scholarly journals Pharmacological Inhibition of S-Nitrosoglutathione Reductase Reduces Cardiac Damage Induced by Ischemia–Reperfusion

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 555
Author(s):  
Oscar Arriagada Castillo ◽  
Gustavo Herrera ◽  
Carlos Manriquez ◽  
Andrea F. Rojas ◽  
Daniel R. González
Keyword(s):  
Ventricular Function ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Protein S ◽  
Isolated Rat Heart ◽  
Cardioprotective Effect ◽  
Mitochondrial Proteins ◽  
Cardiac Damage ◽  
Pharmacological Inhibition ◽  
Cardioprotective Effects

The cardioprotective effects of nitric oxide (NO) have been described through S-nitrosylation of several important proteins in the mitochondria of the cardiomyocyte. S-nitrosoglutathione reductase (GSNOR) is an enzyme involved in the metabolism of S-nitrosothiols by producing denitrosylation, thus limiting the cardioprotective effect of NO. The effect of GSNOR inhibition on the damage by cardiac ischemia–reperfusion is still unclear. We tested the hypothesis that pharmacological inhibition of GSNOR promotes cardioprotection by increasing the levels of protein S-nitrosylation. In a model of ischemia–reperfusion in isolated rat heart, the effect of a GSNOR inhibitor, 5-chloro-3-(2-[4-ethoxyphenyl) (ethyl) amino]-2-oxoethyl)-1H-indole-2-carboxylic acid (C2), was investigated. Ventricular function and hemodynamics were determined, in addition to tissue damage and S-nitrosylation of mitochondrial proteins. Hearts treated with C2 showed a lower release of myocardial damage marker creatine kinase and a reduction in the infarcted area. It also improved post-ischemia ventricular function compared to controls. These results were associated with increasing protein S-nitrosylation, specifically of the mitochondrial complexes III and V. The pharmacological inhibition of GSNOR showed a concentration-dependent cardioprotective effect, being observed in functional parameters and myocardial damage, which was maximal at 1 µmol/L, associated with increased S-nitrosylation of mitochondrial proteins. These data suggest that GSNOR is an interesting pharmacological target for cardiac reperfusion injury.

scholarly journals Peripheral M-choline-reactive systems in the infarct-limited effect implementation of remote ischemic postconditioning during ischemia-reperfusion of myocardium in experiment

2019 ◽  
Vol 16 (4) ◽  
pp. 424-433 ◽  
Author(s):  
F. I. Vismont ◽  
S. N. Chepelev ◽  
P. F. Jushkevich
Keyword(s):  
Clinical Medicine ◽  
Ischemia Reperfusion ◽  
Reactive Systems ◽  
Myocardial Damage ◽  
Ischemic Postconditioning ◽  
Limited Effect ◽  
Systemic Action ◽  
Remote Ischemic Postconditioning ◽  
Old Rats ◽  
Cardioprotective Effects

The search for new effective methods to prevent or mitigate ischemic myocardial damage and the mechanisms for their realization is an important task of modern experimental and clinical medicine. The aim of the study was to elucidate the significance of peripheral M-choline-reactive systems in the realization of the cardioprotective effects of remote ischemic postconditioning (RIPostC) during ischemia-reperfusion of myocardium in experiment. The study revealed that RIPostC has an infarct-limiting effect during ischemia-reperfusion of myocardium in young and old rats, but under the conditions of systemic action of atropine (2 mg/kg), the infarct-limiting effect of RIPostC remained only in old rats. It seems that the activity of peripheral M-choline-reactive systems is important in the mechanisms of realization of the cardioprotective effects of RIPost in young, but not in old rats.

scholarly journals Effect of modulation of hydrogen sulfur and glutathione synthesis on oxidative and nitrosative metabolism under myocardial ischemia-reperfusion

2021 ◽  
Vol 84 (1) ◽  
pp. 43-47
Author(s):  
R. Fedichkina ◽  
Yu. Korkach ◽  
I. Okhai ◽  
Yu. Goshovska ◽  
V. Sagach
Keyword(s):  
Nitrosative Stress ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Redox Balance ◽  
Isolated Rat Heart ◽  
Cardioprotective Effect ◽  
Ros Generation ◽  
Synthesis Inhibitor ◽  
Oxidative And Nitrosative Stress ◽  
Cardiac Tissues

Redox balance maintaining is a prerequisite for normal cardiomyocytes metabolism. Reperfusion injury of the heart is characterized by an explosive increase in ROS generation, cell membranes damage, dysfunction of proteins, the development of muscle contracture etc. It was shown that the hydrogen sulfide (H2S) and the precursor of its synthesis the amino acid L-cysteine provided cardioprotective effect against ischemiareperfusion, In addition, L-cysteine is one of amino acids that form an antioxidant glutathione (GSH). The aim of our work was to investigate the effect of GSH and H2S synthesis modulation on the oxidative and nitrosative stress in cardiac tissues under conditions of ischemia-reperfusion. The H2S synthesis inhibitor propargylglycine (PAG), the GSH synthesis inhibitor butionine sulfoxime (BSO) and L-cysteine were administered intraperitoneally. Next, ischemia-reperfusion of the Langendorff isolated rat heart was performed. In the tissues of rat's hearts, before and after ischemia, we determined the rate of ROS generation, content of POL products, the activity of NO synthesizing enzymes. Results of our study showed that pretreatment with PAG + L-cysteine combination prevented heart function disturbances, ROS formation, increased low molecular weight nitrosothiols content, preserved the activity of constitutive NOS and inhibited the activity of inducible NOS in the pre-ischemic period as well as in the period of reperfusion. Pretreatment with BSO in PAG + L-cysteine group significantly reduced the effectiveness of the combination and abolished cardioprotective effect. Generation of superoxide and hydroxyl anions was increased, activity of inducible NO-synthase was 3.5-fold increased comparing with PAG + L-cysteine pretreated group. Pretreatment with PAG + L-cysteine combination inhibited the formation of ROS and preserved the activity of constitutive NOS, thus providing stable production of NO. Pretreatment with BSO completely abolished an antioxidant effect of PAG + L-cysteine decreasing bioavailability of glutathione.

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

2007 ◽  
Vol 293 (3) ◽  
pp. H1545-H1552 ◽  
Author(s):  
Yilong Fu ◽  
Zhongjing Wang ◽  
Woei Lee Chen ◽  
Philip K. Moore ◽  
Yi Zhun Zhu
Keyword(s):  
Nitric Oxide ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Tween 80 ◽  
Vehicle Group ◽  
Lv Function ◽  
Cardioprotective Effects ◽  
Cox 2

In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg·kg−1·day−1), and NO-aspirin (56 mg·kg−1·day−1). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle ( n = 23), aspirin ( n = 22), and NO-aspirin groups ( n = 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 ± 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin- and NO-aspirin-pretreated groups, 36.7 ± 1.8 and 22.9 ± 4.3%, respectively (both P < 0.05 compared with vehicle group; P < 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemiareperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P < 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P < 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with NG-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. l-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion.

Abstract 3894: Inhibition of iNOS Uncoupling by Tetrahydrobiopterin Confers Cardioprotection through Protein S- Nitrosylation in Streptozotocin-Induced Diabetic Rat

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Toru Okazaki ◽  
Hajime Otani ◽  
Koji Yamashita ◽  
Hiromi Jo ◽  
Kei Yoshioka ◽  
...  
Keyword(s):  
Infarct Size ◽  
Rat Heart ◽  
Ischemia Reperfusion ◽  
Protein S ◽  
Left Ventricular ◽  
Isolated Rat Heart ◽  
Diabetic Rat ◽  
Lv Function ◽  
Oxide Synthase

Although expression of inducible nitric oxide synthase (iNOS) and oxidative stress are increased in diabetic (DM) hearts, the role of iNOS uncoupling in ischemia/reperfusion (IR) injury remains unknown. Because iNOS-derived NO is known to play a crucial role in cardioprotection against IR injury in non-DM hearts, we hypothesized that iNOS uncoupling may compromise tolerance to IR injury in the DM heart by decreasing the bioavailability of NO. The expression and activity of iNOS but not n/eNOS were increased in the streptozotocin-induced DM rat heart. Under Langendorff perfusion, superoxide generation as evaluated by dihydroethidium accumulation in the nucleus was significantly increased in cardiomyocytes of the DM heart, but it was inhibited by treatment with the NOS co-factor tetrahydrobiopterin (BH4; 10 μM) or an iNOS selective inhibitor 1400W (10 μM). BH4 increased NOx, a marker of NO bioavailability, and cGMP in the DM heart. The increase in cGMP by BH4 was abrogated by co-treatment with 1400W or a NO-sensitive guanylyl cyclase inhibitor ODQ (10 μM). BH4 significantly decreased nitrotyrosin formation but increased protein S -nitrosylation in the DM heart. The increase in protein S -nitrosylation by BH4 was abolished by co-treatment with a thiol reducing agent dithiothreitol (DTT; 5 mM). The isolated rat heart was subjected to 30 min global ischemia followed by 120 min reperfusion. Post-ischemic recovery of left ventricular (LV) function and infarct size was comparable between the non-DM and the DM hearts. Pre-ischemic treatment with BH4 significantly improved post-ischemic LV function and reduced infarct size only in the DM heart. Co-treatment with BH4 and 1400W, ODQ, or DTT had no significant effect on post-ischemic LV function and infarct size in the non-DM heart. However, co-treatment with BH4 and 1400W or DTT but not ODQ abolished BH4-induced improvement of post-ischemic LV function and reduction of infarct size in the DM heart. These results suggest that inhibition of iNOS uncoupling by BH4 confers cardioprotection against IR injury in the streptozotocin-induced DM rat heart by increasing the bioavailability of NO and this cardioprotective effect is mediated by protein S -nitrosylation but not cGMP.

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