Coetzee W A, Owen P, Dennis S C, Saman S, Opie L H
Medical Research Council Ischaemic Heart Disease Research Unit, University of Cape Town, Medical School, Observatory, Cape Town, South Africa.
Cardiovasc Res. 1990 Feb;24(2):156-64. doi: 10.1093/cvr/24.2.156.
STUDY OBJECTIVE - The aim of the study was to reassess the role of reactive oxygen species in causing reperfusion arrhythmias, which they might do either by directly generating free oxygen radicals or by using scavengers of free oxygen radicals. DESIGN - Ventricular arrhythmias were studied in isolated rat hearts (n = 8-15 per experiment) subjected to regional ischaemia and treated with various free radical scavengers and spin trap agents. Reoxygenation automaticity was similarly studied in isolated guinea pig papillary muscles (n = 6-13 per experiment). MEASUREMENTS and RESULTS - In isolated rat hearts early reperfusion ventricular arrhythmias were unaltered by superoxide dismutase (1 X 10(5) IU.litre-1), catalase (1 X 10(6) IU.litre-1), N-tert-butyl-alpha-phenylnitrone (30 mumols.litre-1), 5,5-dimethyl-1-pyrroline-N-oxide (1 mmol.litre-1), or the combination of superoxide dismutase 1 X 10(5) IU.litre-1, catalase 1 X 10(6) IU.litre-1, and mannitol 10 mol.litre-1, or by the generation of the free radical .OH (Fe:ADP plus dihydroxyfumerate). In the isolated reoxygenated guinea pig papillary muscle, the incidence of reoxygenation automaticity was significantly reduced by verapamil 5 mumols.litre-1 but not by the following free oxygen radical scavengers: reduced glutathione (0.5 mmol.litre-1), N-acetyl cysteine (1 mmol.litre-1), the combination of superoxide dismutase (3 X 10(4) IU.litre-1) and catalase (5 X 10(3) IU.litre-1), or by pretreatment with allopurinol (30 mg.kg-1). Generating systems of .O2- or .OH induced relatively slow electrophysiological changes, including a decreased action potential duration. Reperfusion ventricular fibrillation in the rat heart was increased by increasing the extracellular calcium concentration from 1.25 to 1.9 or 2.5 mmol.litre-1, or by prolongation of the ischaemic time. CONCLUSIONS - Because of (a) the lack of an arrhythmogenic effect of free radical generating systems or of scavengers of free radicals, (b) the calcium sensitivity of reperfusion arrhythmias, and (c) the relatively slow time course of electrophysiological changes induced by free radical generating systems, we propose that free radicals are unlikely to be the prime cause of early ventricular arrhythmias in the systems that we tested. The mechanism of such arrhythmias is more likely to be a calcium sensitive process. The relatively slow electrophysiological changes mediated by free radicals suggest that these agents can cause delayed membrane change.
研究目的——本研究旨在重新评估活性氧在引发再灌注心律失常中所起的作用，活性氧引发心律失常的方式可能是直接产生游离氧自由基，也可能是通过使用游离氧自由基清除剂。设计——在接受局部缺血并使用各种自由基清除剂和自旋捕捉剂处理的离体大鼠心脏（每次实验n = 8 - 15）中研究室性心律失常。在离体豚鼠乳头肌（每次实验n = 6 - 13）中同样研究复氧自动节律。测量与结果——在离体大鼠心脏中，超氧化物歧化酶（1×10⁵ IU·L⁻¹）、过氧化氢酶（1×10⁶ IU·L⁻¹）、N - 叔丁基 - α - 苯基硝酮（30 μmol·L⁻¹）、5,5 - 二甲基 - 1 - 吡咯啉 - N - 氧化物（1 mmol·L⁻¹），或超氧化物歧化酶1×10⁵ IU·L⁻¹、过氧化氢酶1×10⁶ IU·L⁻¹与甘露醇10 mmol·L⁻¹的组合，或通过产生自由基·OH（铁：二磷酸腺苷加二羟基富马酸），均未改变早期再灌注室性心律失常。在离体复氧的豚鼠乳头肌中，5 μmol·L⁻¹的维拉帕米可显著降低复氧自动节律的发生率，但以下游离氧自由基清除剂则无此作用：还原型谷胱甘肽（0.5 mmol·L⁻¹）、N - 乙酰半胱氨酸（1 mmol·L⁻¹）、超氧化物歧化酶（3×10⁴ IU·L⁻¹）与过氧化氢酶（5×10³ IU·L⁻¹）组合，或用别嘌呤醇（30 mg·kg⁻¹）预处理。·O₂⁻或·OH生成系统诱导相对缓慢的电生理变化，包括动作电位时程缩短。将大鼠心脏细胞外钙浓度从1.25 mmol·L⁻¹提高到1.9或2.5 mmol·L⁻¹，或延长缺血时间，可增加大鼠心脏再灌注室颤发生率。结论——由于（a）自由基生成系统或自由基清除剂缺乏致心律失常作用，（b）再灌注心律失常对钙的敏感性，以及（c）自由基生成系统诱导的电生理变化时间进程相对缓慢，我们认为在我们测试的系统中，自由基不太可能是早期室性心律失常的主要原因。此类心律失常的机制更可能是一个对钙敏感的过程。自由基介导的相对缓慢的电生理变化表明这些物质可导致延迟的膜变化。
