Zhou Ming-Sheng, Jaimes Edgar A, Raij Leopoldo
Nephrology-Hypertension Section, Veterans Affairs Medical Center, Renal Division and Vascular Biology Institute, University of Miami School of Medicine, Fla 33125, USA.
Hypertension. 2004 Aug;44(2):186-90. doi: 10.1161/01.HYP.0000136395.06810.cf. Epub 2004 Jul 6.
Statins, inhibitors of cholesterol biosynthesis, are endowed with pleiotropic effects that may contribute to their favorable clinical results. Hypertensive Dahl salt-sensitive (DS) rats have endothelial dysfunction and cardiorenal injury associated with decreased NO bioavailability and increased superoxide (O2-) production linked to a functional upregulation of angiotensin II. We investigated whether atorvastatin (30 mg/kg per day; by gavage) would prevent endothelial nitric oxide (eNOS) downregulation and the increase in O2- in DS rats, thereby reducing end-organ injury. DS rats given a high-salt diet (4% NaCl) for 10 weeks developed hypertension (systolic blood pressure [SBP] 200+/-8 versus 150+/-2 mm Hg in DS rats fed 0.5% NaCl diet [NS]; P<0.05), impaired endothelium-dependent relaxation, functional upregulation of endothelin-1, left ventricular hypertrophy (LVH; 30%), and proteinuria (167%), accompanied by downregulation of aortic eNOS activity (0.7+/-0.2 versus 1.8+/-0.3 nmol/min per gram protein in NS; P<0.05) and increased aortic O2- (2632+/-316 versus 1176+/-112 counts/min per milligram in NS; P<0.05) and plasma 8-F2alpha isoprostanes. Atorvastatin prevented the decrease in eNOS activity (1.5+/-0.3 nmol/min per gram protein) as well as the increase in O2- (1192+/-243 counts/min per milligram) and plasma 8-F2alpha isoprostanes, reduced LVH and proteinuria, and normalized endothelial function and vascular response to endothelin-1, although reduction in SBP was modest (174+/-8 mm Hg). Atorvastatin combined with removal of high salt normalized aortic eNOS activity, SBP, LVH, and proteinuria. These findings strongly suggest that concomitant prevention of vascular eNOS downregulation and inhibition of oxidative stress may contribute to the protection against end-organ injury afforded by this statin in salt-sensitive hypertension.
他汀类药物作为胆固醇生物合成的抑制剂，具有多种效应，这可能是其产生良好临床效果的原因。高血压的 Dahl 盐敏感（DS）大鼠存在内皮功能障碍和心肾损伤，这与一氧化氮（NO）生物利用度降低以及超氧化物（O2-）生成增加有关，而这又与血管紧张素 II 的功能上调有关。我们研究了阿托伐他汀（每天 30 毫克/千克；通过灌胃给药）是否能预防 DS 大鼠的内皮型一氧化氮合酶（eNOS）下调和 O2-增加，从而减轻靶器官损伤。给予高盐饮食（4%氯化钠）10 周的 DS 大鼠出现了高血压（收缩压[SBP]为 200±8 毫米汞柱，而喂食 0.5%氯化钠饮食[NS]的 DS 大鼠为 150±2 毫米汞柱；P<0.05）、内皮依赖性舒张功能受损、内皮素-1 功能上调、左心室肥厚（LVH；30%）和蛋白尿（167%），同时伴有主动脉 eNOS 活性下调（0.7±0.2 纳摩尔/分钟每克蛋白质，而 NS 组为 1.8±0.3 纳摩尔/分钟每克蛋白质；P<0.05）以及主动脉 O2-增加（2632±316 计数/分钟每毫克，而 NS 组为 1176±112 计数/分钟每毫克；P<0.05）和血浆 8-F2α异前列腺素增加。阿托伐他汀可预防 eNOS 活性降低（1.5±0.3 纳摩尔/分钟每克蛋白质）以及 O2-增加（1192±243 计数/分钟每毫克）和血浆 8-F2α异前列腺素增加，减轻左心室肥厚和蛋白尿，并使内皮功能及血管对内皮素-1 的反应恢复正常，尽管收缩压的降低幅度较小（174±8 毫米汞柱）。阿托伐他汀与去除高盐联合应用可使主动脉 eNOS 活性以及收缩压、左心室肥厚和蛋白尿恢复正常。这些发现有力地表明，同时预防血管 eNOS 下调和抑制氧化应激可能有助于该他汀类药物对盐敏感性高血压靶器官损伤的保护作用。
