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The role of glutathione status in the protection against ischaemic and reperfusion damage: Effects of N-acetyl cysteine

1988; Elsevier BV; Volume: 20; Issue: 1 Linguagem: Inglês

10.1016/s0022-2828(88)80174-3

1095-8584

Claudio Ceconi, Salvatore Curello, Anna Cargnoni, Roberto Ferrari, Alberto Albertini, O Visioli,

Nitric Oxide and Endothelin Effects

It is known that myocardial ischaemia causes a marked decline of cellular thiol pool and of protein sulphydryl groups content. Reperfusion under these conditions results in oxydative damage which is concomitant with poor recovery of mechanical function. We have evaluated the role of glutathione status in the protection against ischaemic and reperfusion damage by treating the isolated rabbit hearts with N-acetylcysteine (10−6 m), a sulphydryl group donor. Ischaemic and reperfusion damage was determined in terms of mechanical function, rate of lactate and creatine kinase (CPK) release, mitochondrial function and tissue content of reduced (GSH) and oxidized (GSSG) glutathione and of protein sulphydryl groups (SH). After 60 mins of ischaemia (induced by reducing coronary flow from 24 to 1 ml/min) followed by 30 mins of reperfusion there was an increase of diastolic pressure to 51.6±3.5 mmHg with only a 22% recovery of systolic pressure, massive CPK release and a deterioration in mitochondrial function. Tissue contents of GSH and of protein SH were severely decreased, while those of GSSG were increased. The GSH/GSSG ratio was reduced from the aerobic value of 50 to 13.4, suggesting that an oxidative stress has occurred. N-acetylcysteine infused for 60 mins before ischaemia determined a 38% increase in tissue content of GSH with no major changes of GSSG or protein SH. The ischaemic-induced decrease of GSH and protein SH was also limited by pretreatment with N-acetylcysteine and there was no accumulation of GSSG after reperfusion. This was correlated with a myocardial protection as the increase of diastolic pressure was reduced to 25.6±4.5 mmHg and the recovery of developed pressure improved to 62%. The rate of CPK leakage was reduced and the mitochondria isolated after ischameia and reperfusion maintained their oxidative phosphorilating capacities. When given only on reperfusion, after ischaemia, N-acetylcysteine failed to alter glutathione status and had no protective effect. These data indicate that maintenance of cellular thiol equilibrium represents a new and important development in cellular protection. It is known that myocardial ischaemia causes a marked decline of cellular thiol pool and of protein sulphydryl groups content. Reperfusion under these conditions results in oxydative damage which is concomitant with poor recovery of mechanical function. We have evaluated the role of glutathione status in the protection against ischaemic and reperfusion damage by treating the isolated rabbit hearts with N-acetylcysteine (10−6 m), a sulphydryl group donor. Ischaemic and reperfusion damage was determined in terms of mechanical function, rate of lactate and creatine kinase (CPK) release, mitochondrial function and tissue content of reduced (GSH) and oxidized (GSSG) glutathione and of protein sulphydryl groups (SH). After 60 mins of ischaemia (induced by reducing coronary flow from 24 to 1 ml/min) followed by 30 mins of reperfusion there was an increase of diastolic pressure to 51.6±3.5 mmHg with only a 22% recovery of systolic pressure, massive CPK release and a deterioration in mitochondrial function. Tissue contents of GSH and of protein SH were severely decreased, while those of GSSG were increased. The GSH/GSSG ratio was reduced from the aerobic value of 50 to 13.4, suggesting that an oxidative stress has occurred. N-acetylcysteine infused for 60 mins before ischaemia determined a 38% increase in tissue content of GSH with no major changes of GSSG or protein SH. The ischaemic-induced decrease of GSH and protein SH was also limited by pretreatment with N-acetylcysteine and there was no accumulation of GSSG after reperfusion. This was correlated with a myocardial protection as the increase of diastolic pressure was reduced to 25.6±4.5 mmHg and the recovery of developed pressure improved to 62%. The rate of CPK leakage was reduced and the mitochondria isolated after ischameia and reperfusion maintained their oxidative phosphorilating capacities. When given only on reperfusion, after ischaemia, N-acetylcysteine failed to alter glutathione status and had no protective effect. These data indicate that maintenance of cellular thiol equilibrium represents a new and important development in cellular protection.