Kagiyama S, Varela A, Phillips M I, Galli S M
Department of Physiology, School of Medicine, University of Florida, Gainesville, Florida, USA.
Hypertension. 2001 Feb;37(2 Pt 2):371-5. doi: 10.1161/01.hyp.37.2.371.
The systemic renin-angiotensin system (RAS) plays an important role in blood pressure (BP) regulation during the development of 2-kidney, 1 clip (2K1C) hypertension. Its contributions decrease with time after constriction of the renal artery. During the chronic phase, the peripheral RAS returns to normal, but the hypertension is sustained for months. We hypothesized that in this phase the brain RAS contributes to the maintenance of high BP. To test the hypothesis, we studied the role of brain RAS by decreasing the synthesis of angiotensinogen (AGT) and the angiotensin II (Ang II) type 1a receptor (AT(1)R) with intracerebroventricular injections of antisense oligonucleotides (AS-ODNs). The response of systolic BP (SBP) to AS-ODNs to AGT mRNA was studied in 2K1C rats at 6 months after clipping, and the response to AS-ODNs to AT(1)R mRNA was studied at 10 months after clipping. Intracerebroventricular injection of AS-ODN-AGT (200 microgram/kg, n=5) significantly decreased SBP (-22+/-6 mm Hg, P<0.05) compared with the sense ODN (n=5) and saline (n=3) groups. Intracerebroventricular injection of AS-ODN-AGT reduced the elevated hypothalamic Ang II level. The hypothalamic Ang II content in sense ODN and saline groups was significantly (P<0.05) higher than in the nonclipped group. Compared with inverted ODN, intracerebroventricular injection of AS-ODN-AT(1)R (250 microgram/kg, n=6) significantly decreased SBP (-26+/-8 mm Hg, P<0.05) for 3 days after injection. This was a brain effect because intravenous AS-ODN-AT(1)R at a dose of 250 to 500 microgram/kg did not affect SBP. These results suggest that the brain RAS plays an important role in maintaining the elevated SBP in chronic 2K1C hypertension.
在二肾一夹（2K1C）高血压形成过程中，全身肾素-血管紧张素系统（RAS）在血压（BP）调节中起重要作用。肾动脉缩窄后，其作用随时间推移而减弱。在慢性期，外周RAS恢复正常，但高血压可持续数月。我们推测在此阶段脑RAS有助于维持高血压状态。为验证该假说，我们通过脑室内注射反义寡核苷酸（AS-ODNs）降低血管紧张素原（AGT）和血管紧张素II（Ang II）1a型受体（AT(1)R）的合成，研究脑RAS的作用。在夹闭后6个月的2K1C大鼠中研究收缩压（SBP）对针对AGT mRNA的AS-ODNs的反应，在夹闭后10个月研究对针对AT(1)R mRNA的AS-ODNs的反应。与正义寡核苷酸组（n = 5）和生理盐水组（n = 3）相比，脑室内注射AS-ODN-AGT（200微克/千克，n = 5）显著降低SBP（-22±6毫米汞柱，P<0.05）。脑室内注射AS-ODN-AGT降低了下丘脑升高的Ang II水平。正义寡核苷酸组和生理盐水组的下丘脑Ang II含量显著高于未夹闭组（P<0.05）。与错义寡核苷酸相比，脑室内注射AS-ODN-AT(1)R（250微克/千克，n = 6）在注射后3天显著降低SBP（-26±8毫米汞柱，P<0.05）。这是一种脑效应，因为静脉注射剂量为250至500微克/千克的AS-ODN-AT(1)R不影响SBP。这些结果表明，脑RAS在慢性2K1C高血压中维持升高的SBP方面起重要作用。
