Sklar J L, Anderson P G, Boor P J
Department of Pathology, University of Texas Medical Branch, Galveston 77550.
Toxicol Appl Pharmacol. 1991 Mar 1;107(3):535-44. doi: 10.1016/0041-008x(91)90316-7.
We assessed the in vitro toxicity of the cardiovascular toxicant allylamine, and its presumed in vivo metabolite, acrolein. In dose-response experiments, rat hearts perfused with allylamine (10-30 mM) or acrolein (0.01-3.0 mM) for 2 hr were assessed by standard histopathology and assay of creatine kinase (CK) in effluent. Allylamine-perfused hearts showed no grossly apparent functional abnormality except at 30 mM, but acrolein-perfused hearts beat irregularly and stopped rapidly (within 15 min at 0.01-0.3 mM, and by 5 min at 3.0 mM). Extensive contraction band necrosis and an apparently dose-dependent loss of CK were evident in allylamine-perfused hearts, whereas acrolein perfusion resulted in no morphologic lesions or CK loss. Additional experiments, however, suggest that acrolein perfusion results in denaturation of CK, making it undetectable in effluent. In hemodynamic preparations of rat hearts perfused with 10 mM allylamine, contraction band necrosis and extensive mitochondrial changes were seen by electron microscopy. Allylamine caused a marked rise in left ventricular pressure at 5 and 10 min, followed by a slow decline to a markedly depressed level at the end of 2 hr. End diastolic pressure rose steadily throughout the 2-hr perfusion. Coronary flow was similar in control and allylamine-perfused hearts for 1 hr, but then declined slowly. These experiments suggest that vascular spasm or alterations in coronary flow are not the cause of allylamine-induced myocardial damage. Allylamine's toxic effect on myocardium in this model may be mediated through its metabolism and subsequent injurious intracellular events.
我们评估了心血管毒物烯丙胺及其推测的体内代谢产物丙烯醛的体外毒性。在剂量反应实验中，通过标准组织病理学和流出液中肌酸激酶（CK）测定，对用烯丙胺（10 - 30 mM）或丙烯醛（0.01 - 3.0 mM）灌注2小时的大鼠心脏进行评估。除了在30 mM时，灌注烯丙胺的心脏未表现出明显的功能异常，但灌注丙烯醛的心脏跳动不规则且迅速停止（在0.01 - 0.3 mM时15分钟内停止，在3.0 mM时5分钟内停止）。在灌注烯丙胺的心脏中，明显可见广泛的收缩带坏死和明显的CK剂量依赖性损失，而灌注丙烯醛则未导致形态学损伤或CK损失。然而，进一步的实验表明，灌注丙烯醛会导致CK变性，使其在流出液中无法检测到。在用10 mM烯丙胺灌注的大鼠心脏血流动力学制剂中，通过电子显微镜观察到收缩带坏死和广泛的线粒体变化。烯丙胺在5分钟和10分钟时导致左心室压力显著升高，随后在2小时末缓慢下降至明显降低的水平。在整个2小时的灌注过程中，舒张末期压力稳步上升。对照心脏和灌注烯丙胺的心脏在1小时内冠状动脉血流相似，但随后缓慢下降。这些实验表明，血管痉挛或冠状动脉血流改变不是烯丙胺诱导心肌损伤的原因。在该模型中，烯丙胺对心肌的毒性作用可能是通过其代谢及随后的细胞内损伤事件介导的。
