Grunfeld S, Hamilton C A, Mesaros S, McClain S W, Dominiczak A F, Bohr D F, Malinski T
Department of Chemistry, Oakland University, Rochester, Mich., USA.
Hypertension. 1995 Dec;26(6 Pt 1):854-7. doi: 10.1161/01.hyp.26.6.854.
We undertook these studies to determine whether a deficient nitric oxide production in genetically hypertensive rats could result from its being scavenged by an excess production of superoxide. In one study we used a porphyrinic microsensor to measure nitric oxide concentrations released by cultured endothelial cells from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). SHRSP cells released only about one third the concentration of nitric oxide as did WKY cells. Treatment of cells with superoxide dismutase increased nitric oxide release, demonstrating that normally nitric oxide is scavenged by endogenous superoxide. The increase in nitric oxide release in response to superoxide dismutase treatment was more than twice as great from SHRSP as from WKY cells, demonstrating the greater amount of superoxide in the hypertensive rats. A direct measure of superoxide with the use of lucigenin demonstrated the presence of 68.1 +/- 7.1 and 27.4 +/- 3.5 nmol/L of this anion in SHRSP and WKY endothelial cells, respectively. The presence of superoxide in the rat aorta was also estimated by quantification of its effect on carbachol relaxation. This relaxation was diminished when endogenous superoxide dismutase was blocked by diethyldithiocarbamic acid. This blockade reduced the relaxation by 51.2 +/- 5.2% in SHRSP aortas and by only 22.0 +/- 8.2% (P = .015) in WKY aortas. Data from these diverse systems are in agreement that superoxide production is excessive in SHRSP tissues. This excess superoxide, by scavenging endothelial nitric oxide, could contribute to the increased vascular smooth muscle contraction and hence to the elevated total peripheral resistance of these rats.
我们开展这些研究，以确定遗传性高血压大鼠体内一氧化氮生成不足是否是由于超氧化物生成过多将其清除所致。在一项研究中，我们使用卟啉微传感器来测量易患中风的自发性高血压大鼠（SHRSP）和正常血压的Wistar - Kyoto大鼠（WKY）的培养内皮细胞释放的一氧化氮浓度。SHRSP细胞释放的一氧化氮浓度仅约为WKY细胞的三分之一。用超氧化物歧化酶处理细胞可增加一氧化氮的释放，表明正常情况下一氧化氮被内源性超氧化物清除。与WKY细胞相比，SHRSP细胞对超氧化物歧化酶处理的一氧化氮释放增加量多出两倍多，这表明高血压大鼠体内超氧化物含量更高。使用光泽精直接测量超氧化物表明，SHRSP和WKY内皮细胞中该阴离子的含量分别为68.1±7.1和27.4±3.5 nmol/L。还通过定量超氧化物对卡巴胆碱舒张作用的影响来估计大鼠主动脉中超氧化物的存在。当内源性超氧化物歧化酶被二乙基二硫代氨基甲酸阻断时，这种舒张作用减弱。这种阻断使SHRSP主动脉的舒张作用降低了51.2±5.2%，而在WKY主动脉中仅降低了22.0±8.2%（P = 0.015）。来自这些不同系统的数据一致表明，SHRSP组织中超氧化物生成过多。这种过量的超氧化物通过清除内皮一氧化氮，可能导致血管平滑肌收缩增加，从而导致这些大鼠的总外周阻力升高。
