Brands Michael W, Bell Tracy D, Gibson Bradford
Department of Physiology and the Vascular Biology Center, Medical College of Georgia, CL-3132, Augusta, GA 30912-3000, USA.
Hypertension. 2004 Jan;43(1):57-63. doi: 10.1161/01.HYP.0000104524.25807.EE. Epub 2003 Dec 1.
The dependence of blood pressure on a balance between superoxide and nitric oxide may be amplified in diabetes. We have shown that the first occurrence of sustained hyperglycemia in type I diabetes causes hypertension when induced in rats that have had nitric oxide synthesis blocked chronically (L-NAME, 10 microg/kg per minute IV). This study used tempol (18 micromol/kg per hour IV) to test the hypothesis that superoxide mediates that hypertensive response. Induction of diabetes in untreated rats had no significant effect on mean arterial pressure (MAP, measured 18 h/d), and glomerular filtration rate (GFR) increased significantly during the 2 weeks of diabetes. Chronic infusion of L-NAME in a separate group of rats increased baseline MAP from approximately 90 mm Hg to a stable level of approximately 120 mm Hg after 6 days of infusion, and induction of diabetes (streptozotocin, 40 mg/kg IV) in those rats caused a rapid, progressive increase in MAP that averaged 156+/-5 mm Hg by day 14 of diabetes that was associated with a decrease in GFR and 4-fold increase in isoprostane excretion. Tempol infusion was begun on day 2 of diabetes in a subgroup of those rats, and the progressive hypertensive response was prevented, with MAP averaging 134+/-10 mm Hg by day 14. In addition, the normal renal hyperfiltration response was restored by tempol and the increase in isoprostane did not occur. Thus, the hypertension and decrease in GFR caused by onset of diabetes in rats without a functioning nitric oxide system was prevented by chronic administration of the superoxide dismutase mimetic tempol.
在糖尿病中，血压对超氧化物和一氧化氮之间平衡的依赖性可能会增强。我们已经表明，在长期阻断一氧化氮合成的大鼠（L-NAME，每分钟静脉注射10微克/千克）中诱导出I型糖尿病首次出现持续性高血糖时会导致高血压。本研究使用tempol（每小时静脉注射18微摩尔/千克）来检验超氧化物介导该高血压反应的假说。在未治疗的大鼠中诱导糖尿病对平均动脉压（MAP，每天测量18小时）没有显著影响，并且在糖尿病的2周内肾小球滤过率（GFR）显著增加。在另一组大鼠中慢性输注L-NAME，输注6天后基线MAP从大约90毫米汞柱增加到稳定的大约120毫米汞柱水平，并且在这些大鼠中诱导糖尿病（链脲佐菌素，静脉注射40毫克/千克）导致MAP迅速、逐渐升高，到糖尿病第14天平均为156±5毫米汞柱，这与GFR降低和异前列腺素排泄增加4倍相关。在这些大鼠的一个亚组中，在糖尿病第2天开始输注tempol，阻止了逐渐的高血压反应，到第14天MAP平均为134±10毫米汞柱。此外，tempol恢复了正常的肾高滤过反应，并且异前列腺素没有增加。因此，在没有功能性一氧化氮系统的大鼠中，糖尿病发作引起的高血压和GFR降低通过长期给予超氧化物歧化酶模拟物tempol得以预防。
