AT1 receptor antagonist combats oxidative stress and restores nitric oxide signaling in the SHR.
AT1 receptor antagonist combats oxidative stress and restores nitric oxide signaling in the SHR.
复制标题
AT1 受体拮抗剂可对抗氧化应激并恢复 SHR 中的一氧化氮信号传导。
DOI：
10.1046/j.1523-1755.2001.0590041257.x
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发表时间：
2001
影响因子：
19.6
通讯作者：
Wilcox,CS
中科院分区：
文献类型：
--
作者：
Welch,WJ;Wilcox,CS
血管紧张素Ⅱ（Ang Ⅱ）1型受体（AT 1-R）对自发性高血压大鼠（SHR）的肾小管-肾小球反馈（TGF-β 1）反应具有过度调节作用。由于AT 1-Rs增强氧自由基（O2-）的产生，我们测试的假设，夸大的TGF是由于减少钝化致密斑（MD）衍生的一氧化氮（NO），因为过度的AT 1-R-依赖的O2-的产生。SHR和对照组WKY大鼠分别给予溶媒（Veh）、AT 1-R拮抗剂坎地沙坦（Cand; 3 mg · kg-1·d-1）或肼苯哒嗪+氢氯噻嗪+利血平（HHR）治疗2周。与WKY大鼠相比，SHR的平均动脉压升高（WKY 125 ± 2 mmHg vs.SHR163 ~ 779 mmHg，P< 0.001）在Cand和HHR的作用下均明显降低（P< 0.001）（121 ± 5 mmHg和116 ± 5 mmHg，P= NS）。SHR的最大TGF反应增加，（在液体的管腔灌注期间停止流动压力的变化：SHR 11.2 ± 0.5对WKY 8.3 ± 0.4 mm Hg，P< 0.01），并且在MD中用管腔7-硝基吲唑阻断神经元NO合酶（nNOS）降低了TGF应答（7-NI：WKY组ΔTGF为2.8 ± 0.4mmHg，SHR组为1.1 ± 0.6mmHg，P< 0.05）。尽管HHR和Cand均能使SHR升高的TGF反应恢复正常，但只有Cand能恢复正常的TGF反应（SHR中7-NI组ΔTGF：Veh + 1.8 ± 0.4vs.Cand + 3.4 ± 0.5mmHg，P< 0.05）。为了消除O2-的局部作用，将tempol（一种膜渗透性超氧化物歧化酶模拟物）灌注到传出小动脉中。在tempol期间，给予载体或HHR的SHR对7-NI阻断nNOS的反应显著增加（在tempol期间，SHR中7-NI的ΔTGF：载体6.3 ± 1.0和HHR 4.5 ± 0.8 mm Hg，P< 0.01，与未给予tempol的SHR相比），这意味着NO的作用由于过量的O2-而被阻止。与此相反，给予Cand的SHR对7-NI的TGF反应不受tempol的影响（tempol期间7-NI的ΔTGF为2.9 ± 0.9，P = NS，与未给予tempol相比）。结论：高血压和AT 1-R的作用使SHR的TGF反应增强。AT 1-R阻断特异性地减少SHR肾小球体中的氧化应激并恢复NO信号传导。
AT1receptor antagonist combats oxidative stress and restores nitric oxide signaling in the SHR.The tubuloglomerular feedback (TGF) responses of the spontaneously hypertensive rat (SHR) are under exaggerated regulation by angiotensin II (Ang II) type 1 receptors (AT1-R). Since AT1-Rs enhance oxygen radical (O2-) generation, we tested the hypothesis that the exaggerated TGF was due to a diminished blunting by macula densa (MD)-derived nitric oxide (NO) because of excessive AT1-R–dependent generation of O2-. Groups of SHR and control Wistar-Kyoto (WKY) rats received vehicle (Veh), the AT1-R antagonist candesartan (Cand; 3 mg · kg-1· day-1), or nonspecific therapy with hydralazine + hydrochlorothiazide + reserpine (HHR) for two weeks. Compared with WKY rats, the elevated mean arterial pressure of SHR (WKY 125 ± 2 vs. SHR 163 to 779 mm Hg,P< 0.001) was reduced (P< 0.001) similarly in SHR by Cand and HHR (121 ± 5 and 116 ± 5 mm Hg,P= NS). The SHR had an increased maximal TGF response (change in stop flow pressure during luminal perfusion of fluid: SHR 11.2 ± 0.5 vs. WKY 8.3 ± 0.4 mm Hg,P< 0.01) and a reduced TGF response to blockade of neuroneal NO synthase (nNOS) in the MD with luminal 7-nitroindazole (7-NI: ΔTGF in WKY 2.8 ± 0.4 vs. SHR 1.1 ± 0.6 mm Hg,P< 0.05). Although the elevated TGF responses of SHR were normalized by both HHR and Cand, only Cand restored a normal TGF response to luminal perfusion of the MD with 7-NI (ΔTGF with 7-NI in SHR: Veh + 1.8 ± 0.4 vs. Cand + 3.4 ± 0.5 mm Hg,P< 0.05). To abrogate the local effects of O2-, tempol (a membrane-permeable superoxide dismutase mimetic) was perfused into the efferent arteriole. During tempol, SHR given vehicle or HHR had a much increased response to blockade of nNOS with 7-NI (ΔTGF in SHR with 7-NI during tempol: Veh 6.3 ± 1.0 and HHR 4.5 ± 0.8 mm Hg,P< 0.01 vs. no tempol for both), implying that the effects of NO had been prevented because of excessive O2-. In contrast, the TGF response to 7-NI in SHR given Cand was unaffected by tempol (ΔTGF with 7-NI during tempol: 2.9 ± 0.9,P= NS, compared with no tempol). In conclusion, TGF responses of SHR are exaggerated because of the effects of hypertension and AT1-R. AT1-R blockade specifically diminishes oxidative stress and restores NO signaling in the juxtaglomerular apparatus of the SHR.