Christensen Frank Holden, Stankevicius Edgaras, Hansen Thomas, Jørgensen Malene Munk, Valverde Vanesa Lopez, Simonsen Ulf, Buus Niels Henrik
Department of Pharmacology, University of Aarhus, 8000 Aarhus C, Denmark.
Eur J Pharmacol. 2007 Jul 2;566(1-3):160-6. doi: 10.1016/j.ejphar.2007.03.058. Epub 2007 Apr 18.
We investigated whether renovascular hypertension alters vasodilatation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) and the influence of the superoxide dismutase mimetic tempol on vasodilatation. One-kidney one-clip hypertensive Sprague-Dawley rats, treated with either vehicle or tempol (from weeks 5 to 10 after placement of the clip), and uninephrectomized control rats were investigated. In renal hypertensive rats systolic blood pressure increased to 171+/-6 mmHg (n=10), while in tempol-treated rats systolic blood pressure remained normal (139+/-7 mmHg, n=5). In isolated pressurized mesenteric small arteries NO-mediated dilatation was obtained by increasing flow rate and EDHF-mediated dilatation by acetylcholine. In arteries from hypertensive rats, flow-induced dilatation was blunted, as compared to normotensive and tempol-treated rats, while acetylcholine-induced dilatation remained normal. Measured by dihydroethidium staining there was an increased amount of superoxide in arteries from vehicle-treated rats, but not from tempol-treated rats. Expression by immunoblotting of endothelial NO synthase and the NAD(P)H oxidase subunit p47phox remained unaffected by high blood pressure and tempol treatment. Simultaneous measurements of NO-concentration and relaxation were performed in isolated coronary arteries from the same animals. As compared to vehicle-treated rats, both acetylcholine-induced relaxation and NO-concentration increased in arteries from tempol-treated animals, while only the relaxation was improved by the NO donor, S-nitroso-N-acetylpenicillamine (SNAP). In conclusion renovascular hypertension selectively inhibits flow-induced NO-mediated vasodilatation, while EDHF-type vasodilatation remains unaffected, suggesting that high blood pressure leads to increased generation of superoxide contributing to decreased NO bioavailability. Furthermore, the abnormal endothelium function can be corrected by tempol treatment, but this seems to involve mechanisms partly independent of NO.
我们研究了肾血管性高血压是否会改变由一氧化氮（NO）和内皮衍生超极化因子（EDHF）介导的血管舒张，以及超氧化物歧化酶模拟物tempol对血管舒张的影响。研究对象包括单肾单夹高血压Sprague-Dawley大鼠（在夹闭后第5至10周，分别用赋形剂或tempol处理）以及单侧肾切除的对照大鼠。肾性高血压大鼠的收缩压升高至171±6 mmHg（n = 10），而tempol处理的大鼠收缩压保持正常（139±7 mmHg，n = 5）。在离体加压肠系膜小动脉中，通过增加流速获得NO介导的舒张，通过乙酰胆碱获得EDHF介导的舒张。与正常血压和tempol处理的大鼠相比，高血压大鼠动脉中流速诱导的舒张减弱，而乙酰胆碱诱导的舒张保持正常。通过二氢乙锭染色测量发现，用赋形剂处理的大鼠动脉中超氧化物含量增加，而tempol处理的大鼠动脉中则没有。通过免疫印迹法检测，内皮型一氧化氮合酶和NAD(P)H氧化酶亚基p47phox的表达不受高血压和tempol处理的影响。对同一动物的离体冠状动脉同时进行NO浓度和舒张的测量。与用赋形剂处理的大鼠相比，tempol处理动物的动脉中乙酰胆碱诱导的舒张和NO浓度均增加，而只有舒张通过NO供体S-亚硝基-N-乙酰青霉胺（SNAP）得到改善。总之，肾血管性高血压选择性抑制流速诱导的NO介导的血管舒张，而EDHF型血管舒张不受影响，这表明高血压导致超氧化物生成增加，从而导致NO生物利用度降低。此外，tempol处理可纠正异常的内皮功能，但这似乎涉及部分独立于NO的机制。
