The stunned myocardium: effect of electrical and mechanical arrest and osmolarity

1988 ◽  
Vol 255 (1) ◽  
pp. H60-H69 ◽  
Author(s):  
W. G. Nayler ◽  
J. S. Elz ◽  
D. J. Buckley
Keyword(s):  
Functional Recovery ◽  
Ischemia Reperfusion ◽  
Complete Recovery ◽  
Inotropic Effect ◽  
Stunned Myocardium ◽  
Equivalent Time ◽  
Rat Hearts ◽  
High K ◽  
Ischemic Episode ◽  
K Concentration

After relatively short periods of ischemia, reperfusion for several hours, or even days, is required to facilitate complete recovery of the ATP stores and mechanical function. The term "stunned" has been applied to these hearts. In the present experiments, isolated, spontaneously beating and electrically paced rat hearts were made ischemic for 10 min and then reperfused with Krebs-Henseleit buffer (KH) for up to 30 min. On reperfusion, functional recovery was impaired and the inotropic effect of Ca2+ blunted. In these experiments, the effect of a period of electrical and/or mechanical quiescence before the ischemic episode was investigated. Electrical quiescence was obtained by raising the KH K+ concentration, whereas mechanical without electrical quiescence was obtained by lowering the KH Ca2+ concentration or adding 2,3-butanedione monoxime (BDM). Mechanical arrest caused by low Ca2+ perfusion before ischemia failed to improve functional recovery on reperfusion. However, introducing a high K+ perfusate or BDM for a few minutes before ischemia significantly improved the recovery during reperfusion. This improvement was neither caused by energy preservation nor an altered "reflow area". The improvement may be caused by the increased osmolarity of KH containing high K+ or BDM, since adding 10 mM sucrose to KH for an equivalent time before ischemia improved recovery and abolished the blunted inotropic effect of Ca2+.

Effects of pyruvate on the energetics of rat ventricles stunned by ischemia–reperfusion

2014 ◽  
Vol 92 (5) ◽  
pp. 386-398 ◽  
Author(s):  
Patricia Bonazzola ◽  
María Inés Ragone ◽  
Alicia E. Consolini
Keyword(s):  
Confocal Microscopy ◽  
Heat Release ◽  
Dynamic Balance ◽  
Ischemia Reperfusion ◽  
Rat Hearts ◽  
High K ◽  
Energetic State ◽  
Contractile Recovery ◽  
Stimulation Of

Pyruvate (Pyr) was proposed as an additive to cold high-K+–low-Ca2+ cardioplegia (CPG) to protect the heart during surgery. We explored whether Pyr and CPG would work synergistically to protect rat hearts from stunning during ischemia–reperfusion (I/R). We measured the heat release and contractility of perfused ventricles during I/R, and the cytosolic and mitochondrial [Ca2+] in cardiomyocytes by confocal microscopy. We found that under cold-CPG (30 °C), 10 mmol·L−1 Pyr reduced the post-ischemic contractile recovery (PICR) as well as muscle economy, when added either before ischemia or during I/R, which was reversed by blockade of UCam. In noncardioplegic hearts, Pyr was cardioprotective when it was present during I/R, more so at 37 °C than at 30 °C, with improved economy. In cardiomyocytes, the addition of Pyr to CPG slightly increased the mitochondrial [Ca2+] but decreased cytosolic [Ca2+]. The results suggest that Pyr only protects hearts from stunning when present before ischemia and during reperfusion, and that it dampens the cardioprotective properties of CPG. The mechanisms underlying such different behavior depend on the dynamic balance between Pyr stimulation of the energetic state and mitochondrial Ca2+ uptake. Our results support the use of Pyr in stunned hearts, but not in cold high-K+ cardioplegia.

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.

scholarly journals Glucosamine cardioprotection in perfused rat hearts associated with increased O-linked N-acetylglucosamine protein modification and altered p38 activation

2007 ◽  
Vol 292 (5) ◽  
pp. H2227-H2236 ◽  
Author(s):  
Norbert Fülöp ◽  
Zhenghao Zhang ◽  
Richard B. Marchase ◽  
John C. Chatham
Keyword(s):  
Functional Recovery ◽  
Protein Modification ◽  
Mapk Pathway ◽  
Ischemia Reperfusion ◽  
Low Flow ◽  
Perfused Heart ◽  
Rat Hearts ◽  
Mitogen Activated Protein ◽  
Hexosamine Biosynthesis ◽  
Nucleocytoplasmic Proteins

We have shown that, in the perfused heart, glucosamine improved functional recovery following ischemia and that this appeared to be mediated via an increase in O-linked N-acetylglucosamine ( O-GlcNAc) levels on nucleocytoplasmic proteins. Several kinase pathways, specifically Akt and the mitogen-activated protein kinases (MAPKs) p38 and ERK1/2, which have been implicated in ischemic cardioprotection, have also been reported to be modified in response to increased O-GlcNAc levels. Therefore, the goals of this study were to determine the effect of ischemia on O-GlcNAc levels and to evaluate whether the cardioprotection resulting from glucosamine treatment could be attributed to changes in ERK1/2, Akt, and p38 phosphorylation. Isolated rat hearts were perfused with or without 5 mM glucosamine and were subjected to 5, 10, or 30 min of low-flow ischemia or 30 min of low-flow ischemia and 60 min of reperfusion. Glucosamine treatment attenuated ischemic contracture and improved functional recovery at the end of reperfusion. Glucosamine treatment increased flux through the hexosamine biosynthesis pathway and increased O-GlcNAc levels but had no effect on ATP levels. Glucosamine did not alter the response of either ERK1/2 or Akt to ischemia-reperfusion; however, it significantly attenuated the ischemia-induced increase in p38 phosphorylation and paradoxically increased p38 phosphorylation at the end of reperfusion. These data support the notion that O-GlcNAc may play an important role as an internal stress response and that glucosamine-induced cardioprotection may be mediated via the p38 MAPK 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.

Energetics of Ca2+ homeostasis during ischemia–reperfusion on neonatal rat hearts under high-[K+] cardioplegia

2008 ◽  
Vol 86 (12) ◽  
pp. 866-879 ◽  
Author(s):  
Alicia E. Consolini ◽  
Patricia Bonazzola
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ischemia Reperfusion ◽  
Fibre Length ◽  
Neonatal Rat ◽  
Main Role ◽  
Adult Rats ◽  
Rat Hearts ◽  
High K ◽  
Contractile Recovery

The mechanocalorimetric consequences and mechanisms involved in Ca2+ homeostasis during ischemia–reperfusion (I/R) as well as the protective role of cardioplegic pretreatment with high [K+] (25 mmol/L) and low or near-normal [Ca2+] (0.5 or 2 mmol/L) were evaluated in a model of neonatal rat heart. Beating hearts from 10–12-day-old rats were perfused with Krebs solution (2 mmol/L Ca2+) under both isotonic and isometric conditions. During pretreatment, hearts were exposed for 20 min to either Krebs (control) or cardioplegia (CPG) before 15 min ischemia and 45 min reperfusion while being continuously measured for either contractility or total heat rate (Ht) in a flow calorimeter. Contractile recovery after reperfusion in hearts exposed to ischemia only (control) was higher in the isometric hearts under optimal length (87.9% ± 8.1%) than in the isotonic hearts (57.3% ± 10.6%). This same behavior was found in hearts pretreated with CPG-0.5 mmol/L Ca2+. Ht in controls was reduced from 11.5 ± 0.8 mW/g in the initial beating condition to 1.11 ± 0.33 mW/g during ischemia and was increased to 13.02 ± 0.93 mW/g (113.8% ± 5.0% of preischemic) after reperfusion. Hearts pretreated with CPG-0.5 mmol/L Ca2+ showed the same behavior. However, when extracellular calcium ([Ca]o) was increased to 2 mmol/L under CPG, isotonic hearts, but not isometric hearts, significantly increased the contractile recovery to a maximum of 88.7% ± 10.8% of preischemic levels. Ht was recovered to 92.1% ± 4.3% of preischemic, suggesting that contractile recovery was less energetically expensive after CPG-2 mmol/L Ca2+ than it was in postischemic hearts exposed to control or CPG-0.5 mmol/L Ca2+. The role of the sarcoplasmic reticulum store was evaluated by pretreating hearts with 10 mmol/L caffeine, which reduced contractile recovery only under isometric conditions or after increasing [Ca]o in CPG under isotonic conditions, suggesting that the contribution of the sarcoplasmic reticulum was dependent on the fibre length or the [Ca]o. The inhibition of the reverse mode of the sarcolemmal Na/Ca exchanger (NCX) and the mitochondrial Ca uniporter (CaU) by KB-R7943 (KBR) at 5 µmol/L in CPG-0.5 mmol/L Ca2+ improved contractile recovery of isotonic hearts, whereas it decreased Ht at the start of reperfusion, suggesting that mitochondria could uptake Ca2+ vía the mitochondrial CaU. Neither the positive inotropism nor Ht were changed by inhibiting the mitochondrial NCX with 10 µmol/L clonazepam in CPG-0.5 mmol/L Ca2+ + 5 µmol/L KBR, which suggests that the mitochondrial NCX does not have a role. Finally, the role of the forward mode of the sarcolemmal NCX was evidenced by the fall in contractile recovery with increased Ht when KBR was increased to 20 µmol/L and added to CPG-2 mmol/L Ca2+ + 10 mmol/L caffeine before I/R. Thus the sarcolemmal NCX was essential for removing the diastolic Ca2+ during the periods of CPG and I/R. In summary, Ca2+ homeostasis during I/R of neonatal rat hearts is different from that of adult rats. High-[K+] CPG protected neonatal hearts only under isotonic conditions, at a near-normal [Ca]o, or by exposure to KBR. Mitochondria were able to uptake Ca2+ via the mitochondrial CaU and reduce the Ca2+ available for contractile recovery. Nevertheless, after increasing [Ca]o in CPG, the sarcoplasmic reticulum had a main role in restoring contractility during reperfusion, as it does in adults. Thus, the degree of maturation of the heart must be taken into account to evaluate the effects of CPG and drugs on I/R.

AT1 and AT2 receptor expression and blockade after acute ischemia-reperfusion in isolated working rat hearts

2002 ◽  
Vol 282 (4) ◽  
pp. H1206-H1215 ◽  
Author(s):  
Yi Xu ◽  
Dinender Kumar ◽  
Jason R. B. Dyck ◽  
William R. Ford ◽  
Alexander S. Clanachan ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Enzyme Inhibitor ◽  
Ischemia Reperfusion ◽  
Positive Control ◽  
Receptor Expression ◽  
Acute Ischemia ◽  
Ang Ii ◽  
Rat Hearts

We assessed ANG II type 1 (AT1) and type 2 (AT2) receptor (R) expression and functional recovery after ischemia-reperfusion with or without AT1R/AT2R blockade in isolated working rat hearts. Groups of six hearts were subjected to global ischemia (30 min) followed by reperfusion (30 min) and exposed to no drug and no ischemia-reperfusion (control), ischemia-reperfusion and no drug, and ischemia-reperfusion with losartan (an AT1R antagonist; 1 μmol/l), PD-123319 (an AT2R antagonist; 0.3 μmol/l), N 6-cyclohexyladenosine (CHA, a cardioprotective adenosine A1 receptor agonist; 0.5 μmol/l as positive control), enalaprilat (an ANG-converting enzyme inhibitor; 1 μmol/l), PD-123319 + losartan, ANG II (1 nmol/l), or ANG II + losartan. Compared with controls, ischemia-reperfusion decreased AT2R protein (Western immunoblots) and mRNA (Northern immunoblots, RT-PCR) and impaired functional recovery. PD-123319 increased AT2R protein and mRNA and improved functional recovery. Losartan increased AT1R mRNA (but not AT1R/AT2R protein) and impaired recovery. Other groups (except CHA) did not improve recovery. The results suggest that, in isolated working hearts, AT2R plays a significant role in ischemia-reperfusion and AT2R blockade induces increased AT2R protein and cardioprotection.

scholarly journals Preconditioning limits mitochondrial Ca2+ during ischemia in rat hearts: role of KATP channels

2001 ◽  
Vol 280 (5) ◽  
pp. H2321-H2328 ◽  
Author(s):  
Lianguo Wang ◽  
Gennady Cherednichenko ◽  
Lisa Hernandez ◽  
Jessica Halow ◽  
S. Albert Camacho ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Calcium Concentration ◽  
Myocardial Function ◽  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Mitochondrial Calcium ◽  
Rat Hearts ◽  
Developed Pressure

Prolonged myocardial ischemia results in an increase in intracellular calcium concentration ([Ca2+]i), which is thought to play a critical role in ischemia-reperfusion injury. Ischemic preconditioning (PC) improves myocardial function during ischemia-reperfusion, a process that may involve opening mitochondrial ATP-sensitive potassium (KATP) channels. Because pharmacological limitation of mitochondrial calcium concentration ([Ca2+]m) overload during ischemia-reperfusion has been shown to improve myocardial function, we hypothesized that PC would reduce [Ca2+]m during ischemia-reperfusion and that this effect was mediated by opening mitochondrial KATP channels. Isolated rat hearts were subjected to 25 min of global ischemia and 30 min of reperfusion with or without PC in the presence of mitochondrial KATP channel opening (diazoxide, 100 μM) and blockade [5-hydroxydecanoic acid (5-HD), 100 μM]. Contracture during ischemia (end-diastolic pressure) and functional recovery on reperfusion (developed pressure) were assessed. Total [Ca2+]i and [Ca2+]m were measured using indo 1 fluorescence. Both PC and diazoxide limited the increase in end-diastolic pressure and resulted in greater functional recovery after 30 min of reperfusion, functional effects that were partially or completely abolished by 5-HD. PC and diazoxide also significantly limited the increase in [Ca2+]m during ischemia-reperfusion. In addition, PC lowered [Ca2+]i during reperfusion, whereas diazoxide paradoxically resulted in increased [Ca2+]iduring reperfusion. There was an inverse linear relationship between [Ca2+]m and developed pressure during reperfusion. PC limits the ischemia-induced increase in mitochondrial, but not total, [Ca2+]i, an effect mediated by opening mitochondrial KATP channels. These data suggest that the lowering of mitochondrial calcium overload is a mechanism of cardioprotection in PC.

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.

Mitochondrial role in ischemia–reperfusion of rat hearts exposed to high-K+ cardioplegia and clonazepam: energetic and contractile consequences

2007 ◽  
Vol 85 (5) ◽  
pp. 483-496 ◽  
Author(s):  
A.E. Consolini ◽  
M.I. Ragone ◽  
P. Conforti ◽  
M.G. Volonté
Keyword(s):  
Heat Release ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphates ◽  
Rat Hearts ◽  
High K ◽  
Pressure Development ◽  
P Recovery

The role of the mitochondrial Na/Ca-exchanger (mNCX) in hearts exposed to ischemia–reperfusion (I/R) and pretreated with cardioplegia (CPG) was studied from a mechano-calorimetric approach. No-flow ischemia (ISCH) and reperfusion (REP) were developed in isolated rat hearts pretreated with 10 µmol/L clonazepam (CLZP), an inhibitor of the mNCX, and (or) a high K+ – low Ca2+ solution (CPG). Left ventricular end diastolic pressure (LVEDP), pressure development during beats (P), and the steady heat release (Ht) were continuously measured and muscle contents of ATP and PCr were analyzed at the end of REP. During REP, Ht increased more than P, reducing muscle economy (P/Ht) and the ATP content. CPG induced an increase in P recovery during REP (to 90% ± 10% of preISCH) with respect to nonpretreated hearts (control, C, to 64% ± 10%, p < 0.05). In contrast, CLZP reduced P recovery of CPG-hearts (50% ± 6.4%, p < 0.05) and increased LVEDP in C hearts. To evaluate effects on sarcoplasmic reticulum (SR) function, ischemic hearts were reperfused with 10 mmol/L caffeine –36 mmol/L Na (C – caff – low Na). It increased LVEDP, which afterwards slowly relaxed, whereas Ht increased (by about 6.5 mW/g). CLZP sped up the relaxation with higher ΔHt, C – caff – low Na produced higher contracture and lower Ht in perfused than in ischemic hearts. Values of ΔHt were compared with reported fluxes of Ca2+-transporters, suggesting that mitochondria may be in part responsible for the ΔHt during C – caff – low Na REP. Results suggest that ISCH–REP reduced the SR store for the recovery of contractility, but induced Ca2+ movement from the mitochondria to the SR stores. Also, mitochondria and SR are able to remove cytosolic Ca2+ during overloads (as under caffeine), through the mNCX and the uniporter. CPG increases Ca2+ cycling from mitochondria to the SR, which contributes to the higher recovery of P. In contrast, CLZP produces a deleterious effect on ISCH–REP associated with higher heat release and reduced resynthesis of high energy phosphates, which suggests the induction of mitochondrial Ca cycling and uncoupling.

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