Impaired glutathione biosynthesis in the ischemic‐reperfused rabbit myocardium

Lapenna, Domenico; Gioia, Sergio de; Ciofani, Giuliano; Mezzetti, Andrea; Pierdomenico, Sante D.; Ilio, Carmine Di; Cuccurullo, Franco

doi:10.1016/0014-5793(96)00705-3

Cited by 10 publications

(6 citation statements)

References 24 publications

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“…Intracellular GSH scavenges ROS, which is an important cell-protective mechanism under the conditions with enhanced oxidative stress (30)(31)(32)(33)(34). In the present study, the effects of ebselen on the tissue contents of GSH were expressed in the endocardial as well as the epicardial side, transmurally (Table 2).…”

Section: Discussionmentioning

confidence: 94%

“…Activity of glutathione reductase (GR) has been found to be increased by ebselen (35), which is a potential mechanism of GSH preservation by ebselen. More importantly, it has been reported that GSH synthesis is impaired (30,31,33,34), and the activity of γ-glutamylcysteine synthetase (GGCS), a rate-limiting enzyme in GSH biosynthesis, is decreased in I/R (32). The gene encoding GGCS contains an AP-1 site (36, 37), a key region for activating transcription, which is known to be activated by extracellularsignal-regulated kinase (ERK) (38).…”

Section: Discussionmentioning

confidence: 99%

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Oral Pretreatment with Ebselen Enhances Heat Shock Protein 72 Expression and Reduces Myocardial Infarct Size

et al. 2006

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Oral Pretreatment with Ebselen Enhances Heat Shock Protein 72 Expression and Reduces Myocardial Infarct Size

et al. 2006

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“…The non‐selective K ATP blocker glibenclamide partially antagonized the beneficial effects of both S ‐diclofenac and NaHS in myocardial ischaemia–reperfusion damage. This seems to indicate that H 2 S, released in sufficient amounts by both S ‐diclofenac and NaHS, not only may have overcome the reduced production of H 2 S in ischaemic cardiomyocytes ( Lapenna et al , 1996 ), but may have also triggered a signalling mechanism similar to that described for metabolic ischaemic preconditioning, where activation of sarcolemmal (and not mitochondrial) K ATP play an important role ( Gross and Peart, 2003 ; Bian et al , 2006 ; Johansen et al , 2006 ). However, additional mechanism/s involved in the cardioprotection provided by S ‐diclofenac may not be ruled out.…”

Section: Discussionmentioning

confidence: 92%

The hydrogen sulphide‐releasing derivative of diclofenac protects against ischaemia–reperfusion injury in the isolated rabbit heart

Rossoni

Sparatore

Tazzari³

et al. 2008

British J Pharmacology

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Background and purpose: Hydrogen sulphide (H 2 S) is an endogenous gaseous mediator active in the multilevel regulation of pathophysiological functions in mammalian cardiovascular tissues. Experimental approach: This study investigated the pharmacological activity of a new H 2 S-releasing derivative of diclofenac, S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester) in the isolated rabbit heart submitted to low-flow ischaemia-reperfusion damage. Key results: S-diclofenac (3, 10 and 30 mM), despite inhibiting prostacyclin generation by cardiac tissues, achieved dosedependent normalization of coronary perfusion pressure, reducing left ventricular contracture during ischaemia and improving left ventricular developed pressure and ± dP/dt max at reperfusion. Creatine kinase and lactate dehydrogenase activities in heart perfusates were significantly reduced during reperfusion. These effects were accompanied by substantial release of reduced glutathione (GSH), indicating that the H 2 S moiety may have up-regulated cysteine transport. The anti-ischaemic activities of S-diclofenac and the H 2 S-donor sodium hydro sulphide (NaHS) were partially prevented by the K ATP channel antagonist glibenclamide, suggesting a mechanism similar to H 2 S-induced cardioprotection in metabolic ischaemic preconditioning. Perfusion with the nitric oxide (NO) synthase inhibitor N G -monomethyl-L-arginine worsened the myocardial ischaemiareperfusion damage, but this was dose-dependently prevented by S-diclofenac and NaHS, suggesting that the released H 2 S may have overcome NO deficiency. Conclusion and implications:These data show that S-diclofenac had marked anti-ischaemic activity in ischaemic-reperfused rabbit hearts despite inhibition of prostaglandin generation. Increased GSH formation leading to activation of K ATP channels may have contributed to this beneficial effect. The pharmacological profile of S-diclofenac and its anti-inflammatory activity, with diminished gastrointestinal side effects, offer therapeutic applications in cardiovascular disease. (2008) Keywords: S-diclofenac; diclofenac; hydrogen sulphide; ischaemia-reperfusion; isolated rabbit heart; cardioprotection Abbreviations: 6-keto-PGF 1a , 6-keto-prostaglandin F 1a ; AUC, area under the curve; CBS, cystathionine b-synthase; CK, creatine kinase; CPP, coronary perfusion pressure; CSE, cystathionine g-lyase; ±dP/dt max , maximum rate of rise and fall of left ventricular pressure; DMSO, dimethylsulphoxide; GSH, reduced glutathione; KHS, Krebs Henseleit solution; British Journal of Pharmacology-monomethyl-L-arginine; LVP, left ventricular pressure; LVDevP, left ventricular developed pressure; LVEDP, left ventricular end-diastolic pressure; LVSP, left ventricular systolic pressure; NaHS, sodium hydrosulphide; PGI 2 , prostacyclin; S-diclofenac, 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester

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“…GPX removes H 2 O 2 by coupling its reduction to H 2 O with oxidation of GSH (20) and plays a crucial role in LV remodeling and failure after myocardial infarction (30). Some studies reported increased activity of myocardial enzymatic antioxidants in ischemia-reperfusion (1), whereas other studies reported decreased (10,27) or unchanged (7,37) activity.…”

Section: Discussionmentioning

confidence: 96%

“…Thus the changes in GPX activity were not likely the major determinant of preserved GSH levels in the present study. GSH is enzymatically synthesized and degraded (20). The changes in metabolic pathways of GSH may facilitate preservation of GSH levels during ischemia-reperfusion in the presence of enhanced oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Ischemic preconditioning enhances scavenging activity of reactive oxygen species and diminishes transmural difference of infarct size

Morihira

Hasebe

Baljinnyam

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Reactive oxygen species (ROS) enhance myocardial ischemia-reperfusion (I/R) injury. Ischemic preconditioning (PC) provides potent cardioprotective effects in I/R. However, it has not been elucidated whether PC diminishes ROS stress in I/R and whether PC protects the myocardium from ROS stress transmurally and homogeneously. Isolated rabbit hearts perfused with Krebs-Henseleit buffer underwent 30 min of ischemia and 60 min of reperfusion. Hemodynamic changes and myocardial damage extent were analyzed in four groups. The control group underwent I/R alone. The H2O2 group underwent I/R with H2O2 infusion (50 microM) in the first minute of reperfusion to enhance oxidative stress. The PC and H2O2+PC groups underwent 5 min of PC before control and H2O2 protocols, respectively. Extracted myocardial DNA was analyzed for 8-hydroxydeoxyguanosine (8-OHdG), an indicator of oxidative DNA damage, with the use of the HPLC-electrochemical detection method. Glutathione peroxidase (GPX) activity and the reduced form of GSH were measured by spectrophotometric assays. The myocardial infarct size was significantly reduced in the PC group (19 +/- 2%) compared with the control group (37 +/- 4%; P < 0.05), particularly in the subendocardium. H2O2 transmurally increased the infarct size by 59 +/- 4% (P < 0.05), which was significantly diminished in the H2O2+PC group (31 +/- 4%; P < 0.01). The GSH levels, but not GPX activity, were well preserved transmurally in protocols with PC. The 8-OHdG levels were significantly decreased in PC and were significantly enhanced in H2O2 (P < 0.01). These changes in oxidative DNA damage were effectively diminished by PC. In conclusion, PC enhanced the scavenging activity of GSH against ROS transmurally, reduced myocardial damage, particularly in the subendocardium, and diminished the transmural difference in myocardial infarct size.

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Impaired glutathione biosynthesis in the ischemic‐reperfused rabbit myocardium

Cited by 10 publications

References 24 publications

Oral Pretreatment with Ebselen Enhances Heat Shock Protein 72 Expression and Reduces Myocardial Infarct Size

Oral Pretreatment with Ebselen Enhances Heat Shock Protein 72 Expression and Reduces Myocardial Infarct Size

The hydrogen sulphide‐releasing derivative of diclofenac protects against ischaemia–reperfusion injury in the isolated rabbit heart

Ischemic preconditioning enhances scavenging activity of reactive oxygen species and diminishes transmural difference of infarct size

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