School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia.
Ren Fail. 2013 Aug;35(7):978-88. doi: 10.3109/0886022X.2013.809563. Epub 2013 Jul 3.
This study investigated the effects of tempol, a superoxide dismutase (SOD) mimetic and L-NAME, a nitric oxide (NO) synthase inhibitor on the renal function and hemodynamics in cyclosporine A (CsA) induced renal insufficiency rats. Male Sprague-Dawley rats were treated with either vehicle (C), tempol (T, 1 mmol/L in drinking fluid), L-NAME (L, 1 mmol/L in drinking fluid), CsA (Cs, 25 mg/kg/day via gavage), CsA plus tempol (TCs), CsA plus L-NAME (LCs) or CsA plus a combination of tempol and L-NAME (TLCs) for 21 consecutive days. At the end of treatment regimen, the renal responses to noradrenaline (NA), phenylephrine (PE), methoxamine and angiotensin II (Ang II) were determined. Cs and LCs rats had lower creatinine clearance (0.7 ± 0.1 and 0.6 ± 0.5 vs. 1.3 ± 0.2 mL/min/kg) and fractional excretion of sodium (0.12 ± 0.02 and 0.17 ± 0.01 vs. 0.67 ± 0.04%) but higher systolic blood pressure (145 ± 2 and 178 ± 4 vs. 116 ± 2) compared to the control (all p < 0.05), respectively. Tempol treatment in TCs or TLCs prevented the increase in blood pressure and improved creatinine clearance and sodium excretion compared to untreated Cs. The renal vasoconstriction in Cs or LCs to NA, PE and Ang II were lower than control by ∼35-48% (all p < 0.05). In TCs or TLCs, there was enhanced renal vasoconstriction to all agonist by ∼39-114% compared to Cs. SOD is important to counterbalance the hypertensive effect of a defective NO system and to allow the normal vasoconstrictor response of the renal vasculature to adrenergic agonists and Ang II in a model of CsA-induced renal insufficiency.
本研究旨在探讨 Tempo，一种超氧化物歧化酶（SOD）模拟物，以及 L-NAME，一种一氧化氮（NO）合酶抑制剂，对环孢素 A（CsA）诱导的肾功能不全大鼠的肾功能和血液动力学的影响。雄性 Sprague-Dawley 大鼠分别用载体（C）、Tempo（T，1mmol/L 于饮用水中）、L-NAME（L，1mmol/L 于饮用水中）、CsA（25mg/kg/天灌胃）、CsA+Tempo（TCs）、CsA+L-NAME（LCs）或 CsA+Tempo 和 L-NAME 的组合（TLCs）连续治疗 21 天。在治疗方案结束时，测定肾对去甲肾上腺素（NA）、苯肾上腺素（PE）、甲氧胺和血管紧张素 II（Ang II）的反应。Cs 和 LCs 组大鼠的肌酐清除率（0.7±0.1 和 0.6±0.5 与 1.3±0.2 mL/min/kg）和钠排泄分数（0.12±0.02 和 0.17±0.01 与 0.67±0.04%）较低，但收缩压（145±2 和 178±4 与 116±2）较高（均 p<0.05）。与未治疗的 Cs 相比，TCs 或 TLCs 中的 Tempo 治疗可预防血压升高并改善肌酐清除率和钠排泄。与对照组相比，Cs 或 LCs 对 NA、PE 和 Ang II 的肾血管收缩降低了约 35-48%（均 p<0.05）。在 TCs 或 TLCs 中，与 Cs 相比，所有激动剂的肾血管收缩增强了约 39-114%。SOD 对于平衡有缺陷的 NO 系统的高血压作用以及允许肾血管对肾上腺素能激动剂和 Ang II 的正常血管收缩反应是重要的，在 CsA 诱导的肾功能不全模型中。
