联合应用氨氯地平与阿托伐他汀对自发性高血压大鼠动脉弹性功能及主动脉重构的影响
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摘要
目的:动脉弹性功能减退、僵硬度增加是高血压患者未来心血管病事件发生的独立危险因素,改善动脉弹性功能是目前抗高血压治疗的靶标之一。作为一线降压药物,氨氯地平已被证实不仅具有出色的平稳降压效果,而且还能改善血管内皮功能,恢复内皮依赖性的血管舒张作用,从而抑制动脉粥样硬化的形成,甚至逆转已经形成的动脉粥样硬化。ASCOT-BPLA的结果表明,以氨氯地平为基础的治疗方案显著优于以阿替洛尔为基础的治疗方案。CAFé研究结果表明氨氯地平为基础治疗方案对终点事件的益处与中心动脉压的改善有关。目前研究发现他汀类药物除了能够降低血胆固醇水平,稳定和缩小动脉粥样硬化斑块,还可直接激活血管内皮细胞中的一氧化氮合酶(eNOS),引起一氧化氮(NO)的迅速释放,减少氧自由基产生,抑制内皮素的生成,抑制平滑肌细胞的增殖和移行,延缓或逆转粥样硬化病变,可能通过强化降脂及多效性非降脂效应降低动脉僵硬度。但在氨氯地平降压治疗的基础上,加用他汀类药物能否进一步改善动脉弹性、降低动脉僵硬度却并不清楚。本研究选择自发性高血压大鼠(SHR)为研究对象,观察氨氯地平、阿托伐他汀单独使用及联合应用对脉搏波速度(Pulse Wave Velocity,PWV)、增强指数(Augmentation Index,AI)及主动脉重构的影响,探讨联合应用氨氯地平及阿托伐他汀是否对动脉弹性功能及主动脉重构有更佳的改善作用。
方法:雄性自发高血压大鼠(SHR)40只随机分为空白对照组(n=10)、氨氯地平组[n=10,氨氯地平10 mg/(kg·d)]、阿托伐他汀组[n=10,阿托伐他汀10 mg/(kg·d)]、氨氯地平与阿托伐他汀联合用药组[n=10 ,氨氯地平[10 mg/(kg·d)],阿托伐他汀(10 mg/(kg·d)],另设10只正常血压的WKY大鼠为标准对照组。对各组灌胃12周,空白对照组及标准对照组以等量的蒸馏水灌胃。12周后检测主动脉脉搏波传导速度(PWV)与增强指数(AI),光镜下测量主动脉中膜厚度、血管内径及中膜厚度与内径比值(MT/LR),Masson三色染色分析胶原纤维含量,碱解法测定羟脯氨酸含量,Tunnel法检测平滑肌细胞(VSMC)凋亡率。
结果:1.治疗12周后,SHR各组间体重及血脂水平无显著差异。2.测量鼠尾血压发现,给药前SHR各组大鼠尾动脉血压无明显差异,且均显著高于WKY正常对照组(P<0.01)。给药6、8、10、12周时,阿托伐他汀组和SHR对照组相比,SBP略有下降,但无明显统计学差异( P >0.05)。给药2、4、6、8、10、12周时,氨氯地平组及联合用药组的SBP均明显低于SHR对照组(均P <0.01)。给药4、6、8、10、12周时联合用药组较氨氯地平组SBP略有下降,但无明显统计学差异(P>0.05)。3.在有创血压的测量中,与WKY组相比,各组SHR大鼠升主动脉收缩压、舒张压及脉压均增高;但与SHR空白对照组相比,氨氯地平组、阿托伐他汀组及联合用药组升主动脉收缩压分别下降(43.8±5.5)mmHg(P<0.05),(4.5±5.5)mmHg(P=0.92)及(50.8±5.5)mmHg(P<0.05);舒张压分别下降(31.8±4.1)mmHg (P<0.05),(1.9±4.1)mmHg(P=0.64)及(35.2±4.1)mmHg(P<0.05);脉压分别下降(12.8±3.2)mmHg(P<0.05),(6.9±3.2)mmHg(P<0.05)及(15.0±3.2)mmHg(P<0.05)。与氨氯地平组相比,联合用药组升主动脉收缩压、舒张压及脉压均略有下降但无统计学差异(P=0.49)。各组大鼠股动脉收缩压、舒张压及脉压均表现出与主动脉血压相一致的变化趋势。SHR大鼠对照组及各给药组的心率明显高于WKY大鼠(均P<0.05),但SHR大鼠各组之间心率未见明显差别(P>0.05)。4.各组大鼠动脉弹性功能指标的改变结果示:与WKY大鼠比,各组SHR大鼠PWV均显著增快(P<0.05)。与SHR空白对照组相比,氨氯地平组及联合用药组PWV显著减慢(P<0.05),但阿托伐他汀组PWV无明显改变(P>0.05)。与氨氯地平组相比,联合用药组PWV有所下降,但无统计学差异(P>0.05)。与WKY大鼠相比,各组SHR大鼠AI均明显增大(P<0.05)。氨氯地平组、阿托伐他汀组、联合用药组大鼠AI均较SHR空白对照组大鼠明显下降(P<0.05),且与氨氯地平组相比,联合用药组AI进一步下降(P<0.05)。5.大血管形态学测定结果显示,与WKY大鼠相比,治疗结束时SHR各组大鼠胸主动脉内径(LR)无明显改变(P>0.05),但各组SHR大鼠胸主动脉中膜厚度(MT)及MT/ LR明显增加(P<0.05)。与SHR空白对照组相比,氨氯地平组、阿托伐他汀组及联合治疗组MT及MT/LR显著降低(P<0.05),联合治疗组的MT及MT/LR进一步减小(P<0.05)。6.各组大鼠主动脉胶原含量的改变,结果示:与WKY大鼠相比,SHR各组血管壁胶原含量均明显增加(P<0.05)。与SHR空白对照组相比,氨氯地平组、阿托伐他汀组胶原含量明显减少,其中胶原面积百分比分别为(32.7±2.5)%及(36.5±2.4)%,而联合用药组血管壁胶原纤维面积百分比进一步减少至(27.2±2.6)%(P<0.05)。各组大鼠主动脉羟脯氨酸含量表现出与胶原面积百分比相似的变化趋势。7.主动脉平滑肌细胞凋亡率测定结果显示,WKY组平滑肌细胞凋亡极少;与WKY大鼠相比,SHR各组大鼠血管平滑肌细胞凋亡率均显著增加。在SHR大鼠中,氨氯地平组、阿托伐他汀组及联合治疗组组均表现出较SHR空白对照组更明显的促进平滑肌细胞凋亡的作用;联合治疗组较阿托伐他汀组或氨氯地平单一用药促进凋亡作用进一步加强(P<0.05)。
结论:1.联合应用氨氯地平与阿托伐他汀可较单用氨氯地平进一步改善高血压大鼠主动脉弹性。2.联合应用两药所发挥的益处可能与降低主动脉胶原纤维含量、改善主动脉重构有关,且这种有益作用是不依赖阿托伐他汀的降脂作用的。
Objective To investigate the effects of combined administration of amlodipine and atrovastatin on aortic elasticity and remodeling in spontaneously hypertensive rats. Methods 40 male spontaneous hypertensive rats (SHR) were randomly allocated into vehicle group (n=10), amlodipine-treated group [n=10, amlodipine 10 mg/(kg·d)], atorvastatin-treated group [n=10, atorvastatin 10 mg/(kg·d)], and combination group [n=10, atorvastatin 10 mg/(kg·d) and amlodipine 10 mg/(kg·d)]. Another 10 normotensive wistar-kyoto (WKY) rats were served as control group. Both the vehicle group and WKY group were intragastrically administrated with the same amount of distilled water for 12 weeks. Arterial pulse wave velocity (PWV), aortic augmentation index (AI), aortic medium thickness (MT), luminal radius (LR), and the ratio of MT/LR were measured 12 weeks after treatment. The content of collagen of aortic segment was evaluated by Masson trichrome staining. The content of hydroxyproline was measured by alkaline hydrolysis. The apoptosis rate of vessel smooth muscular cells in every group was analyzed by TUNEL method. Result After 12 weeks treatment, PWV and AI, aortic MT, MT/LR, and contents of aortic collagen in each SHR groups was significantly higher than those in WKY group (P<0.05). There were no significant differences among the level of lipid in each SHR groups. Although the blood pressure of the amlodipine-treated group and combination group decreased, it showed no significant difference between them. As compared with the vehicle group, aortic AI, aortic MT, MT/LR and contents of collagen in amlodipine-treated group, atorvastatin-treated group and combination group significantly decreased, but the apoptosis rate of smooth muscular cells increased. In amlodipine-treated group and combination group, PWV significantly decreased compared with the vehicle group. Compared with the amlodipine-treated group, the aortic AI, MT, MT/LR, and contents of collagen in the combination group significantly decreased, the apoptosis rate of smooth muscular cells increased. Conclusion Compared with amlodipine, combined application of amlodipine and atrovastatin improves the elastic properties of the aorta. The underlying mechanism may be associated with the decrease of aortic collagen content and improvement of aortic remodeling. These beneficial effects seem to be independent of lipid lowering effect of atorvastatin.
方法:雄性自发高血压大鼠(SHR)40只随机分为空白对照组(n=10)、氨氯地平组[n=10,氨氯地平10 mg/(kg·d)]、阿托伐他汀组[n=10,阿托伐他汀10 mg/(kg·d)]、氨氯地平与阿托伐他汀联合用药组[n=10 ,氨氯地平[10 mg/(kg·d)],阿托伐他汀(10 mg/(kg·d)],另设10只正常血压的WKY大鼠为标准对照组。对各组灌胃12周,空白对照组及标准对照组以等量的蒸馏水灌胃。12周后检测主动脉脉搏波传导速度(PWV)与增强指数(AI),光镜下测量主动脉中膜厚度、血管内径及中膜厚度与内径比值(MT/LR),Masson三色染色分析胶原纤维含量,碱解法测定羟脯氨酸含量,Tunnel法检测平滑肌细胞(VSMC)凋亡率。
结果:1.治疗12周后,SHR各组间体重及血脂水平无显著差异。2.测量鼠尾血压发现,给药前SHR各组大鼠尾动脉血压无明显差异,且均显著高于WKY正常对照组(P<0.01)。给药6、8、10、12周时,阿托伐他汀组和SHR对照组相比,SBP略有下降,但无明显统计学差异( P >0.05)。给药2、4、6、8、10、12周时,氨氯地平组及联合用药组的SBP均明显低于SHR对照组(均P <0.01)。给药4、6、8、10、12周时联合用药组较氨氯地平组SBP略有下降,但无明显统计学差异(P>0.05)。3.在有创血压的测量中,与WKY组相比,各组SHR大鼠升主动脉收缩压、舒张压及脉压均增高;但与SHR空白对照组相比,氨氯地平组、阿托伐他汀组及联合用药组升主动脉收缩压分别下降(43.8±5.5)mmHg(P<0.05),(4.5±5.5)mmHg(P=0.92)及(50.8±5.5)mmHg(P<0.05);舒张压分别下降(31.8±4.1)mmHg (P<0.05),(1.9±4.1)mmHg(P=0.64)及(35.2±4.1)mmHg(P<0.05);脉压分别下降(12.8±3.2)mmHg(P<0.05),(6.9±3.2)mmHg(P<0.05)及(15.0±3.2)mmHg(P<0.05)。与氨氯地平组相比,联合用药组升主动脉收缩压、舒张压及脉压均略有下降但无统计学差异(P=0.49)。各组大鼠股动脉收缩压、舒张压及脉压均表现出与主动脉血压相一致的变化趋势。SHR大鼠对照组及各给药组的心率明显高于WKY大鼠(均P<0.05),但SHR大鼠各组之间心率未见明显差别(P>0.05)。4.各组大鼠动脉弹性功能指标的改变结果示:与WKY大鼠比,各组SHR大鼠PWV均显著增快(P<0.05)。与SHR空白对照组相比,氨氯地平组及联合用药组PWV显著减慢(P<0.05),但阿托伐他汀组PWV无明显改变(P>0.05)。与氨氯地平组相比,联合用药组PWV有所下降,但无统计学差异(P>0.05)。与WKY大鼠相比,各组SHR大鼠AI均明显增大(P<0.05)。氨氯地平组、阿托伐他汀组、联合用药组大鼠AI均较SHR空白对照组大鼠明显下降(P<0.05),且与氨氯地平组相比,联合用药组AI进一步下降(P<0.05)。5.大血管形态学测定结果显示,与WKY大鼠相比,治疗结束时SHR各组大鼠胸主动脉内径(LR)无明显改变(P>0.05),但各组SHR大鼠胸主动脉中膜厚度(MT)及MT/ LR明显增加(P<0.05)。与SHR空白对照组相比,氨氯地平组、阿托伐他汀组及联合治疗组MT及MT/LR显著降低(P<0.05),联合治疗组的MT及MT/LR进一步减小(P<0.05)。6.各组大鼠主动脉胶原含量的改变,结果示:与WKY大鼠相比,SHR各组血管壁胶原含量均明显增加(P<0.05)。与SHR空白对照组相比,氨氯地平组、阿托伐他汀组胶原含量明显减少,其中胶原面积百分比分别为(32.7±2.5)%及(36.5±2.4)%,而联合用药组血管壁胶原纤维面积百分比进一步减少至(27.2±2.6)%(P<0.05)。各组大鼠主动脉羟脯氨酸含量表现出与胶原面积百分比相似的变化趋势。7.主动脉平滑肌细胞凋亡率测定结果显示,WKY组平滑肌细胞凋亡极少;与WKY大鼠相比,SHR各组大鼠血管平滑肌细胞凋亡率均显著增加。在SHR大鼠中,氨氯地平组、阿托伐他汀组及联合治疗组组均表现出较SHR空白对照组更明显的促进平滑肌细胞凋亡的作用;联合治疗组较阿托伐他汀组或氨氯地平单一用药促进凋亡作用进一步加强(P<0.05)。
结论:1.联合应用氨氯地平与阿托伐他汀可较单用氨氯地平进一步改善高血压大鼠主动脉弹性。2.联合应用两药所发挥的益处可能与降低主动脉胶原纤维含量、改善主动脉重构有关,且这种有益作用是不依赖阿托伐他汀的降脂作用的。
Objective To investigate the effects of combined administration of amlodipine and atrovastatin on aortic elasticity and remodeling in spontaneously hypertensive rats. Methods 40 male spontaneous hypertensive rats (SHR) were randomly allocated into vehicle group (n=10), amlodipine-treated group [n=10, amlodipine 10 mg/(kg·d)], atorvastatin-treated group [n=10, atorvastatin 10 mg/(kg·d)], and combination group [n=10, atorvastatin 10 mg/(kg·d) and amlodipine 10 mg/(kg·d)]. Another 10 normotensive wistar-kyoto (WKY) rats were served as control group. Both the vehicle group and WKY group were intragastrically administrated with the same amount of distilled water for 12 weeks. Arterial pulse wave velocity (PWV), aortic augmentation index (AI), aortic medium thickness (MT), luminal radius (LR), and the ratio of MT/LR were measured 12 weeks after treatment. The content of collagen of aortic segment was evaluated by Masson trichrome staining. The content of hydroxyproline was measured by alkaline hydrolysis. The apoptosis rate of vessel smooth muscular cells in every group was analyzed by TUNEL method. Result After 12 weeks treatment, PWV and AI, aortic MT, MT/LR, and contents of aortic collagen in each SHR groups was significantly higher than those in WKY group (P<0.05). There were no significant differences among the level of lipid in each SHR groups. Although the blood pressure of the amlodipine-treated group and combination group decreased, it showed no significant difference between them. As compared with the vehicle group, aortic AI, aortic MT, MT/LR and contents of collagen in amlodipine-treated group, atorvastatin-treated group and combination group significantly decreased, but the apoptosis rate of smooth muscular cells increased. In amlodipine-treated group and combination group, PWV significantly decreased compared with the vehicle group. Compared with the amlodipine-treated group, the aortic AI, MT, MT/LR, and contents of collagen in the combination group significantly decreased, the apoptosis rate of smooth muscular cells increased. Conclusion Compared with amlodipine, combined application of amlodipine and atrovastatin improves the elastic properties of the aorta. The underlying mechanism may be associated with the decrease of aortic collagen content and improvement of aortic remodeling. These beneficial effects seem to be independent of lipid lowering effect of atorvastatin.
引文
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5 Kinlay S, Schwartz GG, Olsson AG, et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation, 2003,108(13):1560-1566
6 Kleemann R, Princen HM, Emeis JJ, et al. Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: evidence for antiinflammatory effects of rosuvastatin. Circulation, 2003,108(11):1368-1374
7 Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med, 2005,352(1):20-28
8 Kaneyuki U, Ueda S, Yamagishi S, et al. Pitavastatin inhibits lysophosphatidic acid-induced proliferation and monocyte chemoattractant protein-1 expression in aortic smooth muscle cells by suppressing Rac-1-mediated reactive oxygen species generation. Vascul Pharmacol, 2007,46 (4):286-292
9 Lacut K, Oger E, Le Gal G, et al. Statins but not fibrates are associated with a reduced risk of venous thromboembolism: a hospital-based case-control study. Fundam Clin Pharmacol, 2004,18(4):477-482
10 Laufs U, Gertz K, Huang P, et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke,2000,31(10):2442-2449
11 Undas A, Brummel-Ziedins KE, Potaczek DP, et al. Atorvastatin and quinapril inhibit blood coagulation in patients with coronary artery disease following 28 days of therapy. J Thromb Haemost, 2006,4(11):2397-2404
12 Susic D, Varagic J, Ahn J, et al. Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models. J Am Coll Cardiol, 2003,42(6):1091-1097
13 Borghi C, Dormi A, Veronesi M, et al. Association between different lipid-lowering treatment strategies and blood pressure control in the Brisighella Heart Study. Am Heart J, 2004,148(2):285-292
14 Terzoli L, Mircoli L, Raco R, et al. Lowering of elevated ambulatory blood pressure by HMG-CoA reductase inhibitors. J Cardiovasc Pharmacol, 2005,46(3):310-315
15 Kanbay M, Yildirir A, Bozbas H, et al. Statin therapy helps to control blood pressure levels in hypertensive dyslipidemic patients. Ren Fail, 2005,27(3):297-303
16 Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med, 2002,166 (10):1403-1408
17 van der Linde NA, Sijbrands EJ, Boomsma F, et al. Effect oflow-density lipoprotein cholesterol on angiotensin II sensitivity: a randomized trial with fluvastatin. Hypertension, 2006,47(6):1125-1130
18 Shiroshita-Takeshita A, Schram G, Lavoie J, et al. Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation, 2004,110(16):2313-2319
19 Liu T, Li GP. Statins may prevent postoperative atrial fibrillation through autonomic modulation. Am J Cardiol, 2006,97(8):1266
20 Marin F, Pascual DA, Roldan V, et al. Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting. Am J Cardiol, 2006,97(1):55-60
21 Pliquett RU, Cornish KG, Zucker IH. Statin therapy restores sympathovagal balance in experimental heart failure. J Appl Physiol, 2003,95(2):700-704
22 Melenovsky V, Wichterle D, Simek J, et al. Effect of atorvastatin and fenofibrate on autonomic tone in subjects with combined hyperlipidemia. Am J Cardiol, 2003,92 (3):337-341
23 Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation, 2003,108(24):3006-3010
24 Sorescu D, Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail, 2002,8(3):132-140
25 Cordle A, Koenigsknecht-Talboo J, Wilkinson B, et al. Mechanisms of statin-mediated inhibition of small G-protein function. J Biol Chem, 2005,280(40):34202-34209
26 Emberson JR, Ng LL, Armitage J, et al. N-terminal Pro-B-type natriuretic peptide, vascular disease risk, and cholesterol reduction among 20,536 patients in the MRC/BHF heart protection study. J Am Coll Cardiol, 2007,49(3):311-319
27 Krum H, Bailey M, Meyer W, et al. Impact of statin therapy on clinical outcomes in chronic heart failure patients according to beta-blocker use: results of CIBIS II. Cardiology, 2007,108(1):28-34
28 Landmesser U, Bahlmann F, Mueller M, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation, 2005,111 (18):2356-2363
29 Laufs U, Wassmann S, Schackmann S, et al. Beneficial effects of statins in patients with non-ischemic heart failure. Z Kardiol, 2004,93(2):103-108
30 Node K, Fujita M, Kitakaze M, et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation, 2003,108(7):839-843
2 Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension, 2005,45 (6):1050-1055
3 Terzoli L, Mircoli L, Raco R, et al. Lowering of elevated ambulatory blood pressure by HMG-CoA reductase inhibitors. J Cardiovasc Pharmacol, 2005,46(3):310-315
4 Leibovitz E, Beniashvili M, Zimlichman R, et al. Treatment with amlodipine and atorvastatin have additive effect in improvement of arterial compliance in hypertensive hyperlipidemic patients. Am J Hypertens, 2003,16 (9):715-718
5 Mizuguchi Y, Oishi Y, Miyoshi H, et al. Impact of statin therapy on left ventricular function and carotid arterial stiffness in patients with hypercholesterolemia. Circ J, 2008,72(4):538-544
6 Wang YX, Fitch RM. Vascular stiffness: measurements, mechanisms and implications. Curr Vasc Pharmacol, 2004,2 (4):379-384
7 Cosson E, Herisse M, Laude D, et al. Aortic stiffness andpulse pressure amplification in Wistar-Kyoto and spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol, 2007,292(5):H2506-2512
8 Bonetti PO, Lerman LO, Napoli C, et al. Statin effects beyond lipid lowering--are they clinically relevant?. Eur Heart J, 2003,24(3):225-248
9 Krzesinski JM. [First evidence of greater cardiovascular protective effects of newer as compared to old antihypertensive drugs treatments: the ASCOT-BPLA results]. Rev Med Liege, 2005,60(10):820-826
10张维忠,丁跃有,邱慧丽.氟伐他汀改善高血压患者脉压和动脉弹性临床研究.高血压杂志, 2003,11(6):511-514
11 McKeage K, Siddiqui MA. Amlodipine/atorvastatin fixed-dose combination: a review of its use in the prevention of cardiovascular disease and in the treatment of hypertension and dyslipidemia. Am J Cardiovasc Drugs, 2008,8(1):51-67
12 Mason RP, Kubant R, Heeba G, et al. Synergistic effect of amlodipine and atorvastatin in reversing LDL-induced endothelial dysfunction. Pharm Res, 2008,25(8):1798-1806
13 Koh KK, Han SH, Ahn JY, et al. Amlodipine improves endothelial function and metabolic parameters in patients with hypertension. Int J Cardiol, 2009,133(1):23-31
14 Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med,2002,166(10):1403-1408
15 Hattori Y, Nakanishi N, Akimoto K, et al. HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. Arterioscler Thromb Vasc Biol, 2003,23(2):176-182
16 Susic D, Varagic J, Ahn J, et al. Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models. J Am Coll Cardiol, 2003,42(6):1091-1097
17 van der Linde NA, Sijbrands EJ, Boomsma F, et al. Effect of low-density lipoprotein cholesterol on angiotensin II sensitivity: a randomized trial with fluvastatin. Hypertension, 2006,47(6):1125-1130
18 Koh KK, Quon MJ, Waclawiw MA. Are statins effective for simultaneously treating dyslipidemias and hypertension?. Atherosclerosis, 2008,196(1):1-8
19 Strazzullo P, Kerry SM, Barbato A, et al. Do statins reduce blood pressure?: a meta-analysis of randomized, controlled trials. Hypertension, 2007,49(4):792-798
20 Ge CJ, Hu SJ, Wu YS, et al. Effects of atorvastatin on vascular remodeling in spontaneously hypertensive rats. J Zhejiang Univ Sci. Science, 2003,4(5):612-615
21 Cohn JN, Wilson DJ, Neutel J, et al. Coadministered amlodipine and atorvastatin produces early improvements in arterial wall compliance in hypertensive patients with dyslipidemia. Am J Hypertens, 2009,22(2):137-144
22 Leibovitz E, Hazanov N, Zimlichman R, et al. Treatmentwith atorvastatin improves small artery compliance in patients with severe hypercholesterolemia. Am J Hypertens, 2001,14(11):1096-1098
23 Smilde TJ, van den Berkmortel FW, Wollersheim H, et al. The effect of cholesterol lowering on carotid and femoral artery wall stiffness and thickness in patients with familial hypercholesterolaemia. Eur J Clin Invest, 2000,30 (6):473-480
1 Brouet A, Sonveaux P, Dessy C, et al. Hsp90 and caveolin are key targets for theproangiogenic nitric oxide-mediated effects of statins. Circ Res, 2001,89(10):866-873
2 Feron O, Dessy C, Desager JP, et al. Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation, 2001, 103(1):113-118
3 Hattori Y, Nakanishi N, Akimoto K, et al. HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. Arterioscler Thromb Vasc Biol, 2003, 23(2):176-182
4 Yue TL, Gu JL, Wang C, et al. Extracellular signal-regulatedkinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. J Biol Chem, 2000,275(48):895-901
5 Kinlay S, Schwartz GG, Olsson AG, et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation, 2003,108(13):1560-1566
6 Kleemann R, Princen HM, Emeis JJ, et al. Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: evidence for antiinflammatory effects of rosuvastatin. Circulation, 2003,108(11):1368-1374
7 Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med, 2005,352(1):20-28
8 Kaneyuki U, Ueda S, Yamagishi S, et al. Pitavastatin inhibits lysophosphatidic acid-induced proliferation and monocyte chemoattractant protein-1 expression in aortic smooth muscle cells by suppressing Rac-1-mediated reactive oxygen species generation. Vascul Pharmacol, 2007,46 (4):286-292
9 Lacut K, Oger E, Le Gal G, et al. Statins but not fibrates are associated with a reduced risk of venous thromboembolism: a hospital-based case-control study. Fundam Clin Pharmacol, 2004,18(4):477-482
10 Laufs U, Gertz K, Huang P, et al. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke,2000,31(10):2442-2449
11 Undas A, Brummel-Ziedins KE, Potaczek DP, et al. Atorvastatin and quinapril inhibit blood coagulation in patients with coronary artery disease following 28 days of therapy. J Thromb Haemost, 2006,4(11):2397-2404
12 Susic D, Varagic J, Ahn J, et al. Beneficial pleiotropic vascular effects of rosuvastatin in two hypertensive models. J Am Coll Cardiol, 2003,42(6):1091-1097
13 Borghi C, Dormi A, Veronesi M, et al. Association between different lipid-lowering treatment strategies and blood pressure control in the Brisighella Heart Study. Am Heart J, 2004,148(2):285-292
14 Terzoli L, Mircoli L, Raco R, et al. Lowering of elevated ambulatory blood pressure by HMG-CoA reductase inhibitors. J Cardiovasc Pharmacol, 2005,46(3):310-315
15 Kanbay M, Yildirir A, Bozbas H, et al. Statin therapy helps to control blood pressure levels in hypertensive dyslipidemic patients. Ren Fail, 2005,27(3):297-303
16 Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med, 2002,166 (10):1403-1408
17 van der Linde NA, Sijbrands EJ, Boomsma F, et al. Effect oflow-density lipoprotein cholesterol on angiotensin II sensitivity: a randomized trial with fluvastatin. Hypertension, 2006,47(6):1125-1130
18 Shiroshita-Takeshita A, Schram G, Lavoie J, et al. Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation, 2004,110(16):2313-2319
19 Liu T, Li GP. Statins may prevent postoperative atrial fibrillation through autonomic modulation. Am J Cardiol, 2006,97(8):1266
20 Marin F, Pascual DA, Roldan V, et al. Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting. Am J Cardiol, 2006,97(1):55-60
21 Pliquett RU, Cornish KG, Zucker IH. Statin therapy restores sympathovagal balance in experimental heart failure. J Appl Physiol, 2003,95(2):700-704
22 Melenovsky V, Wichterle D, Simek J, et al. Effect of atorvastatin and fenofibrate on autonomic tone in subjects with combined hyperlipidemia. Am J Cardiol, 2003,92 (3):337-341
23 Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation, 2003,108(24):3006-3010
24 Sorescu D, Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail, 2002,8(3):132-140
25 Cordle A, Koenigsknecht-Talboo J, Wilkinson B, et al. Mechanisms of statin-mediated inhibition of small G-protein function. J Biol Chem, 2005,280(40):34202-34209
26 Emberson JR, Ng LL, Armitage J, et al. N-terminal Pro-B-type natriuretic peptide, vascular disease risk, and cholesterol reduction among 20,536 patients in the MRC/BHF heart protection study. J Am Coll Cardiol, 2007,49(3):311-319
27 Krum H, Bailey M, Meyer W, et al. Impact of statin therapy on clinical outcomes in chronic heart failure patients according to beta-blocker use: results of CIBIS II. Cardiology, 2007,108(1):28-34
28 Landmesser U, Bahlmann F, Mueller M, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation, 2005,111 (18):2356-2363
29 Laufs U, Wassmann S, Schackmann S, et al. Beneficial effects of statins in patients with non-ischemic heart failure. Z Kardiol, 2004,93(2):103-108
30 Node K, Fujita M, Kitakaze M, et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation, 2003,108(7):839-843