尼群地平对食饵性家兔动脉粥样硬化的影响Ⅱ、血小板聚集性和血浆脂质过氧化的变化

本文报道尼群地平对食饵性动脉粥样硬化家兔血小板聚集性和血浆脂质过氧化的影响。结果表明，尼群地平可抑制高脂血症诱导的血小板聚集性增加和脂过氧化物增多。提示尼群地平抗动脉粥样硬化作用，与这些变化有关。     

尼群地平对食饵性家兔动脉粥样硬化的影响Ⅱ、血小板聚集性和血浆脂质过氧化的变化

本文报道尼群地平对食饵性动脉粥样硬化家兔血小板聚集性和血浆脂质过氧化的影响，结果表明，尼群地平可抑制高脂血症诱导的血小板聚集性增加和脂过氧化物增多，提示尼群地平抗动脉粥样硬化作用，与这些变化有关。     

玉米苞叶煎剂对动脉粥样硬化家兔血管外器官病变的形态学影响

目的 观察玉米苞叶煎剂对AS家兔血管外各器官病变的形态学影响.方法 选用大耳白家兔,雌雄各半,随机分为对照组、高脂组、玉米苞叶煎剂组,复制高脂食饵性家兔AS模型,观察玉米苞叶煎剂预防性用药后对家兔血脂及内脏各器官的病理形态学影响.结果 玉米苞叶煎剂组TC、TG较高脂组明显降低(P<0.01);高脂组各脏器(心、肝、脾、肺、肾)与对照组相比均有明显病理变化,玉米苞叶煎剂组各脏器病变较高脂组明显减轻.结论 玉米苞叶煎剂不但可以减轻AS家兔血管病变,且对心、肝、脾、肺、肾各脏器的高脂损伤同样有干预作用.     

尼群地平对食饵性兔动脉粥样硬化的影响──Ⅱ、血小板聚集性和血浆脂质过氧化物的变化

尼群地平对食饵性兔动脉粥样硬化的影响──Ⅱ、血小板聚集性和血浆脂质过氧化物的变化涂玉林，杨小毅，刘德平，万载阳，周元芳（衡阳医学院心血管病研究所，衡阳４２１００１）我们曾发现，尼群地平对食饵性家兔高脂血症影响不大，但可明显抑制其主动脉壁病变，降低主动...     

黄芩茎叶总黄酮对高脂血症兔主动脉VCAM-1、ICAM-1表达的影响

目的观察黄芩茎叶总黄酮(SSTF)对高脂血症兔主动脉血管细胞黏附分子(VCAM)-1、细胞间黏附分子(ICAM)-1表达的影响,探讨SSTF抗动脉粥样硬化(AS)的可能机制。方法 24只健康雄性家兔随机分为正常对照组(6只),喂养普通饲料,动脉粥样硬化模型组(18只),喂养高脂饲料。8w后,将AS模型组再随机分为模型组,继续喂养高脂饲料,SSTF治疗组,喂养高脂饲料并灌胃给予SSTF(100、200mg·kg-1.d-1),治疗4w后,处死家兔,测定各组家兔TC、TG、LDL-C,取主动脉做病理切片,免疫组化检测主动脉VCAM-1、ICAM-1的表达。结果 SSTF可以降低高脂饮食兔血清TC、TG、LDL-C水平,作用效果呈剂量依赖性。SSTF能够逆转动脉粥样程度、抑制VCAM-1、ICAM-1的表达。结论 SSTF具有抗AS作用,可能与通过下调VCAM-1、ICAM-1表达,从而抑制血管壁炎症反应有关。     

脂泰胶囊对实验性动脉粥样硬化家兔内皮素及一氧化氮合酶基因表达的影响

为在基因水平上探讨痰瘀同治方药脂泰胶囊保护血管内皮、抗动脉粥样硬化形成和发展的机理,采用烟酰胺磷酸腺嘌呤二核苷酸—硫锌酰胺脱氢酶组织化学染色和原位杂交法观察了脂泰胶囊对高脂血症家兔主动脉壁一氧化氮合酶活性及其ｍＲＮＡ表达和内皮素ｍＲＮＡ表达的影响,采用阳性积分法处理数据。结果发现,脂泰胶囊组家兔胸主动脉一氧化氮合酶活性（１．３８±０．６３）明显高于高脂组（０．４０±０．２４）（Ｐ＜０．０１）;脂泰胶囊组家兔胸主动脉一氧化氮合酶ｍＲＮＡ表达（１．３８±０．４８）明显高于高脂组（１．００±０．００）（Ｐ＜０．０５）;脂泰胶囊组家兔胸主动脉内皮素ｍＲＮＡ表达（２．４３±０．５３）明显低于高脂组（３．３３±０．８２）（Ｐ＜０．０５）。此外,脂泰胶囊可以阻止斑块增厚,减少斑块内脂质坏死中心的形成。提示脂泰胶囊能明显升高高脂状态下主动脉血管壁的一氧化氮合酶活性及其ｍＲＮＡ表达,降低内皮素ｍＲＮＡ表达。脂泰胶囊抗动脉粥样硬化形成和发展的作用机制之一可能是通过调控一氧化氮合酶ｍＲＮＡ和内皮素ｍＲＮＡ的表达,从而达到维持一氧化氮合酶的正常活性及一氧化氮的正常水平来实现的。     

红葡萄酒及白藜三醇对血小板聚集的影响

观察红葡萄酒及其提取物白藜三醇对离体和在体条件下血小板聚集的影响 ,以探讨它们对心血管系统的保护作用机制。以高胆固醇饮食造成实验性高脂血症 ,以凝血酶、二磷酸腺苷和胶原为诱导剂 ,采用Born氏法测定血小板聚集率。结果发现 ,高脂饮食明显增加兔血浆胆固醇水平 ,并伴有血小板聚集的明显增强。同时给予红葡萄酒、去酒精红葡萄酒和白藜三醇可以消除高脂饮食对兔血小板聚集的增强作用。离体条件下白藜三醇明显抑制凝血酶、二磷酸腺苷及胶原诱导的健康人的血小板聚集。结果提示 ,红葡萄酒及白藜三醇均具有抑制血小板聚集的作用 ,此作用可能为白藜三醇抗动脉粥样硬化的机制之一。     

痰瘀同治方逆转动脉粥样硬化家兔作用机制研究

目的：研究痰瘀同治方逆转家兔动脉粥样硬化作用机制。方法：采用高脂饮食造成家兔动脉粥样硬化模型。再给予中药治疗，观察不同时期生化指标的变化。结果：高脂血症时，家兔血脂及ET，MDA含量升高，NO，SOD含量降低。结论：痰瘀同治方有明显调节NO，ET，MDA，SOD，TNF含量，抑制细胞过度凋亡，对损伤的内皮细胞有明显的保护作用。     

抗凋亡多肽Gly14-Humanin对动脉粥样硬化模型小鼠血小板高敏感性以及脂质斑块形成的作用

目的抗凋亡多肽Humanin可以延缓动脉粥样硬化脂质斑块形成,其机制可能是抑制氧化型低密度脂蛋白诱导的氧化性应激和内皮细胞凋亡,但Humanin对动脉粥样硬化状态下血小板高敏感性的影响尚无报道。本研究评价了Humanin衍生物([Gly14]-Humanin,HNG)对低密度脂蛋白受体(LDLR)敲除小鼠动脉粥样硬化形成以及血小板高敏感性的影响。方法将8周龄雄性野生型(wild type,WT)和低密度脂蛋白受体敲除小鼠进行实验分组,包括对照组(WT小鼠喂食普通饲料,CD组)、模型组(LDLR-/-小鼠喂食高脂饲料,HFD组)、实验组(LDLR-/-小鼠喂食高脂饲料的同时注射HNG,HFD+HNG组)。分别于4周、12周、24周,进行下腔静脉取血,分离洗涤血小板,进行血小板聚集实验并分离血清进行血脂含量的测量。适时分离主动脉进行苏丹IV染色,观察主动脉内表面粥样脂质斑块形成,利用Image-Pro Plus图像处理软件分析斑块面积大小。结果与对照组相比,喂食高脂饲料24周后,模型组小鼠主动脉内有大量粥样斑块形成,并且随着喂食高脂时间的延长,具有明显的脂蛋白水平的变化。模型组小鼠血小板在二磷酸腺苷(adenosine diphosphate,ADP)诱导下的聚集作用显著增强(P0.01),更重要的是,HFD+HNG组小鼠的斑块面积明显减小(P0.01),且血小板对ADP所诱导的血小板聚集明显低于HFD组(P0.01)。结论 HNG抑制动脉粥样硬化模型小鼠血小板高敏感性,可能是减缓动脉粥样硬化脂质斑块形成的机制之一。     

化瘀复元胶囊抗家兔实验性动脉粥样硬化的研究

目的 :通过建立家兔高脂血症动脉粥样硬化 ( AS)模型 ,观察化瘀复元胶囊对血脂、脂蛋白及动脉病理形态学改变的影响。结果 :化瘀复元胶囊大小剂量两组血清 TC、TG及动脉粥样硬化指数 ( AI)明显降低 ,HDL- C显著升高 ,主动脉内膜脂质沉着明显减轻 ,泡沫细胞明显减少 ,脂质斑块显著缩小 ,与正常组和模型组比较 ,均有显著差异 ,并呈较好的量效、时效关系 ,大剂组明显优于阿斯匹林组 ,提示化瘀复元胶囊具有良好的调脂、抗 AS作用 ,适用于心脑血管疾病的防治     

依那普利、硝苯吡啶和洛伐他汀对家兔实验性动脉粥样硬化的影响

为探讨依那普利、硝苯吡啶和洛伐他丁对高胆固醇兔动脉粥样硬化的影响,本文将３７只新西兰雄性白兔随机分为正常饮食组、胆固醇组、依那普利组、硝苯吡啶组和洛伐他丁组,后三组在高胆固醇饮食的基础上给相应药物。喂养１６周后处死所有动物,测定主动脉组织中胆固醇含量及斑块面积比。结果发现,依那普利和硝苯吡啶不影响血脂水平,洛伐他丁有降低胆固醇,甘油三脂及低密度脂蛋白的作用,洛伐他丁组低密度脂蛋白／高密度脂蛋白的比     

Nifedipine reduces atherogenesis in cholesterol-fed heterozygous WHHL rabbits

We have developed a new model to study the interaction between diet and genetics in atherogenesis, the cholesterol-fed heterozygous WHHL rabbit. To determine the effects of calcium blockers on atherosclerosis in this model, two groups of heterozygous WHHL rabbits were fed 0.25% cholesterol and 2% peanut oil with (n = 6) and without (n = 6) oral nifedipine (40 mg/kg/day) for 16 weeks. Body weights, serum cholesterol, triglycerides and calcium, and blood pressures were not significantly different between the 2 groups during the study period. Heterozygous WHHL rabbits in the nifedipine group had less aortic surface area with sudanophilic lesions (23 +/- 15% vs. 62 +/- 18%, P less than 0.01) and fewer segments of coronary arteries with lesions (19 +/- 9% vs. 35 +/- 8%, P less than 0.02). Total aortic cholesterol, phospholipid, and calcium were also reduced in nifedipine-treated rabbits compared with untreated animals. We conclude that nifedipine reduced atherosclerosis in this model. Although the mechanism is unknown, it is apparent that nifedipine acts independently of changes in plasma lipids and blood pressure.     

Nifedipine suppressed atherosclerosis in cholesterol-fed rabbits but not in Watanabe heritable hyperlipidemic rabbits

We studied the effects of nifedipine, a calcium antagonist, on atherosclerosis in cholesterol-fed rabbits and Watanabe heritable hyperlipidemic rabbits (WHHL rabbits). Japanese White rabbits were fed 120g of 2% cholesterol rabbit chow daily, and WHHL rabbits were fed standard rabbit chow. In each experiment, the rabbits were divided into two groups. Twenty milligrams of nifedipine was given orally twice a day to the nifedipine group, and the control group was given a placebo in the same way. The rabbits were sacrificed at the end of the 12th week in the case of cholesterol-fed rabbits, and the 20th week in the case of WHHL rabbits. Among the cholesterol-fed rabbits, the percentage of aortic intimal surface area covered by atherosclerotic lesions (AS%) was 25.9 +/- 7.6% (mean +/- S.D.) in the nifedipine group (n = 7), and 55.6 +/- 22.8% in the placebo group (n = 8) (p less than 0.01). The cholesterol content of thoracic and abdominal aorta in the nifedipine group was lower than those in the placebo group (p less than 0.05). Among the WHHL rabbits, the AS% was 33.4 +/- 14.1% in the nifedipine group (n = 5), and 27.0 +/- 11.7% in the placebo group (n =6) (n.s.). The aortic cholesterol and calcium contents also showed no significant differences between the two groups. We concluded that nifedipine suppressed atherosclerosis in cholesterol-fed rabbits but not in WHHL rabbits. The different responses suggest that the effect of nifedipine could be mediated by low density lipoprotein receptors or that the early exposure to hyperlipidemic serum from birth might affect cell functions of WHHL rabbits.     

Failure of nifedipine to reduce atherogenesis in cholesterol-fed rabbits

The purpose of this study was to determine if therapeutic dosages of nifedipine, a drug that reduces intracellular calcium concentrations, suppresses atherogenesis in normotensive, cholesterol-fed rabbits. Control groups were fed either normal chow (Group I), or normal chow supplemented with 0.10 and 0.25% cholesterol (wt/wt) (Group II). Group III animals were fed the same diets as Group II animals and received nifedipine (0.625 and 1.250 mg/kg/d). During the course of the study (3 months) no systematic quantitative difference (P greater than 0.05) was observed between Groups II and III with regard to mean arterial blood pressure, serum cholesterol, serum electrolytes (sodium and potassium), plasma renin activity, or serum lipoprotein classes. At necropsy, there likewise was no difference in affected aortic surface area, aortic cholesterol content, or renal renin content. We conclude that nifedipine, at human therapeutic dosages, has no effect on either atherogenesis or the renin-angiotensin system in normotensive rabbits fed a moderately cholesterol-rich diet.     

Probucol reduces plasma and aortic wall oxysterol levels in cholesterol fed rabbits independently of its plasma cholesterol lowering effect.

To understand further the antiatherogenic mechanism of probucol, the antioxidant effect of this agent was studied on specific cholesterol oxidation products in plasma and aortic wall in equally hypercholesterolemic New Zealand white rabbits. In order to maintain equal plasma total cholesterol levels, five control rabbits (C group) received a 1% followed by a 0.5% cholesterol enriched diet, while the probucol treated rabbits (C+P group) received a graded increase in the cholesterol supplemented diet from 1% to 3%; probucol supplementation was constant at 1%. After 9 weeks of feeding, the plasma oxysterols, cholest-5-ene-3 beta,7 alpha-diol, cholest-5-ene-3 beta,7 beta-diol, 5,6 beta-epoxy-5 alpha-cholestan-3 beta-ol, 5,6 alpha-epoxy-5 alpha-cholestan-3 alpha-ol and 5 alpha-cholestane-3 beta,5,6 beta-triol significantly increased over baseline levels in both experimental groups. However, the increase in all these products in plasma was 20-60% less in the C+P group than the C group (P < 0.05). Furthermore, the C+P aortic wall cholesterol oxide concentrations were 50-90% less than the C group (P < 0.05). The oxysterol pattern of the aortic wall was similar to plasma. Additionally, the aortic wall cholesterol content in the C+P group was 50% less than the C group (P < 0.05). The plasma cholesterol levels were not significantly different at any time point during the study and the cholesterol oxide content in the diets was the same. These results are consistent with the contention that the antioxidant properties of probucol serve as the basis for its antiatherogenic effects in vivo.     

Hypertension and atherosclerosis in cholesterol-fed rabbits. II. One-kidney, one clip Goldblatt hypertension treated with nifedipine

Eight groups of New Zealand white rabbits were used to study the effects of moderate chronic one-kidney, one clip hypertension (HT) and long-term nifedipine therapy on atherogenesis. Four groups were fed a normal diet (ND) over an 8-month study period; two groups, one of which was given nifedipine, remained normotensive (NT) throughout the study. Of the two HT groups, one remained hypertensive for 7 months; the blood pressure of the other group was normalized after 2 months with nifedipine. The other four groups of animals were similarly constructed except that they were fed a 0.1% cholesterol diet (CD). The results showed that: although scattered fibromuscular vascular lesions were present in the aortas of normal-diet, HT animals no atheroma was observed; neither moderate chronic HT nor abrupt, short-term HT exacerbated atherogenesis in the CD-animals; nifedipine therapy had no suppressive effect on either fibromuscular lesions or atherogenesis; nifedipine therapy reduced the aorta weight of the normotensive ND and CD groups; the aortic triglyceride content of both dietary groups was reduced by nifedipine; cholesterol content was unaffected; left ventricular hypertrophy was evident only in HT-untreated groups; and only the weight of the left ventricle of the ND-NT-treated group was significantly reduced, but the mitochondria volume per unit volume of left ventricle myocardial cells was reduced only in the NT-CD group treated with nifedipine. It is concluded that an antihypertensive dosage of nifedipine administered to animals with atherosclerosis does not suppress subsequent atherogenesis.     

Hydrophobic surfactant effects on aortic cholesterol accumulation and atherosclerosis in hypercholesterolemic rabbits

Studies were performed in hypercholesterolemic rabbits to determine whether the hydrophobic surfactant, Poloxalene 2930 (Pol), is of benefit under these conditions. Lipoprotein analyses plus chemical and morphologic studies of the aorta were performed to evaluate the results. In one study, rabbits were made hypercholesterolemic by dietary means and then divided into two groups and given a cholesterol-free diet with one group additionally given Pol with treatment continued for 10 weeks. Pol treatment resulted in less atherosclerosis but the mechanism for this effect was not apparent from lipoprotein analysis. In the other study 3 groups of rabbits were given a cholesterol-rich diet for 16 weeks. Two groups received Pol supplement with one of these groups receiving a dose that was too small to prevent hypercholesterolemia. In this group plus the group on diet alone comparable degrees of hypercholesterolemia were maintained throughout the study. Lipoprotein abnormalities were similar in these two groups except that those on Pol had a more normal cholesterol to apolipoprotein B ratio. The amount of atherosclerosis in both groups was mild but aortic cholesterol content was much less for the Pol group. It is concluded that Pol limits cholesterol accumulation in the aortic wall of hypercholesterolemic rabbits and can retard the development of atherosclerosis.     

Cholesterol diet followed by normal diet alters functional and metabolic responses in rabbit aorta

Male New Zealand rabbits were fed a high cholesterol (1%) diet for 8 weeks followed by a normal diet for 8 additional weeks. Rabbits on normal diet were used as controls. Serum cholesterol, elevated at the end of the cholesterol feeding period, returned to normal at the time of observation. Aortic wall lesions were severe and vessel wall cholesterol in the thoracic aorta was approximately 10 times the level in control animals. In vitro, thoracic aortic rings were used to measure contractile response to noradrenaline (NOR); no difference in response was found between normal and treated rabbits. Rings pre-contracted with NOR, were exposed to acetylcholine (Ach), ATP and NaNO2. Proximal and distal rings from normal animals showed a dose-dependent relaxation response to all agents, though maximal dilation occurred at an intermediate concentration of Ach. The rings from treated rabbits relaxed normally in response to NaNO2, but ATP relaxation was reduced in proximal and distal rings and Ach induced a contractile response. HPLC analysis of tissue extracts from aortic arch and distal thoracic aorta showed reduced ATP, ADP, GTP and GDP, and increased AMP. These changes resulted in a reduced energy charge and a reduction in total adenine nucleotides. The data indicate that cholesterol feeding, followed by normal diet, causes severe alterations of aortic vessel wall and that at an advanced stage of the diet-induced experimental disease energy metabolism and endothelium dependent vasodilation remain impaired even in the presence of normal serum lipids.     

Cholesterol feeding increases plasma and aortic tissue cholesterol oxide levels in parallel: further evidence for the role of cholesterol oxidation in atherosclerosis.

To determine the relationship between plasma and arterial wall oxysterols, plasma and aortic tissue from 7 New Zealand White rabbits fed a high cholesterol (1%) diet for 6 weeks was compared to plasma and aortic tissue from 7 normocholesterolemic rabbits fed standard rabbit chow. Cholesterol and cholesterol oxide fractions were isolated and analyzed by gas chromatography. Normocholesterolemic plasma and aortic tissue contained low levels of cholest-5-ene-3 beta, 7 alpha-diol, cholesta-3,5-dien-7-one, 5,6 alpha-epoxy-5 alpha-cholestan-3 alpha-ol, cholest-5-ene-3 beta, 7 beta-diol, and 5 alpha-cholestane-3 beta, 5,6 beta-triol while hypercholesterolemic plasma and atherosclerotic aorta contained significantly higher levels (P less than 0.05) of these products. Furthermore, 5,6 beta-epoxy-5 alpha-cholestan-3 beta-ol not found in normocholesterolemic plasma or aortic tissue was present in substantial amounts in both hypercholesterolemic plasma and atherosclerotic aortic tissue. Cholest-5-ene-3 beta,25-diol and 3 beta-hydroxycholest-5-ene-7- one not present in normocholesterolemic aorta were present in the atherosclerotic aorta. The oxysterol chromatographic patterns of normocholesterolemic plasma and normocholesterolemic aortic tissue were similar to each other as were the oxysterol chromatographic patterns of hypercholesterolemic plasma and atherosclerotic aortic tissue. The chromatographic patterns between the normocholesterolemic and hypercholesterolemic samples differed however. Possible absorption of the low levels of cholesterol oxides present in the cholesterol feed could account for the elevation of only some of the oxysterols. We conclude that cholesterol oxides exist at some basal level in normocholesterolemia and that these levels are increased by cholesterol-feeding which results in hypercholesterolemia. Our findings demonstrate that there is a strong relationship between plasma and aortic arterial wall levels of cholesterol oxides and suggest that in addition to exogenous sources, formation of cholesterol oxides proceeds via free radical oxidation acting upon elevated cholesterol levels resulting in the accumulation of these potentially cytotoxic and atherogenic products.     

Aging influences development and progression of early aortic atherosclerotic lesions in cholesterol-fed rabbits

The arterial wall in aged animals shows an increased susceptibility to develop atherosclerotic lesions, although the mechanisms by which aging acts are still unclear. We investigated early aortic lesions in aged rabbits (5 to 6 years old, AH group) and young rabbits (2 months old, YH group) after 2 months of 0.2% cholesterol feeding. Fatty streaks or spots mainly in the proximal segments occupied a relative surface area that was greater in AH than in YH rabbits, although plasma cholesterol and lipoprotein levels did not differ. YH lesions showed an irregular endothelial profile mainly from accumulations of large, rounded, RAM 11-positive macrophagic foam cells. There was a higher percentage of myocytic, CD-5-positive, proliferating, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells and larger accumulation of glycosaminoglycans in AH fatty streaks than in YH lesions. Ligation-mediated polymerase chain reaction confirmed differences in apoptosis. Early fibromuscular coats and subendothelial plasma-like insudate were also observed in AH lesions. Aged-matched normocholesterolemic rabbits showed a diffuse aortic intimal thickening composed of myocytic cells with a synthetic phenotype and extracellular matrix rich in glycosaminoglycans. In addition, in aged rabbits, we observed a spontaneous increase of monocytes adhering to the endothelial surface and a reduced expression of endothelial nitric oxide synthase in areas distant from the branches. These plasma cholesterol-independent spontaneous changes in the aortic wall of aged rabbits seem to act as a multiple atherogenic risk factor. Moreover, age-related differences in the distribution, composition, and proliferative and apoptotic rates represent crucial events during the progression of early fatty streaks to advanced plaques.