College of Human Medicine, Michigan State University, East Lansing, MI, USA.
J Investig Med. 2010 Oct;58(7):875-82. doi: 10.231/JIM.0b013e3181e5d719.
BACKGROUND/OBJECTIVES: Ischemia-reperfusion (IR) is the restoration of blood flow to a tissue that was formerly deficient of blood flow. Tissue damage after IR is considered an IR injury (IRI). During IR, there is an increased level of cytosolic calcium ([Ca(2+)]i) due to the release of calcium from mitochondrial, sarcoendoplasmic reticulum, and nuclear organelles. Dantrolene sodium (dantrolene) is a 1-[[[5-(4-nitrophenol)-2-furanyl]methylene]amino]-2, 4-imidazolidinedione sodium salt with a nonspecific mechanism, inhibiting organelle release of Ca(2+) into the cytosol. This work reviews the outcomes of administering dantrolene in brain, heart, liver, and kidney animal models of IRI.
An extensive PubMed, MEDLINE, and MEDLAR literature review during the last 30 years on the effect of dantrolene in IRI in animal models was analyzed to determine the clinical implications of this important study. Particular attention was given to dantrolene in heart, brain, liver, and kidney IRI.
Heart: Nine studies of heart IRI were reviewed and include an in vivo dog model (n = 1), in vivo rabbit model (n = 1), isolated dog myocardial fibers (n = 1), and isolated rat hearts (n = 6). Four studies showed decreased infarct size and increased cardiac function after IRI. One in vivo rabbit study found no difference in infarct size or cardiac function after IRI versus controls. Dantrolene may be protective or inductive of post-IRI arrhythmias depending on preestablished myocyte cycling times. Brain: Nine studies of brain IRI were reviewed and include an in vivo dog model (n = 1), in vivo gerbil model (n = 2), and in vivo rat models (n = 6). Dantrolene shows protective decreases in apoptotic markers in 6 studies, but it shows no effect on the necrotic core and mixed effects on reduction of infarct volume. One study found increased mortality in the dantrolene group. Liver: One study of in vivo rat liver IRI found that dantrolene decreased liver function tests, tissue necrosis factor α, tissue necrosis, and increased interleukin 10. Kidney: One study of in vivo rat kidney IRI showed that dantrolene had no effect.
Dantrolene shows protective effects in animal models of heart, brain, and potentially liver IRI, reinforcing the importance of calcium homeostasis during IRI. Variations of dose, timing of administration, route of administration, and outcomes between studies make definitive conclusions difficult. The nonspecific mechanism of action of dantrolene may also account for the variation among studies. Lack of studies in the liver and kidney makes any consensus in these organs premature, and thus, emphasis for this review was put on studies of the heart and brain.
背景/目的：缺血再灌注（IR）是指组织血液供应恢复到先前缺血的状态。IR 后组织损伤被认为是 IR 损伤（IRI）。在 IR 过程中，由于线粒体、肌浆内质网和核细胞器中钙的释放，细胞质中的钙浓度 ([Ca(2+)]i) 会增加。丹曲林钠（dantrolene）是一种 1-[[[5-(4-硝基苯）-2-呋喃]亚甲基]氨基]-2,4-咪唑烷二酮钠盐，具有非特异性机制，可抑制细胞器将 Ca(2+) 释放到细胞质中。这项工作综述了丹曲林钠在脑、心、肝和肾动物模型 IRI 中的作用。
在过去 30 年中，我们在 PubMed、MEDLINE 和 MEDLAR 文献中广泛检索了关于丹曲林钠在动物模型中 IRI 影响的研究，以确定这项重要研究的临床意义。特别关注了丹曲林钠在心脏、大脑、肝脏和肾脏 IRI 中的作用。
心脏：共综述了 9 项心脏 IRI 的研究，包括体内犬模型（n = 1）、体内兔模型（n = 1）、分离的犬心肌纤维（n = 1）和分离的大鼠心脏（n = 6）。四项研究表明 IRI 后梗死面积减小，心功能增强。一项体内兔研究发现，IR 后与对照组相比，梗死面积或心功能无差异。丹曲林钠可能对 IRI 后心律失常有保护作用或诱导作用，具体取决于预先建立的心肌细胞循环时间。大脑：共综述了 9 项大脑 IRI 的研究，包括体内犬模型（n = 1）、体内沙鼠模型（n = 2）和体内大鼠模型（n = 6）。丹曲林钠在 6 项研究中显示出对凋亡标志物的保护作用，但对坏死核心无影响，对梗死体积的减少有混合影响。一项研究发现丹曲林钠组死亡率增加。肝脏：一项体内大鼠肝脏 IRI 的研究发现，丹曲林钠降低了肝功能试验、组织肿瘤坏死因子-α、组织坏死，并增加了白细胞介素 10。肾脏：一项体内大鼠肾脏 IRI 的研究表明，丹曲林钠没有影响。
丹曲林钠在心脏、大脑和潜在的肝脏 IRI 动物模型中显示出保护作用，这强化了钙稳态在 IRI 中的重要性。不同研究之间的剂量、给药时间、给药途径和结果的差异使得得出明确的结论变得困难。丹曲林钠的非特异性作用机制也可能导致了研究之间的差异。由于肝脏和肾脏的研究较少，因此在这些器官中达成任何共识还为时过早，因此，本综述的重点放在了心脏和大脑的研究上。
