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Ganji N, Biouss G, Sabbatini S, Li B, Lee C, Pierro A. Remote ischemic conditioning in necrotizing enterocolitis. Semin Pediatr Surg 2023; 32:151312. [PMID: 37295298 DOI: 10.1016/j.sempedsurg.2023.151312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Necrotizing enterocolitis (NEC) is a devastating intestinal inflammatory disorder, most prevalent in premature infants, and associated with a high mortality rate that has remained unchanged in the past two decades. NEC is characterized by inflammation, ischemia, and impaired microcirculation in the intestine. Preclinical studies by our group have led to the discovery of remote ischemic conditioning (RIC) as a promising non-invasive intervention in protecting the intestine against ischemia-induced damage during early-stage NEC. RIC involves the administration of brief reversible cycles of ischemia and reperfusion in a limb (similar to taking standard blood pressure measurement) which activate endogenous protective signaling pathways that are conveyed to distant organs such as the intestine. RIC targets the intestinal microcirculation and by improving blood flow to the intestine, reduces the intestinal damage of experimental NEC and prolongs survival. A recent Phase I safety study by our group demonstrated that RIC was safe in preterm infants with NEC. A phase II feasibility randomized controlled trial involving 12 centers in 6 countries is currently underway, to investigate the feasibility of RIC as a treatment for early-stage NEC in preterm neonates. This review provides a brief background on RIC as a therapeutic strategy and summarizes the progression of RIC as a treatment for NEC from preclinical investigation to clinical evaluation.
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Affiliation(s)
- Niloofar Ganji
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - George Biouss
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Stella Sabbatini
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Bo Li
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Carol Lee
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Agostino Pierro
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada; Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, 1526-555 University Ave, Toronto, ON M5G 1×8, Canada.
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Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation. Cells 2021; 11:cells11010018. [PMID: 35011580 PMCID: PMC8750852 DOI: 10.3390/cells11010018] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Capsaicin is a potent agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel and is a common component found in the fruits of the genus Capsicum plants, which have been known to humanity and consumed in food for approximately 7000-9000 years. The fruits of Capsicum plants, such as chili pepper, have been long recognized for their high nutritional value. Additionally, capsaicin itself has been proposed to exhibit vasodilatory, antimicrobial, anti-cancer, and antinociceptive properties. However, a growing body of evidence reveals a vasoconstrictory potential of capsaicin acting via the vascular TRPV1 channel and suggests that unnecessary high consumption of capsaicin may cause severe consequences, including vasospasm and myocardial infarction in people with underlying inflammatory conditions. This review focuses on vascular TRPV1 channels that are endogenously expressed in both vascular smooth muscle and endothelial cells and emphasizes the role of inflammation in sensitizing the TRPV1 channel to capsaicin activation. Tilting the balance between the beneficial vasodilatory action of capsaicin and its unwanted vasoconstrictive effects may precipitate adverse outcomes such as vasospasm and myocardial infarction, especially in the presence of proinflammatory mediators.
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Godskesen LE, Lassen TR, Jespersen NR, Siersbæk M, Yan Y, Nielsen MM, Tjønnfjord SK, Grøntved L, Madsen G, Kjems J, Bøtker HE, Schmidt MR, Krag A, Kjeldsen J. Remote ischemic conditioning in active ulcerative colitis: An explorative randomized clinical trial. Sci Rep 2020; 10:9537. [PMID: 32533085 PMCID: PMC7293253 DOI: 10.1038/s41598-020-65692-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 05/06/2020] [Indexed: 02/08/2023] Open
Abstract
Remote ischemic conditioning (RIC) by repetitive brief periods of limb ischemia and reperfusion renders organs more resistant to ischemic injury. The protection is partly through down-regulation of the inflammatory response. Our aim was to investigate the clinical and anti-inflammatory effects of RIC in patients with active ulcerative colitis (UC). We included 22 patients with active UC in this explorative, randomized, sham-controlled clinical trial. The patients were randomly assigned 1:1 to RIC (induced in the arm through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff) or sham (incomplete inflation of the blood-pressure cuff) once daily for 10 days. Outcome variables were measured at baseline and on day 11. When compared with sham, RIC did not affect inflammation in the UC patients measured by fecal calprotectin, plasma C-reactive protein, Mayo Score, Mayo Endoscopic Subscore, Nancy Histological Index or inflammatory cytokines involved in UC and RIC. The mRNA and miRNA expression profiles in the UC patients were measured by RNA sequencing and multiplexed hybridization, respectively, but were not significantly affected by RIC. We used the Langendorff heart model to assess activation of the organ protective mechanism induced by RIC, but could not confirm activation of the organ protective mechanism in the UC patients.
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Affiliation(s)
- Line E Godskesen
- Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark
- OPEN - Odense Patient data Explorative Network, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Thomas R Lassen
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Majken Siersbæk
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Yan Yan
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark
| | - Michael M Nielsen
- Internal Medicine & Emergency Department, Odense University Hospital - Svendborg Sygehus, Svendborg, Denmark
| | - Sara K Tjønnfjord
- Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark
| | - Lars Grøntved
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
| | - Gunvor Madsen
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Hans E Bøtker
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
| | - Michael R Schmidt
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
| | - Aleksander Krag
- Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark.
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
| | - Jens Kjeldsen
- Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Moseley A, Laipply K, Rubinstein J. Capsaicin Mediates Remote Ischemic Pre-Conditioning to Explain Improved Cardiovascular Mortality With Chili Pepper Intake. J Am Coll Cardiol 2020; 75:1865. [DOI: 10.1016/j.jacc.2020.01.060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 01/22/2020] [Indexed: 11/29/2022]
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Circulating mediators of remote ischemic preconditioning: search for the missing link between non-lethal ischemia and cardioprotection. Oncotarget 2019; 10:216-244. [PMID: 30719216 PMCID: PMC6349428 DOI: 10.18632/oncotarget.26537] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 12/10/2018] [Indexed: 12/11/2022] Open
Abstract
Acute myocardial infarction (AMI) is one of the leading causes of mortality and morbidity worldwide. There has been an extensive search for cardioprotective therapies to reduce myocardial ischemia-reperfusion (I/R) injury. Remote ischemic preconditioning (RIPC) is a phenomenon that relies on the body's endogenous protective modalities against I/R injury. In RIPC, non-lethal brief I/R of one organ or tissue confers protection against subsequent lethal I/R injury in an organ remote to the briefly ischemic organ or tissue. Initially it was believed to be limited to direct myocardial protection, however it soon became apparent that RIPC applied to other organs such as kidney, liver, intestine, skeletal muscle can reduce myocardial infarct size. Intriguing discoveries have been made in extending the concept of RIPC to other organs than the heart. Over the years, the underlying mechanisms of RIPC have been widely sought and discussed. The involvement of blood-borne factors as mediators of RIPC has been suggested by a number of research groups. The main purpose of this review article is to summarize the possible circulating mediators of RIPC, and recent studies to establish the clinical efficacy of these mediators in cardioprotection from lethal I/R injury.
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Majumder A, Singh M, George AK, Homme RP, Laha A, Tyagi SC. Remote ischemic conditioning as a cytoprotective strategy in vasculopathies during hyperhomocysteinemia: An emerging research perspective. J Cell Biochem 2018; 120:77-92. [PMID: 30272816 DOI: 10.1002/jcb.27603] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/07/2018] [Indexed: 12/29/2022]
Abstract
Higher levels of nonprotein amino acid homocysteine (Hcy), that is, hyperhomocysteinemia (HHcy) (~5% of general population) has been associated with severe vasculopathies in different organs; however, precise molecular mechanism(s) as to how HHcy plays havoc with body's vascular networks are largely unknown. Interventional modalities have not proven beneficial to counter multifactorial HHcy's effects on the vascular system. An ancient Indian form of exercise called 'yoga' causes transient ischemia as a result of various body postures however the cellular mechanisms are not clear. We discuss a novel perspective wherein we argue that application of remote ischemic conditioning (RIC) could, in fact, deliver anticipated results to patients who are suffering from chronic vascular dysfunction due to HHcy. RIC is the mechanistic phenomenon whereby brief episodes of ischemia-reperfusion events are applied to distant tissues/organs; that could potentially offer a powerful tool in mitigating chronic lethal ischemia in target organs during HHcy condition via simultaneous reduction of inflammation, oxidative and endoplasmic reticulum stress, extracellular matrix remodeling, fibrosis, and angiogenesis. We opine that during ischemic conditioning our organs cross talk by releasing cellular messengers in the form of exosomes containing messenger RNAs, circular RNAs, anti-pyroptotic factors, protective cytokines like musclin, transcription factors, small molecules, anti-inflammatory, antiapoptotic factors, antioxidants, and vasoactive gases. All these could help mobilize the bone marrow-derived stem cells (having tissue healing properties) to target organs. In that context, we argue that RIC could certainly play a savior's role in an unfortunate ischemic or adverse event in people who have higher levels of the circulating Hcy in their systems.
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Affiliation(s)
- Avisek Majumder
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.,Department of Biochemistry and Molecular Genetics, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Mahavir Singh
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.,Eye and Vision Science Laboratory, University of Louisville, Louisville, Kentucky
| | - Akash K George
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.,Eye and Vision Science Laboratory, University of Louisville, Louisville, Kentucky
| | - Rubens Petit Homme
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky.,Eye and Vision Science Laboratory, University of Louisville, Louisville, Kentucky
| | - Anwesha Laha
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Suresh C Tyagi
- Department of Physiology, School of Medicine, University of Louisville, Louisville, Kentucky
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Abdul-Ghani S, Fleishman AN, Khaliulin I, Meloni M, Angelini GD, Suleiman MS. Remote ischemic preconditioning triggers changes in autonomic nervous system activity: implications for cardioprotection. Physiol Rep 2018; 5:5/3/e13085. [PMID: 28193783 PMCID: PMC5309573 DOI: 10.14814/phy2.13085] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Revised: 11/21/2016] [Accepted: 11/22/2016] [Indexed: 01/30/2023] Open
Abstract
Cardioprotective efficacy of remote ischemic preconditioning (RIPC) remains controversial. Experimental studies investigating RIPC have largely monitored cardiovascular changes during index ischemia and reperfusion with little work investigating changes during RIPC application. This work aims to identify cardiovascular changes associated with autonomic nervous system (ANS) activity during RIPC and prior to index ischemia. RIPC was induced in anesthetized male C57/Bl6 mice by four cycles of 5 min of hindlimb ischemia using inflated cuff (200 mmHg) followed by 5 min reperfusion. Electrocardiography (ECG) and microcirculatory blood flow in both hindlimbs were recorded throughout RIPC protocol. Heart rate variability (HRV) analysis was performed using ECG data. Hearts extracted at the end of RIPC protocol were used either for measurement of myocardial metabolites using high‐performance liquid chromatography or for Langendorff perfusion to monitor function and injury during 30 min index ischemia and 2 h reperfusion. Isolated‐perfused hearts from RIPC animals had significantly less infarct size after index ischemia and reperfusion (34 ± 5% vs. 59 ± 7%; mean ± SE P < 0.05). RIPC protocol was associated with increased heart rate measured both in ex vivo and in vivo. Frequency ratio of HRV spectra was altered in RIPC compared to control. RIPC was associated with a standard hyperemic response in the cuffed‐limb but there was a sustained reduction in blood flow in the uncuffed contralateral limb. RIPC hearts (prior to index ischemia) had significantly lower phosphorylation potential and energy charge compared to the control group. In conclusion, RIPC is associated with changes in ANS activity (heart rate, blood flow, HRV) and mild myocardial ischemic stress that would contribute to cardioprotection.
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Affiliation(s)
- Safa Abdul-Ghani
- Bristol Heart Institute, School of Clinical Sciences, Faculty of Medicine & Dentistry, University of Bristol, Bristol, United Kingdom
| | - Arnold N Fleishman
- Research Institute for Complex Problems of Hygiene and Occupational Diseases, Novokuznetsk Kemerovo Oblast, Russia
| | - Igor Khaliulin
- Bristol Heart Institute, School of Clinical Sciences, Faculty of Medicine & Dentistry, University of Bristol, Bristol, United Kingdom
| | - Marco Meloni
- BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Gianni D Angelini
- Bristol Heart Institute, School of Clinical Sciences, Faculty of Medicine & Dentistry, University of Bristol, Bristol, United Kingdom
| | - M-Saadeh Suleiman
- Bristol Heart Institute, School of Clinical Sciences, Faculty of Medicine & Dentistry, University of Bristol, Bristol, United Kingdom
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Rothenberger J, Wittwer M, Tschumi C, Constantinescu MA, Daigeler A, Olariu R. Quantitative impact analysis of remote ischemic conditioning and capsaicin application on human skin microcirculation. Clin Hemorheol Microcirc 2018; 71:291-298. [PMID: 29914012 DOI: 10.3233/ch-180373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Improvement of skin microcirculation would be beneficial in transplanted tissues and thus, there is a demand for effective, reliable and harmless angiogenic treatments. The aim of this study was to assess the effect of capsaicin application (CA), the remote effect of capsaicin application (REC), the impact of remote ischemic conditioning (RIC), and the impact of combined remote ischemic conditioning with capsaicin application (Comb) on human skin microcirculation. METHODS Perfusion changes were assessed using a laser Doppler device (easyLDI, Aimago Lausanne). 30 healthy volunteers were enrolled and divided into two groups: 1) CA and REC: perfusion was assessed on both forearms after application of capsaicin cream on one forearm with an exposure time of 40 minutes. 2) RIC and Comb: perfusion of one forearm was assessed after four cycles of 5 min blood occlusion and 5 min reperfusion using a tourniquet on the contralateral upper arm and application of capsaicin on the ipsilateral forearm. Baseline skin perfusion measurements of both forearms were carried out initially and were used as intra-individual reference. RESULTS 1) Skin perfusion significantly increased after capsaicin application (CA = +328.3% , p > 0.05). There was no remote skin perfusion change due to capsaicin (REC). 2) RIC significantly improves skin perfusion (RIC = +20.0% , p < 0.05). The combination of RIC and CA does not improve skin perfusion compared to CA alone (Comb). CONCLUSIONS The conditioning techniques RIC and CA showed a significant increase in human skin perfusion, CA being superior to RIC. However, the combination of CA and RIC showed no additional improvement potential as compared to CA alone. Furthermore, a remote effect of capsaicin application could not be demonstrated. These results encourage to analyze if the conditioning treatments are also beneficial for transplanted tissue survival.
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Affiliation(s)
- Jens Rothenberger
- Clinic of Hand, Plastic, Reconstructive and Burn Surgery, BG Trauma Center Tuebingen, University Tuebingen, Germany
| | - Matthias Wittwer
- University Clinic of Plastic and Hand Surgery, University Hospital, University of Bern, Inselspital, Switzerland
| | - Christian Tschumi
- University Clinic of Plastic and Hand Surgery, University Hospital, University of Bern, Inselspital, Switzerland
| | - Mihai A Constantinescu
- University Clinic of Plastic and Hand Surgery, University Hospital, University of Bern, Inselspital, Switzerland
| | - Adrien Daigeler
- Clinic of Hand, Plastic, Reconstructive and Burn Surgery, BG Trauma Center Tuebingen, University Tuebingen, Germany
| | - Radu Olariu
- University Clinic of Plastic and Hand Surgery, University Hospital, University of Bern, Inselspital, Switzerland
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Zhao Y, Zheng ZN, Liu X, Dai G, Jin SQ. Effects of preconditioned plasma collected during the late phase of remote ischaemic preconditioning on ventricular arrhythmias caused by myocardial ischaemia reperfusion in rats. J Int Med Res 2018; 46:1370-1379. [PMID: 29436250 PMCID: PMC6091815 DOI: 10.1177/0300060518755268] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Objective The administration of preconditioned plasma collected during the late phase of preconditioning has been shown to reduce myocardial infarct size. This study aimed to investigate if preconditioned plasma could attenuate ventricular arrhythmias in a rat model in vivo. Methods Eighty rats were randomized to eight groups (10 rats/group). Two groups provided preconditioned or non-preconditioned plasma 48 h after transient limb ischaemia or the control protocol. Six groups of ischaemia-reperfusion (IR) rats received normal saline, non-preconditioned plasma, or preconditioned plasma, respectively, 1 h (groups A1, A2, A3) or 24 h (groups B1, B2, B3) before undergoing myocardial IR. Electrocardiograms were monitored using a BIOPAC system, and the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) were analysed. Results No significant differences existed in the incidence and duration of VT or VF among groups A1-A3 or in the incidence and duration of VT among groups B1-B3. However, there was a significantly lower incidence and shorter duration of VF in group B3 rats than in group B1 rats. Conclusion Preconditioned plasma collected during the late phase of preconditioning can reduce the incidence and duration of VF compared with normal saline, suggesting its anti-arrhythmic potential.
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Affiliation(s)
- Yang Zhao
- 1 Department of Anaesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zhi-Nan Zheng
- 1 Department of Anaesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiang Liu
- 1 Department of Anaesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Gang Dai
- 2 The Key Laboratory of Assisted Circulation, Ministry of Health, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - San-Qing Jin
- 1 Department of Anaesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
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Dong W, Yu P, Zhang T, Zhu C, Qi J, Liang J. Adrenomedullin serves a role in the humoral pathway of delayed remote ischemic preconditioning via a hypoxia-inducible factor-1α-associated mechanism. Mol Med Rep 2018; 17:4547-4553. [PMID: 29344650 PMCID: PMC5802232 DOI: 10.3892/mmr.2018.8450] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 01/12/2018] [Indexed: 11/12/2022] Open
Abstract
Remote ischemic preconditioning (RIPC) is a minimally invasive method that provides protection by reducing injury to the heart, kidneys, brain and other tissues or organs. RIPC may improve the outcome in patients undergoing surgery. Although the role of RIPC has been studied, the results remain controversial. It is difficult to confirm whether RIPC has a kidney protective effect and the understanding of the preconditioning signal pathway involved remains unclear. In the present study, the effect of RIPC in urology was evaluated. The protection against renal damage was assessed by investigating the potential mediator, hypoxia-inducible factor-1α (HIF-1α), and the functional adrenomedullin (ADM) pathway. Male Sprague-Dawley (SD) rats were used in the present study. The animal model of kidney damage induced by ischemia reperfusion (IR) was used to investigate the protective effect of the acute and delayed phase RIPC. Furthermore, the protective effects of RIPC mediated by a HIF-1α-ADM pathway were assessed. The indexes of renal function and oxidative damage indicators were measured by Cr, BUN, mALB, β2-MG, MPO, MDA and SOD assays, and the expression of HIF-1α and ADM were detected by western blot analysis, immunohistochemistry and ELISA assays. Tubular score, determined using hematoxylin and eosin staining, was used to evaluate renal tissue damage. Applying RIPC prevented IR-induced renal dysfunction and oxidative damage by decreasing Cr, BUN, mALB, β2-MG, MPO, MDA levels and increasing SOD activity. Findings showed that delayed RIPC had an improved effect compared with acute treatment. Delayed RIPC also upregulated the expression of HIF-1α and ADM, indicating that the protective effect of the delayed RIPC may be associated with a HIF-1α-ADM-mediated mechanism. The effect of the delayed RIPC to reduce IR-induced renal damage and increase ADM expression was enhanced by HIF-1α agonists DMOG and BAY 85–3934, whereas the effect was whittled by HIF-1α antagonists YC-1 and 2-MeOE2. Furthermore, receiving ADM also offered protection to the kidney in comparison with the IR+Vehicle group. These findings suggest that RIPC prevents IR-mediated renal damage by HIF-1α via an ADM humoral pathway. In the present study, RIPC provided an effective renal protection. ADM could also offer protection regulated by HIF-1α in renal tissue. However, the mechanism of ADM as a protective factor in RIPC requires further research.
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Affiliation(s)
- Wenpei Dong
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China
| | - Ping Yu
- School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China
| | - Tielong Zhang
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China
| | - Chenzhuang Zhu
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China
| | - Jun Qi
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China
| | - Junhao Liang
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China
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Cruz RSDO, Pereira KL, Lisbôa FD, Caputo F. Could small-diameter muscle afferents be responsible for the ergogenic effect of limb ischemic preconditioning? J Appl Physiol (1985) 2016; 122:718-720. [PMID: 27815369 DOI: 10.1152/japplphysiol.00662.2016] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 11/01/2016] [Accepted: 11/01/2016] [Indexed: 02/06/2023] Open
Affiliation(s)
| | - Kayo Leonardo Pereira
- Human Performance Research Group, College of Health and Sport Science, Santa Catarina State University, Brazil
| | - Felipe Domingos Lisbôa
- Human Performance Research Group, College of Health and Sport Science, Santa Catarina State University, Brazil
| | - Fabrizio Caputo
- Human Performance Research Group, College of Health and Sport Science, Santa Catarina State University, Brazil
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12
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Epps JA, Smart NA. Remote ischaemic conditioning in the context of type 2 diabetes and neuropathy: the case for repeat application as a novel therapy for lower extremity ulceration. Cardiovasc Diabetol 2016; 15:130. [PMID: 27613524 PMCID: PMC5018170 DOI: 10.1186/s12933-016-0444-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 08/19/2016] [Indexed: 02/07/2023] Open
Abstract
An emerging treatment modality for reducing damage caused by ischaemia–reperfusion injury is ischaemic conditioning. This technique induces short periods of ischaemia that have been found to protect against a more significant ischaemic insult. Remote ischaemic conditioning (RIC) can be administered more conveniently and safely, by inflation of a pneumatic blood pressure cuff to a suprasystolic pressure on a limb. Protection is then transferred to a remote organ via humoral and neural pathways. The diabetic state is particularly vulnerable to ischaemia–reperfusion injury, and ischaemia is a significant cause of many diabetic complications, including the diabetic foot. Despite this, studies utilising ischaemic conditioning and RIC in type 2 diabetes have often been disappointing. A newer strategy, repeat RIC, involves the repeated application of short periods of limb ischaemia over days or weeks. It has been demonstrated that this improves endothelial function, skin microcirculation, and modulates the systemic inflammatory response. Repeat RIC was recently shown to be beneficial for healing in lower extremity diabetic ulcers. This article summarises the mechanisms of RIC, and the impact that type 2 diabetes may have upon these, with the role of neural mechanisms in the context of diabetic neuropathy a focus. Repeat RIC may show more promise than RIC in type 2 diabetes, and its potential mechanisms and applications will also be explored. Considering the high costs, rates of chronicity and serious complications resulting from diabetic lower extremity ulceration, repeat RIC has the potential to be an effective novel advanced therapy for this condition.
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Affiliation(s)
- J A Epps
- School of Science and Technology, The University of New England, Armidale, NSW, 2351, Australia
| | - N A Smart
- School of Science and Technology, The University of New England, Armidale, NSW, 2351, Australia.
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13
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Galagudza MM, Sonin DL, Vlasov TD, Kurapeev DI, Shlyakhto EV. Remote vs. local ischaemic preconditioning in the rat heart: infarct limitation, suppression of ischaemic arrhythmia and the role of reactive oxygen species. Int J Exp Pathol 2016; 97:66-74. [PMID: 26990944 DOI: 10.1111/iep.12170] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 12/30/2015] [Indexed: 12/13/2022] Open
Abstract
The unmet clinical need for myocardial salvage during ischaemia-reperfusion injury requires the development of new techniques for myocardial protection. In this study the protective effect of different local ischaemic preconditioning (LIPC) and remote ischaemic preconditioning (RIPC) protocols was compared in the rat model of myocardial ischaemia-reperfusion, using infarct size and ischaemic tachyarrhythmias as end-points. In addition, the hypothesis that there is involvement of reactive oxygen species (ROS) in the protective signalling by RIPC was tested, again in comparison with LIPC. The animals were subjected to 30-min coronary occlusion and 90-min reperfusion. RIPC protocol included either transient infrarenal aortic occlusion (for 5, 15 and 30 min followed by 15-min reperfusion) or 15-min mesenteric artery occlusion with 15-min reperfusion. Ventricular tachyarrhythmias during test ischaemia were quantified according to Lambeth Conventions. It was found that the infarct-limiting effect of RIPC critically depends on the duration of a single episode of remote ischaemia, which fails to protect the heart from infarction when it is too short or, instead, too prolonged. It was also shown that RIPC is ineffective in reducing the incidence and severity of ischaemia-induced ventricular tachyarrhythmias. According to our data, the infarct-limiting effect of LIPC could be partially eliminated by the administration of ROS scavenger N-2-mercaptopropionylglycine (90 mg/kg), whereas the same effect of RIPC seems to be independent of ROS signalling.
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Affiliation(s)
- Michael M Galagudza
- Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation.,ITMO University, St. Petersburg, Russian Federation
| | - Dmitry L Sonin
- Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation.,Department of Pathophysiology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Timur D Vlasov
- Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation.,Department of Pathophysiology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
| | - Dmitry I Kurapeev
- Institute of Experimental Medicine, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation
| | - Eugene V Shlyakhto
- Institute of Heart and Vessels, Federal Almazov North-West Medical Research Centre, St. Petersburg, Russian Federation.,Department of Internal Medicine, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
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Aimo A, Borrelli C, Giannoni A, Pastormerlo LE, Barison A, Mirizzi G, Emdin M, Passino C. Cardioprotection by remote ischemic conditioning: Mechanisms and clinical evidences. World J Cardiol 2015; 7:621-632. [PMID: 26516416 PMCID: PMC4620073 DOI: 10.4330/wjc.v7.i10.621] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 06/29/2015] [Accepted: 08/14/2015] [Indexed: 02/06/2023] Open
Abstract
In remote ischemic conditioning (RIC), several cycles of ischemia and reperfusion render distant organ and tissues more resistant to the ischemia-reperfusion injury. The intermittent ischemia can be applied before the ischemic insult in the target site (remote ischemic preconditioning), during the ischemic insult (remote ischemic perconditioning) or at the onset of reperfusion (remote ischemic postconditioning). The mechanisms of RIC have not been completely defined yet; however, these mechanisms must be represented by the release of humoral mediators and/or the activation of a neural reflex. RIC has been discovered in the heart, and has been arising great enthusiasm in the cardiovascular field. Its efficacy has been evaluated in many clinical trials, which provided controversial results. Our incomplete comprehension of the mechanisms underlying the RIC could be impairing the design of clinical trials and the interpretation of their results. In the present review we summarize current knowledge about RIC pathophysiology and the data about its cardioprotective efficacy.
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Remote ischemic preconditioning for myocardial protection: update on mechanisms and clinical relevance. Mol Cell Biochem 2015; 402:41-9. [PMID: 25552250 DOI: 10.1007/s11010-014-2312-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 12/20/2014] [Indexed: 02/07/2023]
Abstract
Ischemic heart disease is the leading cause of death for both men and women worldwide, accruing 7.4 million deaths in 2012. There has been a continued search for better cardioprotective modalities that would reduce myocardial ischemia-reperfusion injury. Among these attempts, a more convenient model of ischemic preconditioning, known as remote ischemic preconditioning (RIPC) was first introduced in 1993 by Przyklenk and colleagues who reported that brief regional occlusion-reperfusion episodes in one vascular bed of the heart render protection to remote myocardial tissue. Subsequently, major advances in myocardial RIPC came with the use of skeletal muscle as the ischemic stimulus. To date, numerous studies have revealed that RIPC applied to the kidney, liver, mesentery, and skeletal muscle, have all exhibited cardioprotective effects. The main purpose of this review article is to summarize the new advances in understanding the molecular mechanisms of RIPC during the past 5 years, including those related to capsaicin-activated C sensory fibers, hypoxia-inducible factor 1α, connexin 43, extracellular vesicles, microRNA-144, microRNA-1, and nitrite. In addition, we have discussed results from several recent human clinical trials with RIPC. Taken together, the emerging clinical evidence supports the concept that the effectiveness of RIPC paired with its low-cost and non-invasive features makes it an ideal treatment before reperfusion after sustained ischemia. More carefully designed studies are warranted to fully exploit the clinical benefits of RIPC and its potential implications in patients with cardiovascular disease.
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Pickard JMJ, Bøtker HE, Crimi G, Davidson B, Davidson SM, Dutka D, Ferdinandy P, Ganske R, Garcia-Dorado D, Giricz Z, Gourine AV, Heusch G, Kharbanda R, Kleinbongard P, MacAllister R, McIntyre C, Meybohm P, Prunier F, Redington A, Robertson NJ, Suleiman MS, Vanezis A, Walsh S, Yellon DM, Hausenloy DJ. Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop. Basic Res Cardiol 2014; 110:453. [PMID: 25449895 PMCID: PMC4250562 DOI: 10.1007/s00395-014-0453-6] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 11/14/2014] [Indexed: 12/20/2022]
Abstract
In 1993, Przyklenk and colleagues made the intriguing experimental observation that ‘brief ischemia in one vascular bed also protects remote, virgin myocardium from subsequent sustained coronary artery occlusion’ and that this effect ‘…. may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia/reperfusion’. This seminal study laid the foundation for the discovery of ‘remote ischemic conditioning’ (RIC), a phenomenon in which the heart is protected from the detrimental effects of acute ischemia/reperfusion injury (IRI), by applying cycles of brief ischemia and reperfusion to an organ or tissue remote from the heart. The concept of RIC quickly evolved to extend beyond the heart, encompassing inter-organ protection against acute IRI. The crucial discovery that the protective RIC stimulus could be applied non-invasively, by simply inflating and deflating a blood pressure cuff placed on the upper arm to induce cycles of brief ischemia and reperfusion, has facilitated the translation of RIC into the clinical setting. Despite intensive investigation over the last 20 years, the underlying mechanisms continue to elude researchers. In the 8th Biennial Hatter Cardiovascular Institute Workshop, recent developments in the field of RIC were discussed with a focus on new insights into the underlying mechanisms, the diversity of non-cardiac protection, new clinical applications, and large outcome studies. The scientific advances made in this field of research highlight the journey that RIC has made from being an intriguing experimental observation to a clinical application with patient benefit.
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Affiliation(s)
- Jack M. J. Pickard
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX UK
| | - Hans Erik Bøtker
- Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus N, Denmark
| | - Gabriele Crimi
- Cardiology Department, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
| | | | - Sean M. Davidson
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX UK
| | - David Dutka
- Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ UK
| | - Peter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
- Pharmahungary Group, Szeged, Hungary
| | | | | | - Zoltan Giricz
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | | | | | | | | | | | - Christopher McIntyre
- SchulichSchool of Medicine and Dentistry, University of Western Ontario, Ontario, Canada
| | - Patrick Meybohm
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Fabrice Prunier
- Cardiology Department, L’UNAM Université, University of Angers, EA3860 Cardioprotection, Remodelage et Thrombose, University Hospital, Angers, France
| | - Andrew Redington
- The Division of Cardiology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Nicola J. Robertson
- Neonatology, Institute for Women’s Health, University College London, London, WC1E 6HX UK
| | - M. Saadeh Suleiman
- Bristol Heart Institute Faculty of Medicine and Dentistry, University of Bristol, Bristol, UK
| | - Andrew Vanezis
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | | | - Derek M. Yellon
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX UK
| | - Derek J. Hausenloy
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX UK
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Zhou C, Li L, Li H, Gong J, Fang N. Delayed remote preconditioning induces cardioprotection: role of heme oxygenase-1. J Surg Res 2014; 191:51-7. [PMID: 24746951 DOI: 10.1016/j.jss.2014.03.054] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Revised: 01/25/2014] [Accepted: 03/18/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND The role of heme oxygenase-1 (HO-1) in the cardioprotection induced by delayed remote ischemic preconditioning (DRIPC) has not been investigated. Therefore, this study was designed to investigate whether HO-1 is involved in DRIPC-mediated cardioprotection in an isolated perfused rat heart model. MATERIALS AND METHODS Isolated rat hearts were subjected to 30 min ischemia followed by 60 min reperfusion. DRIPC (four cycles 5-min occlusion and 5-min reflow at the unilateral hind limb once per day for 1, 2, or 3 d before heart isolation, abbreviated as D1RIPC, D2RIPC, or D3RIPC respectively). Infarct size, myocardial troponin levels, and heart function were measured. The protein and messenger RNA levels of HO-1 were determined. RESULTS DRIPC facilitated postischemic cardiac functional recovery and decreased cardiac enzyme release. The infarct size-limiting effect of DRIPC was more pronounced in the D3RIPC group (10.22 ± 2.57%) than the D1RIPC group (22.34 ± 4.02%, P < 0.001) or the D2RIPC group (14.60 ± 3.13%, P = 0.034). These effects in the D1RIPC group could be blocked by Zinc Protoporphyrin IX (ZnPP) (an HO-1 specific inhibitor). DRIPC-mediated cardioprotection was associated with enhanced HO-1 protein expression (D1RIPC, 0.11 ± 0.03; versus 0.15 ± 0.06 in the D2RIPC group, P = 0.06; versus 0.20 ± 0.04 in the D3RIPC group, P = 0.04) and messenger RNA levels of HO-1 expression. CONCLUSIONS Our findings suggest that HO-1 is involved in the cardioprotection induced by DRIPC, and that increase in the number of preconditioning stimuli may enhance cardioprotective effects accompanied with increased HO-1 level.
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Affiliation(s)
- Chenghui Zhou
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Xicheng District, Beijing China
| | - Lihuan Li
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Xicheng District, Beijing China.
| | - Huatong Li
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Xicheng District, Beijing China
| | - Junsong Gong
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Xicheng District, Beijing China
| | - Nengxin Fang
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Xicheng District, Beijing China
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Transient limb ischemia alters serum protein expression in healthy volunteers: complement C3 and vitronectin may be involved in organ protection induced by remote ischemic preconditioning. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2013; 2013:859056. [PMID: 24363825 PMCID: PMC3865631 DOI: 10.1155/2013/859056] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Accepted: 09/30/2013] [Indexed: 12/17/2022]
Abstract
The protective mechanism underlying remote ischemic preconditioning (RIPC) is unclear. This study aims to verify whether the protein expression profile in the serum could be altered by RIPC and to detect potential protein mediators. Transient limb ischemia consisting of three cycles of 5-min ischemia followed by 5-min reperfusion was performed on sixty healthy volunteers. Serum samples were collected at 30 min before transient limb ischemia and at 1 hour (h), 3 h, 8 h, 24 h, and 48 h after completion of three cycles. Changes in the serum protein profile were analyzed by two-dimensional gel electrophoresis and proteins were identified by MALDI-TOF/TOF mass spectrometry. Fourteen differentially expressed proteins were identified and, respectively, involved in immune system, lipid binding and metabolism, apoptosis, and blood coagulation. Complement C3, vitronectin, and apolipoprotein A-I were further confirmed by western blotting, and the results showed that their contents decreased significantly after transient limb ischemia. It is concluded that transient limb ischemia alters the serum protein expression profile in human being, and that reduction of serum contents of complement C3 and vitronectin may represent an important part of the mechanism whereby RIPC confers its protection.
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Costa JF, Fontes-Carvalho R, Leite-Moreira AF. Myocardial remote ischemic preconditioning: From pathophysiology to clinical application. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2013. [DOI: 10.1016/j.repce.2013.10.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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Costa JF, Fontes-Carvalho R, Leite-Moreira AF. Pré-condicionamento isquémico remoto do miocárdio: dos mecanismos fisiopatológicos à aplicação na prática clínica. Rev Port Cardiol 2013; 32:893-904. [DOI: 10.1016/j.repc.2013.02.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 02/21/2013] [Indexed: 12/14/2022] Open
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Yang L, Wang G, Du Y, Ji B, Zheng Z. Remote ischemic preconditioning reduces cardiac troponin I release in cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth 2013; 28:682-9. [PMID: 24103716 DOI: 10.1053/j.jvca.2013.05.035] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To determine whether remote ischemic preconditioning (RIPC) reduces myocardial injury, mortality, morbidity, and resource utilization in cardiac surgery. DESIGN Meta-analysis of controlled clinical trials. The primary outcome was cardiac troponin I (cTnI) concentrations. Secondary outcomes included cardiac troponin T (cTnT) concentrations, myocardial infarction, stroke, renal failure requiring hemodialysis, atrial fibrillation, inotropic score, mechanical ventilation time, length of intensive care unit stay, length of hospital stay, and death. SETTING University hospitals. PATIENTS Adult and pediatric patients undergoing cardiac surgery, including coronary artery bypass grafting, valve procedures, and correction of congenital cardiac anomalies. INTERVENTIONS Remote ischemic preconditioning through limb ischemia. MEASUREMENTS AND MAIN RESULTS Nineteen randomized trials involving 1,235 patients were included in the meta-analysis. The cTnI concentrations at 6 (or 4-8) hours postoperatively and the total cTnI released after surgery showed a statistically significant reduction in the RIPC group compared with a control group (weighted mean difference [WMD] -2.03 ug/L, 95% confidence interval [CI] -3.25 to -0.82 ug/L, p = 0.001; WMD -65.74 ug/L*h, 95% CI -107.88 to -23.61 ug/L*h, p = 0.002, respectively). There were no differences in mortality, morbidity, and resource utilization between groups. CONCLUSIONS Current evidence suggests that RIPC reduces cardiac troponin I release in patients undergoing cardiac surgery. The clinical significance of these observations merits further investigation.
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Affiliation(s)
- Lijing Yang
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guyan Wang
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Yingjie Du
- Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bingyang Ji
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhe Zheng
- Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Ahmed RM, Mohamed EHA, Ashraf M, Maithili S, Nabil F, Rami R, Mohamed TI. Effect of remote ischemic preconditioning on serum troponin T level following elective percutaneous coronary intervention. Catheter Cardiovasc Interv 2013; 82:E647-53. [PMID: 23404916 DOI: 10.1002/ccd.24825] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2012] [Revised: 10/28/2012] [Accepted: 01/10/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Elective percutaneous coronary intervention (PCI) is associated with myocardial necrosis, as evidenced by troponin release, in approximately one-third of cases. This is known to be linked with subsequent cardiovascular events. This study assessed the ability of remote ischemic preconditioning (RIPC) to attenuate cardiac troponin T (cTnT) release after elective PCI. OBJECTIVE Evaluation of effect of RIPC on myocardial markers following elective PCI. METHODS One hundred and forty nine consecutive patients undergoing elective PCI with undetectable preprocedural cTnT were recruited. Subjects were randomized to receive RIPC (induced by three 5-min inflations of a blood pressure cuff to 200 mm Hg around the upper arm, followed by 5-min intervals of reperfusion) or control (cuff deflated) immediately before arrival in the cardiac catheterization room. The primary outcome was cTnT level at approximately 16 hr after PCI. Secondary outcomes included occurrence of postprocedural myocardial infarction (MI), CKMB levels at 16 hr after PCI and assessment of the inflammatory response as measured by C-reactive protein (CRP) levels. RESULTS The mean cTnT at 16 hr after PCI was lower in the RIPC group compared with the control group. (0.020 vs. 0.047 ng/ml; P = 0.047) Occurrence of postprocedural MI, CKMB and CRP levels did not differ in both groups (P = 0.097, 0.537, and 0.481 respectively). CONCLUSION The use of RIPC immediately prior to PCI attenuates procedure-related cTnT release and does not affect occurrence of post procedural MI, CKMB, or CRP levels.
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Affiliation(s)
- Rashed M Ahmed
- Cardiovascular Medicine Department, Dar Al-Fouad Hospital, Giza, Egypt and Department of Cardiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Internal Medicine Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan; Detroit Medical Center, Cardiovascular Institute, Wayne State University School of Medicine, Detroit, Michigan
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Abstract
Remote ischemic conditioning (RIC) is an intervention, in which intermittent episodes of ischemia and reperfusion in an organ or tissue distant from the target organ requiring protection, provide armour against lethal ischemia-reperfusion injury. Although the exact mechanisms underlying the protection mediated through RIC have not been clearly established, the release of humoral factors and the activation of neural pathways have been implicated. There is now clinical evidence suggesting that this form of protection can be induced by a simple, noninvasive, and cost-effective procedure such as inflation and deflation of a blood pressure cuff and that this intervention provides increased organ protection in a variety of clinical scenarios, for example, in myocardial infarction. Here we provide an overview of the history and evolution of RIC, the potential mechanisms underlying its protective effects, and published randomized clinical trials in cardiovascular procedures.
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Szijártó A, Czigány Z, Turóczi Z, Harsányi L. Remote ischemic perconditioning--a simple, low-risk method to decrease ischemic reperfusion injury: models, protocols and mechanistic background. A review. J Surg Res 2012; 178:797-806. [PMID: 22868050 DOI: 10.1016/j.jss.2012.06.067] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Revised: 06/18/2012] [Accepted: 06/26/2012] [Indexed: 12/18/2022]
Abstract
Interruption of blood flow can cause ischemic reperfusion injury, which sometimes has a fatal outcome. Recognition of the phenomenon known as reperfusion injury has led to initial interventional approaches to lessen the degree of damage. A number of efficient pharmacologic agents and surgical techniques (e.g., local ischemic preconditioning and postconditioning) are available. A novel, alternative approach to target organ protection is remote ischemic conditioning triggered by brief repetitive ischemia and reperfusion periods in distant organs. Among the different surgical techniques is so-called remote ischemic perconditioning, a method that applies short periods of ischemic reperfusion to a distant organ delivered during target organ ischemia. Although ischemic reperfusion injury is reduced by this technique, the explanation for this phenomenon is still unclear, and approximately only a dozen reports on the topic have appeared in the literature. In our study, therefore, we investigated the connective mechanisms, signal transduction, and effector mechanisms behind remote perconditioning, with a review on molecular background and favorable effects. In addition, we summarize the various treatment protocols and models to promote future experimental and clinical research.
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Affiliation(s)
- Attila Szijártó
- First Department of Surgery, Semmelweis University, Budapest, Hungary.
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Lim SY, Hausenloy DJ. Remote ischemic conditioning: from bench to bedside. Front Physiol 2012; 3:27. [PMID: 22363297 PMCID: PMC3282534 DOI: 10.3389/fphys.2012.00027] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Accepted: 02/04/2012] [Indexed: 12/13/2022] Open
Abstract
Remote ischemic conditioning (RIC) is a therapeutic strategy for protecting organs or tissue against the detrimental effects of acute ischemia-reperfusion injury (IRI). It describes an endogenous phenomenon in which the application of one or more brief cycles of non-lethal ischemia and reperfusion to an organ or tissue protects a remote organ or tissue from a sustained episode of lethal IRI. Although RIC protection was first demonstrated to protect the heart against acute myocardial infarction, its beneficial effects are also seen in other organs (lung, liver, kidney, intestine, brain) and tissues (skeletal muscle) subjected to acute IRI. The recent discovery that RIC can be induced non-invasively by simply inflating and deflating a standard blood pressure cuff placed on the upper arm or leg, has facilitated its translation into the clinical setting, where it has been reported to be beneficial in a variety of cardiac scenarios. In this review article we provide an overview of RIC, the potential underlying mechanisms, and its potential as a novel therapeutic strategy for protecting the heart and other organs from acute IRI.
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Affiliation(s)
- Shiang Yong Lim
- O'Brien Institute, Department of Surgery, University of Melbourne, St Vincent's Hospital Melbourne, VIC, Australia
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Heart-rate changes in asphyxic preconditioning in rats depend on light-dark cycle. Open Med (Wars) 2011. [DOI: 10.2478/s11536-011-0021-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractGenerally, it is assumed that heart-rhythm disorders during hypoxia result from the interplay between the autonomic nervous system (ANS) and the direct effect of hypoxia on cardiorespiratory structures of the central nervous system and on the myocardium. Circadian variability in the ANS may substantially influence the electrical stability of the myocardium, and thus it is associated with the preconditioning protective mechanism. We designed our study using anaesthetized Wistar rats (ketamine/xylazine 100 mg/15 mg/kg, i.m., open chest experiments) to evaluate the effect of preconditioning (PC) induced by 1 to 3 cycles (1 PC–3 PC) of asphyxia (5 min. of artificial hypoventilation, VT = 0.5 ml/100 g of b.w., 20 breaths/min.) and reoxygenation (5 min. of artificial ventilation, VT = 1 ml/100 g of b.w., 50 breaths/min.) on the heart rate (HR) during followed exposure 20 minutes of hypoventilation after adaptation to a light-dark (LD) cycle of 12 hours:12 hours. Hypoxic HR increases were only minimally prevented by 1 to 2 PC pre-treatment, particularly during the dark part of the day. A statistically significant HR increase required 3 PC and was seen only in the light part of the day. We concluded that possible ANS participation in asphyxic preconditioning depends not only on the number of preconditioned cycles but also on the LD cycle, when the ANS participation in preconditioning can be effective only in the light (nonactive) period.
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Intracerebroventricular administration of morphine confers remote cardioprotection—Role of opioid receptors and calmodulin. Eur J Pharmacol 2011; 656:74-80. [DOI: 10.1016/j.ejphar.2011.01.027] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Revised: 12/10/2010] [Accepted: 01/12/2011] [Indexed: 11/19/2022]
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Hartmann P, Varga R, Zobolyák Z, Héger J, Csősz B, Németh I, Rázga Z, Vízler C, Garab D, Sántha P, Jancsó G, Boros M, Szabó A. Anti-inflammatory effects of limb ischaemic preconditioning are mediated by sensory nerve activation in rats. Naunyn Schmiedebergs Arch Pharmacol 2010; 383:179-89. [DOI: 10.1007/s00210-010-0588-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2010] [Accepted: 12/07/2010] [Indexed: 01/27/2023]
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Saxena P, Newman MAJ, Shehatha JS, Redington AN, Konstantinov IE. Remote ischemic conditioning: evolution of the concept, mechanisms, and clinical application. J Card Surg 2009; 25:127-34. [PMID: 19549044 DOI: 10.1111/j.1540-8191.2009.00820.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Remote ischemic conditioning is a novel concept of protection against ischemia-reperfusion injury. Brief controlled episodes of intermittent ischemia of the arm or leg may confer a powerful systemic protection against prolonged ischemia in a distant organ. This conditioning phenomenon is clinically applicable and can be performed before--preconditioning, during--perconditioning, or after--postconditioning prolonged distant organ ischemia. The remote ischemic conditioning may have an immense impact on clinical practice in the near future.
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Affiliation(s)
- Pankaj Saxena
- Department of Cardiothoracic Surgery, Sir Charles Gairdner Hospital, University of Western Australia, Perth, Australia
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Sadat U. Signaling pathways of cardioprotective ischemic preconditioning. Int J Surg 2009; 7:490-8. [PMID: 19540944 DOI: 10.1016/j.ijsu.2009.06.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2009] [Revised: 06/10/2009] [Accepted: 06/11/2009] [Indexed: 12/26/2022]
Abstract
BACKGROUND Ischemia/reperfusion (I/R) injury is a major contributory factor to cardiac dysfunction and infarct size that determines patient prognosis after acute myocardial infarction. During the last 20 years, since the appearance of the first publication on ischemic preconditioning (IP), our knowledge of this phenomenon has increased exponentially. RESULTS AND CONCLUSION Basic scientific experiments and preliminary clinical trials in humans suggest that IP confers resistance to subsequent sustained ischemic insults not only in the regional tissue but also in distant organs (remote ischemic preconditioning), which may provide a simple, cost-effective means of reducing the risk of perioperative myocardial ischemia. The mechanism may be humoral, neural, or a combination of both, and involves adenosine, bradykinin, protein kinases and K(ATP) channels, although the precise end-effector remains unclear. This review describes different signaling pathways involved in acute ischemic preconditioning in detail.
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Affiliation(s)
- Umar Sadat
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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31
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Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res 2008; 79:377-86. [PMID: 18456674 DOI: 10.1093/cvr/cvn114] [Citation(s) in RCA: 384] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Remote ischaemic preconditioning (RIPC) represents a strategy for harnessing the body's endogenous protective capabilities against the injury incurred by ischaemia and reperfusion. It describes the intriguing phenomenon in which transient non-lethal ischaemia and reperfusion of one organ or tissue confers resistance to a subsequent episode of lethal ischaemia reperfusion injury in a remote organ or tissue. In its original conception, it described intramyocardial protection, which could be relayed from the myocardium served by one coronary artery to another. It soon became apparent that myocardial infarct size could be dramatically reduced by applying brief ischaemia and reperfusion to an organ or tissue remote from the heart before the onset of myocardial infarction. The concept of remote organ protection has now been extended beyond that of solely protecting the heart to providing a general form of inter-organ protection against ischaemia-reperfusion injury. This article reviews the history and evolution of the phenomenon that is RIPC, the potential mechanistic pathways underlying its cardioprotective effect, and its emerging application in the clinical setting.
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Affiliation(s)
- Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London WC1E 6HX, UK.
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Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury--a review. J Surg Res 2008; 150:304-30. [PMID: 19040966 DOI: 10.1016/j.jss.2007.12.747] [Citation(s) in RCA: 264] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2007] [Revised: 10/25/2007] [Accepted: 12/06/2007] [Indexed: 12/15/2022]
Abstract
BACKGROUND Restoration of blood supply to an organ after a critical period of ischemia results in parenchymal injury and dysfunction of the organ referred to as reperfusion injury. Ischemia reperfusion injury is often seen in organ transplants, major organ resections and in shock. Ischemic preconditioning (IPC) is an adaptational response of briefly ischemic tissues which serves to protect against subsequent prolonged ischemic insults and reperfusion injury. Ischemic preconditioning can be mechanical or pharmacological. Direct mechanical preconditioning in which the target organ is exposed to brief ischemia prior to prolonged ischemia has the benefit of reducing ischemia-reperfusion injury (IRI) but its main disadvantage is trauma to major vessels and stress to the target organ. Remote (inter organ) preconditioning is a recent observation in which brief ischemia of one organ has been shown to confer protection on distant organs without direct stress to the organ. AIM To discuss the evidence for remote IPC (RIPC), underlying mechanisms and possible clinical applications of RIPC. METHODS OF SEARCH: A Pubmed search with the keywords "ischemic preconditioning," "remote preconditioning," "remote ischemic preconditioning," and "ischemia reperfusion" was done. All articles on remote preconditioning up to September 2006 have been reviewed. Relevant reference articles from within these have been selected for further discussion. RESULTS Experimental studies have demonstrated that the heart, liver, lung, intestine, brain, kidney and limbs are capable of producing remote preconditioning when subjected to brief IR. Remote intra-organ preconditioning was first described in the heart where brief ischemia in one territory led to protection in other areas. Translation of RIPC to clinical application has been demonstrated by the use of brief forearm ischemia in preconditioning the heart prior to coronary bypass and in reducing endothelial dysfunction of the contra lateral limb. Recently protection of the heart has been demonstrated by remote hind limb preconditioning in children who underwent surgery on cardiopulmonary bypass for congenital heart disease. The RIPC stimulus presumably induces release of biochemical messengers which act either by the bloodstream or by the neurogenic pathway resulting in reduced oxidative stress and preservation of mitochondrial function. Studies have demonstrated endothelial NO, Free radicals, Kinases, Opioids, Catecholamines and K(ATP) channels as the candidate mechanism in remote preconditioning. Experiments have shown suppression of proinflammatory genes, expression of antioxidant genes and modulation of gene expression by RIPC as a novel method of IRI injury prevention. CONCLUSION There is strong evidence to support RIPC. The underlying mechanisms and pathways need further clarification. The effective use of RIPC needs to be investigated in clinical settings.
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Kanoria S, Jalan R, Seifalian AM, Williams R, Davidson BR. Protocols and Mechanisms for Remote Ischemic Preconditioning: A Novel Method for Reducing Ischemia Reperfusion Injury. Transplantation 2007; 84:445-58. [PMID: 17713425 DOI: 10.1097/01.tp.0000228235.55419.e8] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Ischemia reperfusion injury (IRI) results in damage to local and remote organs. Remote ischemic preconditioning (RIPC) is a strategy to protect against IRI by inducing a prior brief period(s) of IRI to an organ remote from that undergoing sustained injury. RIPC has been shown to protect organs against IRI; however, the protocols and mechanisms for RIPC are unclear. For this review, a Medline/Pubmed search (January 1985 to January 2007) was conducted and all relevant articles were included. RIPC protocols are organ and species specific and both humoral and neurogenic pathways are involved in triggering intracellular signal pathways for protection.
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Affiliation(s)
- Sanjeev Kanoria
- HPB and Liver Transplant Unit, University Department of Surgery, Royal Free Hospital, London, United Kingdom.
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Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, Ashley E, Vichare S, Di Salvo C, Kolvekar S, Hayward M, Keogh B, MacAllister RJ, Yellon DM. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 2007; 370:575-9. [PMID: 17707752 DOI: 10.1016/s0140-6736(07)61296-3] [Citation(s) in RCA: 519] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Whether remote ischaemic preconditioning, an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia, is beneficial for patients undergoing coronary artery bypass graft surgery is unknown. We did a single-blinded randomised controlled study to establish whether remote ischaemic preconditioning reduces myocardial injury in these patients. METHODS 57 adult patients undergoing elective coronary artery bypass graft surgery were randomly assigned to either a remote ischaemic preconditioning group (n=27) or to a control group (n=30) after induction of anaesthesia. Remote ischaemic preconditioning consisted of three 5-min cycles of right upper limb ischaemia, induced by an automated cuff-inflator placed on the upper arm and inflated to 200 mm Hg, with an intervening 5 min of reperfusion during which the cuff was deflated. Serum troponin-T concentration was measured before surgery and at 6, 12, 24, 48, and 72 h after surgery. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00397163. FINDINGS Remote ischaemic preconditioning significantly reduced overall serum troponin-T release at 6, 12, 24, and 48 h after surgery. The total area under the curve was reduced by 43%, from 36.12 microg/L (SD 26.08) in the control group to 20.58 microg/L (9.58) in the remote ischaemic preconditioning group (mean difference 15.55 [SD 5.32]; 95% CI 4.88-26.21; p=0.005). INTERPRETATION We have shown that adult patients undergoing elective coronary artery bypass graft surgery at a single tertiary centre could benefit from remote ischaemic preconditioning, using transient upper limb ischaemia.
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Affiliation(s)
- Derek J Hausenloy
- The Hatter Cardiovascular Institute, University College London Hospital, London, UK
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Gupta S, Lozano-Cuenca J, Villalón CM, de Vries R, Garrelds IM, Avezaat CJJ, van Kats JP, Saxena PR, MaassenVanDenBrink A. Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries. Naunyn Schmiedebergs Arch Pharmacol 2007; 375:29-38. [PMID: 17295025 PMCID: PMC1915621 DOI: 10.1007/s00210-007-0137-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2006] [Accepted: 01/15/2007] [Indexed: 11/04/2022]
Abstract
Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 μM), the neurokinin NK1 receptor antagonist L-733060 (0.5 μM), the voltage-sensitive calcium channel blocker ruthenium red (100 μM), the TRPV1 receptor antagonist capsazepine (5 μM), the nitric oxide synthetase inhibitor Nω-nitro-l-arginine methyl ester HCl (l-NAME; 100 μM), the gap junction blocker 18α-glycyrrhetinic acid (10 μM), as well as the RhoA kinase inhibitor Y-27632 (1 μM). Further, we also used the K+ channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 μM) + apamin (0.1 μM) and iberiotoxin (0.5 μM) + apamin (0.1 μM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) α-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK1, NO, vanilloid receptors, voltage-sensitive calcium channels, K+ channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism.
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Affiliation(s)
- Saurabh Gupta
- Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
| | - Jair Lozano-Cuenca
- Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, C.P. 14330 Mexico D.F., Mexico
| | - Carlos M. Villalón
- Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, C.P. 14330 Mexico D.F., Mexico
| | - René de Vries
- Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
| | - Ingrid M. Garrelds
- Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
| | - Cees J. J. Avezaat
- Department of Neurosurgery, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
| | - Jorge P. van Kats
- Thoracic Surgery and Heart Valve Bank, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
| | - Pramod R. Saxena
- Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
| | - Antoinette MaassenVanDenBrink
- Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
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Chai W, Mehrotra S, Jan Danser AH, Schoemaker RG. The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts. Eur J Pharmacol 2006; 531:246-53. [PMID: 16438955 DOI: 10.1016/j.ejphar.2005.12.039] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2005] [Revised: 12/16/2005] [Accepted: 12/19/2005] [Indexed: 11/18/2022]
Abstract
Brief coronary artery occlusion can protect the heart against damage during subsequent prolonged coronary artery occlusion; ischemic preconditioning. The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning is investigated in isolated perfused rat hearts, by measuring CGRP release during ischemic preconditioning and mimicking this by exogenous CGRP infusion, either in the absence or presence of the CGRP antagonist BIBN4096BS. CGRP increased left ventricular pressure and coronary flow in a concentration dependent manner, which was effectively antagonized by BIBN4096BS. Rat hearts (n=36) were subjected to 45 min coronary artery occlusion and 180 min reperfusion, which was preceded by: (1) sham pretreatment, (2) BIBN4096BS infusion (1 microM), (3) preconditioning by 15 min coronary artery occlusion and10 min reperfusion, (4) as 3, but with BIBN4096BS, (5) 15 min CGRP infusion (5 nM) and 10 min washout, (6) as 5, but with BIBN4096BS. Cardiac protection was assessed by reactive hyperaemia, creatine kinase release, infarct size related to the area at risk (%), and left ventricular pressure recovery. Preconditioning increased CGRP release into the coronary effluent from 88+/-13 to 154+/-32 pg/min/g, and significantly protected the hearts by decreasing reactive hyperaemia (35%), reducing creatine kinase release (53%), limiting infarct size (48%), and improving left ventricular pressure recovery (36%). Exogenous CGRP induced preconditioning-like cardioprotection. BIBN completely abolished the cardioprotection induced by preconditioning as well as by exogenous CGRP. In conclusion, since cardioprotection of preconditioning-induced CGRP release can be mimicked by exogenous CGRP, and both can be blocked by a CGRP antagonist, results indicate an important role for CGRP in ischemic preconditioning.
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Affiliation(s)
- Wenxia Chai
- Department of Pharmacology, Erasmus Medical Centre, 3000 DR Rotterdam, P.O. 1738, The Netherlands
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37
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Wolfrum S, Nienstedt J, Heidbreder M, Schneider K, Dominiak P, Dendorfer A. Calcitonin gene related peptide mediates cardioprotection by remote preconditioning. ACTA ACUST UNITED AC 2005; 127:217-24. [PMID: 15680490 DOI: 10.1016/j.regpep.2004.12.008] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2004] [Revised: 11/15/2004] [Accepted: 12/07/2004] [Indexed: 10/26/2022]
Abstract
Excitation of sensory nerves and activation of myocardial protein kinase C (PKC) epsilon contribute to the transduction of remote preconditioning (RPC) to the heart. Since calcitonin gene related peptide (CGRP) is an important mediator of sensory neurons we tried to delineate whether CGRP a) protects the heart from ischemic injury, b) is involved in cardioprotection after RPC, and c) leads to an activation of myocardial PKCepsilon. RPC was achieved by brief mesenteric artery occlusion followed by reperfusion. Myocardial infarct size (IS) was measured by TTC staining after temporary coronary artery occlusion (CAO) in rats. CGRP plasma levels were determined by radioimmunoassay and PKCepsilon was measured by quantitative immunoblotting. CGRP infusion reduced infarct size by 57%, an action that was abolished after co-treatment with the PKC inhibitor chelerythrine. RPC significantly increased CGRP plasma levels, reduced infarct size, and activated myocardial PKCepsilon. Infarct size reduction was abolished and PKCepsilon activation was significantly attenuated by CGRP(8-37), a specific CGRP receptor antagonist. Ganglion blockade with hexamethonium did not influence CGRP release by RPC but abolished CGRP mediated myocardial PKCepsilon activation. In conclusion, CGRP protects the heart from ischemic injury and is involved in RPC, presumably by activating myocardial PKCepsilon.
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Affiliation(s)
- Sebastian Wolfrum
- Institute of experimental and clinical Pharmacology and Toxicology, Medical University of Schleswig Holstein, Campus Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
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Kamada K, Gaskin FS, Yamaguchi T, Carter P, Yoshikawa T, Yusof M, Korthuis RJ. Role of calcitonin gene-related peptide in the postischemic anti-inflammatory effects of antecedent ethanol ingestion. Am J Physiol Heart Circ Physiol 2005; 290:H531-7. [PMID: 16143644 DOI: 10.1152/ajpheart.00839.2005] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The aim of this study was to determine the role of calcitonin gene-related peptide (CGRP) in the postischemic anti-inflammatory effects of antecedent ethanol ingestion. Ethanol was administered to wild-type C57BL/6 mice on day 1 as a bolus by gavage at a dose that produces a peak plasma ethanol of 45 mg/dl 30 min after administration. Twenty-four hours later (day 2), the superior mesenteric artery was occluded for 45 min followed by 70 min of reperfusion (I/R). Intravital fluorescence microscopy was used to quantify the numbers of rolling (LR) and adherent (LA) leukocytes labeled with carboxyfluorescein diacetate succinimidyl ester in postcapillary venules of the small intestine. I/R increased LR and LA, effects that were prevented by antecedent ethanol. The postischemic anti-inflammatory effects of ethanol consumption were abolished by administration of a specific CGRP receptor antagonist [CGRP-(8-37)] or after sensory nerve neurotransmitter depletion using capsaicin administered 4 days before ethanol ingestion, which initially induces rapid release of CGRP from sensory nerves, thereby depleting stored neuropeptide. Administration of exogenous CGRP or induction of endogenous CGRP release by treatment with capsaicin 24 h before I/R mimicked the postischemic anti-inflammatory effects of antecedent ethanol ingestion. Preconditioning with capsaicin 24 h before I/R was prevented by coincident treatment with CGRP-(8-37), while exogenous CGRP induced an anti-inflammatory phenotype in mice depleted of CGRP by capsaicin administration 4 days earlier. Our results indicate that the effect of antecedent ethanol ingestion to prevent postischemic LR and LA is initiated by a CGRP-dependent mechanism.
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Affiliation(s)
- Kazuhiro Kamada
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, USA
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Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ. Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system. J Am Coll Cardiol 2005; 46:450-6. [PMID: 16053957 DOI: 10.1016/j.jacc.2005.04.044] [Citation(s) in RCA: 320] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2004] [Revised: 01/26/2005] [Accepted: 04/13/2005] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The aim of this study was to characterize the time course and neuronal mechanism of remote ischemic preconditioning (RIPC) of the vasculature in humans. BACKGROUND Non-lethal ischemia of internal organs induces local (ischemic preconditioning) and systemic (RIPC) resistance to lethal ischemia-reperfusion (IR) injury. Experimental RIPC has two temporal components, is neuronally mediated, is induced by limb ischemia, and reduces infarct size. In humans, RIPC prevents IR-induced vascular injury. Determining the time course and mechanism is a prelude to clinical outcome studies of RIPC. METHODS Endothelial IR injury was induced by arm ischemia (20 min) and reperfusion, and measured by flow-mediated dilation. To establish if there are early and late phases, RIPC (three 5-min cycles of ischemia of the contralateral arm) was applied immediately, 4, 24, and 48 h before IR. To determine neuronal involvement, trimetaphan (autonomic ganglion blocker; 1 to 6 mg/min intravenous) was infused during the application of the RIPC stimulus. RESULTS Flow-mediated dilation was reduced by IR (8.7 +/- 1.1% before IR, 4.9 +/- 1.2% after IR; p < 0.001), but not when preceded by RIPC (8.0 +/- 0.8% after IR; p = NS); RIPC did not protect after 4 h (4.9 +/- 1.1% after IR; p < 0.001), but protected at 24 (8.7 +/- 1.1% after IR; p = NS) and 48 h (8.8 +/- 1.4% after IR; p = NS). Trimetaphan attenuated early (8.3 +/- 1.1% before IR, 4.2 +/- 0.9% after IR; p < 0.05) and delayed (7.3 +/- 1.0% before IR, 2.3 +/- 0.6% after IR, p < 0.001) RIPC. CONCLUSIONS Remote ischemic preconditioning in humans has two phases of protection against endothelial IR injury; an early (short) and late (prolonged) phase, both of which are neuronally mediated. The potential for late phase RIPC to provide prolonged protection during clinical IR syndromes merits investigation.
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Affiliation(s)
- Stavros P Loukogeorgakis
- Vascular Physiology Unit, Institute of Child Health, University College London, London, United Kingdom.
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40
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Luo D, Deng PY, Ye F, Peng WJ, Deng HW, Li YJ. Delayed preconditioning by cardiac ischemia involves endogenous calcitonin gene-related peptide via the nitric oxide pathway. Eur J Pharmacol 2005; 502:135-41. [PMID: 15464099 DOI: 10.1016/j.ejphar.2004.08.051] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2004] [Revised: 07/29/2004] [Accepted: 08/27/2004] [Indexed: 10/26/2022]
Abstract
Previous investigations have shown separately that calcitonin gene-related peptide (CGRP) or nitric oxide (NO) is involved in mediation of ischemic preconditioning. In the present study, we tested interactions of CGRP with NO in mediation of delayed preconditioning. In Sprague-Dawley rats, ischemia-reperfusion injury was induced by 45-min occlusion followed by 3-h reperfusion of coronary artery, and preconditioning was induced by four cycles of 3-min ischemia and 5-min reperfusion. Infarct size, plasma creatine kinase activity, the plasma level of NO and CGRP, and the expression of CGRP mRNA in dorsal root ganglion were measured. Pretreatment with preconditioning significantly reduced infarct size and the release of creatine kinase during reperfusion, and caused a significant increase in the expression of CGRP mRNA, concomitantly with an elevation in the plasma level of CGRP and NO. The effects of preconditioning were completely abolished by administration of L-nitroarginine methyl ester (L-NAME, 10 mg/kg, i.p.), an inhibitor of NO synthase. Pretreatment with capsaicin (50 mg/kg, s.c.), which depletes transmitters in capsaicin-sensitive sensory nerves, also blocked the cardioprotection of preconditioning and reduced the synthesis and release of CGRP, but did not affect the concentration of NO. The present results suggest the delayed protection afforded by ischemic preconditioning is also mediated by endogenous CGRP via the NO pathway in rat heart.
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Affiliation(s)
- Dan Luo
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No. 110, Xiang-Ya Road Changsha, Hunan 410078, China
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Liem DA, te Lintel Hekkert M, Manintveld OC, Boomsma F, Verdouw PD, Duncker DJ. Myocardium tolerant to an adenosine-dependent ischemic preconditioning stimulus can still be protected by stimuli that employ alternative signaling pathways. Am J Physiol Heart Circ Physiol 2005; 288:H1165-72. [PMID: 15486028 DOI: 10.1152/ajpheart.00899.2004] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 ± 2% to 37 ± 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 ± 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 μg/min iv) still elicited cardioprotection (IS = 40 ± 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 ± 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 ± 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.
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Affiliation(s)
- David A Liem
- Experimental Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
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Brzozowski T, Konturek PC, Konturek SJ, Pajdo R, Kwiecien S, Pawlik M, Drozdowicz D, Sliwowski Z, Pawlik WW. Ischemic preconditioning of remote organs attenuates gastric ischemia-reperfusion injury through involvement of prostaglandins and sensory nerves. Eur J Pharmacol 2005; 499:201-13. [PMID: 15363968 DOI: 10.1016/j.ejphar.2004.07.072] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2004] [Accepted: 07/13/2004] [Indexed: 12/17/2022]
Abstract
Limitation of the stomach damage by its earlier brief ischemia and reperfusion before prolonged ischemia is defined as gastric ischemic preconditioning but whether such brief ischemia of remote organs like heart or liver can also attenuate the gastric damage caused by longer and severe ischemia-reperfusion remains unknown. The cardiac, hepatic and gastric preconditioning were induced by brief ischemia (occlusion of coronary, hepatic and celiac arteries twice for 5 min) applied 30 min before 3 h of ischemia/reperfusion. Standard 3 h ischemia-reperfusion of the stomach produced numerous gastric lesions, decreased gastric blood flow and mucosal prostaglandin E2 generation and increased expression and plasma release of interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha). These effects were significantly attenuated by brief cardiac, hepatic and gastric preconditioning which upregulated cyclooxygenase-2 mRNA but not cyclooxygenase-1 mRNA. The protective effects of brief gastric, cardiac and hepatic preconditioning were attenuated by selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors and capsaicin denervation. We conclude that brief ischemia of remote preconditioning such as heart or liver protects gastric mucosa against severe ischemia-reperfusion-induced gastric lesions as effectively as local preconditioning of the stomach itself via the mechanism involving prostaglandin derived from cyclooxygenase-1 and cyclooxygenase-2 and the activation of sensory nerves releasing calcitonin gene-related peptide (CGRP) combined with the suppression of interleukin-1beta and TNF-alpha expression and release.
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Affiliation(s)
- Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 16, Grzegorzecka Str., 31-531 Cracow, Poland
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43
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Moses MA, Addison PD, Neligan PC, Ashrafpour H, Huang N, Zair M, Rassuli A, Forrest CR, Grover GJ, Pang CY. Mitochondrial KATPchannels in hindlimb remote ischemic preconditioning of skeletal muscle against infarction. Am J Physiol Heart Circ Physiol 2005; 288:H559-67. [PMID: 15458954 DOI: 10.1152/ajpheart.00845.2004] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We previously demonstrated in the pig that instigation of three cycles of 10 min of occlusion and reperfusion in a hindlimb by tourniquet application (∼300 mmHg) elicited protection against ischemia-reperfusion injury (infarction) in multiple distant skeletal muscles subsequently subjected to 4 h of ischemia and 48 h of reperfusion, but the mechanism was not studied. The aim of this project was to test our hypothesis that mitochondrial ATP-sensitive potassium (KATP) (mKATP) channels play a central role in the trigger and mediator mechanisms of hindlimb remote ischemic preconditioning (IPC) of skeletal muscle against infarction in the pig. We observed in the pig that hindlimb remote IPC reduced the infarct size of latissimus dorsi (LD) muscle flaps (8 × 13 cm) from 45 ± 2% to 22 ± 3% ( n = 10; P < 0.05). The nonselective KATPchannel inhibitor glibenclamide (0.3 mg/kg) or the selective mKATPchannel inhibitor 5-hydroxydecanoate (5-HD, 5 mg/kg), but not the selective sarcolemmal KATP(sKATP) channel inhibitor HMR-1098 (3 mg/kg), abolished the infarct-protective effect of hindlimb remote IPC in LD muscle flaps ( n = 10, P < 0.05) when these drugs were injected intravenously at 10 min before remote IPC. In addition, intravenous bolus injection of glibenclamide (1 mg/kg) or 5-HD (10 mg/kg) at the end of hindlimb remote IPC also abolished the infarct protection in LD muscle flaps ( n = 10; P < 0.05). Furthermore, intravenous injection of the specific mKATPchannel opener BMS-191095 (2 mg/kg) at 10 min before 4 h of ischemia protected the LD muscle flap against infarction to a similar extent as hindlimb remote IPC, and this infarct-protective effect of BMS-191095 was abolished by intravenous bolus injection of 5-HD (5 mg/kg) at 10 min before or after intravenous injection of BMS-191095 ( n = 10; P < 0.05). The infarct protective effect of BMS-191095 was associated with a higher muscle content of ATP at the end of 4 h of ischemia and a decrease in muscle neutrophilic myeloperoxidase activity at the end of 1.5 h of reperfusion compared with the time-matched control ( n = 10, P < 0.05). These observations led us to conclude that mKATPchannels play a central role in the trigger and mediator mechanisms of hindlimb remote IPC of skeletal muscle against infarction in the pig, and the opening of mKATPchannels in ischemic skeletal muscle is associated with an ATP-sparing effect during sustained ischemia and attenuation of neutrophil accumulation during reperfusion.
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Affiliation(s)
- Michael A Moses
- Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
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44
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Abstract
This review summarizes the receptor-mediated vascular activities of calcitonin gene-related peptide (CGRP) and the structurally related peptide adrenomedullin (AM). CGRP is a 37-amino acid neuropeptide, primarily released from sensory nerves, whilst AM is produced by stimulated vascular cells, and amylin is secreted from the pancreas. They share vasodilator activity, albeit to varying extents depending on species and tissue. In particular, CGRP has potent activity in the cerebral circulation, which is possibly relevant to the pathology of migraine, whilst vascular sources of AM contribute to dysfunction in cardiovascular disease. Both peptides exhibit potent activity in microvascular beds. All three peptides can act on a family of CGRP receptors that consist of calcitonin receptor-like receptor (CL) linked to one of three receptor activity-modifying proteins (RAMPs) that are essential for functional activity. The association of CL with RAMP1 produces a CGRP receptor, with RAMP2 an AM receptor and with RAMP3 a CGRP/AM receptor. Evidence for the selective activity of the first nonpeptide CGRP antagonist BIBN4096BS for the CGRP receptor is presented. The cardiovascular activity of these peptides in a range of species and in human clinical conditions is detailed, and potential therapeutic applications based on use of antagonists and gene targeting of agonists are discussed.
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Affiliation(s)
- Susan D Brain
- Centre for Cardiovascular Biology and Medicine, King's College London, Guy's Campus, London SE1 1UL, UK.
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45
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Lai IR, Ma MC, Chen CF, Chang KJ. The effect of an intestinal ischemia-reperfusion injury on renal nerve activity among rats. Shock 2003; 19:480-5. [PMID: 12744494 DOI: 10.1097/01.shk.0000054371.57734.b8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
An intestinal ischemia-reperfusion injury (IIR) may induce renal tubular dysfunction and a reduction in renal blood flow that may be related to the alteration of renal-nerve activity. A rat model of IIR injury was established. The superior mesenteric artery was clamped for 120 min, constituting the ischemic period, and was then released for 60 min, thus constituting the reperfusion period. Renal-nerve activity, renal function, and hemodynamic changes were recorded during the different periods. The levels of calcitonin gene-related peptide (CGRP) in portal-vein blood and intestinal tissue were investigated here. In the reperfusion period, the efferent renal-nerve activity (ERNA) was markedly elevated (94.3% +/- 21.6% higher than the baseline value), such an elevation being only partially reversed by fluid expansion (29.3% +/- 5.2% higher than the baseline value). The elevation of ERNA contributed to the renal blood-flow reduction from 6.8 +/- 0.3 mL/min/g to 2.0 +/- 0.4 mL/min/g, and decreased diuretic and natriuretic responses. The afferent renal nerve activity (ARNA) was markedly depressed (45.7% +/- 8.1% lower than the baseline value) during the reperfusion period. This depression was not reversed by fluid expansion, suggesting that the baroreflex was not responsible for this effect. The blunted ARNA also contributed to the elevation of ERNA by way of a renorenal reflex. The potent vasodilator neuropeptide in the gut, CGRP, revealed an increased level in the portal-vein blood (92.2 +/- 4.4 pg/mL vs. 57.8 +/- 0.6 pg/mL) and also in intestinal tissue (655.8 +/- 115.9 pg/mL vs. 60.5 +/- 9.4 pg/mL) with a time-matched related pattern with the change to renal-nerve activity, suggesting CGRP's role regarding changes in renal-nerve activity. This study indicates that the elevated ERNA level associated with IIR injury is related to a systemic hypotension-induced baroreflex, the contra-lateral inhibition of ARNA, and possibly also gut-released CGRP. In regards to an IIR injury, the depressed ARNA reflects the involvement of a renal sensory- impairment mechanism.
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Affiliation(s)
- I-Rue Lai
- Department of Physiology, National Taiwan University College of Medicine, National Taiwan University Hospital, Section 1, Taipei, Taiwan, People's Republic of China
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46
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Abstract
Preconditioning is in experimental studies the most powerful mode of cardioprotection known. The signal transduction pathways involve a variety of trigger substances, mediators, receptors, and effectors. The studies of preconditioning in cardiac surgery provide conflicting results but the majority of studies show that ischemic preconditiong is an effective adjunct to myocardial protection. However, ischemic preconditioning with repeated clamping of the aorta will never get widespread use. If the "preconditioning response" is to be exploited in cardiac surgery, targeting the underlying molecular mechanisms must provide easily applicable techniques or drugs, which are shown in large scale clinical studies to be beneficial.
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Affiliation(s)
- Jarle Vaage
- Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden.
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47
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Hu CP, Peng J, Xiao L, Ye F, Deng HW, Li YJ. Effect of age on alpha-calcitonin gene-related peptide-mediated delayed cardioprotection induced by intestinal preconditioning in rats. REGULATORY PEPTIDES 2002; 107:137-43. [PMID: 12137976 DOI: 10.1016/s0167-0115(02)00096-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
In the present study, we examined whether age-related reduction in cardioprotection of intestinal ischemic preconditioning is related to stimulation of the release and synthesis of calcitonin gene-related peptide (CGRP) in rats. Ischemia-reperfusion injury was induced by a 45-min coronary artery occlusion and 180-min reperfusion, and ischemic preconditioning was induced by six cycles of 4-min ischemia and 4-min reperfusion of the small intestine. The serum concentration of creatine kinase, infarct size, the expression of CGRP isoforms (alpha- and beta-CGRP) mRNA in lumbar dorsal root ganglia and CGRP concentration in plasma were measured. Pretreatment with intestinal ischemic preconditioning for 24 h significantly reduced infarct size and creatine kinase release concomitantly with a significant increase in the expression of alpha-CGRP mRNA, but not beta-CGRP mRNA, and plasma concentrations of CGRP at 6 months of age but not at 24 months of age. These results suggest that the delayed cardioprotective effect of intestinal ischemic preconditioning is decreased in senescent rats, and the age-related change is related to reduction of the synthesis and release of alpha-CGRP.
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Affiliation(s)
- Chang Ping Hu
- Department of Pharmacology, Xiang-Ya School of Medicine, Central South University, Hunan 410078, Changsha, China
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Liem DA, Verdouw PD, Ploeg H, Kazim S, Duncker DJ. Sites of action of adenosine in interorgan preconditioning of the heart. Am J Physiol Heart Circ Physiol 2002; 283:H29-37. [PMID: 12063271 DOI: 10.1152/ajpheart.01031.2001] [Citation(s) in RCA: 137] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The mechanism underlying interorgan preconditioning of the heart remains elusive, although a role for adenosine and activation of a neurogenic pathway has been postulated. We tested in rats the hypothesis that adenosine released by the remote ischemic organ stimulates local afferent nerves, which leads to activation of myocardial adenosine receptors. Preconditioning with a 15-min mesenteric artery occlusion (MAO15) reduced infarct size produced by a 60-min coronary artery occlusion (60-min CAO) from 68 +/- 2% to 48 +/- 4% (P < 0.05). Pretreatment with the ganglion blocker hexamethonium or 8-(p-sulfophenyl)theophylline (8-SPT) abolished the protection by MAO15. Intramesenteric artery (but not intraportal vein) infusion of adenosine (10 microg/min) was as cardioprotective as MAO15, which was also abolished by hexamethonium. Whereas administration of hexamethonium at 5 min of reperfusion following MAO15 had no effect, 8-SPT at 5 min of reperfusion abolished the protection. Permanent reocclusion of the mesenteric artery before the 60-min CAO enhanced the cardioprotection by MAO15 (30 +/- 5%), but all protection was abolished when 8-SPT was administered after reocclusion of the mesenteric artery. Together, these findings demonstrate the involvement of myocardial adenosine receptors. We therefore conclude that locally released adenosine during small intestinal ischemia stimulates afferent nerves in the mesenteric bed during early reperfusion, initiating a neurogenic pathway that leads to activation of myocardial adenosine receptors.
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Affiliation(s)
- David A Liem
- Experimental Cardiology, Thoraxcenter, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
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49
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Abstract
Preconditioning induced by brief ischemia or hyperthermia or some drugs shows two phases, early and delayed protection. The cardioprotection afforded by preconditioning is related to stimulation of endogenous mediators release. Calcitonin gene-related peptide (CGRP), a major transmitter of capsaicin-sensitive sensory nerves, has recently been shown to play an important role in mediation of the preconditioning induced by brief ischemia or hyperthermia or by some drugs, and alpha-CGRP seems to play a major role in the mediation of delayed preconditioning. It has been shown that the cardioprotection afforded by CGRP-mediated preconditioning is due to inhibition of cardiac tumor necrosis factor-alpha (TNF-alpha) production, but not to the activation of the K(ATP) channel.
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Affiliation(s)
- Yuan-Jian Li
- Department of Pharmacology, Xiang-Ya School of Medicine, Central South University, Hunan, Changsha 410078, PR China.
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50
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Zhou ZH, Deng HW, Li YJ. Improvement of preservation with cardioplegic solution by nitroglycerin-induced delayed preconditioning is mediated by calcitonin gene-related peptide. Int J Cardiol 2001; 81:211-8. [PMID: 11744139 DOI: 10.1016/s0167-5273(01)00569-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Improvement of preservation with cardioplegic solution by nitroglycerin-induced delayed preconditioning was studied in the isolated rat heart. The isolated rat heart was arrested using St. Thomas Hospital solution, and then reperfused with normothermic Krebs-Henseleit solution for 40 min after a 4-h hypothermic ischemic period. Heart rate, coronary flow, left ventricular pressure and the maximum value of the first derivatives of left ventricular pressure (+/-dp/dt(max)) were recorded, and plasma concentrations of CGRP-like immunoreactivity (CGRP-LI) and nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha) in myocardial tissues, and creatine kinase in coronary effluent were measured. Delayed preconditioning was induced by i.v. injection of nitroglycerin 24 h before the experiment. Nitroglycerin (60 microg/kg or 120 microg/kg) caused an improvement of cardiac function, a decrease in the release of creatine kinase in coronary effluent and a decrease in the content of TNF-alpha in myocardial tissues. Nitroglycerin significantly increased plasma concentrations of CGRP and NO. After pretreatment with capsaicin, which depletes neurotransmitters in sensory nerves, or methylene blue, a selective guanylate cyclase inhibitor, the protection and the elevated release of CGRP induced by nitroglycerin were abolished. The present study suggests that improvement of preservation with cardioplegic solution by nitroglycerin-induced delayed preconditioning is due to stimulation of CGRP release in the rat heart, and that the protection of CGRP-mediated nitroglycerin is related to inhibition of TNF-alpha production.
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Affiliation(s)
- Z H Zhou
- Department of Pharmacology, Hunan Medical University, Changsha, 410078, Hunan, China
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