AC-NP改善大鼠低氧性肺动脉高压

目的 明确 AC-NP（一种新型的钠尿肽分子）对于低氧性肺动脉高压的在体效应。方法 采用间断性减压低氧的方法复制低氧性肺动脉高压(HPH)大鼠模型,以AC-NP〔50 μg/(kg·d)〕治疗HPH大鼠1周。检测分析血流动力学指标,以及右心室和肺动脉的重构情况。结果 低氧可致大鼠肺动脉压异常升高。AC-NP治疗1周显著降低HPH大鼠的肺动脉压、肺血管阻力、右心室肥厚和肺动脉的肌化,同时肺血流量显著增加。另外,静脉急性给予AC-NP可以显著改善HPH大鼠的血流动力学指标。结论 AC-NP对HPH具有一定的治疗作用。     

C-type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats

C-type natriuretic peptide (CNP) has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether CNP ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Rats received a continuous infusion of CNP or placebo. Significant pulmonary hypertension developed 3 weeks after MCT. However, infusion of CNP significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, CNP enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. CNP significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, CNP significantly increased the survival rate in MCT rats. Finally, infusion of CNP after the establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of CNP ameliorated MCT-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment.     

A combination of oral sildenafil and beraprost ameliorates pulmonary hypertension in rats

Sildenafil, an oral phosphodiesterase type-5 inhibitor, has vasodilatory effects through a cyclic guanosine 3', 5'-monophosphate-dependent mechanism, whereas beraprost, an oral prostacyclin analog, induces vasorelaxation through a cAMP-dependent mechanism. We investigated whether the combination of oral sildenafil and beraprost is superior to each drug alone in the treatment of pulmonary hypertension. Rats were randomized to receive repeated administration of saline, sildenafil, beraprost, or both of these drugs twice a day for 3 weeks. Three weeks after monocrotaline (MCT) injection, there was significant development of pulmonary hypertension. The increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight were significantly attenuated in the Sildenafil and Beraprost groups. Combination therapy with sildenafil and beraprost had additive effects on increases in plasma cAMP and cyclic guanosine 3', 5'-monophosphate levels, resulting in further improvement in pulmonary hemodynamics compared with treatment with each drug alone. Unlike MCT rats given saline, sildenafil, or beraprost alone, all rats treated with both drugs remained alive during 6-week follow-up. These results suggest that combination therapy with oral sildenafil and beraprost attenuates the development of MCT-induced pulmonary hypertension compared with treatment with each drug alone.     

吡咯烷二硫代氨基甲酸酯对2型糖尿病大鼠肝脏的保护作用

目的探讨吡咯烷二硫代氨基甲酸酯(pyrroli dinedithiocarbamate,PDTC)对2型糖尿病大鼠肝脏的保护作用及机制。方法雄性Wistar大鼠,随机分为两组,正常对照组和高脂饮食组。喂养8w后,高脂组腹腔注射小剂量链脲佐菌素(STZ,27mg/kg)制造2型糖尿病大鼠模型,造模成功后随机分为两组:糖尿病模型组和PDTC治疗组。治疗1w后断头处死大鼠,测定血脂,HE染色观察大鼠肝脏形态学变化,RT-PCR检测iN-OSmRNA的表达。结果糖尿病模型组较正常组血脂明显升高(P0.01),PDTC治疗组与模型组相比无明显差别(P0.05);糖尿病模型组与正常组相比较肝脏明显脂肪变性,肝细胞损害,PDTC治疗组肝细胞脂肪变性及损害明显减轻。糖尿病模型组iNOSmRNA的表达较正常组明显升高(P0.01),经PDTC治疗后表达较糖尿病模型组降低(P0.01)。结论 PDTC可以减少iNOSmRNA的表达,减少肝细胞脂肪变性及损伤。     

吡咯烷二硫代氨基甲酸酯对2型糖尿病大鼠大血管损伤的保护作用

目的 观察吡咯烷二硫代氨基甲酸酯(PDTC)的降糖作用,以及对2型糖尿病(T2DM)大鼠主动脉血管内皮诱生型一氧化氮合酶(iNOS)表达及硝基酪氨酸(NT)生成的影响.方法 雄性WistarA大鼠,随机分为两组,正常对照组(NC组)和高脂饮食组(HFD组),喂养8 w后,HED组腹腔注射小剂量链脲佐菌素(STZ),诱导成功的T2DM大鼠随机分为糖尿病组(DM组)和PDTC治疗组(PDTC组),PDTC治疗组接受PDTC(50 mg/kg)治疗,持续1周,断头处死后留取血浆检测血糖及各种生化指标;留取主动脉组织,检测主动脉组织匀浆中丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)的含量;HE染色观察主动脉组织形态学变化,免疫组化观察各组大鼠主动脉内皮iNOS、NT的表达.结果 PDTC治疗1w后,PDTC组大鼠空腹血糖、MDA水平明显低于DM组;SOD和GSH-Px水平明显高于DM组(P<0.01).免疫组化结果显示:iNOS、NT在DM组大鼠主动脉内皮表达水平明显高于NC组;在PDTC治疗组大鼠主动脉内皮表达水平明显低于DM组.结论 PDTC不仅具有降血糖作用,而且可以减少iNOS的表达,进而减少过氧亚硝基阴离子(ONOO<'->)及NT的产生,延缓了糖尿病大血管并发症的发生.早期应用PDTC可预防T2DM因"代谢记忆"所致的大血管损伤.     

Combination of sildenafil and simvastatin ameliorates monocrotaline-induced pulmonary hypertension in rats

Sildenafil, a phosphodiesterase-5 inhibitor, and simvastatin, a cholesterol lowering drug, both have therapeutic effects on PAH; however, the combination of these drugs has not been tested in the treatment of PAH. The purpose of this study was to determine whether the combination of sildenafil and simvastatin is superior to each drug alone in the prevention of MCT-induced PAH. Phosphorylated Smad levels were decreased in lung tissue in MCT-injected rats, whereas ERK protein levels were increased. This indicates a possible role for an increase in mitogenic ERK activity in addition to decreased proapoptotic Smad signaling in the MCT model of PAH. Combination sildenafil and simvastatin treatment prevented the MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH), exerted an anti-proliferative effect on pulmonary artery smooth muscle cells (PASMC). Our results indicate that combination therapy with sildenafil and simvastatin attenuated the development of pulmonary hypertension more than either treatment alone.     

二硫代氨基甲酸吡咯烷对大鼠心肌梗死后心肌细胞肥大的影响

目的:探讨二硫代氨基甲酸吡咯烷(PDTC)对大鼠心肌梗死后心肌细胞肥大的影响及机制。方法:制作大鼠心肌梗死模型,随机分为PDTC干预(PD)组和心肌梗死对照(MI)组,另设假手术(SH)组,每组大鼠6只。PD组于术后24h腹腔注射PDTC(80 mg.kg-1.d-1),MI组及SH组注射0.9%氯化钠液对照。连续给药28 d后处死动物,计算心肌细胞面积、周长、平均直径。RT-PCR和免疫组化分别检测核转录因子-κBp65(NF-κBp65)及白介素-1β(IL-1β)的mRNA和蛋白质表达量。结果:与SH组比较,PD组和MI组的心肌细胞的直径、周长和表面积明显增大,NF-κBp65和IL-1β的mRNA及蛋白质表达量明显增加,差异均有统计学意义(P<0.01)。与MI组比较,PD组的心肌细胞的直径、周长和表面积改变明显减轻,NF-κBp65和IL-1β的mRNA及蛋白质表达量明显降低,差异有统计学意义(P<0.01)。结论:PDTC能一定程度地改善大鼠心肌梗死后心肌细胞肥大,其机制可能与抑制NF-κB激活,下调炎性细胞因子如IL-1β表达有关。     

Activation of nuclear factor-kappa B and effects of pyrrolidine dithiocarbamate on TNBS-induced rat colitis

AIM: To explore the changes of nuclear factor-kappa B (NF-κB) DNA-binding activity, the expression of intercellular adhesion molecule-1(ICAM-1) regulated by IMF-κB at various times and to evaluate the effects of pyrrolidine dithiocarbamate (PDTC) on trinitrobenzene sulfonic acid (TNBS)-induced rat colitis. METHODS: TNBS of 0.6 mL was mixed with ethanol of 0.3 mL solution and instilled into the lumen of the rat colon. The rat models were divided into 6 groups, which were killed at 24 h, 3, 7,14, and 21 d after enema. Colonic inflammation and damage were assessed by macroscopical and histological criteria. Activity of NF-κB DNA-binding was analyzed by electrophoresis mobility shift assays (EMSA). Expression of ICAM-1 was detected by in situ hybridization (ISH) and immunohistochemistry (IH). Then various doses of PDTC were injected into rat abdomen 30 min before enema with TNBS/ethanol as pretreatment. The rats were killed 4 h after enema and the colonic inflammation, myeloperoxidase (MPO) activity, malondialdehyde (MDA) level, and DNA-binding activity of NF-κB were assessed. Finally, PDTC was injected intraperitoneally after colitis was induced. Changes of morphology were assayed. RESULTS: During the first week, hyperemia, hemorrhage, edema and ulceration of the colonic mucosa appeared with predominant infiltration of leukocytes. Neutrophils, macrophages, lymphocytes infiltrated in mucosa and submucosa 14 d later. Fibroblasts and granuloma-like structures were also obviously seen. The binding activity of NF-κB began to increase at 24 h time point and reached a peak at 14 d, then decreased but still was higher than control group at 21 d (P<0.01). Levels of ICAM-1 mRNA and protein significantly elevated at 24 h and the peak was at 21 d. Pretreatment with PDTC could attenuate the development of inflammation but not by reducing NF-KB activity. This attenuation of inflammation had a positive relationship with the dose of PDTC. PDTC at the dose of 100 mg/kg had no therapeutic effect after colitis was induced. CONCLUSION: NF-κB activation is an important event that may be involved in acute and chronic inflammation development and may contribute to self-protection against early inflammation damage. NF-κB also regulates ICAM-1 expression during colonic inflammation. Pretreatment of PDTC may attenuate the inflammation development. But PDTC has no therapeutic effect after the colitis is induced.     

吡咯烷二硫代氨基甲酸盐对大鼠急性坏死性胰腺炎肝损伤的保护作用

目的:探讨核因子KB(NF-κB)抑制剂吡咯烷二硫代氨基甲酸盐(PDTC)对大鼠急性坏死性胰腺炎(ANP)的预防治疗作用。方法:大鼠80只随机分为正常对照组(Z)、胰腺炎组(Y)和干预纽.干预组又分为建模前1h PDTC干预组(A)、建模后1h PDTC干预组(B)和建模后6h干预组(C).干预组按不同时间ip PDTC.建模后6,12,24 h分批处死,临床全自动生化仪检测血清谷丙转氨酶(ALT)和淀粉酶(AMY),用凝胶迁移率改变分析法(EMSA)测定胰腺和肝脏中NF-κB的活性.同时观察胰腺和肝脏的病理改变.结果:正常大鼠组织中几乎测不到NF-κB的活性,与Z组比较,Y组胰腺和肝脏组织中6,12,24 h NF-κB活性分别明显增加(P<0.001).建模前1h,1h后使用PDTC,胰腺和肝脏组织中NF-κB活性均受到抑制(18.14±3.30,23.79±3.62 vs 24.82±4.57:10.68±2.51,13.83±2.70 vs 16.38±2.50;P<0.05),Y组血清ALT,AMY均高于对照组.病理学检查可以见到Y组和A,B,C组的胰腺和肝脏均有炎性改变,但A组较Y组明显为轻.结论:NF-κB的异常活化与SAP以及肝损伤有明显关系:PDTC对SAP时肝损伤的发生有一定的预防作用.     

Portal hypertension ameliorates arterial hypertension in spontaneously hypertensive rats

Systemic hemodynamic effects of portal hypertension in arterial hypertension and their relationship to serum bile acid levels were investigated using spontaneously hypertensive rats 2 and 15 weeks after partial portal vein ligation (SHR-PVL) or sham operation (SHR-SH) and normotensive controls. Mean arterial pressure in SHR-PVL at 2 weeks was decreased to normal due to a decrease in peripheral resistance. Mean arterial pressure and peripheral resistance in SHR-PVL at 15 weeks did not differ from SHR-SH. Resolution of this arterial hypotensive effect and systemic hyperdynamic circulation was associated with decreased portal-systemic shunting. Bile acid levels were increased in both SHR-PVL groups. These results suggest that an endogenous circulating vasodilator(s) associated with portal hypertension ameliorates the systemic vasoconstriction in SHR. Bile acids, while not direct mediators of these hemodynamic events, may be prototypic of this vasodilator. This arterial hypertensive model may aid further investigation of the mechanisms contributing to the hyperdynamic state in portal hypertension.     

铜绿假单胞菌肺炎大鼠核因子-κB表达及二硫代氨基甲酸吡咯烷对其的影响

目的探讨NF-κB及其诱导TNFα在大鼠铜绿假单胞菌（PA）肺炎中的表达及二硫代氨基甲酸吡咯烷（PDTC）对其的影响。方法72只SD大鼠分为健康对照组、PA组、PDTC干预组。每组24只。PA组大鼠制作PA模型,PDTC干预组制作PA模型前腹腔注射PDTC200mg／kg体重。PA组、PDTC干预组接种铜绿假单胞菌悬液0．2ml（6×10^8CFU／m1）。观察大鼠肺组织形态学改变,免疫组化及Western blot检测肺组织NF-κB表达,RT-PCR检测肺组织TNFαmRNA表达。结果PA组大鼠肺组织明显充血、水肿,大量炎性细胞浸润;PDTC干预组大鼠肺组织充血、水肿等炎性表现较PA组明显减轻。PA组大鼠肺组织NF-κB表达阳性细胞明显增多,PDTC干预组NF—κB表达阳性细胞明显减少。Western blot显示,各时间点NF-κB表达不同,3h达高峰。RT—PCR显示,PA组TNFαmRNA高表达,以6h最为明显;PDTC干预组TNFαmRNA表达明显下调,与PA组相比,差异有统计学意义（P〈0．01）。结论NF-κB及其诱导的TNFα在PA肺炎中发挥重要作用,PDTC可能通过抑制NF-κB的活性减轻PA引起的肺损伤。     

核因子κB与慢性阻塞性肺疾病继发的肺动脉高压

核因子κB是一种多功能核转录因子,能调节多种参与炎症免疫反应的细胞因子、炎症介质,黏附分子及蛋白酶类的基因转录过程,从而控制它们的生物合成.肺动脉高压是临床常见的病理生理过程,致病的原因有很多,但慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是最常见的病因.COPD是一种以气道气流受限且不完全可逆为特征的疾病,气道炎症是COPD重要病理基础,而且在肺血管重构中有很重要的作用,肺血管重构进一步导致COPD继发肺动脉高压.通过阐述核因子κB、COPD气道炎症、肺血管重构之间相互作用的机制,可以对COPD继发的肺动脉高压的治疗提供新的思路和方法.