Piotrkowski Barbara, Fraga Cesar G, de Cavanagh Elena M V
Physical Chemistry-PRALIB, Univ. of Buenos Aires, Junín 956, 1113-Buenos Aires, Argentina.
Am J Physiol Regul Integr Comp Physiol. 2007 Apr;292(4):R1494-501. doi: 10.1152/ajpregu.00540.2006. Epub 2006 Dec 21.
The renal and cardiac benefits of renin-angiotensin system (RAS) inhibition in hypertension exceed those attributable to blood pressure reduction, and seem to involve mitochondrial function changes. To investigate whether mitochondrial changes associated with RAS inhibition are related to changes in nitric oxide (NO) metabolism, four groups of male Wistar rats were treated during 2 wk with a RAS inhibitor, enalapril (10 mg x kg(-1) x day(-1); Enal), or a NO synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg x kg(-1) x day(-1)), or both (Enal+L-NAME), or were untreated (control). Blood pressure and body weight were lower in Enal than in control. Electron transfer through complexes I to III and cytochrome oxidase activity were significantly lower, and uncoupling protein-2 content was significantly higher in kidney mitochondria isolated from Enal than in those from control. All of these changes were prevented by L-NAME cotreatment and were accompanied by a higher production/bioavailability of kidney NO. L-NAME abolished mitochondrial NOS activity but failed to inhibit extra-mitochondrial kidney NOS, underscoring the relevance of mitochondrial NO in those effects of enalapril that were suppressed by L-NAME cotreatment. In Enal, kidney mitochondria H(2)O(2) production rate and MnSOD activity were significantly lower than in control, and these effects were not prevented by L-NAME cotreatment. These findings may clarify the role of NO in the interactions between RAS and mitochondrial metabolism and can help to unravel the mechanisms involved in renal protection by RAS inhibitors.
肾素 - 血管紧张素系统（RAS）抑制在高血压治疗中对肾脏和心脏的益处超过了单纯降低血压所带来的益处，而且似乎涉及线粒体功能的改变。为了研究与RAS抑制相关的线粒体变化是否与一氧化氮（NO）代谢的变化有关，将四组雄性Wistar大鼠进行为期2周的治疗，分别给予RAS抑制剂依那普利（10 mg·kg⁻¹·d⁻¹；依那普利组）、NO合酶（NOS）抑制剂Nⁿ-硝基-L-精氨酸甲酯（L-NAME）（1 mg·kg⁻¹·d⁻¹）、两者联合使用（依那普利+L-NAME组），或不进行治疗（对照组）。依那普利组的血压和体重低于对照组。从依那普利组大鼠分离出的肾脏线粒体中，通过复合物I至III的电子传递和细胞色素氧化酶活性显著降低，解偶联蛋白-2含量显著高于对照组。L-NAME联合治疗可防止所有这些变化，并伴有肾脏NO生成/生物利用度的提高。L-NAME消除了线粒体NOS活性，但未能抑制线粒体外肾脏NOS，这突出了线粒体NO在依那普利被L-NAME联合治疗所抑制的那些效应中的相关性。在依那普利组中，肾脏线粒体H₂O₂生成速率和锰超氧化物歧化酶（MnSOD）活性显著低于对照组，且L-NAME联合治疗未能阻止这些效应。这些发现可能阐明NO在RAS与线粒体代谢相互作用中的作用，并有助于揭示RAS抑制剂肾脏保护作用的机制。
