scholarly journals Fingolimod (FTY720) Preserves High Energy Phosphates and Improves Cardiac Function in Heterotopic Heart Transplantation Model

2020 ◽  
Vol 21 (18) ◽  
pp. 6548
Author(s):  
Naseer Ahmed ◽  
Javeria Farooq ◽  
Soban Sadiq ◽  
Sultan Ayoub Meo ◽  
Azam Jan ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Treated Group ◽  
High Energy ◽  
Left Ventricular ◽  
Parp Inhibition ◽  
Control Group ◽  
High Energy Phosphates ◽  
High Energy Phosphate

During heart transplantation, donor heart leads to reduced oxygen supply resulting in low level of high energy phosphate (HEP) reserves in cardiomyocyte. Lower HEP is one of the underlying reasons of cell death due to ischemia. In this study we investigated the role of Fingolimod (FTY720) in heart transplantation ischemia. Eight groups of Sprague-Dawley rats (n = 5 for each subgroup) were made, A1 and C1 were given FTY720 1 mg/kg while B1 and D1 were given normal saline. The hearts were implanted into another set of similar rats after preservation period of 1 h at 4–8 °C. Significantly higher Left ventricular systolic pressure (LVSP), dP/dT maximum (p < 0.05), dP/dT minimum (p < 0.05) were recorded in the FTY720 treated group after 24 h of reperfusion while after 1 h of reperfusion, there were no significant differences in LVSP, maximum and negative dP/dT, and Left ventricular end diastolic pressure (LVEDP) between the control and the FTY720-treated transplant groups. Coronary blood flow (CBF) was enhanced (p < 0.05) in the FTY720 treated group after 1 and 24 h. ATP p < 0.001, p < 0.05 at 1 and 24 h, ADP p < 0.001, p > 0.05 at 1 and 24 h, and phosphocreatine p < 0.05, p > 0.05 at 1 and 24 h were better preserved by FTY720 treatment as compared to control group. The study concluded that pretreatment of grafted hearts with FTY720 improved hemodynamics, CBF, high energy phosphate reserves, reduces the peroxynitrite level and poly (ADP ribose) polymerase (PARP) inhibition that prevents ischemia-reperfusion injury.

scholarly journals Effects of Thyroid Hormone Analogue and a Leukotrienes Pathway-Blocker on Reperfusion Injury Attenuation after Heart Transplantation

2013 ◽  
Vol 2013 ◽  
pp. 1-8
Author(s):  
Fadhil G. Al-Amran ◽  
Najah R. Hadi ◽  
Haider S. H. Al-Qassam
Keyword(s):  
Myocardial Ischemia ◽  
Heart Transplantation ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Treated Group ◽  
Control Group ◽  
Group I ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Background. Global myocardial ischemia reperfusion injury after heart transplantation is believed to impair graft function and aggravate both acute and chronic rejection episodes. Objectives. To assess the possible protective potential of MK-886 and 3,5-diiodothyropropionic acid DITPA against global myocardial ischemia reperfusion injury after heart transplantation. Materials and Methods. Adult albino rats were randomized into 6 groups as follows: group I sham group; group II, control group; groups III and IV, control vehicles (1,2); group V, MK-886 treated group. Donor rats received MK-886 30 min before transplantation, and the same dose was repeated for recipients upon reperfusion; in group VI, DITPA treated group, donors and recipients rats were pretreated with DITPA for 7 days before transplantation. Results. Both MK-886 and DITPA significantly counteract the increase in the levels of cardiac TNF-α, IL-1β, and ICAM-1 and plasma level of cTnI (). Morphologic analysis showed that both MK-886 and DITPA markedly improved () the severity of cardiac injury in the heterotopically transplanted rats. Conclusions. The results of our study reveal that both MK-886 and DITPA may ameliorate global myocardial ischemia reperfusion injury after heart transplantation via interfering with inflammatory pathway.

Myocardial high-energy phosphate metabolism is altered after treatment with anthracycline in childhood

2000 ◽  
Vol 10 (6) ◽  
pp. 610-617 ◽  
Author(s):  
Andrea B. Eidenschink ◽  
Gerrit Schröter ◽  
Stefan Müller-Weihrich ◽  
Heiko Stern
Keyword(s):  
Adenosine Triphosphate ◽  
High Energy ◽  
Left Ventricular ◽  
Control Group ◽  
Left Ventricular Myocardium ◽  
Resonance Spectroscopy ◽  
Phosphate Metabolism ◽  
High Energy Phosphate ◽  
High Energy Phosphate Metabolism

AbstractObjectivesWe aimed to investigate whether changes in high-energy phosphate metabolism after treatment of children and young adults with anthracycline can be demonstrated non-invasively by 31P magnetic resonance spectroscopy.BackgroundAbnormal myocardial energy metabolism has been suggested as a mechanism for anthracycline-induced cardiotoxicity. Deterioration in such has been shown in animal studies by resonance spectroscopy.MethodsWe studied 62 patients, with a mean age of 13.5 ±5 years,3.7±4.3 years after a cumulative anthracycline dose of 270±137 mg/m2. Normal echocardiographic findings had been elicited in 54 patients. The control group consisted of 28 healthy subjects aged 20±7 years. Resonance spectrums of the anterior left ventricular myocardium were obtained at 1.5 Tesla using an image-selected in vivo spectroscopy localization technique.ResultsThe ratio of phosphocreatine to adenosine triphosphate after blood correction was 1.09±0.43 for the patients, and 1.36±0.36 (mean±SD)for controls (p = 0.005), with a significantly reducedmean ratio even in the subgroup of patients with normal echocardiographic results ( l.11 ± 0. 44 versus1.36±0.36, p=0.01). The ratio did not correlate with the cumulative dose of anthracycline. The ratio of phosphodiester to adenosine triphosphate was similar in patients and controls (0.90±0.56 versus 0.88±0.62).ConclusionsIn patients treated with anthracyclines in childhood, myocardial high-energy phosphate metabolism may be impaired even in the absence of cardiomyopathy. Our data support the concept that anthracycline-induced cardiotoxicity is not clearly dose dependent.

scholarly journals Myocardial Po2 does not limit aerobic metabolism in the postischemic heart

2016 ◽  
Vol 310 (2) ◽  
pp. H226-H238 ◽  
Author(s):  
Youngran Chung
Keyword(s):  
Recovery Time ◽  
Spontaneously Hypertensive Rat ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
High Energy Phosphates ◽  
Hypertensive Rats ◽  
High Energy Phosphate ◽  
Spontaneously Hypertensive ◽  
H Nmr ◽  
Time Courses

Reperfused hypertrophic hearts are prone to develop reflow abnormalities, which are likely to impair O2 return to the myocardium. Yet, reflow deficit may not be the only factor determining postischemic oxygenation in the hypertrophic heart. Altered O2 demand may also contribute to hypoxia. In addition, the extent to which myocardial Po2 dictates energy and functional recovery in the reperfused heart remains uncertain. In the present study, moderately hypertrophied hearts from spontaneously hypertensive rats were subjected to ischemia-reperfusion, and the recovery time courses of pH and high-energy phosphates were followed by 31P NMR. 1H NMR measurement of intracellular myoglobin assessed tissue O2 levels. The present study found that the exacerbation of hypoxia in the postischemic spontaneously hypertensive rat heart arises mostly from impaired microvascular supply of O2. However, postischemic myocardial Po2, at least when it exceeds ∼18% of the preischemic level, does not limit mitochondrial respiration and high-energy phosphate resynthesis. It only passively reflects changes in the O2 supply-demand balance.

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.

scholarly journals Cardioprotection against Ischemia/Reperfusion by Licochalcone B in Isolated Rat Hearts

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Jichun Han ◽  
Dong Wang ◽  
Bacui Yu ◽  
Yanming Wang ◽  
Huanhuan Ren ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Left Ventricular Pressure ◽  
Treated Group ◽  
Left Ventricular ◽  
Control Group ◽  
Myocardial Infarct Size ◽  
Triphenyltetrazolium Chloride

The generation of reactive oxygen species (ROS) is a major cause of heart injury induced by ischemia-reperfusion. The left ventricular developed pressure (LVDP) and the maximum up/down rate of left ventricular pressure (±dp/dtmax⁡) were documented by a physiological recorder. Myocardial infarct size was estimated macroscopically using 2,3,5-triphenyltetrazolium chloride staining. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase (CK) release to assess the degree of cardiac injury. The levels of C-reactive protein (CRP), interleukin-8 (IL-8), tumor necrosis factor-α(TNF-α), and interleukin-6 (IL-6) were analyzed to determine the inflammation status of the myocardial tissue. Cardiomyocyte apoptosis analysis was performed using the In Situ Cell Death Detection Kit, POD. Accordingly, licochalcone B pretreatment improved the heart rate (HR), increased LVDP, and decreased CK and LDH levels in coronary flow. SOD level and GSH/GSSG ratio increased, whereas the levels of MDA, TNF-α, and CRP and activities of IL-8 and IL-6 decreased in licochalcone B-treated groups. The infarct size and cell apoptosis in hearts from licochalcone B-treated group were lower than those in hearts from the I/R control group. Therefore, the cardioprotective effects of licochalcone B may be attributed to its antioxidant, antiapoptotic, and anti-inflammatory activities.

Erythropoietin protects against doxorubicin-induced heart failure

2011 ◽  
Vol 301 (6) ◽  
pp. H2413-H2421 ◽  
Author(s):  
Hania Ibrahim Ammar ◽  
Soliman Saba ◽  
Rasha Ibrahim Ammar ◽  
Laila Ahmed Elsayed ◽  
Wael Botros Abu-Alyamin Ghaly ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Ischemia Reperfusion ◽  
Treated Group ◽  
Left Ventricular ◽  
Rate Pressure Product ◽  
Control Group ◽  
Maximal Increase ◽  
Male Wistar Rats ◽  
Developed Pressure

The hormone erythropoietin (EPO) has been demonstrated to have cardioprotective properties. The present study investigates the role of EPO to prevent heart failure following cancer treatment with doxorubicin [adriamycin (AD)]. Male Wistar rats (150 ± 10 g) were treated with saline (vehicle control group); with EPO, subcutaneously at 1,000 IU/kg body wt, three times per week for 4 wk (EPO group); with adriamycin, intraperitoneally at 2.5 mg/kg body wt, three times per week for 2 wk (AD group); and with adriamycin and EPO (EPO-AD group). Echocardiographic measurements showed that EPO-AD treatment prevented the AD-induced decline in cardiac function. Each of the hearts was then exposed to ischemia and reperfusion during Langendorff perfusion. The percentage of recovery after ischemia-reperfusion was significantly greater in EPO-AD than the AD-treated group for left ventricular developed pressure, maximal increase in pressure, and rate pressure product. The level of oxidative stress was significantly higher in AD (5 μM for 24 h)-exposed isolated cardiomyocytes; EPO (5 U/ml for 48 h) treatment prevented this. EPO treatment also decreased AD-induced cardiomyocyte apoptosis, which was associated with the decrease in the Bax-to-Bcl2 ratio and caspase-3 activation. Immunostaining of myocardial tissue for CD31 showed a significant decrease in the number of capillaries in AD-treated animals. EPO-AD treatment restored the number of capillaries. In conclusion, EPO treatment effectively prevented AD-induced heart failure. The protective effect of EPO was associated with a decreased level of oxidative stress and apoptosis in cardiomyocytes as well as improved myocardial angiogenesis.

Creatine kinase-deficient hearts exhibit increased susceptibility to ischemia-reperfusion injury and impaired calcium homeostasis

2004 ◽  
Vol 287 (3) ◽  
pp. H1039-H1045 ◽  
Author(s):  
Matthias Spindler ◽  
Klaus Meyer ◽  
Hinrik Strömer ◽  
Andrea Leupold ◽  
Ernest Boehm ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
Left Ventricular ◽  
Stress Conditions ◽  
High Energy Phosphates ◽  
Baseline Conditions ◽  
Increased Susceptibility

The creatine kinase (CK) system is involved in the rapid transport of high-energy phosphates from the mitochondria to the sites of maximal energy requirements such as myofibrils and sarcolemmal ion pumps. Hearts of mice with a combined knockout of cytosolic M-CK and mitochondrial CK (M/Mito-CK−/−) show unchanged basal left ventricular (LV) performance but reduced myocardial high-energy phosphate concentrations. Moreover, skeletal muscle from M/Mito-CK−/− mice demonstrates altered Ca2+ homeostasis. Our hypothesis was that in CK-deficient hearts, a cardiac phenotype can be unmasked during acute stress conditions and that susceptibility to ischemia-reperfusion injury is increased because of altered Ca2+ homeostasis. We simultaneously studied LV performance and myocardial Ca2+ metabolism in isolated, perfused hearts of M/Mito-CK−/− ( n = 6) and wild-type (WT, n = 8) mice during baseline, 20 min of no-flow ischemia, and recovery. Whereas LV performance was not different during baseline conditions, LV contracture during ischemia developed significantly earlier (408 ± 72 vs. 678 ± 54 s) and to a greater extent (50 ± 2 vs. 36 ± 3 mmHg) in M/Mito-CK−/− mice. During reperfusion, recovery of diastolic function was impaired (LV end-diastolic pressure: 22 ± 3 vs. 10 ± 2 mmHg), whereas recovery of systolic performance was delayed, in M/Mito-CK−/− mice. In parallel, Ca2+ transients were similar during baseline conditions; however, M/Mito-CK−/− mice showed a greater increase in diastolic Ca2+ concentration ([Ca2+]) during ischemia (237 ± 54% vs. 167 ± 25% of basal [Ca2+]) compared with WT mice. In conclusion, CK-deficient hearts show an increased susceptibility of LV performance and Ca2+ homeostasis to ischemic injury, associated with a blunted postischemic recovery. This demonstrates a key function of an intact CK system for maintenance of Ca2+ homeostasis and LV mechanics under metabolic stress conditions.

Energy-linked functional alterations in experimental cardiomyopathies

1991 ◽  
Vol 261 (4) ◽  
pp. L39-L44 ◽  
Author(s):  
V. I. Kapelko ◽  
V. I. Veksler ◽  
M. I. Popovich ◽  
R. Ventura-Clapier
Keyword(s):  
Diastolic Pressure ◽  
Contractile Function ◽  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphates ◽  
Phosphate Content ◽  
High Energy Phosphate ◽  
Cardiac Contractile Function ◽  
Myocardial Stiffness ◽  
Cardiac Contractile

Changes in high-energy phosphate content and cardiac contractile function of isolated rat hearts as well as changes in Ca2+ sensitivity and mitochondrial respiration of myocardial skinned fibers were assessed in hereditary cardiomyopathies and in cardiomyopathies induced by chronic treatment with adriamycin or norepinephrine, by autoimmunization, by diabetes, or by creatine deficiency. The sum of ATP and phosphocreatine contents as well as cardiac output at standard load conditions was substantially lower in almost all groups. The common features of cardiac pump failure were mild bradycardia, elevated left ventricular (LV) diastolic pressure, and stiffness that limited cardiac contractile adaptation to volume or resistance loads. The LV diastolic stiffness at maximal functional load was inversely correlated with high-energy phosphate content. Increased myofibrillar sensitivity to Ca2+ and defective function of mitochondrial creatine kinase were found in skinned myocardial fibers. These results suggested that both increased myofibrillar Ca2+ sensitivity and energy deficiency within myofibrils may contribute to increased myocardial stiffness. Increased stiffness limits LV filling but facilitates pressure development, which partly compensates for decreased contractility of cardiomyopathic hearts. cardiac contractile function; high-energy phosphates; isolated heart; myocardial stiffness

Energy-linked functional alterations in experimental cardiomyopathies

1991 ◽  
Vol 261 (4) ◽  
pp. 39-44 ◽  
Author(s):  
V. I. Kapelko ◽  
V. I. Veksler ◽  
M. I. Popovich ◽  
R. Ventura-Clapier
Keyword(s):  
Diastolic Pressure ◽  
Contractile Function ◽  
High Energy ◽  
Left Ventricular ◽  
High Energy Phosphates ◽  
Phosphate Content ◽  
High Energy Phosphate ◽  
Cardiac Contractile Function ◽  
Myocardial Stiffness ◽  
Cardiac Contractile

Changes in high-energy phosphate content and cardiac contractile function of isolated rat hearts as well as changes in Ca2+ sensitivity and mitochondrial respiration of myocardial skinned fibers were assessed in hereditary cardiomyopathies and in cardiomyopathies induced by chronic treatment with adriamycin or norepinephrine, by autoimmunization, by diabetes, or by creatine deficiency. The sum of ATP and phosphocreatine contents as well as cardiac output at standard load conditions was substantially lower in almost all groups. The common features of cardiac pump failure were mild bradycardia, elevated left ventricular (LV) diastolic pressure, and stiffness that limited cardiac contractile adaptation to volume or resistance loads. The LV diastolic stiffness at maximal functional load was inversely correlated with high-energy phosphate content. Increased myofibrillar sensitivity to Ca2+ and defective function of mitochondrial creatine kinase were found in skinned myocardial fibers. These results suggested that both increased myofibrillar Ca2+ sensitivity and energy deficiency within myofibrils may contribute to increased myocardial stiffness. Increased stiffness limits LV filling but facilitates pressure development, which partly compensates for decreased contractility of cardiomyopathic hearts. cardiac contractile function; high-energy phosphates; isolated heart; myocardial stiffness

Isoflurane Produces Sustained Cardiac Protection after Ischemia–Reperfusion Injury in Mice

2006 ◽  
Vol 104 (3) ◽  
pp. 495-502 ◽  
Author(s):  
Yasuo M. Tsutsumi ◽  
Hemal H. Patel ◽  
N Chin Lai ◽  
Toshiyuki Takahashi ◽  
Brian P. Head ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Adenosine Triphosphate ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Control Group ◽  
Cardiac Protection ◽  
Intact Mouse

Background Isoflurane reduces myocardial ischemia-reperfusion injury within hours to days of reperfusion. Whether isoflurane produces sustained cardiac protection has never been examined. The authors studied isoflurane-induced cardiac protection in the intact mouse after 2 h and 2 weeks of reperfusion and determined the dependence of this protection on adenosine triphosphate-dependent potassium channels and the relevance of this protection to myocardial function and apoptosis. Methods Mice were randomly assigned to receive oxygen or isoflurane for 30 min with 15 min of washout. Some mice received mitochondrial (5-hydroxydecanoic acid) or sarcolemmal (HMR-1098) adenosine triphosphate-dependent potassium channel blockers with or without isoflurane. Mice were then subjected to a 30-min coronary artery occlusion followed by 2 h or 2 weeks of reperfusion. Infarct size was determined at 2 h and 2 weeks of reperfusion. Cardiac function and apoptosis were determined 2 weeks after reperfusion. Results Isoflurane did not change hemodynamics. Isoflurane reduced infarct size after reperfusion when compared with the control groups (27.7 +/- 6.3 vs. 41.7 +/- 6.4% at 2 h and 19.6 +/- 5.9 vs. 28.8 +/- 9.0% at 2 weeks). Previous administration of 5-hydroxydecanoic acid, but not HMR-1098, abolished isoflurane-induced cardiac protection. At 2 weeks, left ventricular end-diastolic diameter was decreased significantly and end-systolic pressure and maximum and minimum dP/dt were improved by isoflurane. Isoflurane-treated mice subjected to ischemia and 2 weeks of reperfusion showed less expression of proapoptotic genes, significantly decreased expression of cleaved caspase-3, and significantly decreased deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling-positive nuclei compared with the control group. Conclusions Cardiac protection induced by isoflurane against necrotic and apoptotic cell death is associated with an acute memory period that is sustained and functionally relevant 2 weeks after ischemia-reperfusion injury in mice in vivo.

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