Amiodarone exacerbates brain injuries after hypoxic-ischemic insult in mice
Amiodarone exacerbates brain injuries after hypoxic-ischemic insult in mice
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DOI：
10.1186/s12868-019-0544-2
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发表时间：
2019-12-21
期刊：
影响因子：
2.4
通讯作者：
Matsukawa, Takashi
中科院分区：
文献类型：
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作者：
Kotoda, Masakazu;Hishiyama, Sohei;Matsukawa, Takashi
背景钠离子转运在缺氧缺血性脑损伤的发病机制中起着重要作用。胺碘酮是一种Vaughan-Williams III类抗心律失常药物，在世界范围内广泛用于治疗危及生命的心律失常和心脏骤停。除了对钾通道的抑制作用外，胺碘酮还阻断各种钠离子转运蛋白，包括电压门控钠通道、钠泵和Na+/Ca+交换剂。考虑到这些药理学特征，胺碘酮可能影响缺氧缺血性脑中钠离子的流入-流出平衡。以往的研究表明，在缺氧缺血性脑损伤中阻断电压门控钠通道可发挥神经保护作用。相反，在缺氧缺血时，钠泵或Na+/Ca+交换器的阻断可能导致细胞内钠的进一步积聚和随后的渗透性细胞死亡。从这些角度来看，胺碘酮对缺氧缺血性脑的钠离子平衡的影响可能是保护性的，也可能是有害的，这取决于临床和病理生理条件。因此，在本研究中，我们使用小鼠实验模型研究胺碘酮对缺氧缺血性脑损伤的影响。结果与对照组相比，缺氧缺血40 min后给予胺碘酮的小鼠7 d存活率明显降低，神经功能明显受损。缺氧缺血性脑损伤25分钟后，胺碘酮治疗的小鼠表现出更大的梗死体积（16.0 +/- 6.9 vs. 24.2 +/- 6.8 mm（3），P < 0.05）和更差的神经功能。此外，从胺碘酮处理的小鼠中收获的脑含有更大量的钠（194.7 +/- 45.1 vs. 253.5 +/- 50.9 mEq/kg干重，P < 0.01）和水（259.3 +/- 8.9 vs. 277.2 +/- 12.5 mg，P < 0.01）。两组间血流动力学参数无显著差异。结论胺碘酮可加重缺氧缺血性脑损伤及神经功能损害。严重的脑钠蓄积和脑水肿与胺碘酮的有害作用相关。临床剂量的胺碘酮可通过影响钠离子转运和促进脑细胞内钠蓄积而加重缺氧缺血性脑损伤。
Background Sodium ion transportation plays a crucial role in the pathogenesis of hypoxic-ischemic brain injury. Amiodarone, a Vaughan-Williams class III antiarrhythmic drug, has been widely used to treat life-threatening arrhythmia and cardiac arrest worldwide. In addition to its inhibitory effects on the potassium channel, amiodarone also blocks various sodium ion transporters, including the voltage-gated sodium channel, sodium pump, and Na+/Ca+ exchanger. Considering these pharmacological profile, amiodarone may affect the influx-efflux balance of sodium ion in the hypoxic-ischemic brain. Previous studies suggest that the blockade of the voltage-gated sodium channel during hypoxic-ischemic brain injury exerts neuroprotection. On the contrary, the blockade of sodium pump or Na+/Ca+ exchanger during hypoxia-ischemia may cause further intracellular sodium accumulation and consequent osmotic cell death. From these perspectives, the effects of amiodarone on sodium ion balance on the hypoxic-ischemic brain can be both protective and detrimental depending on the clinical and pathophysiological conditions. In this study, we therefore investigated the effect of amiodarone on hypoxic-ischemic brain injury using a murine experimental model. Results Compared with the control group mice, mice that received amiodarone after induction of 40-min hypoxic-ischemic brain injury exhibited lower survival rates over 7 days and worse neurological function. After 25-min hypoxic-ischemic brain injury, amiodarone treated mice exhibited larger infarct volumes (16.0 +/- 6.9 vs. 24.2 +/- 6.8 mm(3), P < 0.05) and worse neurological function. In addition, the brains harvested from the amiodarone-treated mice contained larger amounts of sodium (194.7 +/- 45.1 vs. 253.5 +/- 50.9 mEq/kg dry weight, P < 0.01) and water (259.3 +/- 8.9 vs. 277.2 +/- 12.5 mg, P < 0.01). There were no significant differences in hemodynamic parameters between groups. Conclusions Amiodarone exacerbated brain injuries and neurological outcomes after hypoxic-ischemic insults. Severe brain sodium accumulation and brain edema were associated with the detrimental effects of amiodarone. Amiodarone at the clinical dose can exacerbate brain injury after hypoxic-ischemic insult by affecting sodium ion transportation and facilitate intracellular sodium accumulation in the brain.