Nigrovic V, Klaunig J E, Smith S L, Schultz N E, Wajskol A
Anesth Analg. 1986 Nov;65(11):1107-11.
Primary cultures of liver cells isolated from seven rats were used to study the possible toxicity of atracurium and metocurine. The muscle relaxants were separately added to the culture medium and the cells then incubated for 4 hr. The amount of lactic dehydrogenase (LDH) that leaked into the culture medium was determined at the end of incubation. The customary assumption was made that the exudation of LDH reflects the toxic effects of the relaxants. In untreated dishes, approximately 11% of the total intracellular LDH leaked out during the incubation. The net leakage of LDH produced by the relaxants was obtained by subtracting this amount from the LDH activity determined in the media of dishes with the relaxants added. On this basis, metocurine, in concentrations of 12-850 X 10(-6)M, did not cause a net leak of LDH. On the other hand, atracurium, in similar molar concentrations, caused a statistically significant and concentration-dependent leak of LDH that, at its maximum, amounted to more than one half of the intracellular LDH. The results are interpreted in terms of damage to cellular membranes produced by atracurium or its metabolites. Although the exact biochemical process was not identified, we hypothesize that acrylates--produced by Hofmann elimination from atracurium--might be the likely toxic species.
从7只大鼠分离得到的肝细胞原代培养物被用于研究阿曲库铵和米库氯铵的潜在毒性。将肌肉松弛剂分别加入培养基中，然后将细胞孵育4小时。孵育结束时测定渗漏到培养基中的乳酸脱氢酶（LDH）量。通常认为LDH的渗出反映了松弛剂的毒性作用。在未处理的培养皿中，孵育期间约11%的细胞内总LDH渗漏出来。通过从添加了松弛剂的培养皿培养基中测定的LDH活性中减去该量，得到松弛剂产生的LDH净渗漏量。在此基础上，浓度为12 - 850×10⁻⁶M的米库氯铵未引起LDH的净渗漏。另一方面，在相似摩尔浓度下，阿曲库铵引起了具有统计学意义的、浓度依赖性的LDH渗漏，最大时相当于细胞内LDH的一半以上。结果根据阿曲库铵或其代谢产物对细胞膜的损伤来解释。虽然未确定确切的生化过程，但我们推测由阿曲库铵经霍夫曼消除产生的丙烯酸酯可能是潜在的毒性物质。
