吡格列酮对高脂饮食兔主动脉血管内皮细胞黏附分子-1表达的影响

目的探讨吡格列酮对高脂饮食下兔主动脉血管内皮细胞黏附分子(VCAM)-1表达的影响。方法设立正常饮食、高脂饮食及高脂饮食加吡格列酮干预3组,通过比较主动脉病理形态学改变、血脂的变化、VCAM-1分子的表达进行研究,采用苏木素-伊红染色用于主动脉病理形态学观察,采用免疫组织化学检测兔主动脉上VCAM-1的表达。结果吡格列酮能减轻高脂饮食所致的内膜增厚和平滑肌增生。吡格列酮还能明显升高高密度脂蛋白胆固醇(HDL),对总胆固醇(TC)、低密度脂蛋白胆固醇(LDL)、甘油三酯(TG)无明显影响。高脂饮食刺激兔主动脉VCAM-1的表达增加,吡格列酮能显著减轻这种作用(0.78±0.16vs0.42±0.11,P<0.01)。结论吡格列酮能减轻高脂饮食兔主动脉VCAM-1的表达,其作用的机制可能与其干扰核转录因子有关。     

Role of Ox-LDL/LOX-1/NF-κB signaling pathway in regulation of atherosclerotic plaque growth by testosterone in male rabbits

ObjectiveThe purpose of our study is to investigate the role of oxidized low density lipoprotein (Ox-LDL)/lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1)/nuclear factor-κB (NF-κB) signaling pathway in the regulation of atherosclerotic plaque growth by testosterone in male atherosclerotic rabbits.MethodsThe male rabbit model was prepared by castration and feeding cholesterol-rich diet. Pathological sections of thoracic aorta were performed hematoxylin-eosin staining to observe aortic morphological changes. Total serum testosterone was measured with chemical luminescent method. Serum Ox-LDL, soluble intercellular adhesion molecule-1 (sICAM-1) and matrix metalloproteinases-2 (MMP2) were assayed using ELISA kit following the manufacturer's instructions. Serum tumor necrosis factor α (TNFα) and interleukin-6 (IL₆) were assayed using radioimmunoassay. Expressions of LOX-1 of thoracic aorta were measured by RT-PCR, immunohistochemistry and Western blot methods respectively.ResultsThere was no significant difference in Ox-LDL level between all groups. The LOX-1 mRNA and protein expression of thoracic aorta were significantly higher in the castrated rabbits as compared with the sham-operated ones, and testosterone replacement could reduce the mRNA and protein expression of LOX-1 of thoracic aorta in the castrated rabbits. PIA reduced artery intima thickness and plaque area in castrated rabbits, which was further enhanced by testosterone replacement. PDTC reduced artery intima thickness and plaque area in castrated rabbits, which couldn't be enhanced by testosterone replacement.ConclusionsOur study demonstrates that testosterone can regulate atherosclerotic plaque progression, affect expression of LOX-1 and NF-κB in thoracic aorta and play a role in atherosclerotic plaque growth via NF-κB rather than Ox-LDL or LOX-1 in male rabbits.     

Rho kinase inhibitor fasudil mitigates high-cholesterol diet-induced hypercholesterolemia and vascular damage

The current study was designed to investigate the potential beneficial therapeutic outcome of Rho kinase inhibitor (fasudil) against hypercholesterolemia-induced myocardial and vascular injury in rabbits together with diet modification. Sixteen male rabbits were randomly divided into four groups: normal control group which received standard rabbit chow, hypercholesterolemic control group, and treated groups which received cholesterol-rich rabbit chow (1.5% cholesterol) for 8 weeks. Treated groups received either fasudil (100 mg/kg/day) or rosuvastatin (2.5 mg/kg/day) starting from the ninth week for further 4 weeks with interruption of the cholesterol-rich chow. Biochemical assessment of serum cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and myocardial oxidative/antioxidant biomarkers malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH), besides biochemical assessment of serum nitric oxide (NO), creatine kinase (CK), and lactate dehydrogenase (LDH) activities and serum total antioxidant capacity (TAC), was conducted. Serum vascular cell adhesion molecule 1 (VCAM-1) and serum Rho-associated protein kinase 1 (ROCK-1) were also evaluated along with histopathological examination of aorta specimens. Fasudil administration significantly decreased serum cholesterol, triglyceride (TG), and LDL and significantly increased serum HDL, with concomitant decrease in serum CK and LDH activities, NO, and restoration of serum TAC. Myocardial MDA significantly declined; SOD activity and GSH contents were restored. Serum ROCK-1 and VCAM-1 levels significantly declined as well. Vascular improvement was confirmed with histopathological examination, which revealed normal aortic intema with the absence of atheromas. Fasudil has promising anti-atherogenic activity mediated primarily via alleviation of hypercholesterolemia-induced oxidative stress and modulation of inflammatory response.

     

Research and development of pravastatin]

The attempts to find a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the rate limiting step of cholesterol biosynthesis were started from 1971. The first potent inhibitor, ML-236B (compactin), was found from the culture broth of Penicillium citrinum. Among many derivatives of ML-236B, pravastatin sodium (hereafter refer to pravastatin) was finally selected because of its potency and tissue selectivity. Since pravastatin has a hydroxyl group at 6 beta position in the skeleton of decaline of ML-236B, the microbial hydroxylation was adopted for the production of pravastatin. Streptomyces carbophilus was finally chosen as a potent converter with the formation of a lesser amount of by-products. For the sake of industrial production of pravastatin, many devices and improvements were performed for selecting high potent strains and for culturing conditions both with ML-236B and pravastatin. Pravastatin strongly inhibited the sterol synthesis in freshly isolated rat hepatocytes, but only weakly inhibited in the cells from nonhepatic tissues. This selective inhibition of pravastatin in sterol synthesis was further confirmed by ex vivo and in vivo experiments by using rats and mice. Pravastatin markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. Pravastatin showed the preventive effect on the development of coronary atherosclerosis and xanthoma in young WHHL rabbits in consequence of maintaining the serum cholesterol levels low. In the clinical trials, pravastatin significantly reduced serum cholesterol and low density lipoprotein cholesterol levels, whereas inversely increased high density lipoprotein cholesterol levels.     

阿托伐他汀减轻兔血管损伤后再狭窄机制的研究

目的观察阿托伐他汀对兔血管损伤后再狭窄的干预作用,探讨其与PKC、MMPs的关系。方法将40只健康日本大耳兔,♂,分为5组,每组8只,模型组及阿托伐他汀高(2 mg.d 1)、中(1 mg.d 1)、低(0.5 mg.d 1)剂量组均行髂动脉二次损伤造模术,假手术组仅结扎股动脉。一月后取靶血管切片HE染色,图像分析仪检测各组内膜面积、中膜面积、管腔面积、内膜增生指数及狭窄指数;免疫组化检测各靶血管MMP-2、MMP-9、PKC表达。结果经髂动脉二次损伤能成功建立血管成形术后再狭窄模型。与模型组相比,随剂量升高,阿托伐他汀各组内膜面积、中膜面积、膜增生指数及狭窄指数显著降低,管腔面积显著增加(P<0.01),与此同时,靶血管MMP-2、MMP-9及PKC表达均显著降低,差异有统计学意义(P<0.01)。结论阿托伐他汀能显著减轻兔血管成形术后再狭窄,其机制可能与通过PKC途径抑制靶血管MMPs表达有关。     

Comparison of vasculoprotective effects of benidipine and losartan in a rat model of metabolic syndrome

Although antihypertensive drugs confer improvement in endothelial dysfunction and protection from atherogenesis in hypertension, different classes of antihypertensive drugs may elicit different degrees of vasculoprotective effects. We have investigated the effects of a long-acting calcium antagonist, benidipine, and an angiotensin AT(1) receptor antagonist, losartan, on the vascular damage observed in OLETF rats, an animal model of metabolic syndrome. At 34 weeks of age, OLETF rats were treated with either benidipine (3 mg/kg/day, per os) or losartan (25 mg/kg/day, per os) for 8 weeks. The extent of blood pressure reduction, restoration endothelium-dependent aortic relaxation, and elevation of serum nitrite/nitrate concentration did not differ significantly between benidipine- and losartan-treated OLETF rats. Benidipine and losartan also reduced the aortic expression of transforming growth factor-beta1 mRNA and thickening of the vascular wall to a similar extent. Increased cardiac fibrosis was also inhibited by both benidipine and losartan. These data suggest that, when used in an antihypertensive dose, benidipine is as effective as losartan in restoring vascular endothelial function and in suppressing of cardiovascular remodeling in an animal model of metabolic syndrome.     

PPARγ激活剂罗格列酮对兔动脉粥样硬化斑块消退的影响

过氧化物酶体增殖激活受体γ(PPARγ)是一个核受体,在血管壁内皮细胞、巨噬细胞/泡沫细胞及血管平滑肌细胞都有较高表达。PPARγ通过对这些细胞的调控作用,还影响着炎性因子的水平,在动脉粥样硬化(AS)疾病中发挥着重要的作用[1]。本实验通过高选择性PPARγ激动剂罗格列酮对高胆     

Effects of pravastatin sodium alone and in combination with cholestyramine on hepatic, intestinal and adrenal low density lipoprotein receptors in homozygous Watanabe heritable hyperlipidemic rabbits.

Pravastatin sodium (pravastatin), a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was administered alone (50 mg/kg) or in combination with cholestyramine, a bile acid sequestrant resin, at the level of 2% in the diet to homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits for 4 weeks. The low density lipoprotein (LDL)-cholesterol levels were reduced by 29% and 56% with pravastatin alone and the combination treatment, respectively. Hepatic LDL receptor activity was increased by 11.2- and 13.9-fold with pravastatin alone and the combination treatment, respectively. The LDL receptor activity in the untreated homozygous WHHL rabbits was only 2.5% of that in the normal rabbits. mRNA for the LDL receptor in the liver was also increased by 2.1- and 3.4-fold with pravastatin alone and the combination treatment, respectively. On the other hand, mRNA for the LDL receptor in the adrenal gland was not affected by pravastatin and the combination treatment, whereas the mRNA in the intestine was increased in both groups. These results suggest the following: 1) the induction of hepatic LDL receptor activity by the treatment of pravastatin alone or in combination with cholestyramine is the main cause of the reduction of serum cholesterol levels by these treatments even in LDL receptor-deficient animals. 2) The induction of the mRNA for the LDL receptor in the liver and intestine, but not that in the adrenal gland, might be a reflection of the tissue-selective inhibition of cholesterol synthesis by pravastatin.     

Blockade of T-type voltage-dependent Ca2+ channels by benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone production in human adrenocortical cell line NCI-H295R

Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for treatment of hypertension and angina. Benidipine exerts pleiotropic pharmacological features, such as renoprotective and cardioprotective effects. In pathophysiological conditions, the antidiuretic hormone aldosterone causes development of renal and cardiovascular diseases. In adrenal glomerulosa cells, aldosterone is produced in response to extracellular potassium, which is mainly mediated by T-type voltage-dependent Ca2+ channels. More recently, it has been demonstrated that benidipine inhibits T-type Ca2+ channels in addition to L-type Ca2+ channels. Therefore, effect of calcium channel blockers, including benidipine, on aldosterone production and T-type Ca2+ channels using human adrenocortical cell line NCI-H295R was investigated. Benidipine efficiently inhibited KCl-induced aldosterone production at low concentration (3 and 10 nM), with inhibitory activity more potent than other calcium channel blockers. Patch clamp analysis indicated that benidipine concentration-dependently inhibited T-type Ca2+ currents at 10, 100 and 1000 nM. As for examined calcium channel blockers, inhibitory activity for T-type Ca2+ currents was well correlated with aldosterone production. L-type specific calcium channel blockers calciseptine and nifedipine showed no effect in both assays. These results indicate that inhibition of T-type Ca2+ channels is responsible for inhibition of aldosterone production in NCI-H295R cells. Benidipine efficiently inhibited KCl-induced upregulation of 11-beta-hydroxylase mRNA and aldosterone synthase mRNA as well as KCl-induced Ca2+ influx, indicating it as the most likely inhibition mechanism. Benidipine partially inhibited angiotensin II-induced aldosterone production, plus showed additive effects when used in combination with the angiotensin II type I receptor blocker valsartan. Benidipine also partially inhibited angiotensin II-induced upregulation of the above mRNAs and Ca2+ influx inhibitory activities of benidipine for aldosterone production. T-type Ca2+ channels may contribute to additional benefits of this drug for treating renal and cardiovascular diseases, beyond its primary anti-hypertensive effects from blocking L-type Ca2+ channels.     

Protection by scoparone against the alterations of plasma lipoproteins, vascular morphology and vascular reactivity in hyperlipidaemic diabetic rabbit.

1. The in vivo pharmacological effects of scoparone (6,7-dimethoxycoumarin) in a hyperlipidaemic diabetic rabbit model were investigated. 2. Three groups of rabbits were studied: (1) normal, (2) hyperlipidaemic and diabetic-untreated and (3) hyperlipidaemic and diabetic-scoparone treated. The hyperlipidaemic diabetic rabbits were fed with 1% cholesterol and treated with alloxan, a diabetogenic agent. The plasma levels of total cholesterol, total triglyceride, very low-density lipoprotein (VLDL) cholesterol, low density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were markedly increased as soon as the rabbit became diabetic at the second week. Scoparone-treatment (5 mg kg-1 day-1, s.c.) significantly reduced the plasma lipid and lipoprotein cholesterol levels of the hyperlipidaemic diabetic rabbit to 73.3% of total cholesterol, 48.3% of total triglyceride, 66.0% of VLDL cholesterol, 55.7% of LDL cholesterol and 79.5% of HDL cholesterol. 3. Six weeks after cholesterol-feeding, the aortic arch and thoracic aorta were dissected for morphological and functional studies. In vascular rings from the untreated hyperlipidaemic diabetic rabbit, there was intimal thickening with accumulation of fatty streaks, foam cells and migration of smooth muscle cells to the intima. In the rabbits treated with scoparone, there were fewer pathological morphology changes found in vascular segments than in the untreated hyperlipidaemic diabetic rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)     

Benidipine, a dihydropyridine-calcium channel blocker, inhibits lysophosphatidylcholine-induced endothelial injury via stimulation of nitric oxide release.

Benidipine hydrochloride (benidipine), which is a long-lasting dihydropyridine calcium channel blocker, exerts antihypertensive action via inhibition of Ca(2+) influx through L-type voltage-dependent calcium channels. In addition, benidipine is shown to restore endothelial function. However, the mechanisms whereby benidipine has protective effects on endothelium are poorly defined. Nitric oxide (NO), which is produced by endothelial NO synthase (eNOS), plays important roles in endothelial function. In this study, we examined effects of benidipine on NO production from human umbilical vein endothelial cells. Benidipine (0.3-10 microM) augmented eNOS expression and total eNOS enzymatic activities. Benidipine also promoted the production of NO and the accumulation of cGMP, a second messenger of NO. Lysophosphatidylcholine (lysoPC), a component of oxidized low-density lipoproteins, induced caspase-3 activation followed by apoptosis of endothelial cells. Benidipine (0.3-10 microM) prevented lysoPC-induced caspase-3 activation, which was canceled by Nomega-nitro-L-arginine-methyl ester (L-NAME) (250-2500 microM), an inhibitor of NOS. Moreover, diethylenetetraamine NONOate (30-100 microM), a NO donor, inhibited the caspase-3 activation. These results suggested that the increase in NO production by benidipine might be involved in the inhibition of caspase induction. The direct enhancement of endothelial NO release by benidipine may be in part responsible for amelioration of endothelial dysfunction.     

脂质异常家兔抗氧化能力与血管细胞黏附因子-1的变化以及血脂康对其影响

目的：观察脂质异常家兔抗氧化能力及血管细胞黏附因子-1（VCAM-1）的变化以及血脂康的干预。方法：采用高脂饲料喂养法复制血脂异常家兔模型,检测各组家兔血清胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL—C）、丙二醛（MDA）、超氧化物歧化酶（SOD）水平,并用酶联免疫吸附（ELISA）法测定家兔血清VCAM-1的含量。结果：高脂血症组家兔血清TC、TG、LDL—C、MDA、VCAM-1水平升高,SOD水平降低,与之相比,血脂康组家兔血清TC、TG、LDL—C、MDA水平降低（P〈0．05）,家兔血清中VCAM-1的含量降低（P〈0．01）,SOD水平明显升高（P〈0．05）。结论：脂质异常可致家兔抗氧化能力降低,引起脂质过氧化,损伤内皮细胞,导致VCAM-1含量升高。血脂康可改善脂质异常家兔血清抗氧化能力、清除自由基、抗脂质过氧化损伤并下调VCAM-1的表达,提示其具有保护内皮细胞功能的作用。     

Prominent lectin-like oxidized low density lipoprotein (LDL) receptor-1 (LOX-1) expression in atherosclerotic lesions is associated with tissue factor expression and apoptosis in hypercholesterolemic rabbits

BACKGROUND: Despite increasing in vitro evidence that lectin-like oxidized low density lipoprotein (LDL) receptor-1 (LOX-1), a cell-surface receptor for oxidized LDL, is implicated in the atherogenesis and thrombus formation, its in vivo participation to the atherosclerotic plaque destabilization, rupture and thrombus formation remains unclear. Here, we compared the in vivo expression of LOX-1, with tissue factor (TF) expression and cell apoptosis, in atherosclerotic lesions of myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. METHODS AND RESULTS: We prepared sixty series of cross sections in the aortic arch and the thoracic aorta from four WHHLMI rabbits. LOX-1 and TF expression, as well as apoptotic events were determined by immunohistochemical staining and TUNEL methods, respectively. LOX-1 expression was mainly observed in the macrophage-rich lipid areas of vulnerable plaque-like atheromatous lesions where TF expression and apoptotic events were prominent. LOX-1 expression was positively correlated with TF expression (r=0.53, p<0.0001), apoptotic events (r=0.52, p<0.0001) and morphological vulnerability (r=0.63, p<0.0001). CONCLUSIONS: LOX-1 expression appears to be closely associated with TF expression, apoptotic events and the morphological vulnerability, suggesting the in vivo involvement of LOX-1 in the destabilization and rupture of atherosclerotic lesions and the subsequent thrombus formation. The present findings in hypercholesterolemic rabbits should help advance our understanding of the pathophysiology of atherosclerosis.     

Effect of atorvastatin on tumor necrosis factor alpha serum concentration and mRNA expression of adipose in hypercholesterolemic rabbits

Tumor necrosis factor alpha (TNFalpha) is an inflammatory cytokine involved in atherogenesis. Adipose tissue is an important source of endogenous TNFalpha production. The aim of this study was to evaluate the effect of atorvastatin on TNFalpha serum concentration and mRNA expressions of subcutaneous adipose in hypercholesterolemic rabbits. Sixteen rabbits fed with a high-cholesterol diet for 8 weeks were randomly divided into 2 groups: (1) the high-cholesterol group (n=8) was maintained on a high-cholesterol diet for 6 weeks; (2) the atorvastatin group (n=8) had the same high-cholesterol diet plus atorvastatin (2.5 mg/kg/d) for 6 weeks. A control group (n=5) was fed with a normal diet for 14 weeks. Subcutaneous adipose was collected for mRNA analysis. Additionally, the direct effect of atorvastatin on TNFalpha release and mRNA expression was assayed in primary rabbit adipocytes. TNFalpha levels in serum and adipocyte culture supernatant were measured by ELISA. RT-PCR was used to evaluate TNFalpha mRNA expression in adipose and adipocytes. Serum TNFalpha concentration was significantly associated with serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) (both P<0.01). Compared with the control group, rabbits fed with a high-cholesterol diet showed higher levels of TNFalpha serum concentration and mRNA expression of adipose, both of which were significantly reduced by atorvastatin treatment (both P<0.05). TNFalpha mRNA expressions of adipose were significantly correlated with circulating TNFalpha levels among the 3 groups (r=0.51, P<0.05). Atorvastatin dose-dependently inhibited lipopolysaccharide (LPS)-induced TNFalpha secretion and mRNA expression in cultured adipocytes. In conclusion, atorvastatin can directly inhibit TNFalpha expression and secretion in adipocytes. Atorvastatin reduced TNFalpha serum concentration in hypercholesterolemic rabbits, which might be because of its cholesterol-lowering effect and direct inhibition of TNFalpha expression in adipose.     

Inhibition of cholesterol synthesis causes both hypercholesterolemia and hypocholesterolemia in hamsters

Effects of FR194738 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-methyl-2-(3-thienylmethoxy)propyloxy]benzylamine hydrochloride), a squalene epoxidase inhibitor, on lipid metabolism were compared with those of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in hamsters. Drugs were given for 10 d either as a diet mixture or as a bolus oral gavage, and similar results were obtained with each type of administration. FR194738 (0.01-0.32% as a diet mixture; 10-100 mg/kg as an oral gavage) dose-dependently decreased serum total cholesterol, non high density lipoprotein (HDL) cholesterol, HDL cholesterol and triglyceride levels, and the changes in serum parameters were similar. Pravastatin (0.01-0.32% as a diet mixture; 1-100 mg/kg as an oral gavage) increased serum cholesterol levels, and dose-dependently decreased serum triglyceride levels. Although oral gavage of FR194738 at 32 mg/kg and pravastatin at 3.2 and 10 mg/kg increased hepatic HMG-CoA reductase activity, the degree of the changes was far greater with the latter than the former drug. FR194738 slightly increased hepatic cholesterol content at 32 mg/kg, whereas pravastatin dose-dependently increased hepatic cholesterol content until it leveled off at 32 and 100 mg/kg. It is concluded that inhibition of squalene epoxidase and HMG-CoA reductase triggers both hypercholesterolemic (hepatic cholesterol synthesis) and hypocholesterolemic (hepatic cholesterol uptake) mechanisms. FR194738 appears to induce a greater enhancement of the latter rather than the former, whereas pravastatin has a greater effect on the former.     

Fundamental studies on physiological and pharmacological actions of L-ascorbate 2-sulfate. V. On the hypolipidemic and antiatherosclerotic effects of L-ascorbate 2-sulfate in rabbits

Effects of L-ascorbate 2-sulfate (AAS) on lipid metabolism and on pathological changes of aorta and visceral organs were investigated in cholesterol fed rabbits, with ascorbic acid (AA) and clofibrate (CPIB) as reference compounds. Administration of AAS (300 and 150 mg/kg) inhibited an increase in the levels of serum total cholesterol, free cholesterol, triglycerides and phospholipids caused by cholesterol feeding. A high dose of AAS prevented an increase of liver weight. An increase in the level of liver cholesterol was inhibited by a high dose of AAS. Both doses of AAS effectively prevented an accumulation of cholesterol in the aorta. The area rate of atheromatous plaque in aorta was less in specimens from both groups of AAS than in those from control I. Pathological changes in intima and media of aorta were milder in specimens from both groups of AAS. Developed of patholoigcal changes in arteries of various organs were prevented with both doses of AAS.     

Pravastatin attenuates left ventricular remodeling and diastolic dysfunction in angiotensin II-induced hypertensive mice

BACKGROUND: A substantial proportion of patients with heart failure have a normal ejection fraction and diastolic dysfunction. However, there are few data available to guide the therapy of these patients. The effects of statins on cardiac remodeling are well documented in animal models and it is reported that statin therapy revealed a survival benefit in patients with diastolic heart failure (DHF). However, the exact mechanisms of statins possibly explaining the decreased cardiovascular morbidity and mortality in patients with DHF have not been elucidated. METHODS: We used 8-week-old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or pravastatin in daily doses, which did not lower the serum cholesterol levels and blood pressure. RESULTS: Pravastatin improved diastolic dysfunction in angiotensin II-induced hypertensive mice, which was associated with the amelioration of left ventricular hypertrophy and remodeling. However, statin treatment showed no effect on the increased systolic blood pressure or cholesterol levels by angiotensin II infusion. The cardioprotective effects of pravastatin were closely associated with the downregulation of collagen I, transforming growth factor-beta, matrix metalloproteinases-2 and -3, atrial natriuretic factor, interleukin-6, tumor necrosis factor-alpha, ROCK1 gene expression, and the upregulation of endothelial nitric oxide synthase gene expression. CONCLUSIONS: The beneficial effects of pravastatin on DHF and structural remodeling are through cholesterol- independent mechanism of statins or "pleiotropic" effects of statins involving improving or restoring endothelial function and decreasing vascular inflammation. These findings suggest the potential involvement of ROCK1. Thus, treatment with pravastatin might be beneficial in patients with DHF.     

Arteriolar and venular vasodilating properties of benidipine hydrochloride, a 1,4-dihydropyridine Ca2+ antagonist with long-lasting action, assessed in rat mesenteric microcirculation

To obtain direct and visible evidence of the arteriolar vasodilating action in vivo of benidipine hydrochloride, a long-lasting and light-resistant Ca2+ antagonist of the 1,4-dihydropyridine type, we continuously recorded changes in the diameter of mesenteric arterioles (10-40 microm) and venules (20-40 microm) in anesthetized agent-injected Wistar rats by means of digital image processing combined with videomicroscopy. Benidipine injected intravenously brought about a depressor response, and this response persisted much longer than that induced by nifedipine. Benidipine produced a dose-dependent arteriolar vasodilation and a decrease in the blood-flow velocity. It also relaxed the venules during the depressor response, which relaxation was more prominent 1-2 h after the administration. In pithed rats, both pressor response and arteriolar constriction induced by norepinephrine were prevented by benidipine. Benidipine also inhibited adenosine diphosphate (ADP)-induced interruption of arteriolar blood flow. These results suggest that benidipine produced vasodilation in vivo at both the arteriolar and venular levels. The ability of benidipine to prevent microcirculatory disturbance and to produce arteriolar and venular vasodilation seem to account for its long-lasting Ca2+-antagonistic antihypertensive action.