Ischemic preconditioning-mediated restoration of membrane dystrophin during reperfusion correlates with protection against contraction-induced myocardial injury

2004 ◽  
Vol 287 (1) ◽  
pp. H81-H90 ◽  
Author(s):  
Masakuni Kido ◽  
Hajime Otani ◽  
Shiori Kyoi ◽  
Tomohiko Sumida ◽  
Hiroyoshi Fujiwara ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Myocardial Injury ◽  
Contractile Activity ◽  
Integral Membrane Protein ◽  
Contractile Force ◽  
Global Ischemia ◽  
Blue Dye ◽  
Perfused Heart ◽  
Complete Restoration ◽  
Rat Hearts

Dystrophin is an integral membrane protein involved in the stabilization of the sarcolemmal membrane in cardiac muscle. We hypothesized that the loss of membrane dystrophin during ischemia and reperfusion is responsible for contractile force-induced myocardial injury and that cardioprotection afforded by ischemic preconditioning (IPC) is related to the preservation of membrane dystrophin. Isolated and perfused rat hearts were subjected to 30 min of global ischemia, followed by reperfusion with or without the contractile blocker 2,3-butanedione monoxime (BDM). IPC was introduced by three cycles of 5-min ischemia and 5-min reperfusion before the global ischemia. Dystrophin was distributed exclusively in the membrane of myocytes in the normally perfused heart but was redistributed to the myofibril fraction after 30 min of ischemia and was lost from both of these compartments during reperfusion in the presence or absence of BDM. The loss of dystrophin preceded uptake of the membrane-impermeable Evans blue dye by myocytes that occurred after the withdrawal of BDM and was associated with creatine kinase release and the development of contracture. Although IPC did not alter the redistribution of membrane dystrophin induced by 30 min of ischemia, it facilitated the restoration of membrane dystrophin during reperfusion. Also, myocyte necrosis was not observed when BDM was withdrawn after complete restoration of membrane dystrophin. These results demonstrate that IPC-mediated restoration of membrane dystrophin during reperfusion correlates with protection against contractile force-induced myocardial injury and suggest that the cardioprotection conferred by IPC can be enhanced by the temporary blockade of contractile activity until restoration of membrane dystrophin during reperfusion.

Changes in subcellular membranes in rat heart perfused with diethyl ether

1979 ◽  
Vol 57 (12) ◽  
pp. 1412-1420
Author(s):  
Gina M. L. Taam ◽  
Satoshi Takeo ◽  
Vincenzo Panagia ◽  
Attila Ziegelhoffer ◽  
Naranjan S. Dhalla
Keyword(s):  
Calcium Binding ◽  
Electron Microscopic Examination ◽  
Membrane System ◽  
Contractile Force ◽  
Perfused Heart ◽  
Electron Microscopic ◽  
Irreversible Damage ◽  
Control Value ◽  
Subcellular Membrane ◽  
Rat Hearts

Alterations in contractile force as well as heart sarcolemmal, microsomal, and mitochondrial activities were investigated by perfusing rat hearts with different concentrations (0.5–1.5% (v/v)) of ether for 2 min. Contractile force of the perfused heart was depressed by 0.5–1.0% ether and completely abolished by 1.25–1.5% ether. The contractile force recovered fully upon reperfusion when the hearts were preperfused with 0.5–0.75% ether but the recovery was partial in hearts preperfused with 1.0–1.25% ether. The hearts preperfused with 1.5% ether did not recover their ability to generate contractile force upon reperfusion. The Na+–K+-ATPase activity of sarcolemma obtained from hearts perfused with 0.75–1.0% ether was higher than the control value. The sarcolemmal Na+–K+-ATPase, Mg2+-ATPase, Ca2+-ATPase, calcium binding, and adenylate cyclase activities were decreased in hearts perfused with 1.5% ether and these activities were further decreased upon reperfusion. The microsomal calcium binding and uptake activities were depressed in hearts perfused with 1.0–1.5% ether and these changes were irreversible. The mitochondrial calcium binding and uptake activities as well as oxidative phosphorylation activity were also depressed in hearts perfused with 1.0–1.5% ether; however, irreversible damage was seen in hearts perfused with 1.5% ether. Electron microscopic examination showed occasional vacuolization of mitochondria in hearts perfused with 1% ether and swelling of sarcoplasmic reticulum and mitochondria as well as damage to myofilaments were seen in hearts perfused with 1.5% ether. These results suggest the involvement of alterations in subcellular membrane system in the cardiotoxic actions of ether.

Calcium-linked changes in myocardial metabolism in the isolated perfused rat heart

1977 ◽  
Vol 55 (4) ◽  
pp. 925-933 ◽  
Author(s):  
N. S. Dhalla ◽  
J. C. Yates ◽  
V. Proveda
Keyword(s):  
Cyclic Amp ◽  
Myocardial Metabolism ◽  
Contractile Activity ◽  
Control Level ◽  
Creatine Phosphate ◽  
High Energy ◽  
Contractile Force ◽  
Increase Glucose Uptake ◽  
Rat Hearts ◽  
External Calcium

Rat hearts were perfused for 40 min with aerobic medium containing different concentrations of calcium (0–5 mM) and their abilities to take up and oxidize glucose, and to produce lactate and glycerol were examined in addition to measuring glycogen, lipids, cyclic AMP, and high energy phosphate stores. Increasing the concentration of calcium was found to decrease myocardial glycogen but increase glucose uptake, glucose oxidation, and lactate release. A decrease in myocardial triglycerides and an increase in free fatty acid contents as well as glycerol release without any changes in cholesterol and phospholipid contents were observed upon increasing the concentration of external calcium. In comparison with the hearts perfused with Ca2+-free medium, the levels of creatine phosphate and ATP were lower and that of ADP higher in hearts perfused with medium containing 5 mM calcium. No differences in AMP and cyclic AMP contents were seen among hearts perfused with different concentrations of calcium. The contractile activity initially increased upon increasing the concentration of calcium from 1.25 to 5 mM and then declined towards the control level. The hearts were unable to generate contractile force in the absence of calcium, whereas the contractile force decreased and then began to recover upon perfusing the hearts with 0.31 mM calcium. These results indicate that elevated levels of intracellular calcium stimulate glycogenolytic, glycolytic, and lipolytic processes in myocardium directly.

Ischemic preconditioning increases the bioavailability of cardiac enkephalins

2005 ◽  
Vol 289 (4) ◽  
pp. H1652-H1661 ◽  
Author(s):  
Antoine Younès ◽  
Salvatore Pepe ◽  
Darice Yoshishige ◽  
James L. Caffrey ◽  
Edward G. Lakatta
Keyword(s):  
Size Exclusion Chromatography ◽  
Ischemic Preconditioning ◽  
Bioactive Peptides ◽  
Global Ischemia ◽  
Size Exclusion ◽  
Peptidase Inhibitors ◽  
Rat Hearts ◽  
Exclusion Chromatography ◽  
Perfused Rat Hearts ◽  
Isolated Perfused Rat Hearts

Growing evidence suggests that cardiac enkephalins and their receptors are involved in ischemic preconditioning (IPC). Because there is no evidence for vesicular storage of small bioactive enkephalins in the heart, studies were designed to test the hypothesis that ischemia depletes cardiac enkephalins and that IPC preserves the same enkephalins by accelerating their processing from the larger proenkephalin precursor (PEP) pool. The precursors and two bioactive representatives, Met-enkephalin (ME) and Met-enkephalin-Arg-Phe (MEAP), were separated by size-exclusion chromatography and quantified by radioimmunoassay. Isolated perfused rat hearts were prepared and exposed to global ischemia. After 30 min of global ischemia and 40 min of reflow, the PEP pool was reduced (from 17.99 ± 1.52 to 14.20 ± 2.38 pmol/g wet wt), MEAP increased by 53%, and ME declined by 68%. The sum of the two smaller peptides was unchanged (9.78 ± 0.83 vs. 9.33 ± 2.81). Thus the total enkephalin peptide content was not altered (27.77 ± 1.69 vs. 24.10 ± 4.75). Peptide distribution after ischemia and reflow was also unaltered by pretreatment with peptidase inhibitors. However, when the hearts were preconditioned, the PEP pool remained significantly lower and both of the bioactive peptides, MEAP and ME, were elevated (+49% and +86%, respectively). The decline in the PEP pool was prevented by peptidase inhibition and the rise in MEAP was exaggerated. In separate protocols, synthetic enkephalins (ME, MEAP, and Leu-enkephalin) were added to the coronary inflow before 30 min of global ischemia and throughout the subsequent reflow. The added enkephalins (10−8 M) had no inotropic effect on baseline function but completely prevented the mechanical dysfunction observed in untreated controls during reflow. Thus IPC appears to increase available bioactive enkephalins (MEAP + ME) within the heart by enhancing synthesis of precursors and their subsequent processing from the PEP pool.

Limb ischemia preconditions the heart against reperfusion tachyarrhythmia

1997 ◽  
Vol 273 (4) ◽  
pp. H1707-H1712 ◽  
Author(s):  
Tatyana Oxman ◽  
Michael Arad ◽  
Rodica Klein ◽  
Natalie Avazov ◽  
Babeth Rabinowitz
Keyword(s):  
Ischemic Preconditioning ◽  
Reference Group ◽  
Limb Ischemia ◽  
Antiarrhythmic Effect ◽  
The Body ◽  
Perfused Heart ◽  
Group Iii ◽  
Group I ◽  
Rat Hearts

We investigated the hypothesis that a cardioprotective, antiarrhythmic effect might be obtained by brief ischemia of a remote part of the body before ischemia of the heart. Regional ischemia (RI) was induced in isolated Langendorff-perfused rat hearts: group I, 30-min RI and reperfusion (control hearts; n = 18); group II, 5-min RI before 30-min RI (a reference group of “classic” ischemic preconditioning; n = 12); and group III, ischemic preconditioning with in vivo 10-min limb ischemia (LI) before 30-min RI in the perfused heart ( n = 20). A significant decrease in reperfusion arrhythmia was found in groups II and III compared with group I ( P < 0.02). Release of norepinephrine (NE) and prostacyclin was higher in hearts from animals pretreated with LI ( P < 0.05). Prostacyclin increased in all groups at minute 1 of reperfusion, but there was no correlation to the antiarrhythmic effect. NE increased at the beginning of reperfusion after 30 min of ischemia; this release was significantly diminished after preconditioning with LI ( P < 0.05). We further investigated the role of NE in preconditioning with LI using drug interventions. Pretreatment with exogenous NE protected against tachyarrhythmia. Reserpine given 24 h before LI partially abolished the antiarrhythmic effect of LI preconditioning. However, the α1-adrenoreceptor blocker prazosin did not prevent the effect of LI preconditioning on either ischemic or reperfusion tachyarrhythmia. Therefore, brief ischemia of an extremity protects against reperfusion tachyarrhythmia. One of the humoral mediators involved in this response appears to be NE; others remain to be identified.

Pyruvate increases threshold for preconditioning in globally ischemic rat hearts

1994 ◽  
Vol 267 (4) ◽  
pp. H1403-H1409 ◽  
Author(s):  
C. A. Sargent ◽  
S. Dzwonczyk ◽  
P. Sleph ◽  
M. Wilde ◽  
G. J. Grover
Keyword(s):  
Lactate Dehydrogenase ◽  
Ischemic Preconditioning ◽  
Enhanced Recovery ◽  
Recovery Of Function ◽  
High Energy ◽  
Global Ischemia ◽  
High Energy Phosphates ◽  
Lactate Dehydrogenase Release ◽  
Rat Hearts ◽  
Isolated Rat

Isolated rat hearts can be protected by preconditioning, although this has not been found when they are perfused with pyruvate. We addressed the question of whether pyruvate could increase the threshold for preconditioning in isolated rat hearts and whether this could be overcome with increased durations of ischemia. A protocol of four periods of 5 min of ischemic preconditioning (4 x 5 min) protected hearts (improved recovery of function, reduced lactate dehydrogenase release) not perfused with pyruvate from a subsequent 30-min period of global ischemia, but did not protect pyruvate-perfused hearts. Pilot studies indicated that hearts perfused in the presence of pyruvate must be ischemic for approximately 40% longer to produce equivalent ischemic damage in nonpyruvate-treated hearts. Thus the preconditioning period of 5 min was increased by approximately 40% to 7 min to produce equivalent degrees of preconditioning. Hearts preconditioned with the 4 x 7 min protocol with pyruvate were significantly protected against a subsequent severe global ischemia (enhanced recovery of function, reduced lactate dehydrogenase release). High-energy phosphates were measured at the end of the preconditioning protocol (before final global ischemia) to determine whether there was a correlation between cardioprotection and high-energy phosphate levels. There was no correlation between ATP, ADP, or AMP levels and the efficacy of preconditioning. However, an increase in creatine phosphate was associated with cardioprotection, although the importance of this in mediating preconditioning is doubtful. Thus the ability to precondition rat hearts is somewhat dependent on their energy source, but this appears to be due to changes in the severity of the ischemic preconditioning event.

Independent dual perfusion of left and right coronary arteries in isolated rat hearts

1991 ◽  
Vol 261 (6) ◽  
pp. H2082-H2090 ◽  
Author(s):  
M. Avkiran ◽  
M. J. Curtis
Keyword(s):  
High Energy ◽  
Low Flow ◽  
Blue Dye ◽  
Ischemia And Reperfusion ◽  
Langendorff Preparation ◽  
Rat Hearts ◽  
Left And Right ◽  
Conventional Models ◽  
Aortic Cannula ◽  
Isolated Rat

A novel dual lumen aortic cannula was designed and constructed to permit independent perfusion of left and right coronary beds in isolated rat hearts without necessitating the cannulation of individual arteries. Stability of the dual-perfusion preparation was shown to be similar to that of the conventional Langendorff preparation, in terms of coronary flow, heart rate, and high-energy phosphate content. The independence of left and right perfusion beds was confirmed by unilateral infusion of disulfine blue dye and spectrophotometric detection of the dye in ventricular homogenates. Transient cessation of flow to the left coronary bed resulted in severe ventricular arrhythmias upon reperfusion, as in conventional models of regional ischemia and reperfusion. The dual-perfusion model is technically undemanding, reproducible, inexpensive, and can be used in several species. It enables studies with 1) regional low flow ischemia, 2) regional zero-flow ischemia without coronary ligation (with attendant damage to vasculature), 3) selective application of drugs or interventions to the ischemic-reperfused zone, and 4) selective application of components of ischemia and reperfusion to a site anatomically relevant to ischemic heart disease.

scholarly journals Mechanism of uncoupling protein 2-mediated myocardial injury in hypothermic preserved rat hearts

2016 ◽  
Vol 14 (2) ◽  
pp. 1857-1864 ◽  
Author(s):  
Gai-Ge Chen ◽  
Jin-Bin Yan ◽  
Xu-Ming Wang ◽  
Ming-Zhi Zheng ◽  
Jian-Ping Jiang ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Rat Hearts

scholarly journals Exercise Training Preserves Ischemic Preconditioning in Aged Rat Hearts by Restoring the Myocardial Polyamine Pool

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Weiwei Wang ◽  
Hao Zhang ◽  
Guo Xue ◽  
Li Zhang ◽  
Weihua Zhang ◽  
...  
Keyword(s):  
Exercise Training ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion ◽  
Polyamine Metabolism ◽  
Aged Rat ◽  
Isolated Hearts ◽  
Age Related ◽  
Rat Hearts ◽  
Myocardial Ischemia Reperfusion

Background. Ischemic preconditioning (IPC) strongly protects against myocardial ischemia reperfusion (IR) injury. However, IPC protection is ineffective in aged hearts. Exercise training reduces the incidence of age-related cardiovascular disease and upregulates the ornithine decarboxylase (ODC)/polyamine pathway. The aim of this study was to investigate whether exercise can reestablish IPC protection in aged hearts and whether IPC protection is linked to restoration of the cardiac polyamine pool.Methods. Rats aging 3 or 18 months perform treadmill exercises with or without gradient respectively for 6 weeks. Isolated hearts and isolated cardiomyocytes were exposed to an IR and IPC protocol.Results. IPC induced an increase in myocardial polyamines by regulating ODC and spermidine/spermine acetyltransferase (SSAT) in young rat hearts, but IPC did not affect polyamine metabolism in aged hearts. Exercise training inhibited the loss of preconditioning protection and restored the polyamine pool by activating ODC and inhibiting SSAT in aged hearts. An ODC inhibitor,α-difluoromethylornithine, abolished the recovery of preconditioning protection mediated by exercise. Moreover, polyamines improved age-associated mitochondrial dysfunctionin vitro.Conclusion. Exercise appears to restore preconditioning protection in aged rat hearts, possibly due to an increase in intracellular polyamines and an improvement in mitochondrial function in response to a preconditioning stimulus.

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