Mickelson J K, Simpson P J, Jackson C V, Lucchesi B R
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
J Cardiovasc Pharmacol. 1988 Aug;12(2):186-95. doi: 10.1097/00005344-198808000-00009.
Coronary artery reperfusion established by thrombolytic agents early in the evolution of an acute myocardial infarction is known to result in the salvage of otherwise jeopardized heart muscle. Recently, experimental evidence has suggested that reactive products of oxygen are formed as a result of reperfusion and can increase the amount of myocardial tissue that becomes irreversibly damaged. The purpose of the present study was to determine if the thrombolytic agent, streptokinase, could serve to scavenge reactive species of oxygen, thereby protecting the myocardium by a mechanism independent of its ability to lyse an occlusive thrombus. Rabbit isolated hearts were perfused at a constant rate with Krebs-Henseleit buffer (25 ml/min, 31 degrees C, pH 7.4) using a modified Langendorff method. Changes in the permeability of the coronary vascular bed were determined with 125I-labeled albumin added to the perfusion buffer. An intraventricular fluid-filled latex balloon connected to a pressure transducer maintained the left ventricle in an isovolumic state and was used to detect changes in myocardial contractility throughout the study protocol. Electrolysis of the oxygenated Krebs-Henseleit perfusion buffer with a 20 mA direct current for 2 min, delivered with a stainless-steel anode (proximal) and a platinum cathode (distal), resulted in the generation of reactive products of oxygen. Perfusion of the isolated heart with buffer containing the products of electrolysis resulted in an increase in mean coronary artery perfusion pressure, from 48 +/- 3 to 121 +/- 6 mm Hg [mean +/- SEM (n = 17)], and an increase in the left ventricular end-diastolic pressure, from 10 +/- 1 to 54 +/- 6 mm Hg. The addition of streptokinase (150 U/ml) or heparin (20 U/ml) to the perfusion medium attenuated the observed increase in coronary artery perfusion pressure from 42 +/- 3 to 73 +/- 9 mm Hg (n = 9) or from 43 +/- 2 to 98 +/- 9 mm Hg (n = 9), respectively. In addition, streptokinase prevented the increase in the left ventricular end-diastolic pressure (11 +/- 1 to 36 +/- 5 mm Hg, n = 9) and preserved left ventricular function as determined by the pressure-volume relationship. Myocardial accumulation of 125I-labeled albumin after exposure of the heart to the reactive products of oxygen was attenuated by the addition of streptokinase or heparin to the buffer solution. The data suggest that streptokinase and, to a lesser extent, heparin may preserve myocardial and coronary vascular function by scavenging reactive oxygen species.
已知在急性心肌梗死发展早期通过溶栓剂建立冠状动脉再灌注可挽救原本濒临危险的心肌。最近，实验证据表明，再灌注会产生活性氧产物，可增加不可逆受损的心肌组织量。本研究的目的是确定溶栓剂链激酶是否可清除活性氧，从而通过一种独立于其溶解闭塞性血栓能力的机制保护心肌。采用改良的Langendorff方法，用Krebs-Henseleit缓冲液（25毫升/分钟，31℃，pH 7.4）以恒定速率灌注兔离体心脏。通过向灌注缓冲液中加入125I标记的白蛋白来测定冠状动脉血管床通透性的变化。连接到压力传感器的心室内充满液体的乳胶气球使左心室保持等容状态，并用于在整个研究方案中检测心肌收缩力的变化。用20毫安直流电对含氧的Krebs-Henseleit灌注缓冲液进行2分钟电解，通过不锈钢阳极（近端）和铂阴极（远端）进行，可产生活性氧产物。用含有电解产物的缓冲液灌注离体心脏会导致平均冠状动脉灌注压从48±3毫米汞柱升高到121±6毫米汞柱[平均值±标准误（n = 17）]，左心室舒张末期压力从10±1毫米汞柱升高到54±6毫米汞柱。向灌注介质中加入链激酶（150单位/毫升）或肝素（20单位/毫升）可使观察到的冠状动脉灌注压升高分别从42±3毫米汞柱降低到73±9毫米汞柱（n = 9）或从43±2毫米汞柱降低到98±9毫米汞柱（n = 9）。此外，链激酶可防止左心室舒张末期压力升高（从11±1毫米汞柱升高到36±5毫米汞柱，n = 9），并通过压力-容积关系确定保留左心室功能。在心脏暴露于活性氧产物后，向缓冲溶液中加入链激酶或肝素可减少125I标记白蛋白在心肌中的蓄积。数据表明，链激酶以及程度较轻的肝素可能通过清除活性氧来保留心肌和冠状动脉血管功能。
