurane anesthesia), RIPC (single dose isoflurane anesthesia and single dose RIPC), RepISO + RIPC (7-day isoflurane anesthesia and single dose RIPC) and RepISO + RepRIPC (7-day isoflurane anesthesia with 7-day RIPC). RIPC was applied by 3×5 min of cuff inflation on both thighs. Serum creatinine and urea levels were measured and histology was obtained at day two.ResultsRepISO diminished renal IRI, as reflected by a significant reduction in serum creatinine levels as compared to the control group, 170 ± 74 resp. 107 ± 29 μmol/L. The other preconditioning protocols showed similar reduction in serum creatinine levels as compared to the control group. No significant differences were observed between the different preconditioning protocols. For urea levels, only RepISO + RIPC resulted in significantly lower levels as compared to the control group, 14 ± 4 resp. 22 ± 7 mmol/L (p = 0.010). In the preconditioning groups only RepISO showed less histological damage as compared to controls 1.73 ± 1.19 resp. 2.91 ± 1.22 (p = 0.032).ConclusionsIn this study no additional protective effect of repeated ischemic preconditioning was observed as compared to single dose RIPC. Repeated administration of isoflurane provided stronger protection against renal IRI as compared to single dose isoflurane.

Protective Effect of Ischemic Preconditioning on Myocardium Against Remote Tissue Injury Following Transient Focal Cerebral Ischemia in Diabetic Rats.

BackgroundRemote ischemic preconditioning (IPreC) could provide tissue-protective effect at a remote site by anti-inflammatory, neuronal, and humoral signaling pathways.ObjectivesThe aim of the study was to investigate the possible protective effects of remote IPreC on myocardium after transient middle cerebral artery occlusion (MCAo) in streptozotocin- induced diabetic (STZ) and non-diabetic rats.Methods48 male Spraque Dawley rats were divided into eight groups: Sham, STZ, IPreC, MCAo, IPreC+MCAo, STZ+IPreC, STZ+MCAo and STZ+IPreC+MCAo groups. We induced transient MCAo seven days after STZ-induced diabetes, and performed IPreC 72 hours before transient MCAo. Remote myocardial injury was investigated histopathologically. Bax, Bcl2 and caspase-3 protein levels were measured by Western blot analysis. Total antioxidant status (TAS), total oxidant status (TOS) of myocardial tissue were measured by colorimetric assay. Oxidative stress index(OSI) was calculated as TOS-to-TAS ratio. For all statistical analysis, p values < 0.05 were considered significant.ResultsWe observed serious damage including necrosis, congestion and mononuclear cell infiltration in myocardial tissue of the diabetic and ischemic groups. In these groups TOS and OSI levels were significantly higher; TAS levels were lower than those of IPreC related groups (p < 0.05). IPreC had markedly improved histopathological alterations and increased TAS levels in IPreC+MCAo and STZ+IPreC+MCAo compared to MCAo and STZ+MCAo groups (p < 0.05). In non-diabetic rats, MCAo activated apoptotic cell death via increasing Bax/Bcl2 ratio and caspase-3 levels. IPreC reduced apoptotic cell death by suppressing pro-apoptotic proteins. Diabetes markedly increased apoptotic protein levels and the effect did not reversed by IPreC.ConclusionsWe could suggest that IPreC attenuates myocardial injury via ameliorating histological findings, activating antioxidant mechanisms, and inducing antiapoptotic activity in diabetic rats.

Remote ischemic preconditioning as prevention of transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion medicine, considered now as the leading cause of transfusion-related mortality. It may occur in up to 1 in 5000 transfusions and carries an elevated morbidity and mortality. Clinically it presents as hypoxia and non-cardiogenic pulmonary edema, usually within 6h of transfusion. It consists of an immunological phenomenon involving the activation of neutrophils and endothelial injury, leading to capillary leak and pulmonary edema, mechanisms shared with lung ischemia–reperfusion (IR) injury. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIPC). Limb RIP has been shown to protect the lung against IR injury trough modulation of endothelial function as well as neutrophil activation and infiltration. The protective effects of RIPC on the lung have been confirmed in clinical trials of orthopedic and cardiothoracic surgery. RIPC is a safe, tolerable and cheap procedure. I propose that limb RIPC could be used as a preventive strategy against the development of TRALI.

Cardioprotection by Remote Ischemic Preconditioning Exhibits a Signaling Pattern Different From Local Ischemic Preconditioning

Remote ischemic preconditioning (RIPC) and local ischemic preconditioning (IPC) protect the myocardium from subsequent ischemia/reperfusion (I/R) injury. In this study, the protective effects of early RIPC, IPC, and the combination of both (RIPC-IPC) were characterized. Furthermore, the hypothesis was tested that protein kinase C (PKC) and mitogen-activated protein kinases (MAPKs), important mediators of IPC, are activated in RIPC. Infarct size, serum troponin T, and creatine kinase levels were assessed after 4 × 5-min noninvasive RIPC, local IPC, or a combination of both and 35 min of regional ischemia and 120 min of reperfusion. Protein kinase C ε and the MAPKs extracellular signal-regulated MAPK (ERK), c-jun N-terminal kinase (JNK), and p38 MAPK were analyzed by Western blot analysis and activity assays in the myocardium and skeletal muscle immediately after the preconditioning protocol. Remote ischemic preconditioning, IPC, and RIPC-IPC significantly reduced myocardial infarct size (RIPC-I/R: 54% ± 15%; IPC-I/R: 33% ± 15%; RIPC-IPC-I/R: 33% ± 15%; P < 0.05 vs. I/R [76% ± 14%]) and troponin T release (RIPC-I/R: 15.4 ± 6.4 ng/mL; IPC-I/R: 10.9 ± 7.0 ng/mL; RIPC-IPC-I/R: 9.8 ± 5.6 ng/mL; P < 0.05 vs. I/R [27.1 ± 12.0 ng/mL]) after myocardial I/R. Ischemic preconditioning led to an activation of PKCε and ERK 1/2, whereas RIPC did not lead to a translocation of PKCε to the mitochondria or phosphorylation of the MAPKs ERK 1/2, JNK 1/2, and p38 MAPK. Remote ischemic preconditioning did not induce translocation of PKCε to the mitochondria or phosphorylation of MAPKs in the preconditioned muscle tissue. Remote ischemic preconditioning, IPC, and RIPC-IPC exert early protection against myocardial I/R injury. Remote ischemic preconditioning and local IPC exhibit different activation dynamics of signal transducers in the myocardium. The studied PKC-MAPK pathway is likely not involved in the protective effects of RIPC.

Remote Ischemic Preconditioning Reduces Myocardial and Renal Injury After Elective Abdominal Aortic Aneurysm Repair: A Randomized Controlled Trial

Conclusion: Remote ischemic preconditioning (RIPC) reduces postoperative myocardial injury, myocardial infarction, and renal impairment in patients undergoing elective open abdominal aortic aneurysm (AAA) repair. Summary: Remote ischemic preconditioning is a phenomenon where brief periods of ischemia, followed by reperfusion, can provide systemic protection from prolonged ischemia. The authors sought to investigate whether RIPC could reduce the incidence of myocardial and renal injury in patients undergoing elective AAA repair. This was a randomized trial, and 82 patients were randomized to undergo AAA repair with RIPC or AAA repair without RIPC. Remote ischemic preconditioning was performed using two cycles of intermittent cross-clamping of the common iliac arteries with 10 minutes of ischemia, followed by 10 minutes of reperfusion. Cardiac troponin levels were used to assess postoperative myocardial injury and myocardial infarction. Renal injury was assessed by serum creatinine level. Baseline characteristics were well matched in both groups. The incidence of myocardial injury was reduced 27% by RIPC (39% vs 12%; 95% confidence interval [CI], 8.8%-45%; P = .005). Also reduced in the RIPC patients were myocardial infarction (27% vs 5%; 95% CI, 7.3%-38%; P = .006) and renal impairment (30% vs 7%; 95% CI, 6.4%-39%; P = .009. The effect of covariables was assessed with multivariable analysis. The protective effect of RIPC on myocardial injury (odds ratio, 0.22; 95% CI, 0.07-0.67; P = .008), myocardial infarction (odds ratio, 0.18; 95% CI, 0.04-0.75; P = .006) was independent of the covariables. Comment: Studies suggest that ischemia at a site distal from the heart can confer ischemic protection at remote sites. This must occur through some sort of neural mechanism or a circulating humoral mechanism. It is intriguing to think that a simple maneuver that is feasible in most AAA open repairs could reduce cardiac and renal impairment after open AAA repair.

Inducing late phase of infarct protection in skeletal muscle by remote preconditioning: efficacy and mechanism

We have previously demonstrated that remote ischemic preconditioning (IPC) by instigation of three cycles of 10-min occlusion/reperfusion in a hindlimb of the pig elicits an early phase of infarct protection in local and distant skeletal muscles subjected to 4 h of ischemia immediately after remote IPC. The aim of this project was to test our hypothesis that hindlimb remote IPC also induces a late phase of infarct protection in skeletal muscle and that K(ATP) channels play a pivotal role in the trigger and mediator mechanisms. We observed that pig bilateral latissimus dorsi (LD) muscle flaps sustained 46 +/- 2% infarction when subjected to 4 h of ischemia/48 h of reperfusion. The late phase of infarct protection appeared at 24 h and lasted up to 72 h after hindlimb remote IPC. The LD muscle infarction was reduced to 28 +/- 3, 26 +/- 1, 23 +/- 2, 24 +/- 2 and 24 +/- 4% at 24, 28, 36, 48 and 72 h after remote IPC, respectively (P < 0.05; n = 8). In subsequent studies, hindlimb remote IPC or intravenous injection of the sarcolemmal K(ATP) (sK(ATP)) channel opener P-1075 (2 microg/kg) at 24 h before 4 h of sustained ischemia (i.e., late preconditioning) reduced muscle infarction from 43 +/- 4% (ischemic control) to 24 +/- 2 and 19 +/- 3%, respectively (P < 0.05, n = 8). Intravenous injection of the sK(ATP) channel inhibitor HMR 1098 (6 mg/kg) or the nonspecific K(ATP) channel inhibitor glibenclamide (Glib; 1 mg/kg) at 10 min before remote IPC completely blocked the infarct- protective effect of remote IPC in LD muscle flaps subjected to 4 h of sustained ischemia at 24 h after remote IPC. Intravenous bolus injection of the mitochondrial K(ATP) (mK(ATP)) channel inhibitor 5-hydroxydecanoate (5-HD; 5 mg/kg) immediately before remote IPC and 30-min intravenous infusion of 5-HD (5 mg/kg) during remote IPC did not affect the infarct-protective effect of remote IPC in LD muscle flaps. However, intravenous Glib or 5-HD, but not HMR 1098, given 24 h after remote IPC completely blocked the late infarct-protective effect of remote IPC in LD muscle flaps. None of these drug treatments affected the infarct size of control LD muscle flaps. The late phase of infarct protection was associated with a higher (P < 0.05) muscle content of ATP at the end of 4 h of ischemia and 1.5 h of reperfusion and a lower (P < 0.05) neutrophilic activity at the end of 1.5 h of reperfusion compared with the time-matched control. In conclusion, these findings support our hypothesis that hindlimb remote IPC induces an uninterrupted long (48 h) late phase of infarct protection, and sK(ATP) and mK(ATP) channels play a central role in the trigger and mediator mechanism, respectively.

Does nitric oxide generation contribute to the mechanism of remote ischemic preconditioning?

The protective effect of local or remote ischemic preconditioning (IPC) on subsequent 40-min ischemic and 120-min reperfusion myocardial damage was investigated. Preconditioned rats underwent one cycle of myocardial ischemia/reperfusion consisting of 5-min ischemia produced as a left coronary artery (LCA) occlusion and 5 min of reperfusion. Remote IPC was produced as 15 min of small intestinal ischemia with 15 min of reperfusion as well as 30 min of limb ischemia with 15 min of reperfusion. A marked protective action was afforded by both IPC protocols with a more significant effect of local (classic) ischemic preconditioning. Since the protective effect of remote IPC was not abolished by nitric oxide (NO) synthase inhibition with Nω-nitro- l-arginine ( l-NNA) it is concluded that NO generation may not be involved in the mechanism of remote IPC.