Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit.

The purpose of this study was to determine if chronic administration of L-arginine, the precursor of endothelium-derived relaxing factor (EDRF), normalizes endothelium-dependent relaxation and decreases atherosclerosis in hypercholesterolemic animals. Male rabbits were fed (a) normal rabbit chow; (b) 1% cholesterol diet; or (c) 1% cholesterol diet supplemented by 2.25% L-arginine HCl in drinking water. Arginine supplementation doubled plasma arginine levels without affecting serum cholesterol values. After 10 wk, the thoracic aorta was harvested for studies of vascular reactivity and histomorphometry. Endothelium-dependent relaxations (to acetylcholine and calcium ionophore A23187) were significantly impaired in thoracic aortae from animals fed a 1% cholesterol diet. By contrast, vessels from hypercholesterolemic animals receiving L-arginine supplementation exhibited significantly improved endothelium-dependent relaxations. Responses to norepinephrine or nitroglycerin were not affected by either dietary intervention. Histomorphometric analysis revealed a reduction in lesion surface area and intimal thickness in thoracic aortae from arginine-supplemented animals compared to those from untreated hypercholesterolemic rabbits. This is the first study to demonstrate that supplementation of dietary L-arginine, the EDRF precursor, improves endothelium-dependent vasorelaxation. More importantly, we have shown that this improvement in EDRF activity is associated with a reduction in atherogenesis.     

Amphotericin B lipid complex or amphotericin B multiple-dose administration to rabbits with elevated plasma cholesterol levels: pharmacokinetics in plasma and blood, plasma lipoprotein levels, distribution in tissues, and renal toxicities

The purpose of the present study was to determine if a relationship exists between the plasma cholesterol concentration, the severity of amphotericin B (AmpB)-induced renal toxicity, and the pharmacokinetics of AmpB in plasma in hypercholesterolemic rabbits administered multiple doses of amphotericin B (AmB) deoxycholate (Doc-AmB) and AmB lipid complex (ABLC). After 7 days of administration of a cholesterol-enriched diet (0.50% [wt/vol]) or a regular rabbit diet, each rabbit was administered a single intravenous bolus of Doc-AmB (n = 8) or ABLC (n = 10) (1.0 mg/kg of body weight) daily for 7 consecutive days (a total of eight doses). Blood samples were obtained daily before and 24 h after the administration of each dose and serially thereafter following the administration of the last dose for the assessment of pharmacokinetics in plasma, kidney toxicity, plasma lipoprotein levels, and drug distribution in tissue. The pharmacokinetics of AmB in blood following the administration of ABLC were also determined in rabbits fed cholesterol-enriched and regular diets (n = 3 each group). Before drug treatment, cholesterol-fed rabbits demonstrated marked increases in total, low-density lipoprotein (LDL), and triglyceride-rich lipoprotein (TRL) cholesterol levels in plasma compared with the levels in rabbits on a regular diet. No significant differences in total plasma triglyceride levels were observed. Significant increases in plasma creatinine levels were observed in rabbits fed a cholesterol-enriched diet (P < 0.05) and rabbits fed a regular diet (P < 0.05) when administered AmB. However, the magnitude of this increase was twofold greater in rabbits fed a regular diet than in rabbits fed a cholesterol-enriched diet. An increase in plasma creatinine levels was observed only in rabbits on a cholesterol-enriched diet administered ABLC. The pharmacokinetics of AmB were significantly altered in rabbits on a cholesterol-enriched diet administered Doc-AmB or ABLC compared to those in rabbits on a regular diet administered each of these compounds. The pharmacokinetics of AmB in blood were significantly different following ABLC administration but not following Doc-AmB administration in both rabbits fed cholesterol-enriched diets and rabbits fed regular diets compared to their corresponding pharmacokinetics in plasma. An increased percentage of AmB was recovered in the TRL fraction when Doc-AmB was administered to rabbits fed a cholesterol-enriched diet than when it was administered to rabbits fed a regular diet. Furthermore, an increased percentage of AmB was recovered in the LDL and TRL fractions when ABLC was administered to rabbits fed a cholesterol-enriched diet rabbits fed a regular diet. These findings suggest that an increase in plasma cholesterol levels modifies the pharmacokinetics of AmB and renal toxicity following the administration of multiple intravenous doses of Doc-AmB and ABLC.     

Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta.

We examined the hypothesis that impaired endothelium-dependent vasodilation in atherosclerosis is associated with decreased synthesis of nitrogen oxides by the vascular endothelium. The descending thoracic aortae of rabbits fed either normal diet, a high cholesterol diet for 2-5 wk (hypercholesterolemic, HC), or a high cholesterol diet for 6 mo (atherosclerotic, AS) were perfused in a bioassay organ chamber with physiologic buffer containing indomethacin. Despite a dramatic impairment in the vasodilator activity of endothelium-dependent relaxing factor (EDRF) released from both HC and AS aortae (assessed by bioassay), the release of nitrogen oxides (measured by chemiluminescence) from these vessels was not reduced, but markedly increased compared to NL. Thus, impaired endothelium-dependent relaxation in atherosclerosis is neither due to decreased activity of the enzyme responsible for the production of nitrogen oxides from arginine nor to arginine deficiency. Because the production of nitrogen oxides increased in response to acetylcholine in both hypercholesterolemic and atherosclerotic vessels, impairments in signal transduction are not responsible for abnormal endothelium-dependent relaxations. Impaired vasodilator activity of EDRF by cholesterol feeding may result from loss of incorporation of nitric oxide into a more potent parent compound, or accelerated degradation of EDRF.     

心肌缺血日负荷对新西兰兔血管内皮生长因子表达的影响

要目的:观察心肌缺血日负荷对新西兰兔血管内皮生长因子(VEGF)表达的影响。方法:健康成年新西兰兔38只,体重2.0—2.5kg。根据日缺血次数随机分为2次/日组、4次/日组、6次/日组、假手术组以及正常组。将气囊梗阻器安装在冠状动脉左室支,制作间断性心肌缺血模型。缺血负荷为2min/h,缺血刺激4周。取缺血区心肌观察形态学变化;WesternBlotting方法检测VEGF蛋白在缺血区心肌的表达水平;取兔术前和缺血刺激前、后24h血清检测肌钙蛋白(cTnI)。结果:气囊充气可以有效、迅速地诱发心肌缺血;与假手术组和正常组相比,缺血刺激2次/日组、4次/日组、6次/日组缺血心肌VEGF表达升高(P<0.05),各缺血刺激组间的VEGF表达无差异;各组左室支支配区未见心肌坏死和血栓形成;兔缺血刺激后24h血清肌钙蛋白无明显升高。结论:持续4周的间断性心肌缺血对心肌无损伤,可以显著提高缺血区心肌VEGF表达增加,不同刺激频率对其表达无明显影响。     

Reperfusion after acute coronary occlusion in dogs impairs endothelium-dependent relaxation to acetylcholine and augments contractile reactivity in vitro.

Endothelial injury may contribute to the augmented coronary vascular tone seen in myocardial ischemia by impairing endothelial production or release of vasodilators. In vitro reactivity of arterial rings was studied after 60 min of coronary occlusion and 60 min of reperfusion in anesthetized dogs. Ischemia without reperfusion blunted contractile reactivity to potassium chloride (KCl), whereas ischemia plus reperfusion augmented contractile responses to both KCl and ergonovine. The response to acetylcholine, an endothelium-dependent vasodilator, was abolished in reperfused arteries, whereas the response to nitroprusside, an endothelium-independent vasodilator, was intact. Verapamil pretreatment restored KCl contractile responses to normal in reperfused coronary rings and partially restored endothelium-dependent relaxation. Electron microscopy revealed a nondenuding epicardial coronary endothelial injury in reperfused arteries. These data support the hypothesis that reperfusion of ischemic myocardium augments reactivity to vasoconstrictor agents by causing endothelial cell damage, excessive calcium influx, and loss of modulating vasodilator function.     

Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits.

The purpose of this study was to investigate whether endothelium-derived nitric oxide (NO) is involved in the plasma lipid-independent antiatherogenic effect of estrogen and levormeloxifene, a partial estrogen receptor agonist. 85 rabbits were ovariectomized and balloon-injured in the middle thoracic aorta. The rabbits were fed a cholesterol-enriched diet supplemented with 17beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 microg/ml NG-nitro- -arginine methyl ester (-NAME), an NO synthase inhibitor, in their drinking water for 12 wk. Plasma cholesterol was maintained at 25-30 mmol/liter by individualized cholesterol feeding. In the undamaged aorta, the extent of atherosclerosis in the estrogen group was only one-third that in the placebo group. Simultaneous administration of -NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given -NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas -NAME combined with estrogen significantly increased atherogenesis (P < 0.05). The effects of levormeloxifene were almost similar to those of estrogen. Active vascular concentrations of -NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given -NAME. Thus, in this study a considerable part of the plasma lipid-independent antiatherogenic effect of estrogen was mediated through its effect on endothelial NO in cholesterol-fed rabbits. The results for levormeloxifene suggest a common mechanism of action for estrogen and partial estrogen receptor agonists on atherogenesis.     

Protective effect of selenium and vitamin E against changes induced in heart vessels of rabbits fed chronically on a high-fat diet.

The effect of selenium and vitamin E on lipid level in the blood serum, on the oxygen free radicals generation and on morphology of heart was tested after separate and combined administration to mongrel male rabbits fed on a high-fat diet (HFD). The lipid level and oxygen free radical generation was depressed markedly in animals fed on a HFD and receiving simultaneously selenium and vitamin E. In animals on a HFD the walls of the heart vessels were thickened, always to their complete obliteration. The presence of lipid droplets in endocardium could be observed as well. The hearts of the rabbits receiving selenium showed markedly fewer atheromatously changed vessels. Moreover, no accumulation of lipid droplets was seen in the endocardium of these animals. The least atherosclerotic alterations were observed in the myocardium of rabbits given HFD with addition of selenium and vitamin E in combination, no accumulation of lipids was shown in endocardium of these rabbits. An important finding of this study is, that the combination of selenium and vitamin E results in an intensified protective effect against changes evoked in the heart muscle of rabbits fed on a HFD.     

直接心肌内注射血管内皮生长因子基因对慢性缺血心肌侧枝循环生成的影响

目的观察血管内皮生长因子基因(rAAV2-hVEGF165)直接心肌内注射促进慢性缺血心肌侧枝循环生成的作用。方法小型猪左冠状动脉回旋支放置血管缩窄环,建立慢性心肌缺血模型。5周后应用心电图、冠脉造影和心脏核磁共振成像确认左回旋支闭塞或相应心肌的缺血。动物随机分为实验组和对照组,分别在缺血心肌内直接注射rAAV2-VEGF165(1×1012virus genomeml)或同等量的磷酸盐缓冲液或rAAV2-LACZ(1×1012virus genomeml)。治疗后6个月,冠状动脉造影了解有无侧枝循环生成。结果放置血管缩窄环后5周,所有动物均出现左回旋支完全、次全闭塞和旋支供血区域的心肌缺血。治疗后3个月,缺血心肌内可检测到LACZ和VEGF蛋白的阳性表达;治疗后6个月,VEGF组缺血心肌内毛细血管和小动脉密度均高于对照组(P<0.05);结论直接在小型猪慢性缺血心肌内注射rAAV2-VEGF165,VEGF165基因可转染入心肌组织内,并可在缺血部位显著促进侧枝循环形成。     

心肌缺血日负荷对冠状动脉侧支血流量的影响

目的:探讨心肌缺血日负荷对新西兰兔冠状动脉侧支血流量(CCBF)的影响。方法:健康成年新西兰兔34只,体重2.4±0.2kg。随机分为缺血组和假手术组,缺血组根据日缺血负荷分为2、4、6次/日亚组。将气囊梗阻器安装在冠状动脉左室支上,以建立间断性心肌缺血模型。气囊充气造成心肌缺血(2min/次,间隔1h),以各日缺血负荷持续4周。取缺血区心肌观察形态学改变;微球技术检测缺血区CCBF;取兔术前和首次缺血刺激前、后24h血清检测肌钙蛋白(cTn-I)。结果:4周间断性缺血刺激后,缺血组与假手术组相比,CCBF明显增加(P<0.05);各缺血亚组间CCBF差异无显著性意义(P>0.05)。各组缺血区心肌未见变性坏死灶,兔首次缺血刺激后24h血清肌钙蛋白无明显升高。结论:4周间断性心肌缺血对心肌无损伤,可促进缺血区CCBF增加;不同日缺血负荷对CCBF无明显影响。     

血液稀释和小肠缺血预处理对兔心肌缺血再灌注损伤的保护作用

目的探讨小肠缺血预处理和急性等容性血液稀释对缺血心肌的保护作用。方法 18只新西兰大白兔作心肌缺血造模,分别行缺血再灌注(Ⅰ组)、小肠缺血预处理(Ⅱ组)和小肠缺血预处理+血液稀释(Ⅲ组)。监测HR和MAP,血浆CK、CK-MB、LDH、CTnI及心梗面积,并在电镜下观察心肌细胞结构的改变。结果 (1)肠系膜上动脉阻断期间,Ⅱ、Ⅲ组HR、BP低于Ⅰ组(P<0.05)。(2)Ⅱ、Ⅲ组的CK、CK-MB、LDH及CTnI值低于Ⅰ组(P<0.05)。(3)Ⅱ、Ⅲ组的心梗面积小于Ⅰ组(P<0.05)。(4)电镜下,Ⅱ、Ⅲ组细胞损伤轻于Ⅰ组。结论小肠缺血预处理能减少心肌缺血再灌注损伤,急性等容性血液稀释不会减弱前者的保护作用。     

Evaluation of Statin Therapy on Endothelial Function in Hypercholesterolemic Rabbits by Automatic Measurement of Arterial Wall Movement Using Ultrasound Images

The aim of this study was to evaluate arterial endothelial function, assessed as acetylcholine-mediated dilation (AMD), in a hypercholesterolemic atherosclerotic rabbit model to investigate the effects of atorvastatin in the atherosclerotic process, using a new computerized analysis model and ultrasound images. Twenty-seven rabbits were fed a high-cholesterol (2%) diet for 6 wk and then divided into three groups for an additional 9 wk: Group A received regular chow food, group B received a 2% cholesterol-rich diet plus atorvastatin drug, and group C received regular chow food plus atorvastatin. Ultrasound examinations of endothelial function of the rabbit abdominal aorta artery were performed immediately after the 6 weeks (0 wk) and then 3, 6 and 9 wk after that. For off-line analysis, a computerized analysis method for evaluating instantaneous changes in the wall of the rabbit abdominal aorta was used. As parameters of improvement resulting from treatment, endothelium-dependent acetylcholine-induced dilation and endothelium-independent nitroglycerin-induced dilation were evaluated in treated rabbits. Differences among groups were tested using analysis of variance. On histopathology, intima-media thickness decreased after treatment in all groups. There were no significant differences in arterial diameter and blood velocity changes among treated rabbits at 0, 3, 6 and 9 wk of treatment in all groups, except in end-diastolic velocity, radial strain percentage, pulse index and resistance index in group C. In group A, AMD did not significantly improve after 3, 6 and 9 wk, as compared with 0 wk. Atorvastatin treatment significantly increased AMD (18%) at 3 wk in group B, compared with week 0. AMD significantly increased after 3 (26%), 6 (124%) and 9 (182%) wk in group C, compared with 0 wk. It is concluded that the new automatic method enables accurate and repeated evaluation of endothelial function during the progression and regression of atherosclerosis. Also, the results obtained in this study indicate that short-term administration of atorvastatin can improve endothelial function in cholesterol-fed rabbits.     

The rapid and reversible activation of a calcium-independent plasmalogen-selective phospholipase A2 during myocardial ischemia.

Recent studies have demonstrated the existence of two members of a novel family of calcium-independent plasmalogen-selective phospholipases A2 in mammalian myocardium (Wolf, R. A., and R. W. Gross. 1985. J. Biol. Chem. 260:7295-7303; and Hazen, S. L., D. A. Ford, and R. W. Gross. 1991. J. Biol. Chem. 266:5629-5633). To examine the potential role of these calcium-independent phospholipases A2 in mediating membrane dysfunction during early myocardial ischemia, the temporal course of alterations in phospholipase A2 activity during global ischemia in Langendorf perfused rabbit hearts was quantified and compared with traditionally accepted markers of myocytic ischemic injury and anaerobic metabolism. We now report that membrane-associated calcium-independent plasmalogen-selective phospholipase A2 activity increased over 400% during 2 min of global ischemia (P less than 0.01), was near maximally activated (greater than 10-fold) after only 5 min of ischemia, and remained activated throughout the entire ischemic interval examined (2-60 min). Activation of membrane-associated plasmalogen-selective phospholipase A2 after 5 min of myocardial ischemia was rapidly reversible during reperfusion of ischemic tissue. Both the activation of phospholipase A2 and its reversibility during reperfusion were temporally correlated to alterations in myocytic anaerobic metabolism. Furthermore, activation of membrane-associated phospholipase A2 was essentially complete before electron microscopic evidence of cellular damage. Collectively, these results identify dynamic alterations in calcium-independent plasmalogen-selective phospholipase A2 activity during myocardial ischemia which precede irreversible cellular injury and demonstrate that activation of plasmalogen-selective phospholipase A2 is amongst the earliest biochemical alterations in ischemic myocardium.     

Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion.

We studied the effects of MAbR15.7, an antibody directed against the common beta-chain (CD-18) of a family of neutrophil adherence glycoproteins, on endothelial dysfunction and myocardial injury in a model of myocardial ischemia and reperfusion in cats. Pentobarbital-anesthetized cats were subjected to 1.5 h occlusion of the left anterior descending coronary artery (LAD) and 4.5 h of reperfusion. MI + R resulted in severe myocardial injury and endothelial dysfunction, including significant elevation of plasma creatine kinase (CK) activity, marked myocardial necrosis, high cardiac myeloperoxidase (MPO) activity in ischemic cardiac tissue, and loss of response of LAD coronary rings to the endothelium-dependent vasodilators, acetylcholine (ACh) and A-23187. In contrast, MAbR15.7-treated cats exhibited a lower plasma CK activity at every time point observed after 2 h, a reduced area of cardiac necrosis (2 +/- 1 vs. 30.8 +/- 2.5% of area-at-risk, P less than 0.001), lower MPO activity in the ischemic region (P less than 0.01), and significantly preserved vasorelaxant responses of LAD coronary rings to endothelium-dependent vasodilators, ACh (P less than 0.001), and A-23187 (P less than 0.001). These results indicate that myocardial ischemia and reperfusion induces significant myocardial injury and endothelial dysfunction in the cat involving a CD18-dependent neutrophil adherence mechanism. Inhibition of neutrophil adherence to the endothelium exerts significant protective effects in this model of reperfusion injury.     

Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic, isolated, perfused rat hearts.

Three lines of investigation indicated that hydrogen peroxide (H2O2) from xanthine oxidase (XO) contributes to cardiac dysfunction during reperfusion after ischemia. First, addition of dimethylthiourea (DMTU), a highly permeant O2 metabolite scavenger (but not urea) simultaneously with reperfusion improved recovery of ventricular function as assessed by ventricular developed pressure (DP), contractility (+dP/dt), and relaxation rate (-dP/dt) in isolated Krebs-Henseleit-perfused rat hearts subjected to global normothermic ischemia. Second, hearts from rats fed tungsten or treated with allopurinol had negligible XO activities (less than 0.5 mU/g wet myocardium compared with greater than 6.0 mU/g in control hearts) and increased ventricular function after ischemia and reperfusion. Third, myocardial H2O2-dependent inactivation of catalase occurred after reperfusion following ischemia, but not after ischemia without reperfusion or perfusion without ischemia. In contrast, myocardial catalase did not decrease during reperfusion of ischemic hearts treated with DMTU, tungsten, or allopurinol.     

1,6-二磷酸果糖和地塞米松对家兔失血性休克缺血-再灌注损伤的影响

目的　在家兔失血性休克模型上 ,探讨心肌缺血再灌注损伤机制 ,比较 1,6二磷酸果糖(FDP)和地塞米松 (DXM)对心肌缺血再灌注的保护作用。方法　按照 Wiggers改良法制作兔失血性休克模型。4 8只家兔随机分成 3组 : 组为对照组 ; 组为休克前给药组 (又分为 FDP 、DXM 及 FDP DXM 3组 ) ; 组为再灌注时给药组 (又分为 FDP 和 DXM 2组 )。观察血浆肌酸激酶 (CK)、心肌肌钙蛋白 I(c Tn I)含量及心肌细胞凋亡情况。结果　各组 CK、c Tn I基础值均无统计学差异 ;与对照组相比 , 组 CK、c Tn I及心肌细胞凋亡指数下降或明显下降 (P<0 .0 5或 P<0 .0 1) ; 组在休克时间点均无统计学意义 ,而再灌注时间点有下降或下降趋势 ,有统计学差异 (P<0 .0 5或 P<0 .0 1) ;与 FDP 和 DXM 组相比 ,FDP 和DXM 组的 CK和 c Tn I上升幅度均有减慢趋势 ,以 FDP组减慢趋势更加明显 ;休克给药组间比较 ,FDP DXM 组的 CK和 c Tn I上升幅度均减慢。结论　 FDP和 DXM对失血性休克引起的缺血再灌注损伤均有保护作用 ,但 FDP仅在缺血开绐给药才能充分发挥其效应 ,二者联合用药对心肌保护有更好的效果。     

Reduction of Myocardial Infarct Size in the Rabbit by a Carbohydrate Analog of Sialyl Lewis(x)

BACKGROUND: Available data suggest that the accumulation of neutrophils within the myocardium following an ischemic event plays an important role in the pathogenesis of myocardial ischemia/reperfusion injury. It is of interest, therefore, to develop pharmacologic agents designed to inhibit neutrophil adhesion to the endothelium. METHODS AND RESULTS: A synthetic carbohydrate analog to the P-selectin ligand sialyl Lewis(x) (sLe(x)) was evaluated for its ability to protect the myocardium from ischemia/reperfusion injury. Open chest anesthetized rabbits were subjected to 30 minutes occlusion of the left circumflex artery followed by 5 hours of reperfusion. Vehicle or sLe(x) analog (10 mg/kg) was administered intravenously before the onset of reperfusion and every hour during the reperfusion period. Myocardial infarct size in rabbits treated with the sLe(x) analog (10 mg/kg) was administered intravenously before the onset of reperfusion and every hour during the reperfusion period. Myocardial infarct size in rabbits treated with the sLe(x) analog was significantly reduced when compared to rabbits treated with vehicle (28 +/- 9% vs 57 +/- 10% of the area at risk, p <.05). The compound did not alter circulating neutrophil counts or myocardial oxygen demand as determined by the rate-pressure product. Furthermore, neutrophil accumulation within the ischemic region was decreased by 44% (P <.05) in the hearts of animals receiving sLe(x) analog as compared to vehicle. CONCLUSIONS: Carbohydrate derivatives of sLe(x) may be effective in reducing the degree of myocardial injury after ischemia/reperfusion.     

促红细胞生成素对兔心肌缺血/再灌注损伤保护作用的研究

目的 建立兔心肌缺血/再灌注损伤(I/R)模型,观察促红细胞生成素(EPO)对兔血清CK-MB 浓度及心肌细胞凋亡的影响,探讨EPO 对兔心肌I/R 的保护作用及机制.方法 新西兰大白兔16 只,随机分为I/R 组和EPO 组.结扎兔左冠状动脉前降支制备兔I/R 模型.EPO 组于结扎左冠状动脉前降支的同时经耳缘静脉注入重组EPO,I/R 组注入等量的生理盐水.检测指标:(1)分别于缺血前5 min、缺血60 min、再灌注60 min 和再灌注180 min 检测血清CK-MB 浓度.(2)再灌注180 min 时取缺血区心肌组织,检测凋亡指数.(3)制作心肌组织标本,观察心肌组织的病理变化.结果 血清CK-MB 浓度随缺血及再灌注时间的延长而增加(与前一时间点比较,P <0.01);缺血前EPO 组与I/R 组血清CK-MB 浓度无统计学差异(P >0.05);缺血60 min、再灌注60 min、再灌注180 min 时,EPO 组血清CK-MB 浓度均显著低于I/R 组(均P <0.01).与I/R 组相比,EPO 组的缺血区心肌细胞的凋亡指数显著下降(P <0.01).结论 EPO 对兔心肌I/R 具有明显的保护作用,其机制可能与稳定心肌细胞膜结构,减少心肌酶的释放和抑制心肌细胞凋亡有关.     

Effects of lovastatin and pravastatin on the survival of hamsters with inherited cardiomyopathy

Cardiomyopathic hamsters develop heart disease early in life, which leads to congestive heart failure and death as these hamsters age. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to reduce ubiquinone concentrations and to deteriorate myocardial function in humans and in experimental animals. HMG-CoA reductase inhibitors differ regarding their ability to penetrate extrahepatic tissues. As a consequence, lovastatin inhibits cholesterol biosynthesis at least 100-fold more effectively than pravastatin in extrahepatic cells. We examined the effect of lovastatin and pravastatin (approximately 10 mg per kilogram of body weight and per day mixed in the diet) compared with controls on the lifespan of cardiomyopathic hamsters (BIO 8262 strain) in the heart-failure period. In male hamsters, neither lovastatin nor pravastatin significantly affected survival. In female hamsters, lovastatin reduced median survival time from 89 days (control animals) to 30 days (P <.05); pravastatin (median survival, 115 days) had no statistically significant effect. We conclude that lovastatin, but not pravastatin, at a daily dose of 10 mg per kilogram of body weight significantly increases the mortality of cardiomyopathic hamsters. This effect may be the result of inhibition of myocardial ubiquinone supply.     

Influence of high cholesterol feeding on the pattern and progression of experimental cerebral ischemia.

The aim of our research was to study if cholesterol feeding might affect the ischemic changes in the vessels surrounding infarction foci in Sephadex G-75-induced cerebral ischemia model (SG-75). One hundred-twenty-four rabbits were divided as follows: group I was given standard food for 5 weeks; group II: as group I and then injected with SG-75; group III: standard food plus 1% cholesterol for 5 weeks; and group IV: as group III and then injected with SG-75. Rabbits were sacrificed 3 h, 6 h and 2, 5 and 7 days after ischemia had occurred. Vessels surrounding infarction foci (SIF) were identified by using a 6% carbon perfusion. Samples were examined by light microscopy and transmission electron microscopy (TEM). The occurrence of hemorrhagic infarction (HI) showed a clear time/course increase in group II whereas a decrease after 2 days in group IV was observed. The rate of HI was 40% and 20% in group II and IV, respectively. SIF vessels showed red blood cells leakage in group II, whereas multiple platelet thrombi appeared in group IV. This phenomenon caused a more extensive ischemic damage, when compared to group II. By making use of a widely employed model of high cholesterol diet and of a more physiological model of cerebral ischemia devised by us, we have provided the evidence that the hypercholesterolemia-induced changes in the SIF vessels strongly affect the pattern and progression of cerebral ischemia.     

L-arginine normalizes endothelial function in cerebral vessels from hypercholesterolemic rabbits.

We hypothesized that normal vascular reactivity could be restored in vessels from hypercholesterolemic animals by exposing them to L-arginine, the precursor of endothelium-derived relaxing factor (EDRF). Basilar arteries were harvested from New Zealand white rabbits fed normal chow or that supplemented with 2% cholesterol for 10 wk. Vessels were cannulated for perfusion at physiologic pressure. Changes in vessel diameter were monitored by videomicroscopy. In comparison to normal vessels, those from hypercholesterolemic animals vasoconstricted more to KCl, endothelin (E), and 5-hydroxytryptamine (5-HT). Conversely, vasodilation to acetylcholine (ACh) (but not that to verapamil) was significantly impaired in the hypercholesterolemic animals. In vitro administration of L-arginine (3 mM) for 45 min normalized vasodilation to ACh and vasoconstriction to E, 5-HT, and KCl in the isolated vessels from hypercholesterolemic animals. This effect was stereospecific, since D-arginine had no effect. To conclude, these data confirm that hypercholesterolemia attenuates endothelium-derived relaxation, and enhances the sensitivity of these vessels to vasoconstrictors. In vitro administration of L-arginine normalized vascular reactivity of isolated vessels from hypercholesterolemic animals. Thus, hypercholesterolemia induces a reversible endothelial dysfunction that may be corrected by supplying the precursor of EDRF, L-arginine.