Role of angiotensin II and reactive oxygen species in cyclosporine A-dependent hypertension
Role of angiotensin II and reactive oxygen species in cyclosporine A-dependent hypertension
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DOI：
10.1161/01.hyp.0000085195.38870.44
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发表时间：
2003-10-01
期刊：
影响因子：
8.3
通讯作者：
Abe, Y
中科院分区：
文献类型：
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作者：
Nishiyama, A;Kobori, H;Abe, Y
环孢素A(CysA)是一种有效的免疫抑制剂，其治疗与全身和肾脏血管收缩有关，从而导致高血压。本研究旨在阐明血管紧张素II(Ang II)在CysA诱导的高血压和活性氧(ROS)生成中的作用。环孢素A(30 mg/kg/d，SC)连续给药3周，使大鼠的收缩压(SBP)由119+/-2升至145+/-3 mm Hg(n=7)。CsA组大鼠血浆和肾脏Ang II水平(136+/-10fmoL/m L和516+/-70fm o l/g)显著高于赋形剂组(1 m L橄榄油)(76+/-10fm o l/m L和222+/-21 fm ol/g，n=7)。用CysA治疗后，主动脉AT(1)受体蛋白表达增加(251+/-35%)，而肾脏AT(1)受体蛋白表达减少(-32+/-4%)。环孢素A组大鼠主动脉段超氧阴离子生成量和肾脏硫代巴比妥酸反应物质(TBARS)含量(26+/-2次/毫克和37+/-3nmol/g)高于赋形剂组(17+/-1次/毫克和24+/-3nmol/g)。同时给予服用CysA的大鼠(n=7)同时给予AT(1)受体拮抗剂valsartan(每天30 mg/kg)，可显著降低SBP(113+/-4 mm Hg)，并阻止血管超氧化物歧化(16+/-2次/min/mg)和肾脏TBARS含量(21+/-3nmoL/g)的增加。同样，用超氧化物歧化酶的模拟物4-羟基-2，2，6，6，-四甲基哌啶-N-氧(坦普尔；饮用水中的3 mmol/L，n=7)处理，可以阻止CySA诱导的SBP(115+/-3 mm Hg)、血管超氧化物歧化(16+/-1次/分钟/毫克)和肾脏TBARS含量(19+/-2nmol/g)的增加。这些数据表明，血管紧张素Ⅱ水平升高导致的ROS生成参与了环孢素A诱导的高血压的发展。环孢素A(CysA)是一种有效的免疫抑制剂，它与全身和肾脏血管收缩有关，从而导致高血压。本研究旨在阐明血管紧张素II(Ang II)在CysA诱导的高血压和活性氧(ROS)生成中的作用。环孢素A(30 mg/kg/d，SC)连续给药3周后，大鼠的收缩压(SBP)由119±2升至145+/-3 mm Hg(n=7)。CsA组大鼠血浆和肾脏Ang II水平(136+/-10fmoL/m L和516+/-70fm o l/g)显著高于赋形剂组(1 m L橄榄油)(76+/-10fm o l/m L和222+/-21 fm ol/g，n=7)。用CysA治疗后，主动脉AT(1)受体蛋白表达增加(251+/-35%)，而肾脏AT(1)受体蛋白表达减少(-32+/-4%)。环孢素A组大鼠主动脉段超氧阴离子生成量和肾脏硫代巴比妥酸反应物质(TBARS)含量(26+/-2次/毫克和37+/-3nmol/g)高于赋形剂组(17+/-1次/毫克和24+/-3nmol/g)。给予CysA组大鼠(n=7)同时给予AT受体拮抗剂valsartan(每天30 mg/kg)，可显著降低SBP(113+/-4 mm Hg)，并阻止血管超氧化物歧化酶(16+/-2次/分钟/毫克)和肾脏总胆红素含量(21+/-3nmoL/g)的增加。同样，用超氧化物歧化酶的模拟物4-羟基-2，2，6，6，-四甲基哌啶-N-氧基(Tempol；饮用水中的3 mmol/L，n=7)处理，可以阻止CySA诱导的SBP(115+/-3转汞)、血管超氧化物歧化(16+/-1次/分钟/毫克)和肾脏TBARS含量(19+/-2nmol/g)的增加。这些数据表明，血管紧张素Ⅱ水平升高导致的ROS生成参与了环孢素A诱导的高血压的发生。
Treatment with cyclosporine A (CysA), a potent immunosuppressive agent, is associated with systemic and renal vasoconstriction, leading to hypertension. The present study was conducted to elucidate the contribution of angiotensin II (Ang II) to CysA-induced hypertension and reactive oxygen species (ROS) generation. CysA (30 mg/kg per day SC), given for 3 weeks in rats, increased systolic blood pressure (SBP) from 119+/-2 to 145+/-3 mmHg (n=7). Plasma and kidney Ang II levels were significantly higher in CysA-treated rats (136+/-10 fmol/mL and 516+/-70 fmol/g) than in vehicle-treated (1 mL olive oil) rats (76+/-10 fmol/mL and 222+/-21 fmol/g, n=7). CysA treatment increased AT(1) receptor protein expression in the aorta (by 251+/-35%), whereas it was reduced in the kidney (by -32+/-4%). Superoxide anion production in aortic segments and kidney thiobarbituric acid-reactive substance (TBARS) contents were higher in CysA-treated rats (26+/-2 counts/min per milligram and 37+/-3 nmol/g) than in vehicle-treated rats (17+/-1 counts/min per milligram and 24+/-3 nmol/g). Concurrent administration of an AT(1) receptor antagonist, valsartan (30 mg/kg per day, in drinking water), to CysA-treated rats (n=7) significantly decreased SBP (113+/-4 mm Hg) and prevented increases in vascular superoxide (16+/-2 counts/min per milligram) and kidney TBARS contents (21+/-3 nmol/g). Similarly, treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6,-tetramethylpiperidine-N-oxyl (Tempol; 3 mmol/L in drinking water, n=7), prevented CysA-induced increases in SBP (115+/-3 mm Hg), vascular superoxide (16+/-1 counts/min per milligram), and kidney TBARS contents (19+/-2 nmol/g). These data suggest that ROS generation induced by augmented Ang II levels contributes to the development of CysA-induced hypertension.Treatment with cyclosporine A (CysA), a potent immunosuppressive agent,,is associated with systemic and renal vasoconstriction, leading to hypertension. The present study was conducted to elucidate the contribution of angiotensin II (Ang II) to CysA-induced hypertension and reactive oxygen species (ROS) generation. CysA (30 mg/kg per day SC), given for 3 weeks in rats, increased systolic blood pressure (SBP) from 119+/-2 to 145+/-3 mm Hg (n=7). Plasma and kidney Ang II levels were significantly higher in CysA-treated rats (136+/-10 fmol/mL and 516+/-70 fmol/g) than in vehicle-treated (1 mL olive oil) rats (76+/-10 fmol/mL and 222+/-21 fmol/g, n=7). CysA treatment increased AT(1) receptor protein expression in the aorta (by 251+/-35%), whereas it was reduced in the kidney (by -32+/-4%). Superoxide anion production in aortic segments and kidney thiobarbituric acid-reactive substance (TBARS) contents were higher in CysA-treated rats (26+/-2 counts/min per milligram and 37+/-3 nmol/g) than in vehicle-treated rats (17+/-1 counts/min per milligram and 24+/-3 nmol/g). Concurrent administration of an AT, receptor antagonist, valsartan (30 mg/kg per day, in drinking water), to CysA-treated rats (n=7) significantly decreased SBP (113+/-4 mm Hg) and prevented increases in vascular superoxide (16+/-2 counts/min per milligram) and kidney TBARS contents (21+/-3 nmol/g). Similarly, treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6,-tetramethylpiperidine-N-oxyl (Tempol; 3 mmol/L in drinking water, n=7), prevented CysA-induced increases in SBP (115+/-3 turn Hg), vascular superoxide (16+/-1 counts/min per milligram), and kidney TBARS contents (19+/-2 nmol/g). These data suggest that ROS generation induced by augmented Ang II levels contributes to the development of CysA-induced hypertension.