Welder A A
College of Pharmacy, University of Oklahoma Health Sciences Center, Department of Medicinal Chemistry and Pharmacodynamics, Oklahoma City 73190.
Toxicol Lett. 1992 Apr;60(2):183-96. doi: 10.1016/0378-4274(92)90273-m.
It is now well documented that both cocaine (Coc) and methamphetamine (Meth) are independently capable of inducing injurious effects on the adult and developing myocardium. In addition, when these drugs are used concomitantly such as in polydrug abuse, it has been suggested that they may cause synergistic adverse effects on the myocardium. In this investigation, primary myocardial cell cultures were established from 3-5-day-old Sprague-Dawley rats to describe the adverse effects of Coc and Meth on the myocardium. After the cells were in culture for 4 days, they were exposed to 1 x 10(-5) and 1 x 10(-3) M Coc alone; 1 x 10(-5) and 1 x 10(-3) M Meth alone; and combinations of 1 x 10(-3) M Coc with 1 x 10(-5) M Meth and 1 x 10(-5) M Coc with 1 x 10(-5) M Meth. Lactate dehydrogenase (LDH) release, morphology, and beating activity were evaluated after exposure to the drugs for 1, 4 and 24 h. With all treatment groups for the first 4 h, LDH release was not significantly different from untreated controls. Significant LDH release (P less than 0.001) was exhibited at 24 h with 1 x 10(-3) M Coc alone, 1 x 10(-3) M Meth alone, and 1 x 10(-3) M Coc with 1 x 10(-5) M Meth. For 24 h of treatment, cellular injury (pseudopodia, vacuolization, granulation) induced by 1 x 10(-3) M and 1 x 10(-5) M Coc alone was extensive and minimal, respectively. When 1 x 10(-5) M Meth was added with 1 x 10(-5) M Coc, pseudopodia formation was extensive. No measurable beating activity was observed at 1, 4 and 24 h exposure to 1 x 10(-3) M Coc alone and 1 x 10(-3) M Coc with 1 x 10(-5) M Meth. At 1 h, beating activity after treatment with 1 x 10(-5) M Coc alone and 1 x 10(-5) M Meth alone was not significantly different from untreated controls; however, the percentage of areas exhibiting contractile activity was depressed. Addition of Meth (1 x 10(-5) M) potentiated Coc-induced (1 x 10(-5) M) depression of contractile activity at all 3 time-points. These data suggest that Coc and Meth may interact synergistically at the cellular level to directly potentiate injury to postnatal myocardial cell cultures.
现已充分证明，可卡因（Coc）和甲基苯丙胺（Meth）都能够独立地对成年和发育中的心肌产生有害影响。此外，当这些药物同时使用时，比如在多药滥用的情况下，有人认为它们可能会对心肌产生协同的不良反应。在本研究中，从3至5日龄的斯普拉格-道利大鼠建立了原代心肌细胞培养物，以描述可卡因和甲基苯丙胺对心肌的不良影响。细胞培养4天后，将它们分别暴露于1×10⁻⁵和1×10⁻³ M的可卡因；1×10⁻⁵和1×10⁻³ M的甲基苯丙胺；以及1×10⁻³ M可卡因与1×10⁻⁵ M甲基苯丙胺和1×10⁻⁵ M可卡因与1×10⁻⁵ M甲基苯丙胺的组合。在药物暴露1、4和24小时后，评估乳酸脱氢酶（LDH）释放、形态和跳动活性。在最初4小时的所有治疗组中，LDH释放与未处理的对照组无显著差异。在24小时时，单独使用1×10⁻³ M可卡因、1×10⁻³ M甲基苯丙胺以及1×10⁻³ M可卡因与1×10⁻⁵ M甲基苯丙胺组合时，出现了显著的LDH释放（P小于0.001）。对于24小时的治疗，单独使用1×10⁻³ M和1×10⁻⁵ M可卡因诱导的细胞损伤（伪足形成、空泡化、颗粒化）分别广泛和轻微。当1×10⁻⁵ M甲基苯丙胺与1×10⁻⁵ M可卡因一起添加时，伪足形成广泛。在暴露于1×10⁻³ M可卡因单独以及1×10⁻³ M可卡因与1×10⁻⁵ M甲基苯丙胺组合1、4和24小时时，未观察到可测量的跳动活性。在1小时时，单独使用1×10⁻⁵ M可卡因和1×10⁻⁵ M甲基苯丙胺处理后的跳动活性与未处理的对照组无显著差异；然而，表现出收缩活性的区域百分比降低。添加甲基苯丙胺（1×10⁻⁵ M）在所有3个时间点增强了可卡因诱导的（1×10⁻⁵ M）收缩活性抑制。这些数据表明，可卡因和甲基苯丙胺可能在细胞水平上协同相互作用，直接增强对产后心肌细胞培养物的损伤。
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