氟伐他汀对野百合碱所致的大鼠肺血管重塑和右心室肥厚的影响

目的观察氟伐他汀对野百合碱(MCT)所致的大鼠肺血管重塑和右心室肥厚的影响。方法66只大鼠被随机分为3组:(1)M+F组(n=24):本组大鼠首先给予每日1次MCT(60mg/kg)皮下注射,连续2周,第3周至第6周末给予氟伐他汀(1mg/kg)灌胃,每日1次。(2)MCT组(n=24):实验前2周给予每日1次MCT(60mg/kg)皮下注射,第3周至第6周末给予与氟伐他汀等体积的0.9盐水灌胃;(3)Saline组(n=18):分别于实验前2周及第2周末至第6周末给予等体积的0.9盐水皮下注射和灌胃。MCT注射前记为第0周,实验共观察6周。分别于不同时间点观察大鼠肺组织形态学变化,并对平均肺动脉压(mPAP)、管壁厚度百分比(PWT)、右心室肥厚指数(RVHI)进行测定。结果MCT注射2周后,大鼠出现显著的肺血管重塑和右心室肥厚,MCT组大鼠在MCT停止注射后mPAP、PWT及RVHI进一步增高。而M+F组大鼠在给予连续4周氟伐他汀1mg/(kg.d)灌胃处理后,mPAP(23.3±3.2)mmHg及PWT(42.3±2.7)均较MCT组减轻。RVHI(0.32±0.02)亦较MCT组(0.54±0.03)显著降低,且与正常对照组(Saline组)比较无显著差异。结论氟伐他汀能有效减轻MCT诱导的大鼠肺血管重塑和右心室肥厚。     

齐墩果酸对氟伐他汀在大鼠体内药动学的影响

目的 探讨齐墩果酸对氟伐他汀在大鼠体内的药代动力学影响。方法 将16只健康大鼠随机分为单药组(5.0mg?kg-1 氟伐他汀)和联合用药组(5.0mg?kg-1氟伐他汀 60mg?kg-1 齐墩果酸),单药组和联合用药组分别灌胃空白溶剂和齐墩果酸5天,每天一次。第6天两组均给予氟伐他汀灌胃,给药后不同时间点采血,LC-MS法测定大鼠体内血药浓度,比较两组间主要的药代动力学参数。结果 与单药组比较,联合用药组氟伐他汀主要药代动力学参数Cmax、AUC0-t参数值显著上升,组间比较差异具有统计学意义(P＜0.05)。结论 联合应用齐墩果酸可能影响大鼠体内氟伐他汀的药代动力学特性。     

不同剂量氟伐他汀对慢性心力衰竭大鼠心肌组织血管紧张素Ⅱ和脑利钠肽水平影响的实验研究

目的 探讨不同剂量氟伐他汀对阿霉素诱导的慢性心力衰竭大鼠心肌组织血管紧张素Ⅱ(AngⅡ)和脑利钠肽(BNP)水平的影响. 方法将60只SD大鼠随机分为正常对照组、心力衰竭对照组、小剂量氟伐他汀组和大剂量氟伐他汀组,除正常对照组予0.9%氯化钠注射液腹腔注射外,余3组均采用阿霉素腹腔注射的方法建立慢性心力衰竭大鼠模型.模型制作成功后正常对照组与心力衰竭对照组予0.9%氯化钠注射液灌胃,小剂量氟伐他汀组给予氟伐他汀5 mg/(kg·d),大剂量氟伐他汀组给予氟伐他汀20 mg/(kg·d).6周后检测大鼠局部心肌组织AngⅡ及BNP水平. 结果 与正常对照组比较,心力衰竭对照组AngⅡ和BNP水平明显升高,差异有统计学意义(P＜0.05);与心力衰竭对照组比较,大、小剂量氟伐他汀组AngⅡ和BNP水平明显下降,差异均有统计学意义(P＜0.05);大、小剂量氟伐他汀组心肌组织BNP水平比较差异有统计学意义(P＜0.05). 结论 氟伐他汀可显著降低慢性心力衰竭大鼠心肌组织AngⅡ和BNP水平,说明他汀类药物能改善心功能,延缓左室重构,并且大剂量治疗效果更明显.     

TRPM8通道激活剂薄荷醇对肺动脉高压大鼠的治疗作用

目的 探讨瞬时受体电位M8(transient receptor potential melastatin-8,TRPM8)通道激活剂薄荷醇(menthol)对野百合碱(monocrotaline, MCT)诱导的肺动脉高压(pulmonary arterial hypertension, PAH)大鼠的治疗作用。方法 SPF级雄性Sprague-Dawley大鼠随机分为6组：正常对照组、MCT组、MCT+menthol(1 mg·kg^-1·d^-1)治疗组、MCT+menthol(2 mg·kg^-1·d^-1)治疗组、MCT+menthol(5 mg·kg^-1·d^-1)治疗组、MCT+menthol(10 mg·kg^-1·d^-1)治疗组。腹腔注射MCT(50 mg·kg^-1)构建PAH大鼠模型。造模1周后治疗组分别给予不同剂量的menthol灌胃治疗,持续2周。通过血流动力学检测、肺组织病理学...     

鲁斯可皂苷元对野百合碱诱导的肺动脉高压大鼠炎症反应的影响

目的研究鲁斯可皂苷元(ruscogenin,RUS)对野百合碱(monocrotaline,MCT)诱导的肺动脉高压(pulmonary arteryhypertension,PAH)大鼠炎症反应的影响。方法将36只清洁级SD大鼠随机分为对照(Control)组、MCT组、RUS+MCT(RUS)组(每组12只)。MCT组及RUS组大鼠给予MCT 60 mg.kg-1腹腔注射1次,第1～21天,RUS组每天给予RUS 0.4 mg.kg-1灌胃,Control组和MCT组给予相同量溶剂灌胃。第22天测量各组大鼠体重、平均肺动脉压(mPAP),HE染色观察肺小动脉血管壁病理变化,酶联免疫吸附法(ELISA)测定第各组大鼠外周血及肺组织炎症因子白细胞介素-1β(IL-1β)的含量,ED1+单核细胞免疫组化测定肺小动脉周围单核细胞的浸润。结果 RUS可抑制MCT诱导的大鼠mPAP升高、肺动脉壁(pulmonary aterial wallthickness,PAWT)增厚、肺动脉周围单核细胞浸润,降低大鼠外周血及肺组织IL-1β的水平。结论 RUS可能通过抑制肺血管炎症反应、降低肺动脉压及肺小动脉厚度防治肺动脉高压。     

舍曲林和氟西汀对慢性肺动脉高压模型大鼠的保护作用研究

目的:研究选择性5-羟色胺重吸收抑制剂(SSRI)舍曲林和氟西汀对野百合碱(MCT)诱导的慢性肺动脉高压(PAH)大鼠的保护作用。方法:40只大鼠随机分为对照组、MCT组、MCT+舍曲林(MCT+Ser)组和MCT+氟西汀(MCT+Flu)组,后3组大鼠腹腔注射MCT造模。MCT+Ser组和MCT+Flu组大鼠每天分别给予Ser和Flu,MCT组和对照组大鼠给予相应溶剂。各组大鼠常规饲养3周后检测肺动脉压、右心指数;HE染色法测定并计算非肌型动脉、部分肌型动脉及肌型动脉所占比例,比较各组肺动脉肌化程度;逆转录-聚合酶链反应法测定5-羟色胺转运体(SERT)mRNA表达变化。结果:与对照组比较,MCT组肺动脉压、右心指数、动脉肌化程度及SERTmRNA表达升高;与MCT组比较,MCT+Ser组和MCT+Flu组上述各指标均降低(P<0.05或P<0.01)。结论:Ser和Flu对MCT诱导的PAH具有抑制作用,作用机制可能与抑制SERTmRNA表达有关。     

氯沙坦和氟伐他汀对残肾大鼠氧化型低密度脂蛋白受体1表达的影响

目的探讨氧化型低密度脂蛋白受体1(LOX-1)在大鼠残肾模型中的作用及他汀和沙坦类药物延缓慢性肾脏病(CKD)进展的可能机制。方法 SD大鼠制作残肾模型,残肾大鼠随机分为4组:残肾模型组、氯沙坦组、氟伐他汀组和联合用药组,假手术组作为正常对照。大鼠残肾模型制作1周后,氯沙坦组以氯沙坦30 mg.kg-1.d-1灌胃,氟伐他汀组以氟伐他汀15 mg.kg-1.d-1灌胃,联合用药组以氯沙坦和氟伐他汀组按上述剂量联合灌胃,假手术组和残肾模型组予等量溶剂灌胃,灌胃共8周。大鼠处死前,检测24 h尿蛋白和血尿素氮、肌酐和胆固醇、甘油三酯和LDL水平。RT-PCR检测肾脏LOX-1及单核细胞趋化蛋白-1(MCP-1)的表达,免疫组织化学检测肾脏及主动脉LOX-1的表达。结果与假手术组比较,残肾模型组血肌酐、胆固醇、甘油三酯、LDL水平和尿蛋白定量明显增高(P<0.01);与残肾模型组相比,氯沙坦组、氟伐他汀组及联合用药组血肌酐、胆固醇、甘油三酯、LDL水平和尿蛋白定量明显下降(P<0.05)。RT-PCR结果显示残肾大鼠肾脏LOX-1和MCP-1 mRNA表达明显增加(P<0.05),氯沙坦、氟伐他汀和联合应用明显下调了肾脏LOX-1和MCP-1的表达(P<0.05)。免疫组化显示残肾大鼠肾间质和主动脉壁LOX-1表达明显增加,氯沙坦、氟伐他汀和联合用药均使LOX-1表达明显下调,并减轻了肾脏病理改变。结论氯沙坦和氟伐他汀的肾脏保护作用可能部分与其对LOX-1表达的抑制及抗炎作用有关,二者联合应用可能具有协同作用。     

阿托伐他汀对慢性肾病大鼠血清及肾组织microRNA-92a表达的影响

目的明确阿托伐他汀对慢性肾病的保护作用部分是通过其对microRNA-92a/KLF2通路的影响实现的。方法 24只健康SD大鼠随机分为正常对照组、肾病组和治疗组。肾病组与治疗组均行5/6肾脏切除制备动物模型,治疗组给予阿托伐他汀6 mg/kg·d进行干预治疗,肾病组和正常对照组每天给予等量的生理盐水灌胃,大鼠自由进食、饮水。末次术后8周处死大鼠。测定血生化,使用ELISA方法测血清中hs-CRP及IL-1β含量;采用RT-PCR方法测定血清及肾组织中miR-92a的含量;用RT-PCR和Western Blot方法测定肾组织中KLF2及其mRNA的表达。结果 5/6肾脏切除术后8周,血尿素氮(BUN)、肌酐(SCr)明显增高(P<0.01),肾功能异常,miR-92a表达增加,KLF2表达减少,炎症指标hs-CRP及IL-1β明显增加。阿托伐他汀治疗后血清及肾组织miR-92a均显著下降,KLF2表达较肾病组增加,hs-CRP及IL-1β表达较肾病组明显下降。结论阿托伐他汀除纠正脂代谢紊乱外,还可以有效降低血清及肾组织miR-92a表达,使KLF2表达增加,抑制CKD炎症反应,延缓肾功能不全进展。     

辛伐他汀对野百合碱所致大鼠右心室肥大的抑制作用

目的 :观察辛伐他汀 (Sim)抑制大鼠右心室肥大的作用。方法 :一次性皮下注射野百合碱 (MCT) 5 0mg·kg-1 ,引起大鼠肺动脉高压和右心室肥大。 2周后 ,分组灌胃给予Sim 1 .5 ,3.0mg·kg-1 ·d-1 或纯化水 (对照组 ) ,连续治疗 1 4d。测定各组大鼠的平均肺动脉压、右心室和左心室 室间隔的重量比 [R/(L S) ]、右心室组织的蛋白和羟脯氨酸含量 ,并观察右心室和肺的病理形态。结果 :Sim 3.0mg·kg-1 ·d-1 给药 1 4d ,使R/(L S)、蛋白质和羟脯氨酸含量分别比对照组大鼠减少 35 %,6 2 %,38%(P <0 .0 1 )。但对MCT引起的大鼠肺动脉压升高和肺组织形态改变无影响。结论 :Sim对MCT引起的大鼠右心室肥大的进程具有抑制作用。     

氟伐他汀对心力衰竭大鼠心室重构及血管性血友病因子的影响

目的研究氟伐他汀对慢性心衰大鼠心室重构和心功能的保护作用，并探讨其对血管性血友病因子（VWF）的影响。方法皮下注射异丙基肾上腺素（170 mg/kg）2次,建立心力衰竭大鼠模型，将18只慢性心衰大鼠随机分为氟伐他汀组(20 mg ·kg-1·d-1)、安慰剂组和正常对照组，安慰剂组和正常对照组给予等量生理盐水。灌胃灌药6周后，超声心动图观察各组大鼠心脏结构和功能的变化，测定心室质量分数，酶联免疫吸附试验（ELISA）检测血浆VWF和B型脑钠肽（BNP)的含量，逆转录多聚酶链反应（RT-PCR）检测心脏组织VWF mRNA的表达。结果与正常对照组相比较，安慰剂组和氟伐他汀组左心室舒张末期内径（LVEDD）和左心室收缩末期内径（LVESD）均显著增加，左心室射血分数（LVEF）和左室射血分数缩短率（LVFS）均显著降低（P＜0.05），左心室湿质量/体质量（LVRW）及右室湿质量/体质量（RVRW）显著增加，心脏组织VWF mRNA表达明显增强（P＜0.01）；与安慰剂组相比，氟伐他汀组LVEDD、LVRW及RVRW均降低，心脏组织VWF mRNA表达明显降低（P＜0.01），LVEF和LVFS均显著增加（P＜0.05）；VWF与BNP呈高度正相关（r=0.996）。结论氟伐他汀能改善心室重构及心功能，其作用机制可能与调节VWF的水平、改善内皮功能有关。     

Tachykinin dysfunction attenuates monocrotaline-induced pulmonary hypertension

We explored the dysfunction of tachykinins on monocrotaline (MCT)-induced pulmonary hypertension by using double-stranded preprotachykinin (ds PPT) RNA and neurokinin receptor (NK) antagonists. Here, we showed the possibility to attenuate the PPT gene expression by ds RNA, RNA interference (RNAi), in fully developed tissue of rats. We designed four groups (control, MCT, RNAi + MCT, and solvent + MCT) of experiments in series 1 and seven groups (control, MCT, MCT + CP-96345-3.4, MCT + CP-96345-10, MCT + CP-96344-10, MCT + SR-48968, and MCT + SR-48965) of experiments in series 2. Rats in the control groups received saline injection. MCT-treated rats received a single MCT injection (60 mg/kg sc). One day prior to MCT, bilateral nodose ganglia were microinjected with ds PPT RNA in rats of the RNAi + MCT group or with solvent in the solvent + MCT group. Beginning from 1 day post-MCT, MCT-treated rats received a daily injection of the NK(1) receptor antagonist, CP-96345 (3.4 or 10 mg/kg ip) or its inactive enantiomer CP-96344 (10 mg/kg ip). The NK(2) receptor antagonist SR-48968 (3 mg/kg ip) or its inactive enantiomer SR-48965 (3 mg/kg ip) was injected to MCT-treated rats every other day starting 1 day post-MCT. Functional study was carried out 2 weeks (series 1) or 3 weeks (series 2) after MCT. MCT induced right ventricular hypertrophy, as well as increases in pulmonary arterial pressure, PPT mRNA (nodose ganglia and lung tissue), and lung tissue substance P level. All of the above MCT-induced alterations were attenuated by either RNAi or NK receptor antagonists. We conclude that tachykinins play an important role in MCT-induced pulmonary hypertension.     

苯那普利与氟伐他汀单用及联用对阿霉素肾病大鼠单核细胞趋化蛋白-1的影响

目的探讨苯那普利与氟伐他汀单用及联用对阿霉素肾病大鼠单核细胞趋化蛋白-1(MCP-1)的影响。方法雄性SD大鼠120只,适应性喂养2周后,随机抽取18只为正常对照组(A组),另外102只制作阿霉素肾病模型。84只造模成功的大鼠随机分为4组:B组为模型对照组(生理盐水,3mL/d,n=21),C组为苯那普利治疗组[苯那普利3.5mg/(kg·d),n=21],D组为氟伐他汀治疗组[氟伐他汀10mg/(kg·d),n=21],E组为苯那普利与氟伐他汀联合治疗组[苯那普利3.5mg/(kg·d)+氟伐他汀10mg/(kg·d),n=21]。分别于2、6、10周末,遵循随机化原则,按n=6分层抽取各组样本,收集24h尿液、血液及肾脏标本待测。结果与B组比较,C组、D组及E组血清MCP-1及甘油三酯、胆固醇浓度均降低,24h尿蛋白减少;肾脏局部MCP-1的表达明显减少。E组疗效更为明显。结论苯那普利与氟伐他汀可以减轻阿霉素肾病大鼠蛋白尿,降低血清甘油三酯、总胆固醇及MCP-1浓度,抑制MCP-1在肾脏的表达,联用时疗效更好。     

缬沙坦与氟伐他汀单用及联用对阿霉素肾病大鼠血清肝细胞生长因子的影响

目的：探讨缬沙坦与氟伐他汀单用及联用对阿霉素肾病大鼠肝细胞生长因子（hepatocyte growth factor,HGF）的影响。方法：雄性SD大鼠120只,适应性喂养2周后,随机抽取18只为正常对照细（A组）;另外102只制作阿霉素肾病模型。84只造模成功大鼠随机分为4组：B组为模型对照组（等容积生理盐水,n=21）,C组为缬沙坦治疗组（缬沙坦35mg·kg^-1·d^-1,n=21）,D组为氟伐他汀治疗组（氟伐他汀10mg·kg^-1·d^-1,n=21）,E组为缬沙坦与氟伐他汀联合治疗组（缬沙坦35mg·kg^-1·d^-1加氟伐他汀10mg·kg^-1·d^-1,n=21）。分别于2、6、10周末,遵循随机化原则,按n=6分层抽取各组样本,收集24h尿液、血液及肾组织标本待测。结果：和A组相比,B组、C组、D组和E组24h尿蛋白排泄、血清TC、TG及HGF浓度明显升高（P〈0．01）;缬沙坦与氟伐他汀单用及联用能减少尿蛋白排泄,降低血清TC、TG浓度（P〈0．05或P〈0．01）,升高血清及肾脏HGF浓度（P〈0．05或P〈0．01）。结论：缬沙坦与氟伐他汀可减轻阿霉素肾病大鼠蛋白尿,降低血清TG、TC浓度,升高HGF浓度,联用时疗效更明显。提示缬沙坦与氟伐他汀至少部分通过升高HGF浓度而减轻肾脏损害。     

Reactive oxygen species and substance P in monocrotaline-induced pulmonary hypertension

We attempted to evaluate whether the antioxidants 1,3-dimethyl-2-thiourea (DMTU) and hexa(sulfobutyl)fullerenes (FC(4)S) attenuate monocrotaline (MCT)-induced pulmonary hypertension (PH) by lowering lung substance P (SP) in Wistar rats. Sixty-three rats weighing 297 +/- 8 g were divided into six groups: control; MCT; capsaicin + MCT; MCT + DMTU-1; MCT + DMTU-2; and MCT + FC(4)S. Three weeks before the functional study, saline was injected into each control rat, whereas each MCT rat received 60 mg/kg sc MCT. Rats in the third group received capsaicin pretreatment followed by MCT. A 3-day injection of DMTU was performed during the early (DMTU-1) or the late (DMTU-2) post-MCT period. For the last group, each MCT-treated rat received a daily FC(4)S injection until the commencement of the functional study. Compared to the control group, MCT caused significant increases in pulmonary arterial pressure (Ppa), right ventricular hypertropy, pulmonary arterial medial thickness, lung SP level, and luminol-enhanced chemiluminescence counts in bronchoalveolar lavage. Both capsaicin and antioxidants significantly attenuated the above MCT-induced alterations. SP-induced acute increase in Ppa was exaggerated in MCT-treated rats. These results suggest that oxygen radicals play an important role in MCT-induced PH via elevating lung SP level.     

CONTINUOUS FLUOXETINE ADMINISTRATION PREVENTS RECURRENCE OF PULMONARY ARTERIAL HYPERTENSION AND PROLONGS SURVIVAL IN RATS

• 1 The serotonin transporter (SERT) is strongly implicated in the pathogenesis of pulmonary arterial hypertension (PAH) in patients and animal models. Inhibitors of SERT have been reported to attenuate or reverse experimental PAH, which makes them potential therapeutic options for the treatment of PAH in humans. However, little is known about pathophysiological features after reversal or attenuation of PAH; moreover, the long‐term therapeutic effects of SERT inhibitors on PAH remain undetermined. Thus, the aim of the present study was to investigate the short‐ and long‐term effects of fluoxetine on monocrotaline (MCT)‐induced PAH and associated pathophysiological changes in PAH models.
• 2 Rats were randomly divided into four groups as follows: (i) an M + F group, in which rats received a single injection of MCT (60 mg/kg, s.c.) and then after 3 weeks were given fluoxetine (10 mg/kg) once daily by gavage from Week 4 to Week 12; (ii) an M/F group, in which 3 weeks after a single MCT (60 mg/kg, s.c.) injection, rats were given fluoxetine (10 mg/kg) by daily gavage from Week 4 to Week 6 and were then given an equivalent volume of saline once daily by gavage from Week 7 to Week 12; (iii) an MCT group, in which 3 weeks after a single MCT (60 mg/kg, s.c.) injection rats were given an equivalent volume of saline by gavage from Week 4 to Week 12; and (iv) a saline group, in which rats received an equivalent volume of saline injection or gavage over the 12 week treatment period. Morphometric changes, pulmonary arterial pressure, percentage wall thickness, right ventricular hypertrophy index and SERT expression were detected at various times during the 12 week treatment period. Survival analysis was performed in each group.
• 3 After 12 weeks treatment, it was found that even through fluoxetine treatment resulted in complete reversal of PAH, PAH recurred after fluoxetine withdrawal. In contrast, continuous administration of fluoxetine prevented the recurrence of PAH and prolonged survival. Analysis of SERT protein levels in rat lung indicated that, compared with values obtained at Week 0, SERT protein increased significantly after discontinuation of fluoxetine but continuous fluoxetine administration inhibited this increase.
• 4 In conclusion, SERT overexpression correlates with the recurrence of PAH after withdrawal of fluoxetine in rats. Continuous fluoxetine administration prevents recurrence of PAH and prolongs survival.

     

Efficacy and safety of high dose fluvastatin in patients with familial hypercholesterolaemia

Summary The efficacy and safety of the HMG CoA reductase inhibitor fluvastatin have been evaluated in a double blind study in 52 patients with familial hypercholesterolaemia. A standard AHA Phase II lipid lowering diet was prescribed throughout the study. After 6 weeks of a single blind dosage stabilisation period, in which patients received fluvastatin 40 mg qPM, patients were randomly allocated to one of two double blind treatment groups: group A (n=24) received fluvastatin 20 mg b. d. for 12 weeks and fluvastatin 20 mg AM + 40 mg PM for an additional 12 weeks; Group B (n=28) received fluvastatin 40 mg qPM during the entire study. Safety and tolerability were evaluated by the analysis of biochemical and haematological parameters, and ophthalmological and physical examinations. Efficacy was analysed by the determination of plasma lipids, lipoproteins and apoproteins.Fluvastatin 40 mg/d was associated with up to a 27.4% decrease in LDL-C and a 9.6% increase in HDL-C concentrations. Increasing the dose of fluvastatin from 20 mg b. d. to 60 mg per day in Group A was associated with a 7.1% decrease in LDL-C, a 12.1% increase of HDL-C and a 12.8% decrease in the LDL-C/HDL-C ratio. In comparison with Group B (40 mg qPM) LDL-C, HDL-C and the LDL-C/HDL-C ratio in Group A (60 mg) differed by –8.9%, 6.6% and –12%, respectively. During treatment with 40 mg qPM, one patient developed an asymptomatic but notable elevation of CK to 1823 U/l (normal range 0–100 U/l) that was caused by strenuous exercise. No other notable biochemical or haematological abnormalities were recorded.It is concluded that in patients with heterozygous FH the increase of fluvastatin from 40 to 60 mg/d provided an additional significant effect on plasma LDL-C and HDL-C levels and in the LDL-C/HDL-C ratio, without producing any deleterious effect.     

Effect of 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statins) on tissue paraoxonase 1 and plasma platelet activating factor acetylhydrolase activities

The authors investigated the effect of pravastatin and fluvastatin on paraoxonase 1 (PON1) activity in plasma, liver, heart, and kidney, as well as on plasma platelet activating factor acetylhydrolase (PAF-AH) in the rat. The animals received pravastatin at doses of 4 and 40 mg/kg/d or fluvastatin at doses of 2 or 20 mg/kg/d for 3 weeks. Fluvastatin (20 mg/kg/d) reduced plasma PON1 activity toward paraoxon and phenyl acetate by 23.6% and 17.4%, respectively. The lower dose of this drug as well as both doses of pravastatin had no effect on plasma PON1. PON1 activity toward paraoxon in the liver of rats treated with 20 mg/kg/d fluvastatin was 27.5% lower than in the control group, and the activity toward phenyl acetate was reduced by 25.4% and 35.9% in rats receiving 2 and 20 mg/kg/d of this drug, respectively. Fluvastatin at 2 and 20 mg/kg/d also decreased cardiac PON1 by 31.3% and 27.3%, respectively. Both statins reduced PON1 activity in the renal cortex and medulla. Statins had no effect on plasma PAF-AH. It is concluded that fluvastatin reduces PON1 activity more efficiently than does pravastatin. Reducing effect on PON1 may negatively modulate atheroprotective potential of statins and may contribute to differences in antiatherosclerotic properties of different drugs in this group.     

Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats

Pulmonary arterial hypertension is a progressive and fatal disease for which Rho-kinase may be substantially involved. In this study, we examined the acute vasodilator effects of fasudil, a Rho-kinase inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. Three weeks after a single subcutaneous injection of MCT (60 mg/kg), hemodynamic variables were measured under conscious and free-moving conditions before and after oral administration of fasudil. MCT caused a significant elevation of mean pulmonary arterial pressure (mPAP). Although a low dose of fasudil (3 mg/kg) had no effect on mPAP, a middle dose (10 mg/kg) caused a significant reduction in mPAP without change in mean systemic arterial pressure (mSAP), and a high dose (30 mg/kg) significantly reduced both mPAP and mSAP. Rho-kinase activity was significantly increased by MCT injection in pulmonary arteries but not in the aorta. Fasudil (10 mg/kg) inhibited only the Rho-kinase activity in pulmonary arteries without any effect in the aorta. Plasma concentration of hydroxyfasudil, a metabolite of fasudil, was within its clinical range in humans. These results demonstrate that fasudil exerts effective and selective vasodilatation of pulmonary arteries in rats with MCT-induced PH at a given dose, suggesting its usefulness for the treatment of the fatal disorder.     

胸腺肽α1对老年重症医院获得性肺炎患者免疫功能的影响

目的:探讨胸腺肽α1治疗对老年重症医院获得性肺炎(SHAP)患者细胞免疫功能的影响及其临床意义。方法:48例SHAP患者随机分为治疗组和对照组。治疗组在对照组基础上给予胸腺肽α1 1.6 mg皮下注射,qd,持续1周,之后改为1.6 mg,皮下注射,隔日一次,共2周。结果:治疗组治疗后单核细胞人类白细胞抗原(HLA-DR)、自然杀伤(NK)细胞、CD4+细胞及CD4+/CD8+比值明显上升;治疗组住院死亡率明显低于对照组,其存活者抗生素应用时间亦比对照组明显缩短。结论:胸腺肽α1能提高SHAP患者免疫功能,有利于感染控制,并降低住院死亡率。