Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function.

Forman, Mervyn B.; Puett, David; Cates, Christopher U.; McCroskey, D E; Beckman, Jeffrey K.; Greene, Harry L.; Virmani, Renu

doi:10.1161/01.cir.78.1.202

Cited by 117 publications

(49 citation statements)

References 66 publications

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“…Activated neutrophils are more adherent and, along with aggregated platelets and erythrocytes, can physically obstruct capillaries. Activated neutrophils produce vasoconstrictive arachidonic acid metabolites, which may potentiate vascular obstruction (24). In the setting ofleukocyte activation and vasoconstriction, we propose that ischemia enhances ICAM-1 expression in the vasa recta, which further increases I<#~* .<.. (25).…”

mentioning

confidence: 92%

Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury.

Kelly

Williams

Colvin

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

453

237

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The pathophysiology of ischemic acute renal failure is complex, and the role of leukocyte adhesion in this process is not well defined. A monoclonal antibody (mAb) against intracellular adhesion molecule 1 (anti-ICAM-1), administered at the time of bilateral renal ischemia in the rat, prevented both functional impairment and histologic changes of acute renal failure. Plasma creatinine measured (mg/dl) 24 hr after 30 min of ischemia was 0.61 ± 0.05 in the anti-ICAM-1-treated animals compared with 2.4 ± 0.14 (P < 0.0001) in the vehicle-treated ischemic group. Forty-eight hours after ischemia, creatinine values were 0.46 ± 0.05 and 2.03 ± 0.22 (P < 0.0001) in anti-ICAM-1 and vehicle-treated groups, respectively. A low dose of anti-ICAM-1 that was itself nonprotective, when given with partially protective doses of a mAb against lymphocyte function-associated antigen-i (anti-LFA-1), acted synergistically to prevent renal failure. Anti-ICAM-1 mAb also protected the kidney when administered 0.5 or 2 hr but not 8 hr after restoration of blood flow and when the ischemic period was extended to 40 min. Ischemia-induced increases in tissue myeloperoxidase, a marker of neutrophil infitration, were mitigated with anti-ICAM-1 treatment. Thus, anti-ICAM-1 mAb protected the kidney against ischemic renal failure, even when the antibody was administered after the ischemic period. These results suggest a critical role for leukocytes and adhesion molecules in the pathophysiology of ischemic inijury and may have important therapeutic implications.The pathophysiology of acute ischemic renal failure is poorly understood. Therapeutic interventions designed to inhibit cellular injury have frequently been either ineffective or equivocal in their effectiveness in both experimental animals and man, and rarely has an agent been effective when administered after the ischemic insult (1).We hypothesized that leukocyte adhesion plays a critical role in renal ischemia-reperfusion injury. Outer medullary vascular congestion that occurs in ischemic acute renal failure (2) may result from leukocyte-endothelial cell interactions with obstruction of the vasa recta or leukocyte-mediated increases in endothelial permeability leading to erythrocyte aggregation (3). This would sustain ischemia to the outer medulla, even if total renal blood flow were restored.Leukocyte adhesion to various cell types is mediated in large part by the three P2 integrins: CD11a/CD18 [lymphocyte function-associated antigen 1 (LFA-1)], CD11b/CD18 (Mac-i), and CD11c/CD18. The intercellular adhesion molecule 1 (ICAM-1, CD54) is a ligand for CD11a/CD18 and CD11b/CD18. The CD54-CD11/CD18 interactions are important determinants of leukocyte-endothelial cell adhesion (4). The purpose of our studies was to evaluate the effects of a monoclonal antibody (mAb) directed against ICAM-1 on ischemic acute renal failure in the rat.Ischemia results in increased tissue levels of proinflammatory mediators, including cytokines (5, 6) and products of arachidonic acid metabolism (7), which ...

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mentioning

confidence: 92%

Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury.

Kelly

Williams

Colvin

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

453

237

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“…It has received attention as an antioxidant for components of cigarette smoke (16,17) and for treatment of various respiratory diseases (18). Recently, there have been several reports suggesting that N-acetylcysteine is cardioprotective against ischemialreperfusion injury (19,20) and finally several authors '~u t h o r to whom correspondence should be addressed.…”

Section: Introductionmentioning

confidence: 99%

On N-acetylcysteine. Part II. Oxidation of N-acetylcysteine by hydrogen peroxide: kinetic study of the overall process

Abedinzadeh¹,

Arroub²,

Gardès-Albert³

1994

Can. J. Chem.

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ZOHREH A B E D~E H ,JLJL ARROUB, and MOMQUE GARD~S-ALBERT. Can. J. Chem. 72,2102Chem. 72, (1994.The oxidation kinetics of N-acetylcysteine (RSH) by hydrogen eroxide has been studied at neutral pH at different concentration ratios from 0.2 to 20 (4 x lo4 rnol L-I B [RSH], r 2 x 10-' mol L-I, lo4 rnol L-I 5 [H202], 5 lo-' rnol L-I). In all the cases studied, N-acetylcystine (RSSR) is the only oxidized product formed. Our kinetic data have focused on the importance of the concentration ratio to reach the stoichiometric oxidation of N-acetylcysteine by hydrogen peroxide. Indeed non-stoichiometric oxidation of RSH occurs at relatively low concentration ratios (R < 2.5) whereas stoichiometric oxidation is observed when R > 2.5. Moreover, it has been shown that in the first minutes of the reaction there is the formation of a complex between RSH and H202, the stoichiometry of the complex being RSH concentration-dependent for a given R (R > 2

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“…NAC and Cys are sulphydryl (SH) compounds which have been used recently as antioxidant agents in myocardial ischaemia and reperfusion and have shown some beneficial effects (Forman et al, 1988;Ceconi et al, 1988;Tang & Tang, 1991 (Suguhara et al, 1977;Doroshow et al, 1980;Forman et al, 1983;Betts et al, 1984) through such effects as: reacting directly with free radicals, promoting the resynthesis of glutathione (GSH) or acting as an alternative substrate for glutathione peroxidase. It has also been shown that NAC potentiates both the peripheral and coronary vasodilator effects of nitroglycerin (Horowitz et al, 1983;Winniford et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of N‐acetylcysteine and cysteine in stunned myocardium in perfused rat heart

Li-da

Sun²,

et al. 1991

British J Pharmacology

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1 The objective of this study was to evaluate the effects of three sulphydryl (SH) compounds, Nacetylcysteine (NAC), cysteine (Cys) and cystamine, on functional recovery and ventricular arrhythmias (VF) in stunned myocardium in the isolated perfused heart of the rat. 2 Hearts (n = 7-8 per group) were perfused by the Langendorff procedure for 20min to stabilize and then assigned to one of five groups: saline, sham, NAC, Cys and cystamine. After the stabilizing period, the drugs (at 3.6,uMmin-1) or their vehicle (saline) were infused into coronary vessels throughout the experimental period. Ten min after administration of drugs, the left anterior descending coronary artery (LAD) was ligatured for 20 min and then untied to reperfuse for 30 min. In the sham group, a ligature was placed around the LAD but not tied. 3 NAC and Cys had a significant effect in attenuating myocardial stunning: the percentage recovery of rate-pressure product measured 30min after reperfusion as an index of heart function, was improved with the NAC (98.3 + 4.5) and Cys groups (104.0 + 6.5) compared with the saline (only 73.6 + 3.8, P < 0.01) group. Cystamine did not show these beneficial effects. This may be due to the difference in chemical structure between NAC, Cys and cystamine since the latter does not have a free SH group with a disulphide bond formed. This phenomenon suggests that a free SH group is essential for the protective effects of compounds like NAC and Cys in myocardial injury. 4 NAC and Cys prevented the fall in coronary flow during the LAD occlusion and enhanced coronary flow during reperfusion but cystamine did not have such a beneficial effect. 5 The incidence of VF in the saline, cystamine, Cys and NAC groups was 6/8 (75.0%), 4/7 (57.1%), 3/8 (37.5%) and 2/7 (28.6%), respectively, and no significant differences (P > 0.05) were noted between the saline-and drug-treated groups. 6 An in vitro study with electron spin resonance indicated that Cys effectively scavenged the hydroxyl radical (-OH) generated by Fenton's reaction but did not scavenge superoxide generated in an irradiated riboflavin system. NAC and cystamine showed a scavenging effect on -OH to a certain extent but this effect did not reach statistical significance (P > 0.05 vs saline). 7 Our results demonstrate that NAC and Cys treatment before ischaemia and reperfusion can reduce myocardial stunning. This beneficial effect may be mainly due to their ability to preserve and enhance coronary flow during coronary occlusion and reperfusion and in part due to scavenging -OH and/or replenishing intracellular glutathione. The results also indicate that the condition of coronary perfusion can produce a great impact on postischaemic ventricular performance.

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Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function.

Cited by 117 publications

References 66 publications

Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury.

Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury.

On N-acetylcysteine. Part II. Oxidation of N-acetylcysteine by hydrogen peroxide: kinetic study of the overall process

Beneficial effects of N‐acetylcysteine and cysteine in stunned myocardium in perfused rat heart

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