Dantrolene, an inhibitor of intracellular calcium release, fails to increase survival in a rat model of intra-abdominal sepsis
Dantrolene, an inhibitor of intracellular calcium release, fails to increase survival in a rat model of intra-abdominal sepsis
复制标题
DOI：
10.1097/00003246-199609000-00018
复制
发表时间：
1996-09-01
影响因子：
8.8
通讯作者：
Fink, MP
中科院分区：
文献类型：
--
作者：
Cameron, EM;Zhuang, J;Fink, MP
目的：细胞内钙释放的增加与内毒素血症和脓毒症中的细胞死亡和器官衰竭有关。我们试图在使用丹曲林钠（细胞内钙释放的特异性抑制剂）的经抗生素治疗的腹膜内脓毒症大鼠模型中检验这一假设。设计：前瞻性随机对照试验，设置：大学医院的实验动物实验室，受试者：214只雄性Sprague-Dawley大鼠，干预：通过腹膜内植入与活大肠杆菌混合的无菌粪便使大鼠脓毒症，并将其分配至对照组、溶媒组或丹曲林治疗组，另一组大鼠植入动脉导管，以采集血液样本测定循环肿瘤坏死因子（TNF）。在静脉内注射内毒素后，将另外的大鼠随机接受赋形剂或丹曲林，测量和主要结果：在7天的研究期间，接受剂量为10 mg/kg的丹曲林的大鼠的存活率显著更差，无论治疗是在诱导腹膜炎之前还是之后开始，各组的平均全血乳酸在诱导感染后6小时达到峰值。在任何检查的时间点，各组之间的乳酸浓度均无显著差异。同样，任何组之间的TNF-α循环浓度也无差异。在大鼠挑战与内毒素，丹曲林既不影响生存，也不影响TNF-α的循环浓度，结论：我们得出结论，丹曲林降低生存在细菌性脓毒症，并没有影响生存在大鼠内毒素血症，过度的细胞内钙释放在脓毒症的重要性仍有待阐明。
Objective: Increased release of intracellular calcium has been implicated in cell death and organ failure in endotoxemia and sepsis, We sought to test this hypothesis in a rat model of antibiotic-treated intraperitoneal sepsis with the use of dantrolene sodium, a specific inhibitor of intracellular calcium release,Design: A prospective, randomized controlled trial,Setting: An experimental animal laboratory in a university hospital,Subjects: Two hundred fourteen male Sprague-Dawley rats, Interventions: Rats were rendered septic by intraperitoneal implantation of sterile feces mixed with live Escherichia coli and allocated to control, vehicle, or dantrolene treatment, A separate group of rats had arterial catheters implanted to allow blood sampling for determination of circulating tumor necrosis factor (TNF)-alpha and lactate concentrations, Additional rats were randomized to receive vehicle or dantrolene after intravenous injection of endotoxin,Measurements and Main Results: Over the 7 day study period, survival was significantly worse among rats that received dantrolene at a dose of 10 mg/kg, irrespective of whether treatment was started before or after induction of peritonitis, Mean whole blood lactate for each group peaked at 6 hrs after induction of infection, There were no significant differences in lactate con centration among the groups at any of the time points examined. Similarly, there were no differences among any of the groups for circulating concentrations of TNF-alpha. In rats challenged with endotoxin, dantrolene affected neither survival nor circulating concentrations of TNF-alpha, Conclusions: We conclude that dantrolene decreases survival in bacterial sepsis and has no effect on survival in endotoxemia in rats, The importance of excessive intracellular calcium release in sepsis remains to be elucidated.