Venditti P, Balestrieri M, De Leo T, Di Meo S
Dipartimento di Fisiologia Generale ed Ambientale di Napoli, Italy.
Cardiovasc Res. 1998 Jun;38(3):695-702. doi: 10.1016/s0008-6363(98)00034-0.
This work was designed to determine whether the doxorubicin-induced changes in heart electrical activity are due to increased free radical production and membrane oxidative damage.
Four groups of rats (60 days old) were used. One group was untreated and the others were treated with doxorubicin (DXR), DXR and vitamin E, and DXR and N-acetylcysteine (NAC), respectively. DXR was administered by single i.p. injection (20 mg/kg b.wt.). Vitamin E was administered by ten daily i.m. injections (100 mg/kg), while NAC (100 mg/kg) was injected i.p. 1 h before and 7 h after DXR. The effectiveness of the drug in inducing oxidative stress in different tissues and of the antioxidants in offering protection was established by determining antioxidant capacity, susceptibility to oxidative stress, and lipid peroxidation in heart, liver, and blood. The drug effect on heart electrical activity was determined by measuring the heart rate in vivo and action potential configuration in papillary muscle fibres in vitro. Heart lipid peroxidation and electrical activity were also examined in both vitamin E and NAC-treated rats.
DXR treatment decreased antioxidant capacity and increased lipid peroxidation and susceptibility to oxidative stress in heart and blood, but not in liver. DXR administration to rats treated with antioxidants did not produce significant changes in antioxidant capacity and susceptibility to oxidative stress even in heart and blood. Furthermore, lipid peroxidation in heart and liver from DXR- and vitamin E-treated rats, and in liver from DXR- and NAC-treated rats was lower than in untreated controls. DXR treatment also increased the duration of ventricular action potentials in untreated rats, but not in antioxidant-treated rats. The treatment of control animals with the antioxidants affected lipid peroxidation, but not cardiac electrical activity.
The protection offered by antioxidants against electrophysiological alterations indicates a free radical involvement in such alterations. In contrast, although electrical modifications are associated with increased peroxidative processes and both are prevented by the antioxidants, it is not yet clear whether a causative relationship exists between them.
本研究旨在确定阿霉素引起的心脏电活动变化是否归因于自由基生成增加和膜氧化损伤。
使用四组60日龄大鼠。一组未接受治疗，其他三组分别用阿霉素（DXR）、阿霉素与维生素E、阿霉素与N - 乙酰半胱氨酸（NAC）进行治疗。阿霉素通过单次腹腔注射（20mg/kg体重）给药。维生素E通过每日10次肌肉注射（100mg/kg）给药，而NAC（100mg/kg）在阿霉素注射前1小时和注射后7小时腹腔注射。通过测定心脏、肝脏和血液中的抗氧化能力、对氧化应激的敏感性以及脂质过氧化作用，确定药物在不同组织中诱导氧化应激的效果以及抗氧化剂提供保护的效果。通过测量体内心率和体外乳头肌纤维的动作电位形态，确定药物对心脏电活动的影响。还对维生素E和NAC治疗的大鼠的心脏脂质过氧化和电活动进行了检查。
DXR治疗降低了心脏和血液中的抗氧化能力，增加了脂质过氧化和对氧化应激的敏感性，但肝脏中未出现这种情况。给用抗氧化剂治疗的大鼠施用DXR，即使在心脏和血液中，抗氧化能力和对氧化应激的敏感性也没有产生显著变化。此外，DXR与维生素E治疗的大鼠心脏和肝脏以及DXR与NAC治疗的大鼠肝脏中的脂质过氧化低于未治疗的对照组。DXR治疗还增加了未治疗大鼠心室动作电位的持续时间，但在抗氧化剂治疗的大鼠中未增加。用抗氧化剂治疗对照动物会影响脂质过氧化，但不影响心脏电活动。
抗氧化剂对电生理改变的保护作用表明自由基参与了此类改变。相比之下，虽然电活动改变与过氧化过程增加相关，且两者均被抗氧化剂阻止，但它们之间是否存在因果关系尚不清楚。
