Guan Z, Willgoss D A, Matthias A, Manley S W, Crozier S, Gobe G, Endre Z H
Renal Research Centre, Department of Medicine, Royal Brisbane Hospital, Brisbane, Queensland, Australia.
Acta Physiol Scand. 2003 Oct;179(2):189-201. doi: 10.1046/j.1365-201X.2003.01125.x.
This study was designed to investigate the influence of angiotensin II (Ang II) and nitric oxide (NO) on autoregulation of renal perfusion.
Autoregulation was investigated in isolated perfused kidneys (IPRK) from Sprague-Dawley rats during stepped increases in perfusion pressure.
Ang II (75-200 pM) produced dose-dependent enhancement of autoregulation whereas phenylephrine produced no enhancement and impaired autoregulation of GFR. Enhancement by Ang II was inhibited by the AT1 antagonist, Losartan, and the superoxide scavenger, Tempol. Under control conditions nitric oxide synthase (NOS) inhibition by 10 microm N-omega-nitro-L-arginine methyl ester (L-NAME) facilitated autoregulation in the presence of non-specific cyclooxygenase (COX) inhibition by 10 microm indomethacin. Both COX and combined NOS/COX inhibition reduced the autoregulatory threshold concentration of Ang II. Facilitation by 100 pm Ang II was inhibited by 100 microm frusemide. Methacholine (50 nm) antagonised Ang II-facilitated autoregulation in the presence and absence of NOS/COX inhibition. Infusion of the NO donor, 1 microm sodium nitroprusside, inhibited L-NAME enhancement of autoregulation under control conditions and during Ang II infusion.
The results suggest than an excess of NO impairs autoregulation under control conditions in the IPRK and that endogenous and exogenous NO, vasodilatory prostaglandins and endothelium-derived hyperpolarizing factor (EDHF) activity antagonise Ang II-facilitated autoregulation. Ang II also produced a counterregulatory vasodilatory response that included prostaglandin and NO release. We suggest that Ang II facilitates autoregulation by a tubuloglomerular feedback-dependent mechanism through AT1 receptor-mediated depletion of nitric oxide, probably by stimulating generation of superoxide.
本研究旨在探讨血管紧张素II（Ang II）和一氧化氮（NO）对肾灌注自身调节的影响。
在逐步增加灌注压力的过程中，对来自Sprague-Dawley大鼠的离体灌注肾（IPRK）的自身调节进行研究。
Ang II（75 - 200 pM）产生剂量依赖性的自身调节增强作用，而去氧肾上腺素未产生增强作用且损害了肾小球滤过率（GFR）的自身调节。Ang II的增强作用被AT1拮抗剂氯沙坦和超氧化物清除剂Tempol抑制。在对照条件下，10 μM N-ω-硝基-L-精氨酸甲酯（L-NAME）抑制一氧化氮合酶（NOS），在存在10 μM吲哚美辛非特异性抑制环氧化酶（COX）的情况下促进了自身调节。COX抑制以及联合NOS/COX抑制均降低了Ang II的自身调节阈值浓度。100 μM速尿抑制了100 pM Ang II的促进作用。在存在和不存在NOS/COX抑制的情况下，乙酰甲胆碱（50 nM）拮抗Ang II促进的自身调节。在对照条件下以及Ang II输注期间，输注NO供体1 μM硝普钠抑制了L-NAME对自身调节的增强作用。
结果表明，在IPRK的对照条件下，过量的NO损害自身调节，内源性和外源性NO、血管舒张性前列腺素以及内皮衍生超极化因子（EDHF）活性拮抗Ang II促进的自身调节。Ang II还产生了一种包括前列腺素和NO释放的反调节血管舒张反应。我们认为，Ang II通过肾小管-肾小球反馈依赖性机制，可能通过刺激超氧化物的生成，经AT1受体介导的一氧化氮消耗来促进自身调节。
