Carbon monoxide increases inducible NOS expression that mediates CO-induced myocardial damage during ischemia-reperfusion

2015 ◽  
Vol 308 (7) ◽  
pp. H759-H767 ◽  
Author(s):  
Grégory Meyer ◽  
Lucas André ◽  
Adrien Kleindienst ◽  
François Singh ◽  
Stéphane Tanguy ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Myocardial Damage ◽  
Environmental Pollutant ◽  
No Synthase ◽  
No Production ◽  
Cellular Mechanisms ◽  
Mortality And Morbidity ◽  
Before And After

We investigated the role of inducible nitric oxide (NO) synthase (iNOS) on ischemic myocardial damage in rats exposed to daily low nontoxic levels of carbon monoxide (CO). CO is a ubiquitous environmental pollutant that impacts on mortality and morbidity from cardiovascular diseases. We have previously shown that CO exposure aggravates myocardial ischemia-reperfusion (I/R) injury partly because of increased oxidative stress. Nevertheless, cellular mechanisms underlying cardiac CO toxicity remain hypothetical. Wistar rats were exposed to simulated urban CO pollution for 4 wk. First, the effects of CO exposure on NO production and NO synthase (NOS) expression were evaluated. Myocardial I/R was performed on isolated perfused hearts in the presence or absence of S-methyl-isothiourea (1 μM), a NOS inhibitor highly specific for iNOS. Finally, Ca2+ handling was evaluated in isolated myocytes before and after an anoxia-reoxygenation performed with or without S-methyl-isothiourea or N-acetylcystein (20 μM), a nonspecific antioxidant. Our main results revealed that 1) CO exposure altered the pattern of NOS expression, which is characterized by increased neuronal NOS and iNOS expression; 2) cardiac NO production increased in CO rats because of its overexpression of iNOS; and 3) the use of a specific inhibitor of iNOS reduced myocardial hypersensitivity to I/R (infarct size, 29 vs. 51% of risk zone) in CO rat hearts. These last results are explained by the deleterious effects of NO and reactive oxygen species overproduction by iNOS on diastolic Ca2+ overload and myofilaments Ca2+ sensitivity. In conclusion, this study highlights the involvement of iNOS overexpression in the pathogenesis of simulated urban CO air pollution exposure.

scholarly journals Influence of Low Concentrations of Carbon Monoxide on Metabolism of Isolated Heart under Conditions of Ischemia-Reperfusion

2021 ◽  
Vol 6 (6) ◽  
pp. 230-238
Author(s):  
S. P. Beschasnyi ◽  
◽  
Ye. M. Lysenko
Keyword(s):  
Carbon Monoxide ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
Volumetric Flow Rate ◽  
Myocardial Damage ◽  
Mouse Heart ◽  
Triphenyltetrazolium Chloride ◽  
Isolated Hearts ◽  
Low Concentrations ◽  
Vasoconstrictor Effect

The purpose of the study was to determine the effect of different concentrations of carbon monoxide on the metabolism of isolated mice hearts. Materials and methods. To elucidate the effect of low concentrations of carbon monoxide on the myocardium, we performed retrograde perfusion of isolated hearts of laboratory mice with Krebs-Henseleit solution, which was saturated with carbon monoxide for 5, 10, and 30 minutes. We then determined how different concentrations of carbon monoxide affected coronary volumetric flow rate, myocardial glucose and calcium uptake, creatinine release, and aspartate aminotransferase release. During perfusion, R-wave amplitude and R-R interval were measured using an electrocardiograph. To determine the effect of ischemia on the heart muscle during perfusion with solutions of different concentrations, we measured the area of the affected myocardium after staining with 2,3,5-triphenyltetrazolium chloride. Results and discussion. After these studies, it was found that different concentrations of carbon monoxide had a dose-dependent effect on the isolated mouse heart. However, the dependence of the effects does not follow the pattern «lowest concentration – lowest effect». At the same time, an increase in concentration did not mean an increase in adverse effects on the myocardium. Even on the contrary, the smallest concentration led to increased signs of ischemic myocardial damage. In particular, the use of the solution, through which carbon monoxide was passed for 5 minutes, caused vasoconstrictor effect during perfusion. At the end of reperfusion, vasoconstrictor effect was observed after using a solution through which carbon monoxide was passed for 10 minutes. Increased glucose uptake was observed in the group with 30-minute carbon monoxide permeation against the background of the minimal myocardial creatinine release. In this group there was also a decrease in Ca2+ loss at the beginning of reperfusion (immediately after ischemia). The above phenomenon explains the least degree of ischemic myocardial damage in the isolated mouse heart. The obtained data should be expanded. Since it is difficult to accurately determine the dose of carbon monoxide, then the use of donor compounds is promising. Such compounds include CORM-2 and CORM-3. Under physiological conditions, they decompose in a controlled manner, releasing a specific amount of carbon monoxide. Conclusion. The obtained results indicate that at different concentrations of carbon monoxide can differently influence different structures of cardiomyocyte: at one concentration it binds to calcium channels, other concentrations influence ion channels of plasma membrane, which can explain all these dependencies

scholarly journals Cardioprotective mechanism of FTY720 in ischemia reperfusion injury

2019 ◽  
Vol 30 (5) ◽  
Author(s):  
Naseer Ahmed
Keyword(s):  
Heart Failure ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
New Drugs ◽  
Mortality And Morbidity ◽  
Coronary Syndrome

Abstract Cardioprotection is a very challenging area in the field of cardiovascular sciences. Myocardial damage accounts for nearly 50% of injury due to reperfusion, yet there is no effective strategy to prevent this to reduce the burden of heart failure. During last couple of decades, by combining genetic and bimolecular studies, many new drugs have been developed to treat hypertension, heart failure, and cancer. The use of percutaneous coronary intervention has reduced the mortality and morbidity of acute coronary syndrome dramatically. However, there is no standard therapy available that can mitigate cardiac reperfusion injury, which contributes to up to half of myocardial infarcts. Literature shows that the activation of sphingosine receptors, which are G protein-coupled receptors, induces cardioprotection both in vitro and in vivo. The exact mechanism of this protection is not clear yet. In this review, we discuss the mechanism of ischemia reperfusion injury and the role of the FDA-approved sphingosine 1 phosphate drug fingolimod in cardioprotection.

Excessive NO production dose not account for the inhibition of hepatic gluconeogenesis in endotoxemia

1996 ◽  
Vol 271 (4) ◽  
pp. G621-G628 ◽  
Author(s):  
J. Ou ◽  
L. Molina ◽  
Y. M. Kim ◽  
T. R. Billiar
Keyword(s):  
No Synthase ◽  
No Production ◽  
Wild Type ◽  
Gapdh Activity ◽  
Nos Inhibitors ◽  
Before And After ◽  
Gluconeogenic Substrates ◽  
Fasted Rats

The pattern of inhibition of gluconeogenesis in hepatocytes was compared between endotoxemia in vivo and nitric oxide (NO) exposure in vitro. Fasted rats were injected with lipopolysaccharide (LPS; 12 mg/kg) or with vehicle alone. After 2-24 h, hepatocytes were isolated, placed in suspension, and incubated for 1 h with various gluconeogenic substrates that enter at different sites of the gluconeogenic pathway. Hepatocytes from LPS-treated rats exhibited up to a 50% decrease in gluconeogenesis for substrates that enter proximal to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) beginning at 6 h, followed by a nadir at 12 h after LPS. Although hepatocytes exposed to exogenous NO (S-nitroso-N-acetylpenicillamine) also exhibited a depressed gluconeogenesis, the pattern was not the same with inhibition in gluconeogenesis for substrates that enter the pathway both before and after GAPDH. Furthermore, when rats injected with LPS were subjected to a constant portal infusion (Alzet pump) of the NO synthase (NOS) inhibitors, NG-monomethyl-L-arginine or aminoguanidine, no changes in the LPS-induced gluconeogenesis suppression were seen. In addition, no difference in LPS-induced inhibition of gluconeogenesis was detected when hepatocytes from inducible NO synthase (NOS-2) knockout mice were compared with cells obtained from wild-type mice. Minimal decreases in GAPDH activity were measured in hepatocytes from the LPS-treated rats, whereas the activity of phosphoenol pyruvate carboxykinase (PEPCK) declined up to 40%, independent of NO synthesis. These data indicate that NO does not account for the inhibition of gluconeogenesis in endotoxemia, and they provide support for NO-independent reduction in PEPCK activity as a more plausible explanation.

scholarly journals Baicalin Improves Cardiac Outcome and Survival by Suppressing Drp1-Mediated Mitochondrial Fission after Cardiac Arrest-Induced Myocardial Damage

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jun Wu ◽  
Hui Chen ◽  
Jiahong Qin ◽  
Nan Chen ◽  
Shiqi Lu ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Mitochondrial Dysfunction ◽  
Myocardial Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Specific Inhibitor ◽  
Myocardial Damage ◽  
Spontaneous Circulation ◽  
Flavonoid Compound

Myocardial injury after cardiac arrest (CA) often results in severe myocardial dysfunction and death involving mitochondrial dysfunction. Here, we sought to investigate whether baicalin, a natural flavonoid compound, exerts cardioprotection against CA-induced injury via regulating mitochondrial dysfunction. We subjected the rats to asphyxia CA after a daily baicalin treatment for 4 weeks. After the return of spontaneous circulation, baicalin treatment significantly improved cardiac function performance, elevated survival rate from 35% to 75%, prevented necrosis and apoptosis in the myocardium, which was accompanied by reduced phosphorylation of Drp1 at serine 616, inhibited Drp1 translocation to the mitochondria and mitochondrial fission, and improved mitochondrial function. In H9c2 cells subjected to simulated ischemia/reperfusion, increased phosphorylation of Drp1 at serine 616 and subsequently enhanced mitochondrial Drp1 translocation as well as mitochondrial fission, augmented cardiomyocyte death, increased reactive oxygen species production, released cytochrome c from mitochondria and injured mitochondrial respiration were efficiently improved by baicalin and Drp1 specific inhibitor with Mdivi-1. Furthermore, overexpression of Drp1 augmented excessive mitochondrial fission and abolished baicalin-afforded cardioprotection, indicating that the protective impacts of baicalin are linked to the inhibition of Drp1. Altogether, our findings disclose for the first time that baicalin offers cardioprotection against ischemic myocardial injury after CA by inhibiting Drp1-mediated mitochondrial fission. Baicalin might be a prospective therapy for the treatment of post-CA myocardial injury.

Abstract 3663: Characterization of Cerebrovascular Parameters using MRI in Endothelial Nitric Oxide Synthase Knockout Mice

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Ji-Yeon Suh ◽  
Shunning Huang ◽  
Dmitriy N Atochin ◽  
Jeong Kon Kim ◽  
WH Shim ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Exchange Rate ◽  
Water Permeability ◽  
Water Exchange ◽  
No Synthase ◽  
Systemic Hypertension ◽  
No Production ◽  
Wild Type ◽  
Water Exchange Rate ◽  
Before And After

Endothelial-derived nitric oxide (NO) is important for properly regulating vascular tone and maintaining blood pressure. Mice lacking endothelial NO synthase (eNOS), i.e. loss of endothelial NO production, have systemic hypertension and develop larger cerebral infarction upon cerebral ischemia. Given that constitutively produced NO is necessary for a normal endothelial function, we posit that cerebrovascular characters in eNOS KO mice brain may differ in structure and physiology. In this study, we aim to establish MRI-derived vascular parameters such as cerebral blood volume (CBV), water exchange index (WEI), and vessel size index (VSI) using two different MRI intravascular contrast agents (Gd-PGC (Protected graft copolymer bearing covalently linked Gd- DTPA residues) and SPION (superparamagnetic iron oxide nanoparticle)). We also investigated whether perivascular aquaporine (AQP) proteins, which play a central role in the pathophysiology of many diseases, are differently expressed in eNOS KO mice. Flip angle dependence of the MRI signal intensity on transvascular water exchange rate was used to quantify CBV and WEI before and after intravenous administration of Gd-PGC using wild type mice (C57BL/6, n=8) and eNOS KO mice (n=5). 2D T2 and T2* maps were also acquired before and after SPION administration for measurements of cerebral VSI. As results, eNOS KO mice have lower VSI than that that in wild type mice ( Fig. A ). The CBV of eNOS KO mice is not significantly different from that of wild type mice ( Fig. B ). Furthermore, baseline WEI significantly increased in the eNOS KO mice, indicating higher BBB water permeability. However, both AQP1 and AQP4 were less expressed in eNOS KO mice than those in wild type mice ( Fig. D ). These suggest that the loss of eNOS contribute to the decrease of the vessel diameter and increase of water permeability under a baseline physiological condition. However, expression of AQP proteins forming vascular water channels is not involved with the observed water exchange rate increase across the BBB in eNOS KO mice. The study warrants future investigations to elucidate the relationship between NO synthase and the BBB integrity and its involvement with ischemic damage.

PPAR-α activation protects the type 2 diabetic myocardium against ischemia-reperfusion injury: involvement of the PI3-Kinase/Akt and NO pathway

2009 ◽  
Vol 296 (3) ◽  
pp. H719-H727 ◽  
Author(s):  
Aliaksandr A. Bulhak ◽  
Christian Jung ◽  
Claes-Göran Östenson ◽  
Jon O. Lundberg ◽  
Per-Ove Sjöquist ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
No Synthase ◽  
Ischemic Myocardium ◽  
No Production ◽  
Gk Rats ◽  
Nitrite Nitrate ◽  
Type 2 Diabetic

Several clinical studies have shown the beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. The ligands of peroxisome proliferator-activated receptor-α (PPAR-α) reduce ischemia-reperfusion injury in nondiabetic animals. We hypothesized that the activation of PPAR-α would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. GK rats and age-matched Wistar rats (n ≥ 7) were given either 1) the PPAR-α agonist WY-14643 (WY), 2) dimethyl sulfoxide (DMSO), 3) WY and the NO synthase inhibitor NG-nitro-l-arginine (l-NNA), 4) l-NNA, 5) WY and the PI3K inhibitor wortmannin, or 6) wortmannin alone intravenously before a 35-min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of endothelial NO synthase (eNOS), inducible NO synthase, and Akt as well as nitrite/nitrate were determined. The IS was 75 ± 3% and 72 ± 4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56 ± 3% in Wistar ( P < 0.05) and to 46 ± 5% in GK rats ( P < 0.001). The addition of either l-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS, 70 ± 5% and 65 ± 5%, respectively) and GK (IS, 66 ± 4% and 64 ± 4%, P < 0.05, respectively) rats. The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473, and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial nitrite/nitrate levels were reduced in GK rats ( P < 0.05). The results suggest that PPAR-α activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via the activation of the PI3K/Akt and NO pathway.

Ca2+ loading and adrenergic stimulation reveal male/female differences in susceptibility to ischemia-reperfusion injury

2002 ◽  
Vol 283 (2) ◽  
pp. H481-H489 ◽  
Author(s):  
Heather R. Cross ◽  
Elizabeth Murphy ◽  
Charles Steenbergen
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
No Synthase ◽  
No Production ◽  
Adrenergic Stimulation ◽  
Enos Expression ◽  
Endothelial Nitric Oxide ◽  
Perfused Hearts

To compare ischemia-reperfusion injury in males versus females under hypercontractile conditions, perfused hearts from 129J mice pretreated with 3 mmol/l Ca2+ or 10−8 mol/l isoproterenol ± 10−6 mol/l N ω-nitro-l-arginine methyl ester (l-NAME) were subjected to 20 min of ischemia and 40 min of reperfusion while 31P NMR spectra were acquired. Basal contractility increased equivalently in female versus male hearts with isoproterenol- or Ca2+ treatment. Injury was equivalent in untreated male versus female hearts but was greater in isoproterenol or Ca2+-treated male than female hearts, as indicated by lower postischemic contractile function, ATP, and PCr. Endothelial nitric oxide (NO) synthase (eNOS) expression was higher in female than male hearts, neuronal NOS (nNOS) did not differ, and inducible NOS (iNOS) was undetectable. Ischemic NO production was higher in female than male hearts, andl-NAME increased injury in female isoproterenol-treated hearts. In summary, isoproterenol or high Ca2+ pretreatment increased ischemia-reperfusion injury in males more than females. eNOS expression and NO production were higher in female than male hearts, and l-NAME blocked female protection. Females were therefore protected from the detrimental effects of adrenergic stimulation and Ca2+ loading via a NOS-mediated mechanism.

scholarly journals The Effect of the Nitric Oxide Synthase Inhibitor L-NMMA on Basal CBF and Vasoneuronal Coupling in Man: A PET Study

1999 ◽  
Vol 19 (6) ◽  
pp. 673-678 ◽  
Author(s):  
Richard P. White ◽  
Claire Hindley ◽  
Peter M. Bloomfield ◽  
Vincent J. Cunningham ◽  
Patrick Vallance ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Animal Models ◽  
No Synthase ◽  
No Production ◽  
Finger Movements ◽  
Nitric Oxide Synthase Inhibitor ◽  
Positron Emission ◽  
Animal Data ◽  
Before And After ◽  
Synthase Inhibitor

Nitric oxide (NO) regulates basal CBF. In a number of animal models NO has been implicated in the mediation of the regional changes in CBF (rCBF) that accompany neuronal activation (vasoneuronal coupling). However, some results in animal models have failed to confirm this finding, and the validity of extrapolation to man from animal data is uncertain. To determine the contribution of NO to basal global CBF and activation-induced changes in rCBF, the authors have performed quantitative H215O positron emission tomography (PET) studies before and after administration of the non-isoform-specific NO synthase inhibitor, NG-monomethyl-l-arginine (L-NMMA), in 10 healthy male volunteers. Learning a novel sequence of finger movements was used as a paradigm to induce regional frontal cortex activation. The effect of NO synthase inhibition on the magnitude and pattern of activation was determined. Resting global CBF fell from 33.3 ± 5.3 mL·100 g−1·min−1 at rest before L-NMMA, to 26.5 ± 7.7 mL·100 g−1·min−1 after L-NMMA ( P = 0.001). This fall was reversed by l-arginine administration. Learning sequential finger movements induced increases in rCBF in the left motor, right prefrontal, and bilateral premotor cortices. After NO synthase inhibition with L-NMMA, there was no change in this pattern of activation and no reduction in the magnitude of rCBF responses at the foci of maximal stimulation before and after L-NMMA. These findings confirm that NO production contributes to basal CBF regulation in man, but show that systemic NO synthase inhibition with L-NMMA does not impair regional vasoneuronal coupling.

scholarly journals Oxidative Stress-Related Biomarkers in Essential Hypertension and Ischemia-Reperfusion Myocardial Damage

2013 ◽  
Vol 35 ◽  
pp. 773-790 ◽  
Author(s):  
Ramón Rodrigo ◽  
Matías Libuy ◽  
Felipe Feliú ◽  
Daniel Hasson
Keyword(s):  
Oxidative Stress ◽  
Essential Hypertension ◽  
Cardiac Tissue ◽  
Nitrosative Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Antioxidant Defense System ◽  
Mortality And Morbidity ◽  
Total Antioxidant ◽  
Novel Association

Cardiovascular diseases are a leading cause of mortality and morbidity worldwide, with hypertension being a major risk factor. Numerous studies support the contribution of reactive oxygen and nitrogen species in the pathogenesis of hypertension, as well as other pathologies associated with ischemia/reperfusion. However, the validation of oxidative stress-related biomarkers in these settings is still lacking and novel association of these biomarkers and other biomarkers such as endothelial progenitor cells, endothelial microparticles, and ischemia modified albumin, is just emerging. Oxidative stress has been suggested as a pathogenic factor and therapeutic target in early stages of essential hypertension. Systolic and diastolic blood pressure correlated positively with plasma F2-isoprostane levels and negatively with total antioxidant capacity of plasma in hypertensive and normotensive patients. Cardiac surgery with extracorporeal circulation causes an ischemia/reperfusion event associated with increased lipid peroxidation and protein carbonylation, two biomarkers associated with oxidative damage of cardiac tissue. An enhancement of the antioxidant defense system should contribute to ameliorating functional and structural abnormalities derived from this metabolic impairment. However, data have to be validated with the analysis of the appropriate oxidative stress and/or nitrosative stress biomarkers.

Cardioprotective role of endogenous hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo

2006 ◽  
Vol 291 (3) ◽  
pp. H1138-H1146 ◽  
Author(s):  
Toyotaka Yada ◽  
Hiroaki Shimokawa ◽  
Osamu Hiramatsu ◽  
Yoshisuke Haruna ◽  
Yoshitaka Morita ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Protective Role ◽  
No Production ◽  
Coronary Vasodilatation ◽  
Before And After ◽  
Nos Inhibitor

We have recently demonstrated that endogenous H2O2 plays an important role in coronary autoregulation in vivo. However, the role of H2O2 during coronary ischemia-reperfusion (I/R) injury remains to be examined. In this study, we examined whether endogenous H2O2 also plays a protective role in coronary I/R injury in dogs in vivo. Canine subepicardial small coronary arteries (≥100 μm) and arterioles (<100 μm) were continuously observed by an intravital microscope during coronary I/R (90/60 min) under cyclooxygenase blockade ( n = 50). Coronary vascular responses to endothelium-dependent vasodilators (ACh) were examined before and after I/R under the following seven conditions: control, nitric oxide (NO) synthase (NOS) inhibitor NG-monomethyl-l-arginine (l-NMMA), catalase (a decomposer of H2O2), 8-sulfophenyltheophylline (8-SPT, an adenosine receptor blocker), l-NMMA + catalase, l-NMMA + tetraethylammonium (TEA, an inhibitor of large-conductance Ca2+-sensitive potassium channels), and l-NMMA + catalase + 8-SPT. Coronary I/R significantly impaired the coronary vasodilatation to ACh in both sized arteries (both P < 0.01); l-NMMA reduced the small arterial vasodilatation (both P < 0.01), whereas it increased ( P < 0.05) the ACh-induced coronary arteriolar vasodilatation associated with fluorescent H2O2 production after I/R. Catalase increased the small arterial vasodilatation ( P < 0.01) associated with fluorescent NO production and increased endothelial NOS expression, whereas it decreased the arteriolar response after I/R ( P < 0.01). l-NMMA + catalase, l-NMMA + TEA, or l-NMMA + catalase + 8-SPT further decreased the coronary vasodilatation in both sized arteries (both, P < 0.01). l-NMMA + catalase, l-NMMA + TEA, and l-NMMA + catalase + 8-SPT significantly increased myocardial infarct area compared with the other four groups (control, l-NMMA, catalase, and 8-SPT; all, P < 0.01). These results indicate that endogenous H2O2, in cooperation with NO, plays an important cardioprotective role in coronary I/R injury in vivo.

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