Dose-dependent protection of cardiac function by propofol during ischemia and early reperfusion in rats: effects on 15-F2t-isoprostane formation

2003 ◽  
Vol 81 (1) ◽  
pp. 14-21 ◽  
Author(s):  
Zhengyuan Xia ◽  
David V Godin ◽  
Thomas K.H Chang ◽  
David M Ansley
Keyword(s):  
Antioxidant Capacity ◽  
Functional Recovery ◽  
Ischemia Reperfusion ◽  
Oxidant Injury ◽  
Control Groups ◽  
Early Reperfusion ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Dose Dependent ◽  
Myocardium Ischemia Reperfusion

We examined the effects of propofol (2,6-diisopropylphenol) on functional recovery and 15-F2t-isoprostane generation during ischemia–reperfusion in Langendorff-perfused rat hearts. Before the induction of 40 min of global ischemia, hearts were perfused (10 min) with propofol at 5 (lo-P) or 12 μg/mL (hi-P) in saline or with saline only (control). During ischemia, saline, lo-P, or hi-P was perfused through the aorta at 60 μL/min. During the first 15 min of reperfusion, propofol (5 or 12 μg/mL) was continued, followed by perfusion with 5 μg/mL propofol for 75 min in both propofol-treated groups. After 90 min of reperfusion (Rep-90), heart tissues were harvested for assessment of antioxidant status. In hi-P, we observed increased latency to and greater reduction of ischemic contracture relative to the lo-P or control groups. 15-F2t-Isoprostane concentrations increased during ischemia and were significantly lower in hi-P and lo-P than in control (P < 0.01). At Rep-90, myocardial functional recovery was greater in both propofol-treated groups relative to control, and it correlated positively with tissue antioxidant capacity preservation. Tissue antioxidant capacity was better preserved in hi-P than in lo-P treatment (P < 0.05). We conclude that oxidant injury occurs during ischemia and reperfusion, and propofol provides dose-dependent protection primarily by enhancing tissue antioxidant capacity and reducing lipid peroxidation.Key words: propofol, myocardium, ischemia–reperfusion, 15-F2t-isoprostane.

Ischemic preconditioning affects hexokinase activity and HKII in different subcellular compartments throughout cardiac ischemia-reperfusion

2009 ◽  
Vol 106 (6) ◽  
pp. 1909-1916 ◽  
Author(s):  
Ebru Gürel ◽  
Kirsten M. Smeele ◽  
Otto Eerbeek ◽  
Anneke Koeman ◽  
Cihan Demirci ◽  
...  
Keyword(s):  
Protein Content ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion ◽  
Glycolytic Enzyme ◽  
Cardiac Ischemia ◽  
Biphasic Response ◽  
Control Groups ◽  
Rat Hearts ◽  
Before And After ◽  
Perfused Rat Hearts

The glycolytic enzyme hexokinase (HK) is suggested to play a role in ischemic preconditioning (IPC). In the present study we determined how ischemic preconditioning affects HK activity and HKI and HKII protein content at five different time points and three different subcellular fractions throughout cardiac ischemia-reperfusion. Isolated Langendorff-perfused rat hearts (10 groups of 7 hearts each) were subjected to 35 min ischemia and 30 min reperfusion (control groups); the IPC groups were pretreated with 3 times 5-min ischemia. IPC was without effect on microsomal HK activity, and only decreased cytosolic HK activity at 35 min ischemia, which was mimicked by decreased cytosolic HKII, but not HKI, protein content. In contrast, mitochondrial HK activity at baseline and during reperfusion was elevated by IPC, without changes during ischemia. No effect of IPC on mitochondrial HK I protein content was observed. However, mitochondrial HK II protein content during reperfusion was augmented by IPC, albeit not following the IPC stimulus. It is concluded that IPC results in decreased cytosolic HK activity during ischemia that could be explained by decreased HKII protein content. IPC increased mitochondrial HK activity before ischemia and during reperfusion that was only mimicked by increased HK II protein content during reperfusion. IPC was without effect on the phosphorylation status of HK before ischemia. We conclude that IPC is associated with 1) a biphasic response of increased mitochondrial HK activity before and after ischemia, 2) decreased cytosolic HK activity during ischemia, and 3) cellular redistribution of HKII but not HKI.

scholarly journals Transient Acidosis during Early Reperfusion Attenuates Myocardium Ischemia Reperfusion Injury via PI3k-Akt-eNOS Signaling Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Xin Qiao ◽  
Jinjin Xu ◽  
Qing-Jun Yang ◽  
Yun Du ◽  
Shaoqing Lei ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Early Reperfusion ◽  
Rat Hearts ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Myocardium Ischemia Reperfusion ◽  
Isolated Rat

In this paper, we concluded that transient acidosis reperfusion conferred cardioprotection against myocardial ischemia reperfusion injury in isolated rat hearts through activating PI3K-Akt-eNOS pathway.

scholarly journals Inhibition of LINE-1 expression in the heart decreases ischemic damage by activation of Akt/PKB signaling

2006 ◽  
Vol 25 (2) ◽  
pp. 314-324 ◽  
Author(s):  
Eliana Lucchinetti ◽  
Jianhua Feng ◽  
Rafaela da Silva ◽  
Genrich V. Tolstonog ◽  
Marcus C. Schaub ◽  
...  
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Rat Heart ◽  
Cardiac Tissue ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Immunoblot Analysis ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Antisense Odns

Microarray analyses indicate that ischemic and pharmacological preconditioning suppress overexpression of the non-long terminal repeat retrotransposon long interspersed nuclear element 1 (LINE-1, L1) after ischemia-reperfusion in the rat heart. We tested whether L1 overexpression is mechanistically involved in postischemic myocardial damage. Isolated, perfused rat hearts were treated with antisense or scrambled oligonucleotides (ODNs) against L1 for 60 min and exposed to 40 min of ischemia followed by 60 min of reperfusion. Functional recovery and infarct size were measured. Effective nuclear uptake was determined by FITC-labeled ODNs, and downregulation of L1 transcription was confirmed by RT-PCR. Immunoblot analysis was used to assess changes in expression levels of the L1-encoded proteins ORF1p and ORF2p. Immunohistochemistry was performed to localize ORF1/2 proteins in cardiac tissue. Effects of ODNs on prosurvival protein kinase B (Akt/PKB) expression and activity were also determined. Antisense ODNs against L1 prevented L1 burst after ischemia-reperfusion. Inhibition of L1 increased Akt/PKBβ expression, enhanced phosphorylation of PKB at serine 473, and markedly improved postischemic functional recovery and decreased infarct size. Antisense ODN-mediated protection was abolished by LY-294002, confirming the involvement of the Akt/PKB survival pathway. ORF1p and ORF2p were found to be expressed in rat heart. ORF1p showed a predominantly nuclear localization in cardiomyocytes, whereas ORF2p was exclusively present in endothelial cells. ORF1p levels increased in response to ischemia, which was reversed by antisense ODN treatment. No significant changes in ORF2p were noted. Our results demonstrate that L1 suppression favorably affects postischemic outcome in the heart. Modifying transcriptional activity of L1 may represent a novel anti-ischemic therapeutic strategy.

scholarly journals Increased O-GlcNAc levels during reperfusion lead to improved functional recovery and reduced calpain proteolysis

2007 ◽  
Vol 293 (3) ◽  
pp. H1391-H1399 ◽  
Author(s):  
Jia Liu ◽  
Richard B. Marchase ◽  
John C. Chatham
Keyword(s):  
Functional Recovery ◽  
Stress Responses ◽  
Ischemia Reperfusion ◽  
Protein Levels ◽  
Rat Hearts ◽  
Hexosamine Biosynthesis ◽  
Perfused Rat Hearts ◽  
Dependent Protein ◽  
Troponin Release ◽  
Hexosamine Biosynthesis Pathway

We have previously shown that preischemic treatment with glucosamine improved cardiac functional recovery following ischemia-reperfusion, and this was mediated, at least in part, via enhanced flux through the hexosamine biosynthesis pathway and subsequently elevated O-linked N-acetylglucosamine ( O-GlcNAc) protein levels. However, preischemic treatment is typically impractical in a clinical setting; therefore, the goal of this study was to investigate whether increasing protein O-GlcNAc levels only during reperfusion also improved recovery. Isolated perfused rat hearts were subjected to 20 min of global, no-flow ischemia followed by 60 min of reperfusion. Administration of glucosamine (10 mM) or an inhibitor of O-GlcNAcase, O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino- N-phenylcarbamate (PUGNAc; 200 μM), during the first 20 min of reperfusion significantly improved cardiac functional recovery and reduced troponin release during reperfusion compared with untreated control. Both interventions also significantly increased the levels of protein O-GlcNAc and ATP levels. We also found that both glucosamine and PUGNAc attenuated calpain-mediated proteolysis of α-fodrin as well as Ca2+/calmodulin-dependent protein kinase II during reperfusion. Thus two independent strategies for increasing protein O-GlcNAc levels in the heart during reperfusion significantly improved recovery, and this was correlated with attenuation of calcium-mediated proteolysis. These data provide further support for the concept that increasing cardiac O-GlcNAc levels may be a clinically relevant cardioprotective strategy and suggest that this protection could be due, at least in part, to inhibition of calcium-mediated stress responses.

scholarly journals Cardioprotection by post-conditioning with exogenous triiodothyronine in isolated perfused rat hearts and isolated adult rat cardiomyocytes

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Helmut Raphael Lieder ◽  
Felix Braczko ◽  
Nilgün Gedik ◽  
Merlin Stroetges ◽  
Gerd Heusch ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Retention Capacity ◽  
Tetrazolium Chloride ◽  
Rat Cardiomyocytes ◽  
Early Reperfusion ◽  
Adult Rat ◽  
Risk Pathway ◽  
Rat Hearts ◽  
Perfused Rat Hearts

AbstractIschemic post-conditioning (iPoCo) by coronary re-occlusion/reperfusion during immediate reperfusion after prolonged myocardial ischemia reduces infarct size. Mechanical manipulation of culprit lesions, however, carries the risk of coronary microembolization which may obscure iPoCo’s cardioprotection. Pharmacological post-conditioning with exogenous triiodothyronine (T3) could serve as an alternative conditioning strategy. Similar to iPoCo, T3 may activate cardioprotective prosurvival pathways. We aimed to study T3’s impact on infarct size and its underlying signal transduction. Hearts were isolated from male Lewis rats (200–380 g), buffer-perfused and subjected to 30 min/120 min global zero-flow ischemia/reperfusion (I/R). In additional hearts, either iPoCo (2 × 30 s/30 s I/R) was performed or T3 (100–500 µg/L) infused at reperfusion. Infarct size was demarcated with triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass. Infarct size was reduced with iPoCo to 16 ± 7% vs. 36 ± 4% with I/R only. The maximum infarct size reduction was observed with 300 µg/L T3 (14 ± 2%). T3 increased the phosphorylation of protein kinase B and mitogen extracellular-regulated-kinase 1/2, both key enzymes of the reperfusion injury salvage kinase (RISK) pathway. Pharmacological RISK blockade (RISK-BL) during reperfusion abrogated T3’s cardioprotection (35 ± 10%). Adult ventricular cardiomyocytes were isolated from buffer-perfused rat hearts and exposed to 30 min/5 min hypoxia/reoxygenation (H/R); reoxygenation was initiated without or with T3, respectively, and without or with RISK-BL, respectively. Maximal preservation of viability was observed with 500 µg/L T3 after H/R (27 ± 4% of all cells vs. 5 ± 3% in time-matched controls). Again, RISK-BL abrogated protection (11 ± 3%). Mitochondria were isolated at early reperfusion from buffer-perfused rat hearts without or with iPoCo or 300 µg/L T3, respectively, at reperfusion. T3 improved mitochondrial function (i.e.: increased respiration, adenosine triphosphate production, calcium retention capacity, and decreased reactive oxygen species formation) to a similar extent as iPoCo. T3 at reperfusion reduces infarct size by activation of the RISK pathway. T3’s protection is a cardiomyocyte phenomenon and targets mitochondria.

Purinergic Component in the Coronary Vasodilatation to Acetylcholine after Ischemia-Reperfusion in Perfused Rat Hearts

2014 ◽  
Vol 51 (4) ◽  
pp. 283-289 ◽  
Author(s):  
Ángel Luis García-Villalón ◽  
Miriam Granado ◽  
Luis Monge ◽  
Nuria Fernández ◽  
Gonzalo Carreño-Tarragona ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Rat Hearts ◽  
Coronary Vasodilatation ◽  
Perfused Rat Hearts

scholarly journals Cardiac Ischemia and Ischemia/Reperfusion Cause Wide Proteolysis of the Coronary Endothelial Luminal Membrane: Possible Dysfunctions

2011 ◽  
Vol 5 (1) ◽  
pp. 239-245 ◽  
Author(s):  
Blanca Arroyo-Flores ◽  
Erika Chi-Ahumada ◽  
Erika Briones-Cerecero ◽  
Alma Barajas-Espinosa ◽  
Sandra Perez-Aguilar ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Biochemical Changes ◽  
Vascular Endothelial ◽  
Luminal Membrane ◽  
Rat Hearts ◽  
Isoelectric Points ◽  
Perfused Rat Hearts ◽  
Hydrolyzing Enzymes ◽  
2D Gel ◽  
G Protein Coupled

Background: Ischemia and ischemia-reperfusion (I/R) are common clinical insults that disrupt the molecular structure of coronary vascular endothelial luminal membrane (VELM) that result in diverse microvasculature dysfunctions. However, the knowledge of the associated biochemical changes is meager. We hypothesized that ischemia and I/R-induced structural and functional VELM alterations result from biochemical changes. First, these changes need to be described and later the mechanisms behind be identified. Methods: During control conditions, in isolated perfused rat hearts VELM proteins were labeled with biotin. The groups of hearts were: control (C), no flow ischemia (I; 25 min), and I/R (I; 25 min, reperfusion 30 min). The biotinylated luminal endothelial membrane proteins in these three different groups were examined by 2-D electrophoresis and identified. But, it must be kept in mind the proteins were biotin-labeled during control. Results: A comparative analysis of the protein profiles under the 3 conditions following 2D gel electrophoresis showed differences in the molecular weight distribution such that MWC > MWI > MWI/R. Similar analysis for isoelectric points (pHi) showed a shift toward more acidic pHi under ischemic conditions. Of 100 % proteins identified during control 66% and 88% changed their MW-pHi during ischemia and I/R respectively. Among these lost proteins there were 9 proteins identified as adhesins and G-protein coupled receptors. General significance: I and I/R insults alter MW-pHi of most luminal glycocalyx proteins due to the activation of nonspecific hydrolizing mechanisms; suspect metalloproteases and glycanases. This makes necessary the identification of hydrolyzing enzymes reponsible of multiple microvascular dysfunctions in order to maintain the integrity of vascular endothelial membrane. VELM must become a target of future therapeutics.

Abstract 404: High-throughput Screening Reveals the Mitochondrial Complex I Inhibitor Nornicotine is Cardioprotective in Ischemia-reperfusion Injury When Delivered at Reperfusion

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jimmy Zhang ◽  
Marcin K Karcz ◽  
Sergiy M Nadtochiy ◽  
Paul S Brookes
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Functional Recovery ◽  
Complex I ◽  
Ischemia Reperfusion ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Early Reperfusion ◽  
Perfused Hearts

Background: To date, there are no FDA-approved therapies for the reduction of infarct size in acute myocardial infarction. Previously, we developed a cell-based phenotypic assay of ischemia-reperfusion (IR) injury, which was used to identify novel cytoprotective agents delivered prior to ischemia. Herein, we sought to identify cytoprotective agents in a more clinically relevant model: drug delivery at reperfusion, and to investigate possible underlying mechanisms of protection. Methods: Primary adult mouse cardiomyocytes were subjected to simulated IR injury using a modified Seahorse XF24 apparatus with drug addition at the onset of reperfusion. Cell death was estimated using LDH release. Drugs which protected cardiomyocytes in vitro were tested in a Langendorff model of IR injury, measuring functional recovery and infarct size. In separate experiments, metabolites extracted from perfused hearts were resolved by HPLC. Results: Nornicotine was identified as a cardioprotective agent in the screen. In perfused hearts, 10 nM nornicotine injected at the onset of reperfusion improved functional recovery and decreased in infarct size (13.1% ± 2.4 vs 49.2% ± 2.5 in non-treated hearts, p<0.05, n=16-20). Nornicotine also exhibited profound inhibitory effects on mitochondrial complex I activity. Succinate is known to accumulate in ischemia, and its rapid consumption during early reperfusion exacerbates reperfusion injury via ROS generation from electron backflow through complex I [PMID: 25383517]. In non-treated hearts, we confirmed that high post ischemic levels of succinate rapidly declined during the first 2 min of reperfusion. In contrast, nornicotine slowed post-ischemic succinate consumption, suggesting that electron backflow through complex I is the major pathway driving succinate consumption. Conclusions: Herein, we demonstrated that nornicotine was cardioprotective when delivered at early reperfusion in vitro and ex vivo. The mechanism of cardioprotection may be due to inhibition of rapid succinate consumption during early reperfusion via reverse electron flow back through complex I.

scholarly journals Real-Time 2-Photon Imaging of Mitochondrial Function in Perfused Rat Hearts Subjected to Ischemia/Reperfusion

Circulation ◽  
2006 ◽  
Vol 114 (14) ◽  
pp. 1497-1503 ◽  
Author(s):  
Madoka Matsumoto-Ida ◽  
Masaharu Akao ◽  
Toshihiro Takeda ◽  
Masashi Kato ◽  
Toru Kita
Keyword(s):  
Real Time ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Photon Imaging
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