法舒地尔动、静脉给药治疗颅内动脉瘤栓塞后脑血管痉挛的对比研究

目的探讨法舒地尔动脉推注(IAF)与静脉给药对脑动脉瘤栓塞后脑血管痉挛(CVS)的疗效对比并评估其安全性。方法介入栓塞治疗后出现脑血管痉挛39名患者,随机分成A、B二组。A组,改用静脉法舒地尔治疗,30 mg,3次/d;B组立即行动脉内注射盐酸法舒地尔(60 mg+生理盐水100 ml,60 min缓慢推注治疗),连续3 d,3 d后予常规静脉法舒地尔治疗。结果 B组IAF治疗后血管痉挛程度明显改善,第3 d、7 d、14 d的GCS评分均高于A组,3月后GOS评分明显高于A组。结论 IAF能安全有效地缓解蛛网膜下腔出血后脑血管痉挛的临床症状并改善预后。     

甲磺酸法舒地尔对麻醉猫心血管作用的影响

目的观察甲磺酸法舒地尔对麻醉猫心血管系统的影响。方法采用股静脉连续给药法，观察给药后2h内麻醉猫收缩压（SBP）、舒张压（DBP）、平均动脉压（MABP）、心率（HR）和心电图（ECG）的变化。结果（1）甲磺酸法舒地尔0．35mg／kg给药后对SBP、DBP和MABP影响较轻微；2mg／kg、7mg／kg给药后5min可使SBP、DBP和MABP降低且持续至给药后60min。甲磺酸法舒地尔2mg／kg与等剂量的参比制剂盐酸法舒地尔比较，对血压的降压程度一致，两种制剂之间的差异无统计学意义（P〉0．05）。（2）甲磺酸法舒地尔对心率的影响：2mg／kg和7mg／kg给药后，在血压下降时可反射性引起心率轻度加快，当血压恢复到正常水平后心率即恢复正常。（3）甲磺酸法舒地尔对心电图的影响：0．35mg／kg、2mg／kg和7mg／kg给药后对心电图QT间期、PR间期、ST段、QRS间期均无明显影响。结论甲磺酸法舒地尔静脉注射给药对麻醉猫SBP、DBP和MABP有剂量依赖性的降低作用,对心率和心电图无明显影响。     

Rho-kinase inhibition improves ischemic perfusion deficit in hyperlipidemic mice

Hyperlipidemia is a major cardiovascular risk factor associated with progressive cerebrovascular dysfunction and diminished collateral perfusion in stroke. Rho-associated kinase (ROCK) may be an important mediator of hyperlipidemic vascular dysfunction. We tested the efficacy of acute or chronic ROCK inhibition on the size of dynamic perfusion defect using laser speckle flowmetry in hyperlipidemic apolipoprotein E knockout mice fed on a high-fat diet for 8 weeks. Mice were studied at an age before the development of flow-limiting atherosclerotic stenoses in aorta and major cervical arteries. Focal ischemia was induced by distal middle cerebral artery occlusion (dMCAO) during optical imaging. The ROCK inhibitor fasudil (10 mg/kg) was administered either as a single dose 1 hour before ischemia onset, or daily for 4 weeks. Fasudil decreased both baseline arterial blood pressure and cerebrovascular resistance (CVR) by ∼15%, and significantly improved tissue perfusion during dMCAO. Interestingly, peri-infarct depolarizations were also reduced. Chronic treatment did not further enhance these benefits compared with acute treatment with a single dose. These data show that ROCK inhibition improves CVR and ischemic tissue perfusion in hyperlipidemic mice.     

Targeting RhoA/ROCK pathway in pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease with a complex pathogenesis. It is often associated with an increased vascular resistance, whilst in the more advanced stages there is a remodelling of the vascular walls. PAH has an intricate involvement of various signaling pathways, including the ras homolog family member A (RhoA)–Rho kinase (ROCK) axis. Currently, available therapies are not always able to significantly slow PAH progression. Therefore, newer approaches are needed.

Areas covered: In this review, areas covered include the role of the RhoA/ROCK in PAH pathogenesis and the plausibility of its therapeutic targeting. Furthermore, various inhibitory compounds are discussed, including Fasudil and SB-772077-B.

Expert opinion: Currently, specific RhoA/ROCK inhibition is the most promising therapeutic approach for PAH. Research has shown that it suppresses both the components of this axis and the upstream upregulating mediators. An inhaled RhoA/ROCK inhibitor may be a successful future therapy; however, further clinical trials are needed to support this approach.     

盐酸法舒地尔对PCI术后慢血流冠心病患者内皮细胞损伤的作用及其机制研究*

目的 探讨采用盐酸法舒地尔治疗对减轻经皮冠脉介入术（PCI）后慢血流冠状动脉粥样硬化性心脏病（以下简称冠心病）患者血管内皮细胞损伤的临床价值。方法 选取2015年5月—2016年8月华北石油管理局总医院实施PCI治疗慢血流冠心病患者120例作为研究对象。按入院顺序随机分为治疗组和对照组,每组 60例。两组患者术后均采用常规治疗,治疗组术后同时给予盐酸法舒地尔治疗,疗程2周。对比两组的血管内皮损伤、内皮舒张及炎症指标。治疗后随访3个月,记录两组患者发生的心血管不良事件。结果 治疗前两组患者外周血内皮细胞微粒（EMPs）、血管性假血友病因子（vWF）、内皮素-1（ET-1）、一氧化氮NO、一氧化氮合酶（eNOS）、血管舒张功能（FMD）、血管内皮舒张功能（NMD）、白细胞介素-6（IL-6）、C反应蛋白（CRP）及肿瘤细胞坏死因子-α（TNF-α）比较,差异无统计学意义（P?>0.05）;治疗后两组患者上述指标比较,差异 有统计学意义（P?<0.05）,治疗组EMPs、vWF、ET-1、IL-6、CRP和TNF-α降低,NO、eNOS、FMD及NMD 升高;治疗前后两组比较,治疗后患者外周血EMPs、vWF、ET-1、IL-6、CRP及TNF-α较治疗前降低（P?<0.05）,NO、eNOS、FMD及NMD较治疗前升高（P?<0.05）;与对照组比较,治疗组治疗后的心血管不良事件发生降低 （P?<0.05）。结论 冠心病PCI术后采用盐酸法舒地尔治疗能减轻慢血流冠心病患者的炎症反应程度及血管内皮细胞损伤。     

Fasudil regulates T cell responses through polarization of BV-2 cells in mice experimental autoimmune encephalomyelitis

Aim:

Fasudil, a selective Rho kinase (ROCK) inhibitor, has been shown to alleviate the severity of experimental autoimmune encephalomyelitis (EAE) via attenuating demyelination and neuroinflammation. The aim of this study was to investigate the effects of fasudil on interactions between macrophages/microglia and T cells in a mice EAE model.

Methods:

Mouse BV-2 microglia were treated with IFN-γ and fasudil. Cell viability was detected with MTT assay. BV-2 microglia polarization was analyzed using flow cytometry. Cytokines and other proteins were detected with ELISA and Western blotting, respectively. Mice were immunized with MOG_35–55 to induce EAE, and then treated with fasudil (40 mg/kg, ip) every other day from d 3 to d 27 pi. Encephalomyelitic T cells were prepared from the spleen of mice immunized with MOG_35–55 on d 9 pi.

Results:

Treatment of mouse BV-2 microglia with fasudil (15 μg/mL) induced significant phenotype polarization and functional plasticity, shifting M1 to M2 polarization. When co-cultured with the encephalomyelitic T cells, fasudil-treated BV-2 microglia significantly inhibited the proliferation of antigen-reactive T cells, and down-regulated IL-17-expressing CD4⁺ T cells and IL-17 production. Furthermore, fasudil-treated BV-2 microglia significantly up-regulated CD4⁺CD25^high and CD4⁺IL-10⁺ regulatory T cells (Tregs) and IL-10 production, suggesting that the encephalomyelitic T cells had converted to Tregs. In EAE mice, fasudil administration significantly decreased both CD11b⁺iNOS⁺ and CD11b⁺TNF-α⁺ M1 microglia, and increased CD11b⁺IL-10⁺ M2 microglia.

Conclusion:

Fasudil polarizes BV-2 microglia into M2 cells, which convert the encephalomyelitic T cells into Tregs in the mice EAE model.     

盐酸法舒地尔后适应对大鼠心肌缺血再灌注损伤的保护作用

目的通过主动脉根部模拟冠状动脉内给药,观察盐酸法舒地尔后适应对大鼠急性心肌缺血再灌注损伤的保护作用。方法选择SD大鼠48只,随机分为假手术组、缺血再灌注组、缺血后适应组、法舒地尔组,每组12只。各组于再灌注3 h后处死大鼠,分别测定心功能参数、血浆心肌酶、心肌梗死范围和心肌细胞凋亡指数。结果与假手术组比较,缺血再灌注组、缺血后适应组和法舒地尔组血浆心肌酶含量明显升高,差异有统计学意义(P<0.01)。与缺血再灌注组比较,法舒地尔组心功能参数明显改善,血浆心肌酶含量、心肌梗死范围、心肌细胞凋亡指数明显下降,差异有统计学意义(P<0.01)。结论盐酸法舒地尔可以模拟缺血后适应效应,减轻心肌缺血再灌注损伤,减少缺血心肌细胞凋亡,缩小心肌梗死范围。     

法舒地尔对压力超负荷大鼠左心室肥厚的改善作用

目的:探讨法舒地尔对压力超负荷大鼠左心室肥厚的影响及可能的作用机制。方法:42只6周龄SD大鼠行腹主动脉缩窄术制备压力超负荷模型作为手术组,另取8只大鼠作为假手术组(Sham组)。术后4周将存活的28只腹主动脉缩窄大鼠随机分为模型组(Model组)、法舒地尔高剂量组(FH组)和法舒地尔低剂量组(FL组)。4周后,计算各组大鼠左心室质量指数(LVMI),观察心肌病理改变,检测心肌细胞直径(MD),碱水法测定心肌羟脯氨酸(HYP)含量,酶联免疫吸附试验测定血浆和心肌血管紧张素Ⅱ(AngⅡ)浓度,免疫组织化学法半定量分析心肌磷酸化肌球蛋白磷酸酶靶蛋白亚基1(p-MYPT1)、基质金属蛋白酶9(MMP9)和组织金属蛋白酶组织抑制剂1(TIMP1)的表达水平。结果:与Sham组比较,Model组心肌细胞肥大,间质大量胶原沉积,LVMI、MD、HYP含量和AngⅡ浓度均明显升高,p-MYPT1、MMP9和TIMP1的表达显著上调,MMP9/TIMP1比值明显下降(P<0.01);与Model组比较,FH组和FL组心肌细胞肥大和胶原沉积有所改善,LVMI、MD、HYP和AngⅡ含量均下降(P<0.05~P<0.01),p-MYPT1、MMP9和TIMP1的表达均明显下调(P<0.01)。结论:法舒地尔改善压力超负荷大鼠左心室肥厚的作用可能与调节心肌MMP9和TIMP1表达有关。     

法舒地尔治疗慢性心力衰竭临床观察

目的：观察法舒地尔对心力衰竭患者心脏功能及炎症因子的影响。方法：连续入选2009年1月-2012年12月住院的慢性心力衰竭患者86例,随机分为法舒地尔治疗组与对照组,连续治疗14 d,观察治疗前后患者血压、心率、舒张早期左心室充盈峰速度（E）、心房收缩期左心室充盈峰速度（A）、左室射血分数（LVEF）、6 min步行试验（6MWT）、血浆BNP、CRP、IL-6、IL-10、TNF-α水平。结果：与对照组相比,治疗组患者EF改善显著（P<0.05）;6MWT显著增加（P<0.05）,收缩压、舒张压降低（P<0.05）,及心率无明显变化（P>0.05）,血浆BNP、IL-6、TNF-α水平明显降低（P<0.05,P<0.01）。结论：法舒地尔在治疗慢性心力衰竭有一定疗效,可能与其降低血压和干预炎症细胞因子相关。