Hauser Balázs, Gröger Michael, Ehrmann Ulrich, Albicini Maura, Brückner Uwe Bernd, Schelzig Hubert, Venkatesh Balasubramanian, Li Hongshan, Szabó Csaba, Speit Günter, Radermacher Peter, Kick Jochen
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, Ulm, Germany.
Shock. 2006 Jun;25(6):633-40. doi: 10.1097/01.shk.0000209561.61951.2e.
Inhibition of poly (ADP-ribose) polymerase 1 (PARP-1) improved hemodynamics and organ function in various shock models induced by sepsis or ischemia/reperfusion. PARP-1, however, is also referred to play a pivotal role for the maintenance of genomic integrity. Therefore, we investigated the effect of the PARP-1 blocker INO-1001 on hemodynamics, kidney function, and DNA damage and repair during porcine thoracic aortic cross-clamping. The animals underwent 45 min of aortic cross-clamping after receiving vehicle (n=9) or i.v. INO-1001 (n=9; total dose, 4 mg.kg, administered both before clamping and during reperfusion), data were recorded before clamping, before declamping, and 2 and 4 h after declamping. During reperfusion, continuous i.v. norepinephrine was incrementally adjusted to maintain blood pressure greater than or equal to 80% of the pre-clamping level. The plasma INO-1001 levels analyzed with high-pressure liquid chromatography were 1 to 1.4 micromol/L and 0.4 to 0.6 micromol/L before and after clamping, respectively. Although INO-1001-treated animals required less norepinephrine support, kidney function was comparable in the 2 groups. There was no intergroup difference either in the time course of DNA damage and repair (comet assay) as assessed both in vivo in whole blood before surgery, before clamping, before declamping, 2 h after declamping, and ex vivo in isolated lymphocytes (Ficoll gradient) sampled immediately before clamping and analyzed before, immediately, and 1 and 2 h after exposure to 4 bar 100% O2 for 2 h. There was no difference either in the expression of the cyclin-dependent kinase inhibitor gene, p27, in the kidney (immunohistochemistry). The reduced norepinephrine requirements during reperfusion suggest a positive inotropic effect of INO-1001, as demonstrated by other authors. In our model, INO-1001 proved to be safe with respect to DNA repair.
在脓毒症或缺血/再灌注诱导的各种休克模型中，抑制聚（ADP - 核糖）聚合酶1（PARP - 1）可改善血流动力学和器官功能。然而，PARP - 1也被认为在维持基因组完整性方面起关键作用。因此，我们研究了PARP - 1阻滞剂INO - 1001在猪胸主动脉交叉钳夹期间对血流动力学、肾功能以及DNA损伤和修复的影响。动物在接受载体（n = 9）或静脉注射INO - 1001（n = 9；总剂量4 mg/kg，在钳夹前和再灌注期间均给药）后进行45分钟的主动脉交叉钳夹，在钳夹前、松开钳夹前以及松开钳夹后2小时和4小时记录数据。在再灌注期间，持续静脉注射去甲肾上腺素逐渐调整以维持血压大于或等于钳夹前水平的80%。用高压液相色谱分析的血浆INO - 1001水平在钳夹前和钳夹后分别为1至1.4微摩尔/升和0.4至0.6微摩尔/升。尽管接受INO - 1001治疗的动物需要较少的去甲肾上腺素支持，但两组的肾功能相当。在手术前、钳夹前、松开钳夹前、松开钳夹后2小时的全血体内评估以及在钳夹前立即采集并在暴露于4巴100%氧气2小时之前、之后立即、1小时和2小时进行分析的离体分离淋巴细胞（Ficoll梯度）中评估的DNA损伤和修复的时间进程方面，两组之间没有差异。在肾脏中细胞周期蛋白依赖性激酶抑制剂基因p27的表达（免疫组织化学）方面也没有差异。再灌注期间去甲肾上腺素需求的减少表明INO - 1001具有正性肌力作用，正如其他作者所证明的那样。在我们的模型中，就DNA修复而言，INO - 1001被证明是安全的。
