Cellular response to reperfused oxygen in the postischemic myocardium

1996 ◽  
Vol 271 (2) ◽  
pp. H687-H695 ◽  
Author(s):  
Y. Chung ◽  
T. Jue
Keyword(s):  
Cellular Response ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Formation Rate ◽  
Lactate Concentration ◽  
High Energy ◽  
O2 Consumption ◽  
1H Nuclear Magnetic Resonance ◽  
Lactate Formation ◽  
Postischemic Myocardium

Perfused rat heart experiments focused on determining the critical O2 level in postischemic myocardium. After a 20-min global ischemia, reperfusion began with O2-saturated saline buffer reflowing at different rates (0.5-12 ml/min). The 1H nuclear magnetic resonance (NMR) signal of the Val E11 myoglobin (Mb) gave an index of the intracellular oxygenation, whereas the 31P-NMR spectra reflected the high-energy phosphate and pH status. At the same time, physiological monitors recorded both contractile function and O2 consumption. Biochemical analysis determined the lactate concentration. Within 6-12 min of reperfusion, the O2 reached a new steady state, which depended directly on the flow rate. Below 12 ml/min reflow, the postischemic O2 level was consistently lower than the corresponding control values. Phosphocreatine, P(i), pH, myocardial O2 consumption, and lactate formation rate exhibited a similar linear relationship with MbO2 saturation in both the control and postischemic myocardium. It appears that neither the cellular energy production nor the steep intracellular O2 gradient has changed substantially in the postischemic myocardium.

Critical intracellular O2 in myocardium as determined by 1H nuclear magnetic resonance signal of myoglobin

1995 ◽  
Vol 268 (4) ◽  
pp. H1675-H1681 ◽  
Author(s):  
U. Kreutzer ◽  
T. Jue
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Magnetic Resonance ◽  
Cellular Response ◽  
Room Temperature ◽  
31P Nmr ◽  
Formation Rate ◽  
Rate Pressure Product ◽  
1H Nuclear Magnetic Resonance ◽  
Lactate Formation ◽  
Nuclear Magnetic

The 1H nuclear magnetic resonance (NMR) signal of tissue myoglobin has provided an opportunity to determine the critical O2 level in saline-perfused myocardium at room temperature. Above the intracellular PO2 of 4 mmHg, the myocardium exhibits no sign of hypoxia. At 4 mmHg, the rate pressure product (RPP) decreases, and the lactate formation rate, measured enzymatically, increases. However, O2 consumption and the 31P-NMR signal of phosphocreatine level remain relatively constant until the cellular PO2 reaches 2 mmHg. The ATP signal intensity dips only when cellular O2 reaches 0.8 mmHg, while pH remains unchanged at 7.2. The sequential nature of the cellular response to limiting O2, starting with alterations in the lactate formation rate and RPP, indicates that NADH, rather than ADP, signals tissue hypoxia. Moreover, the study suggests that the O2 gradient from capillary to cell is larger than that from cytosol to mitochondria.

Carbon monoxide inhibition of regulatory pathways in myocardium

1998 ◽  
Vol 274 (6) ◽  
pp. H2143-H2151 ◽  
Author(s):  
Alan Glabe ◽  
Youngran Chung ◽  
Dejun Xu ◽  
Thomas Jue
Keyword(s):  
Myocardial Function ◽  
Formation Rate ◽  
Control Level ◽  
High Energy ◽  
Rate Pressure Product ◽  
High Energy Phosphate ◽  
Regulatory Pathways ◽  
The Face ◽  
Lactate Formation

The 1H nuclear magnetic resonance (NMR) myoglobin (Mb) Val E11 signal provides a unique opportunity to assess the functional role of Mb in the cell. On CO infusion in perfused myocardium, the MbO2 signal at −2.76 parts per million (ppm) gradually disappears, whereas the corresponding MbCO signal emerges at −2.26 ppm, reflecting the state of Mb inhibition. Up to 76.8% MbCO saturation, myocardial O2 consumption (MV˙o 2) remains constant, whereas the rate-pressure product (RPP) has already dropped to 92% of the control level. At 87.6% MbCO saturation, the lactate formation rate has increased by a factor of two, and MV˙o 2 begins to decline. However, the ratio CO/O2 is still 1/10, well below the inhibition threshold for cytochrome oxidase activity. The MV˙o 2 decline in the face of an adequate O2supply and an unperturbed high-energy phosphate level implies that Mb may play a role in directly regulating respiration, mediated potentially by a shift in NADH/NAD. Although nitrite inhibits Mb, nitrite also directly affects the myocardial function.

Adenosine deaminase inhibitors attenuate ischemic injury and preserve energy balance in isolated guinea pig heart

1993 ◽  
Vol 265 (4) ◽  
pp. H1249-H1256 ◽  
Author(s):  
G. S. Sandhu ◽  
A. C. Burrier ◽  
D. R. Janero
Keyword(s):  
Guinea Pig ◽  
Adenosine Deaminase ◽  
Flow Rate ◽  
Coronary Flow ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
High Energy ◽  
High Energy Phosphates ◽  
Postischemic Recovery

We investigated the effect of the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and coformycin on high-energy phosphate metabolism, tissue nucleotides and nucleosides, and recovery of contractile function in isolated, perfused guinea pig hearts. EHNA and coformycin (10 microM) improved postischemic recovery of contractile function approximately 85% and enhanced coronary flow rate in reperfused tissue approximately 40%. The protective effect of EHNA on recovery of contractile function was concentration dependent. Although adenosine (10 microM) increased coronary flow rate on reperfusion approximately twofold over vehicle, it failed to improve postischemic recovery of contractile function. EHNA and coformycin preserved cardiac ATP levels and increased endogenous tissue adenosine during ischemia. During reperfusion, these agents enhanced recovery of high-energy phosphates approximately twofold and potentiated adenosine release into the perfusate with concentration dependency. Furthermore, EHNA and coformycin reduced the extent of myocardial ischemia-reperfusion injury, as indicated by the approximately 55% reduction in creatine phosphokinase release. We conclude that inhibitors of adenosine deaminase attenuate myocardial ischemic injury and improve postischemic recovery of contractile function and metabolism through endogenous myocardial adenosine enhancement and ATP preservation.

Abstract 649: Does Chronic Increase of Glucose Uptake Cause Cardiac “glycotoxicity”?

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jie Yan ◽  
Ivan Luptak ◽  
Lei Cui ◽  
Mohit Jain ◽  
Ronglih Liao ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Functional Recovery ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
Atp Depletion ◽  
Metabolic Phenotype ◽  
Acid Oxidation

A shift of substrate preference toward glucose in the heart is considered a reversion to fetal metabolic profile but its role in the pathogenesis of cardiac diseases is incompletely understood. We performed a 2-year follow-up study in transgenic mice with sustained high glucose uptake and utilization in the heart by cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (GLUT1-TG). Compared to wildtype (WT) littermates, the GLUT1-TG mice showed normal survival rate and unaltered contractile function of the heart monitored by serial echocardiography and by pressure-volume studies in isolated perfused hearts in the 2-year period. When the hearts were subjected to ischemia-reperfusion, an age-related impairment in functional recovery was observed in WT; cardiac function recovered to 35% vs. 52% of the preischemic level in old (22 months) vs. young (3 months) WT hearts respectively (p<0.05). Ischemic tolerance was markedly enhanced in GLUT1-TG hearts, and importantly, the greater functional recovery in GLUT1-TG hearts was sustained at older age (83% vs. 86% for old and young GLUT1-TG, respectively, p=ns). 31 P NMR spectroscopic measurement showed delayed ATP depletion, reduced acidosis during ischemia and improved recovery of high energy phosphate content in old GLUT1-TG hearts (p<0.05 vs. old WT). These differences were found to be independent of alterations in the activations of Akt and AMPK by ischemia. During reperfusion, glucose oxidation was 3-fold higher while fatty acid oxidation was 45% lower in old GLUT1-TG hearts compared to old WT (p<0.05) suggesting that the deleterious effects of excessive fatty acid oxidation during reperfusion was prevented in old GLUT1-TG hearts. Thus, these results suggest that a normal heart is capable of adapting to chronic increases in basal glucose entry into cardiomyocytes without developing “glucotoxicity”, and furthermore, life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against aging-associated increase of susceptibility to ischemic injury.

scholarly journals Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium

2012 ◽  
Vol 303 (7) ◽  
pp. H844-H852 ◽  
Author(s):  
Ashwin Akki ◽  
Jason Su ◽  
Toshiyuki Yano ◽  
Ashish Gupta ◽  
Yibin Wang ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Functional Recovery ◽  
Contractile Function ◽  
Atp Synthesis ◽  
High Energy ◽  
Rate Pressure Product ◽  
Lactate Dehydrogenase Release ◽  
Biochemical Assays ◽  
Perfused Hearts ◽  
Postischemic Myocardium

Reduced myofibrillar ATP availability during prolonged myocardial ischemia may limit post-ischemic mechanical function. Because creatine kinase (CK) is the prime energy reserve reaction of the heart and because it has been difficult to augment ATP synthesis during and after ischemia, we used mice that overexpress the myofibrillar isoform of creatine kinase (CKM) in cardiac-specific, conditional fashion to test the hypothesis that CKM overexpression increases ATP delivery in ischemic-reperfused hearts and improves functional recovery. Isolated, retrograde-perfused hearts from control and CKM mice were subjected to 25 min of global, no-flow ischemia and 40 min of reperfusion while cardiac function [rate pressure product (RPP)] was monitored. A combination of 31P-nuclear magnetic resonance experiments at 11.7T and biochemical assays was used to measure the myocardial rate of ATP synthesis via CK (CK flux) and intracellular pH (pHi). Baseline CK flux was severalfold higher in CKM hearts (8.1 ± 1.0 vs. 32.9 ± 3.8, mM/s, control vs. CKM; P < 0.001) with no differences in phosphocreatine concentration [PCr] and RPP. End-ischemic pHi was higher in CKM hearts than in control hearts (6.04 ± 0.12 vs. 6.37 ± 0.04, control vs. CKM; P < 0.05) with no differences in [PCr] and [ATP] between the two groups. Post-ischemic PCr (66.2 ± 1.3 vs. 99.1 ± 8.0, %preischemic levels; P < 0.01), CK flux (3.2 ± 0.4 vs. 14.0 ± 1.2 mM/s; P < 0.001) and functional recovery (13.7 ± 3.4 vs. 64.9 ± 13.2%preischemic RPP; P < 0.01) were significantly higher and lactate dehydrogenase release was lower in CKM than in control hearts. Thus augmenting cardiac CKM expression attenuates ischemic acidosis, reduces injury, and improves not only high-energy phosphate content and the rate of CK ATP synthesis in postischemic myocardium but also recovery of contractile function.

Effects ofS-nitroso-N-acetylcysteine on contractile function of reperfused skeletal muscle

1998 ◽  
Vol 274 (3) ◽  
pp. R822-R829 ◽  
Author(s):  
Long-En Chen ◽  
Anthony V. Seaber ◽  
Rima M. Nasser ◽  
Jonathan S. Stamler ◽  
James R. Urbaniak
Keyword(s):  
Skeletal Muscle ◽  
Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
Control Group ◽  
Group Vi ◽  
No Donor ◽  
Early Reperfusion ◽  
Reconstructive Operations

The ultimate goal of replantation and microsurgical reconstructive operations is to regain or improve impaired function of the tissue. However, the data related to the influence of NO on tissue function are limited. This study evaluated the effects of the NO donor S-nitroso- N-acetylcysteine (SNAC) on contractile function of skeletal muscle during reperfusion. Forty-nine rats were divided into six groups. The extensor digitorum longus (EDL) muscles in groups I and II were not subjected to ischemia-reperfusion but were treated with a low (100 nmol/min) or high (1 μmol/min) dose of SNAC. In groups III- V, the EDL underwent 3 h of ischemia and 3 h of reperfusion and was also treated with low (100 nmol/min) or high doses (1 or 5 μmol/min) of SNAC. Group VI was a phosphate-buffered saline (PBS)-treated control group. Twenty additional animals were used to document systemic effects of SNAC and PBS only. SNAC or PBS was infused for 6.5 h, beginning 30 min before ischemia and continuing throughout the duration of reperfusion. Contractile testing compared the maximal twitch force, isometric tetanic contractile forces, fatigue, and fatigue half time of the experimental EDL and the contralateral nontreated EDL. The findings indicate that 1) SNAC does not influence contractile function of EDL muscle not subjected to ischemia-reperfusion, 2) SNAC significantly protects the contractile function of ischemic skeletal muscle against reperfusion injury in the early reperfusion period, and 3) the protective role of SNAC is critically dosage dependent; protection is lost at higher doses. The conclusion from this study is that supplementation with exogenous NO exerts a protective effect on the tissue against reperfusion injury.

Reduced substrate oxidation in postischemic myocardium: 13C and 31P NMR analyses

1990 ◽  
Vol 258 (5) ◽  
pp. H1357-H1365 ◽  
Author(s):  
E. D. Lewandowski ◽  
D. L. Johnston
Keyword(s):  
Steady State ◽  
31P Nmr ◽  
Tca Cycle ◽  
High Energy ◽  
Substrate Oxidation ◽  
High Energy Phosphates ◽  
Atp Content ◽  
And Control ◽  
13C And 31P Nmr ◽  
Postischemic Myocardium

13C and 31P nuclear magnetic resonance (NMR) spectra were used to assess substrate oxidation and high-energy phosphates in postischemic (PI) isolated rabbit hearts. Phosphocreatine (PCr) increased in nonischemic controls on switching from glucose perfusion to either 2.5 mM [3-13C]pyruvate (120%, n = 7) or [2-13C]acetate (114%, n = 8, P less than 0.05). ATP content, oxygen consumption (MVO2), and hemodynamics (dP/dt) were not affected by substrate availability in control or PI hearts. dP/dt was 40-60% lower in PI hearts during reperfusion after 10 min ischemia. Hearts reperfused with either pyruvate (n = 11) or acetate (n = 8) regained preischemic PCr levels within 45 s. Steady-state ATP levels were 55-70% of preischemia with pyruvate and 52-60% with acetate. Percent maximum [4-13C]glutamate signal showed reduced conversion of pyruvate to glutamate via the tricarboxylic acid (TCA) cycle at 4-min reperfusion (PI = 24 +/- 4%, means +/- SE; Control = 48 +/- 4%). The increase in 13C signal from the C-4 position of glutamate was similar to control hearts within 10.5 min. The increase in [4-13C]glutamate signal from acetate was not different between PI and control hearts. The ratio of [2-13C]Glu:[4-13C]Glu, reflecting TCA cycle activity, was reduced in PI hearts with acetate for at least 10 min (Control = 0.76 +/- 0.03; PI = 0.51 +/- 0.09) until steady state was reached. Despite rapid recovery of oxidative phosphorylation, contractility remained impaired and substrate oxidation was significantly slowed in postischemic hearts.

Stress-induced opening of the permeability transition pore in the dystrophin-deficient heart is attenuated by acute treatment with sildenafil

2011 ◽  
Vol 300 (1) ◽  
pp. H144-H153 ◽  
Author(s):  
Alexis Ascah ◽  
Maya Khairallah ◽  
Frédéric Daussin ◽  
Céline Bourcier-Lucas ◽  
Richard Godin ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Clinical Signs ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mdx Mice ◽  
Uptake Velocity ◽  
Ptp Opening

Susceptibility of cardiomyocytes to stress-induced damage has been implicated in the development of cardiomyopathy in Duchenne muscular dystrophy, a disease caused by the lack of the cytoskeletal protein dystrophin in which heart failure is frequent. However, the factors underlying the disease progression are unclear and treatments are limited. Here, we tested the hypothesis of a greater susceptibility to the opening of the mitochondrial permeability transition pore (PTP) in hearts from young dystrophic ( mdx) mice (before the development of overt cardiomyopathy) when subjected to a stress protocol and determined whether the prevention of a PTP opening is involved in the cardioprotective effect of sildenafil, which we have previously reported in mdx mice. Using the 2-deoxy-[3H]glucose method to quantify the PTP opening in ex vivo perfused hearts, we demonstrate that when compared with those of controls, the hearts from young mdx mice subjected to ischemia-reperfusion (I/R) display an excessive PTP opening as well as enhanced activation of cell death signaling, mitochondrial oxidative stress, cardiomyocyte damage, and poorer recovery of contractile function. Functional analyses in permeabilized cardiac fibers from nonischemic hearts revealed that in vitro mitochondria from mdx hearts display normal respiratory function and reactive oxygen species handling, but enhanced Ca2+ uptake velocity and premature opening of the PTP, which may predispose to I/R-induced injury. The administration of a single dose of sildenafil to mdx mice before I/R prevented excessive PTP opening and its downstream consequences and reduced tissue Ca2+ levels. Furthermore, mitochondrial Ca2+ uptake velocity was reduced following sildenafil treatment. In conclusion, beyond our documentation that an increased susceptibility to the opening of the mitochondrial PTP in the mdx heart occurs well before clinical signs of overt cardiomyopathy, our results demonstrate that sildenafil, which is already administered in other pediatric populations and is reported safe and well tolerated, provides efficient protection against this deleterious event, likely by reducing cellular Ca2+ loading and mitochondrial Ca2+ uptake.

scholarly journals Molecular Characterization of Reactive Oxygen Species in Myocardial Ischemia-Reperfusion Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Tingyang Zhou ◽  
Chia-Chen Chuang ◽  
Li Zuo
Keyword(s):  
Reactive Oxygen Species ◽  
Myocardial Ischemia ◽  
Energy Demand ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
High Energy ◽  
Protective Mechanism ◽  
Oxygen Species ◽  
Myocardial Ischemia Reperfusion

Myocardial ischemia-reperfusion (I/R) injury is experienced by individuals suffering from cardiovascular diseases such as coronary heart diseases and subsequently undergoing reperfusion treatments in order to manage the conditions. The occlusion of blood flow to the tissue, termed ischemia, can be especially detrimental to the heart due to its high energy demand. Several cellular alterations have been observed upon the onset of ischemia. The danger created by cardiac ischemia is somewhat paradoxical in that a return of blood to the tissue can result in further damage. Reactive oxygen species (ROS) have been studied intensively to reveal their role in myocardial I/R injury. Under normal conditions, ROS function as a mediator in many cell signaling pathways. However, stressful environments significantly induce the generation of ROS which causes the level to exceed body’s antioxidant defense system. Such altered redox homeostasis is implicated in myocardial I/R injury. Despite the detrimental effects from ROS, low levels of ROS have been shown to exert a protective effect in the ischemic preconditioning. In this review, we will summarize the detrimental role of ROS in myocardial I/R injury, the protective mechanism induced by ROS, and potential treatments for ROS-related myocardial injury.

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