Wang Dan, Chen Yifan, Chabrashvili Tina, Aslam Shakil, Borrego Conde Lillian J, Umans Jason G, Wilcox Christopher S
Division of Nephrology and Hypertension and Center for Hypertension and Renal Disease Research, Georgetown University, Washington, DC 20007, USA.
J Am Soc Nephrol. 2003 Nov;14(11):2783-9. doi: 10.1097/01.asn.0000090747.59919.d2.
The hypothesis that O(2)(.-) enhances angiotensin II (AngII)-induced vasoconstriction and impairs acetylcholine-induced vasodilation of afferent arterioles (Aff) in AngII-induced hypertension was investigated. Rabbits (n = 6 per group) received 12 to 14 d of 0.154 M NaCl (Sham), subpressor AngII (60 ng/kg per min; AngII 60) or slow pressor AngII (200 ng/kg per min; AngII 200). Individual Aff were perfused in vitro at 60 mmHg. AngII 200 increased mean arterial pressure (mean +/- SD; 103 +/- 9 versus 73 +/- 6 mmHg; P < 0.01), plasma lipid peroxides (2.6 +/- 0.3 versus 2.0 +/- 0.3 nM; P < 0.05), renal cortical NADPH- and NADH-dependent O(2)(.-) generation, and Aff mRNA for p22(phox) 5-fold (P < 0.001) but decreased that for AT(1)-receptor 2.4-fold (P < 0.01). AngII 60 increased only NADH-dependent O(2)(.-) generation by renal cortex. Aff from AngII 200 rabbits had diminished acetylcholine relaxations (+50 +/- 4 versus +85 +/- 6%; P < 0.001), but these became similar in the presence of nitro-L-arginine (10(-4) M). Aff from AngII 60 and AngII 200 rabbits had unchanged norepinephrine contractions (10(-7) M) but significantly (P < 0.05) enhanced AngII contractions (10(-8) M: Sham -52 +/- 5 versus AngII 60 to 77 +/- 5 versus AngII 200 to 110 +/- 10%). The superoxide dismutase mimetic tempol (10(-4) M) moderated the AngII responses of Aff from AngII 200 rabbits to levels of AngII 60 rabbits (-64 +/- 7%). The AngII slow pressor response enhances renal cortical O(2)(.-) and p22(phox) expression. Increased O(2)(.-) generation in Aff mediates an impaired nitric oxide synthase-dependent endothelium-derived relaxing factor response and paradoxically enhances contractions to AngII despite downregulation of the mRNA for AT(1) receptors. A subpressor dose of AngII enhances Aff responses to AngII independent of O(2)(.-).
研究了超氧阴离子（O(2)(.-)）增强血管紧张素II（AngII）诱导的血管收缩并损害乙酰胆碱诱导的AngII诱导高血压模型中传入小动脉（Aff）血管舒张的假说。家兔（每组n = 6）接受12至14天的0.154 M NaCl（假手术组）、亚升压剂量的AngII（60 ng/kg每分钟；AngII 60）或缓慢升压剂量的AngII（200 ng/kg每分钟；AngII 200）。体外以60 mmHg灌注单个Aff。AngII 200使平均动脉压升高（平均值±标准差；103±9对73±6 mmHg；P < 0.01）、血浆脂质过氧化物增加（2.6±0.3对2.0±0.3 nM；P < 0.05）、肾皮质NADPH和NADH依赖性O(2)(.-)生成增加，以及Aff中p22(phox)的mRNA增加5倍（P < 0.001），但使AT(1)受体的mRNA减少2.4倍（P < 0.01）。AngII 60仅增加肾皮质NADH依赖性O(2)(.-)生成。来自AngII 200组家兔的Aff对乙酰胆碱的舒张反应减弱（+50±4对+85±6%；P < 0.001），但在存在硝基-L-精氨酸（10(-4) M）时变得相似。来自AngII 60和AngII 200组家兔的Aff对去甲肾上腺素的收缩反应（10(-7) M）未改变，但对AngII的收缩反应显著增强（10(-8) M：假手术组-52±5对AngII 60组至77±5对AngII 200组至110±10%）。超氧化物歧化酶模拟物tempol（10(-4) M）将来自AngII 200组家兔的Aff对AngII的反应调节至AngII 60组家兔的水平（-64±7%）。AngII的缓慢升压反应增强肾皮质O(2)(.-)和p22(phox)表达。Aff中O(2)(.-)生成增加介导了一氧化氮合酶依赖性内皮源性舒张因子反应受损，且尽管AT(1)受体mRNA下调，但反常地增强了对AngII的收缩反应。亚升压剂量的AngII增强Aff对AngII的反应，且不依赖于O(2)(.-)。
