盐酸法舒地尔对老年急性脑梗死患者神经功能缺损评分的影响

目的 探讨Rho激酶抑制剂盐酸法舒地尔治疗老年急性脑梗死患者的临床疗效.方法 选择符合入选标准的急性期老年脑梗死患者,随机分入治疗组和对照组,每组各48例.在常规治疗基础上治疗组应用法舒地尔进行治疗,对照组应用盐酸川芎嗪进行治疗,根据治疗前及治疗后第7天、第14天神经功能缺损评分观察临床治疗效果,应用相关分析.结果 两组治疗第7天时神经功能缺损评分有显著改善(P<0.05或P<0.01),但治疗组第14d疗效更为明显,与对照组相比差异有统计学意义(P<0.01).治疗组显效率达62.50%(30/48),对照组显效率45.83%(22/48),两组间显效率相比差异有统计学意义(P<0.05).结论 老年脑梗死患者急性期应用法舒地尔可有效改善神经功能缺损评分,临床疗效明显.     

ROCK induced inflammation of the microcirculation during endotoxemia mediated by nitric oxide synthase

Sepsis may be modeled using lipopolysaccharide (LPS), which alters levels of nitric oxide (NO), synthesized via endothelial and inducible nitric oxide synthase (eNOS and iNOS). This study aimed to determine whether the Rho kinase (ROCK) inhibitor fasudil protected against LPS-induced (endotoxemia) macromolecular leak and leukocyte adhesion via NOS pathways. Male Wistar rats (283 ± 8 g, n = 36) were anaesthetized with thiopental and the mesentery prepared for fluorescent intravital microscopy (IVM). Animals received either (i) LPS alone (150 μg kg^− 1 h⁻¹ i.v., n = 6); (ii) fasudil (FAS, 3 mg kg^− 1 i.v., n = 6) or (iii) fasudil (10 mg kg^− 1 i.v., n = 6), immediately prior to LPS administration, (iv) fasudil (FAS, 3 mg kg^− 1 i.v., n = 6) alone or (v) fasudil (FAS, 10 mg kg^− 1 i.v., n = 6) alone, or (vi) saline alone (1 ml kg^− 1 h^− 1 i.v, n = 6) for 4 h (240 min). LPS increased macromolecular leak (cumulative normalized grey levels, arbitrary units) from post capillary venules (< 40 μm) and this was reduced by 3 mg kg^− 1 fasudil, however, 10 mg kg^− 1 was less effective (t = 240 min, control: 3.3 ± 1.7; LPS: 15.1 ± 2.0; LPS + 3 mg kg^− 1 fasudil: 3.3 ± 1.1 (p < 0.05), LPS + 10 mg kg^− 1 fasudil: 8.4 ± 3.2 NS). The numbers of leukocytes adhering for > 1 min/100 μm venule were reduced by fasudil (t = 240 min, control: 1.8 ± 0.7; LPS: 7.0 ± 1.0; LPS + 3 mg kg^− 1 fasudil: 1.75 ± 0.25, p < 0.05; LPS + 10 mg kg^− 1 fasudil: 1.8 ± 0.8, p < 0.05). Immunohistochemistry demonstrated that fasudil increased endothelial cell expression of eNOS during sepsis, and decreased LPS-induced up-regulation of iNOS. Inhibition of ROCK in rats increases eNOS and decreases iNOS during endotoxemia, concomitantly reducing microvascular inflammation. Thus, targeting the ROCK pathway during sepsis could have therapeutic potential for reducing inflammation via a NO dependent mechanism.     

Amelioration of endothelial damage/dysfunction is a possible mechanism for the neuroprotective effects of Rho-kinase inhibitors against ischemic brain damage

We investigated the neuroprotective effects of fasudil's active metabolite, hydroxyfasudil, a Rho-kinase inhibitor, in a rat stroke model in which endothelial damage and subsequent thrombotic occlusion were selectively induced in perforating arteries. By examining the effects on the endothelial damage/dysfunction, we thought to explore the mechanism of Rho-kinase inhibitors. Hydroxyfasudil (10 mg/kg, i.p., once daily for 3 days) significantly improved neurological functions and reduced the size of the infarct area produced by internal carotid artery injection of sodium laurate in a rat cerebral microthrombosis model. Treatment with fasudil or hydroxyfasudil concentration-dependently inhibited tumor necrosis factor α-induced tissue factor expression on the surface of cultured human umbilical vein endothelial cells. They also inhibited thrombin-induced endothelial hyperpermeability. The present findings suggest that hydroxyfasudil is efficacious in preventing brain damage associated with cerebral ischemia, and is partially responsible for fasudil's cytoprotective potential. The results also suggest that the therapeutic benefits against ischemic injury of Rho-kinase inhibitors are attributed, at least in part, to activity upon endothelial damage/dysfunction.     

葛根素注射液联合盐酸法舒地尔治疗缺血性脑梗死的临床研究

目的探究葛根素注射液联合盐酸法舒地尔治疗缺血性脑梗死的临床疗效。方法选取2014年6月—2015年6月广州市花都区花山镇卫生院收治的缺血性脑梗死患者84例,按照治疗方法的不同分为对照组和治疗组,每组各42例。对照组静脉滴注盐酸法舒地尔注射液,60 mg加入到250 m L生理盐水中,1次/d。治疗组在对照组治疗的基础上静脉滴注葛根素注射液,400 mg加入生理盐水250 m L,1次/d。两组患者均连续治疗14 d。观察两组的临床疗效,同时比较两组治疗前后红细胞沉降率(ESR)、血细胞比容(HCT)、纤维蛋白原(FIB)、红细胞聚集指数(RF)、全血高切黏度(HS)、神经功能缺损(NIHSS)评分、血管内皮素-1(ET-1)的变化情况。比较两组不良反应发生情况。结果治疗后,对照组和治疗组的总有效率分别为80.95%、95.24%,两组比较差异具有统计学意义(P0.05)。治疗后,两组ESR、HCT、FIB、RF、HS、NIHSS评分、ET-1均较治疗前显著降低,同组治疗前后差异有统计学意义(P0.05);且治疗组这些观察指标的降低程度优于对照组,两组比较差异有统计学意义(P0.05)。对照组和治疗组的不良反应发生率分别为9.52%、7.14%;两组比较差异无统计学意义。结论葛根素注射液联合盐酸法舒地尔治疗缺血性脑梗死具有较好的临床疗效,能够明显改善患者的血液流变学状态,并能显著降低ET-1的表达,具有一定的临床推广应用价值。     

法舒地尔对戊四氮点燃大鼠海马丝切蛋白及苔藓纤维出芽的影响

目的 探讨法舒地尔对戊四氮(PTZ)点燃大鼠海马组织中丝切蛋白(cofilin,非磷酸化形式)表达与苔藓纤维出芽程度关系的影响.方法 210只SD雄性大鼠分成戊四氮组、法舒地尔干预组和生理盐水对照组,采用PTZ慢性点燃癫癎模型,应用SABC法检测cofilin表达,用Timm染色检测苔鲜纤维出芽情况.结果 PTZ组大鼠点燃率、病死率与法舒地尔组比较差异无统计学意义.PTZ组和法舒地尔组CA3区苔藓纤维出芽评分差异无统计学意义,与对照组相比差异均有统计学意义(P＜0.05).PTZ组和法舒地尔组海马非磷酸化cofilin表达差异无统计学意义.结论 丝切蛋白可能通过苔藓纤维出芽与癫癎的发生相关.     

The influence of fasudil on the epithelial-mesenchymal transdifferentiation of renal tubular epithelial cells from diabetic rats

To investigate the influence of fasudil on the epithelial-mesenchymal transdifferentiation of renal tubular epithelial cells from diabetic rats and explore the mechanisms of this effect. Wistar rats were randomly divided into the following three groups: control, diabetes and fasudil-treatment. All rats were sacrificed after three months of feeding with or without fasudil treatment. Pathological changes to the glomeruli and renal interstitium were studied using Periodic acid-Schiff's staining and Masson staining, respectively. Expression of ROCK1, α-SMA, E-cadherin and the distribution of β-catenin in rat renal cortex were revealed by immunohistochemistry. Changes in the MYPT1 phosphorylation profile and α-SMA, E-cadherin and membrane β-catenin expression were revealed by western blot. Changes in the levels of ROCK1, E-cadherin and total β-catenin mRNA expression were analyzed by real-time PCR. Fasudil treatment notably attenuates renal interstitial fibrosis in diabetic rats. Compared to the control rats, diabetic rats showed elevated phosphorylation of MYPT1, increased expression of ROCK1 and α-SMA, decreased expression of E-cadherin and membrane β-catenin, and increased expression of ROCK1 and total β-catenin mRNA, decreased expression of E-cadherin mRNA. Fasudil treatment of diabetic rats resulted in attenuated MYPT1 phosphorylation, decreased ROCK1 and α-SMA expression, increased E-cadherin and membrane β-catenin expression, and reduced ROCK1 and total β-catenin mRNA expression, increased expression of E-cadherin mRNA. In conclusion, fasudil may reduce the epithelial-mesenchymal transdifferentiation and renal interstitial fibrosis in diabetic rats through a mechanism by which ROCK activity is inhibited, which further facilitates the recovery of the cell-cell adhesions among renal tubular epithelial cells and adhesion complex formation.     

盐酸法舒地尔治疗后循环缺血74例患者的临床观察

目的观察盐酸法舒地尔治疗后循环缺血临床疗效。方法选取2011年5月至2013年5月在我科住院治疗的后循环缺血患者152例,随机分成对照组(n=78)和治疗组(n=74)。对照组在治疗基础病的基础上加阿司匹林及银杏达莫治疗,治疗组在对照组的基础上加用盐酸法舒地尔静脉滴注。疗程为10 d,疗程结束后复查经颅多普勒PSV,并将数据统计分析。结果与治疗前对比及与对照组患者治疗后对比,盐酸法舒地尔治疗组在改善症状及增快PSV等方面,具有显著性差异(P<0.05)。结论盐酸法舒地尔治疗后循环缺血疗效确切,优于对照组,值得临床运用。     

法舒地尔对脑出血大鼠神经功能的影响

目的 探讨法舒地尔对脑出血大鼠神经功能的保护作用及机制。方法 将60只SD大鼠随机分为:假手术组、模型组、低剂量法舒地尔组（低剂量组）和高剂量法舒地尔组（高剂量组）；每组15只。通过注射自体脑内动脉血制作脑出血模型，假手术组只暴露硬脑膜，不注射动脉血。低剂量组腹腔注射1 mg/（kg·d）法舒地尔，高剂剂量组腹腔注射10 mg/（kg·d）法舒地尔。模型组和假手术组腹腔注射等体积生理盐水。药物干预4周后，使用Y-迷宫法评价大鼠学习记忆功能，记录大鼠错误反应次数；使用Longa法评价大鼠神经功能。干湿重法测定脑组织含水量，使用硝酸溶解法测定Na+、K+含量，TUNEL染色分析神经细胞凋亡率，免疫印迹法分析凋亡相关蛋白表达（Bax、Bcl-2和Caspase-3）。结果 相比假手术组，模型组大鼠逃离错误次数、Longa神经功能评分、脑组织含水量、脑组织Na+离子水平、神经细胞凋亡率、Caspase-3和Bax蛋白表达水平显著升高（P<0.01），脑组织K+离子水平、Bcl-2蛋白表达水平显著降低（P<0.01）。相比模型组，法舒地尔模型逆转大鼠脑出血后上述变化（P<0.01），而且高剂量法舒地尔明显优于低剂量法舒地尔（P<0.01）。结论 大鼠脑出血后，法舒地尔可以调节神经细胞Na+、K+离子平衡并减少脑组织水肿、抑制神经细胞凋亡，保护大鼠神经功能