Siragy H M, Carey R M
Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA.
J Clin Invest. 1997 Jul 15;100(2):264-9. doi: 10.1172/JCI119531.
The angiotensin AT2 receptor modulates renal production of cyclic guanosine 3',5'-monophosphate (cGMP; J. Clin. Invest. 1996. 97:1978-1982). In the present study, we hypothesized that angiotensin II (Ang II) acts at the AT2 receptor to stimulate renal production of nitric oxide leading to the previously observed increase in cGMP. Using a microdialysis technique, we monitored changes in renal interstitial fluid (RIF) cGMP in response to intravenous infusion of the AT2 receptor antagonist PD 123319 (PD), the AT1 receptor antagonist Losartan, the nitric oxide synthase (NOS) inhibitor nitro--arginine-methyl-ester (-NAME), the specific neural NOS inhibitor 7-nitroindazole (7-NI), or Ang II individually or combined in conscious rats during low or normal sodium balance. Sodium depletion significantly increased RIF cGMP. During sodium depletion, both PD and -NAME caused a similar decrease in RIF cGMP. Combined administration of PD and -NAME decreased RIF cGMP to levels observed with PD or -NAME alone or during normal sodium intake. During normal sodium intake, Ang II caused a twofold increase in RIF cGMP. Neither PD nor -NAME, individually or combined, changed RIF cGMP. Combined administration of Ang II and either PD or -NAME produced a significant decrease in RIF cGMP compared with that induced by Ang II alone. Combined administration of Ang II, PD, and -NAME blocked the increase in RIF cGMP produced by Ang II alone. During sodium depletion, 7-NI decreased RIF cGMP, but the reduction of cGMP in response to PD alone or PD combined with 7-NI was greater than with 7-NI alone. During normal sodium intake, 7-NI blocked the Ang II-induced increase in RIF cGMP. PD alone or combined with 7-NI produced a greater inhibition of cGMP than did 7-NI alone. During sodium depletion, 7-NI (partially) and -NAME (completely) inhibited RIF cGMP responses to -arginine. These data demonstrate that activation of the renin- angiotensin system during sodium depletion increases renal nitric oxide production through stimulation by Ang II at the angiotensin AT2 receptor. This response is partially mediated by neural NOS, but other NOS isoforms also contribute to nitric oxide production by this pathway.
血管紧张素AT2受体调节肾脏中环磷酸鸟苷（cGMP）的生成（《临床研究杂志》，1996年，97卷：1978 - 1982页）。在本研究中，我们假设血管紧张素II（Ang II）作用于AT2受体以刺激肾脏一氧化氮的生成，从而导致先前观察到的cGMP增加。使用微透析技术，我们监测了清醒大鼠在低钠或正常钠平衡状态下，静脉输注AT2受体拮抗剂PD 123319（PD）、AT1受体拮抗剂氯沙坦、一氧化氮合酶（NOS）抑制剂硝基 - 精氨酸甲酯（L - NAME）、特异性神经元NOS抑制剂7 - 硝基吲唑（7 - NI）或单独或联合使用Ang II时肾间质液（RIF）中cGMP的变化。钠耗竭显著增加RIF cGMP。在钠耗竭期间，PD和L - NAME均使RIF cGMP出现类似程度的降低。PD和L - NAME联合给药使RIF cGMP降至单独使用PD或L - NAME时或正常钠摄入时所观察到的水平。在正常钠摄入期间，Ang II使RIF cGMP增加两倍。单独或联合使用PD或L - NAME均未改变RIF cGMP。与单独使用Ang II相比，Ang II与PD或L - NAME联合给药均使RIF cGMP显著降低。Ang II、PD和L - NAME联合给药阻断了单独使用Ang II所引起的RIF cGMP增加。在钠耗竭期间，7 - NI降低RIF cGMP，但单独使用PD或PD与7 - NI联合使用时cGMP的降低幅度大于单独使用7 - NI时。在正常钠摄入期间，7 - NI阻断了Ang II诱导的RIF cGMP增加。单独使用PD或PD与7 - NI联合使用对cGMP的抑制作用大于单独使用7 - NI时。在钠耗竭期间，7 - NI（部分）和L - NAME（完全）抑制RIF cGMP对精氨酸的反应。这些数据表明，钠耗竭期间肾素 - 血管紧张素系统的激活通过Ang II作用于血管紧张素AT2受体刺激增加肾脏一氧化氮生成。这种反应部分由神经元NOS介导，但其他NOS同工型也通过该途径对一氧化氮生成有贡献。
