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首页> 外文期刊>Medical Gas Research >Defining the minimally effective dose and schedule for parenteral hydrogen sulfide: long-term benefits in a rat model of hindlimb ischemia
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Defining the minimally effective dose and schedule for parenteral hydrogen sulfide: long-term benefits in a rat model of hindlimb ischemia

机译：定义肠胃外硫化氢的最低有效剂量和时间表：在后肢缺血大鼠模型中的长期益处

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Background Peripheral arterial disease (PAD) affects millions of Americans and leads to critical limb ischemia (CLI) in the most severe cases. Investigators have demonstrated the utility of hydrogen sulfide for restoring perfusion in rodent models of chronic ischemia. We sought to determine the minimum effective dose (MED) of sulfide necessary to restore perfusion in the rat hindlimb, to assess the persistence of limb perfusion after cessation of treatment, and to compare perfusion measurements between laser doppler and ultrasound methods. Methods In 3 separate experiments, sodium sulfide (1.0, 0.5, or 0.25?mg/kg twice daily for 14?days, 0.25?mg/kg twice daily for 7?days, 0.5?mg/kg once daily for 7?days, or 0.25?mg/kg twice daily for 3?days) or vehicle was administered after left femoral artery ligation and transection. Hindlimb perfusion was assessed by laser doppler flowmetry and contrast enhanced ultrasound over the duration of each study, and cellular proliferation and vascular density were assessed by immunohistochemical means in the initial experiment. Results Intravenous sodium sulfide at 0.25, 0.5, or 1.0?mg/kg twice daily for 2?weeks significantly enhanced the recovery of blood flow to the ischemic hindlimb by 7?days. The enhancement of blood flow with 1.0?mg/kg dosing was coincident with an increase in cellular proliferation and vascular density in the ischemic tissue. In a final experiment, i.v. administration of sodium sulfide at 0.5?mg/kg once daily for 7?days or 0.25?mg/kg twice daily for 7?days significantly elevated blood flow and skeletal muscle perfusion in the ischemic hindlimb, whereas 0.25?mg/kg twice daily for 3?days had no effect. This enhancement of blood flow appeared long lived, as blood flow remained elevated 3?weeks after cessation of treatment. Conclusions These data, together with other published observations, demonstrate the efficacy of hydrogen sulfide in restoring perfusion to chronically ischemic tissue and establish a minimum efficacious dose in the rat hindlimb model.
机译：背景技术外周动脉疾病（PAD）影响数百万美国人，并在最严重的情况下导致严重的肢体缺血（CLI）。研究人员已经证明了硫化氢在慢性缺血的啮齿动物模型中恢复灌注的效用。我们试图确定恢复大鼠后肢灌注，评估停药后肢体灌注的持久性以及比较激光多普勒和超声方法之间的灌注测量值所需的最小硫化物有效剂量（MED）。方法在3个独立的实验中，每天两次，两次分别为1.0、0.5或0.25？mg / kg的硫化钠，持续14天;每天两次，分别为0.25？mg / kg的硫化钠，持续7天;或每天两次，每次0.25？mg / kg，共3？天），或在左股动脉结扎和横切后给予媒介物。在每项研究期间，通过激光多普勒血流仪和对比增强超声评估后肢灌注，并在初始实验中通过免疫组织化学方法评估细胞增殖和血管密度。结果每天两次0.25、0.5或1.0？mg / kg的静脉注射硫化钠，持续2？周，显着增强了缺血后肢的血流恢复7天。用1.0？mg / kg的剂量增加血流与缺血组织中细胞增殖和血管密度的增加相吻合。在最后的实验中，每天一次0.5？mg / kg的硫化钠给药7？天，或每天两次？0.25？mg / kg硫化钠7天，显着提高缺血后肢的血流量和骨骼肌灌注，而每天两次给予0.25？mg / kg 3天没有影响。停止治疗后3周，这种血流量的增加似乎是长寿的，因为血流量仍然升高。结论这些数据与其他已发表的观察结果一起证明了硫化氢在恢复对慢性缺血组织的灌注中的功效，并在大鼠后肢模型中确定了最低有效剂量。

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