Song Wei-zhong, Chen Alex F, Wang Donna H
Department of Medicine and Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
Acta Pharmacol Sin. 2004 Dec;25(12):1626-32.
To test the hypothesis that production of superoxide in mesenteric resistance arteries is increased and contributes to the development of hypertension induced by sensory denervation plus high salt intake.
Newborn Wistar rats were given capsaicin 50 mg/kg sc on the 1st and 2nd d of life. After weaning, male rats were grouped as follows and treated for 3 weeks with: capsaicin pretreatment plus normal sodium diet (0.5 %, CAP-NS), CAP plus high sodium diet (4 %, CAP-HS), control plus NS (CON-NS), or CON-HS. Both tail-cuff systolic blood pressure and mean arterial pressure (MAP) were measured in each of the groups. Western blot analysis was used for measurement of manganese superoxide dismutase (MnSOD) and endothelial nitric oxide synthase (eNOS) in the mesenteric resistance arteries. Lucigenin chemiluminescence assay was used for superoxide production in the mesenteric resistance arteries. The Griess method was used for measurement of nitrite/nitrate levels in plasma.
Both tail-cuff pressure and MAP were higher in CAP-HS compared with CAP-NS, CON-HS, and CON-NS rats (P<0.05). Both MnSOD and eNOS in the mesenteric resistance arteries were increased in CAP-HS compared with CAP-NS, CON-HS, and CON-NS (P<0.05). However, nitrite/nitrate levels in plasma were not different among 4 groups. Acute iv administration of tempol, a membrane-permeable superoxide scavenger, decreased MAP in both CAP-HS and CON-HS when compared with their respective controls. However, the decreases of MAP between these two groups were not different. Chronic treatment with tempol failed to prevent the development of hypertension in CAP-HS rats. Superoxide production in the mesenteric resistance arteries was increased in CAP-HS compared with CAP-NS, CON-HS, and CON-NS (P<0.05). However, chronic treatment with tempol did not prevent the increase of mesenteric superoxide production in CAP-HS rats.
Regardless of increased vascular MnSOD levels, salt sensitive hypertension induced by sensory degeneration is associated with increased vascular superoxide production. Although tempol is incapable of preventing the development of hypertension in sensory denervated rats fed a high salt diet, increased superoxide levels may contribute to exacerbated vascular impairment which may take longer time to develop. Given that superoxide may be produced by sources other than mitochondrion, future studies using other inhibitors (eg, inhibitors of NADPH oxidase and xanthine oxidase) may unveil the effectiveness of reducing superoxide on lowering blood pressure in this model.
验证以下假说，即肠系膜阻力动脉中超氧化物的生成增加，并促进感觉神经去传入加高盐摄入诱导的高血压的发展。
新生Wistar大鼠在出生第1天和第2天皮下注射50 mg/kg辣椒素。断奶后，将雄性大鼠分组如下，并进行3周的处理：辣椒素预处理加高钠饮食（4%，CAP-HS）、辣椒素预处理加正常钠饮食（0.5%，CAP-NS）、对照加高钠饮食（CON-HS）或对照加正常钠饮食（CON-NS）。测量每组大鼠的尾袖收缩压和平均动脉压（MAP）。采用蛋白质免疫印迹分析测定肠系膜阻力动脉中的锰超氧化物歧化酶（MnSOD）和内皮型一氧化氮合酶（eNOS）。采用光泽精化学发光法测定肠系膜阻力动脉中的超氧化物生成。采用格里斯方法测定血浆中亚硝酸盐/硝酸盐水平。
与CAP-NS、CON-HS和CON-NS组大鼠相比，CAP-HS组大鼠的尾袖血压和MAP均更高（P<0.05）。与CAP-NS、CON-HS和CON-NS组相比，CAP-HS组大鼠肠系膜阻力动脉中的MnSOD和eNOS均增加（P<0.05）。然而，4组大鼠血浆中的亚硝酸盐/硝酸盐水平并无差异。急性静脉注射可渗透细胞膜的超氧化物清除剂tempol后，与各自对照组相比，CAP-HS组和CON-HS组大鼠的MAP均降低。然而，两组之间MAP的降低幅度并无差异。tempol长期治疗未能预防CAP-HS组大鼠高血压的发展。与CAP-NS、CON-HS和CON-NS组相比，CAP-HS组大鼠肠系膜阻力动脉中的超氧化物生成增加（P<0.05）。然而，tempol长期治疗未能预防CAP-HS组大鼠肠系膜超氧化物生成的增加。
尽管血管MnSOD水平升高，但感觉神经退变诱导的盐敏感性高血压与血管超氧化物生成增加有关。虽然tempol无法预防高盐饮食喂养的感觉神经去传入大鼠高血压的发展，但超氧化物水平升高可能会导致血管损伤加剧，而这种损伤可能需要更长时间才会显现。鉴于超氧化物可能由线粒体以外的其他来源产生，未来使用其他抑制剂（如NADPH氧化酶抑制剂和黄嘌呤氧化酶抑制剂）的研究可能会揭示在该模型中降低超氧化物对降低血压的有效性。
