Iyer S N, Lu D, Katovich M J, Raizada M K
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville 32610, USA.
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9960-5. doi: 10.1073/pnas.93.18.9960.
The renin-angiotensin system plays a crucial role in the development and establishment of the hypertensive state in the spontaneously hypertensive (SH) rat. Interruption of this system's activity by pharmacological means results in the lowering of blood pressure (BP) and control of hypertension. However, such means are temporary and require the continuous use of drugs for the control of this pathophysiological state. Our objective in this investigation was to determine if a virally mediated gene-transfer approach using angiotensin type 1 receptor antisense (AT1R-AS) could be used to control hypertension on a long-term basis in the SH rat model of human essential hypertension. Injection of viral particles containing AT1R-AS (LNSV-AT1R-AS) in 5-day-old rats resulted in a lowering of BP exclusively in the SH rat and not in the Wistar Kyoto normotensive control. A maximal anti-hypertensive response of 33 +/- 5 mmHg was observed, was maintained throughout development, and still persisted 3 months after administration of LNSV-AT1R-AS. The lowering of BP was associated with the expression of AT1R-AS transcript and decreases in AT1-receptor in many peripheral angiotensin II target tissues such as mesenteric artery, adrenal gland, heart, and kidney. Attenuation of angiotensin II-stimulated physiological actions such as contraction of aortic rings and increase in BP was also observed in the LNSV-AT1R-AS-treated SH rat. These observations show that a single injection of LNSV-AT1R-AS normalizes BP in the SH rat on a long-term basis. They suggest that such a gene-transfer strategy can be successfully used to control the development of hypertension on a permanent basis.
肾素-血管紧张素系统在自发性高血压（SH）大鼠高血压状态的发生和发展过程中起着关键作用。通过药理学手段阻断该系统的活性可导致血压降低并控制高血压。然而，这种方法是暂时的，需要持续使用药物来控制这种病理生理状态。我们本次研究的目的是确定使用血管紧张素1型受体反义（AT1R-AS）的病毒介导基因转移方法是否可用于在人类原发性高血压的SH大鼠模型中长期控制高血压。在5日龄大鼠中注射含有AT1R-AS的病毒颗粒（LNSV-AT1R-AS）仅导致SH大鼠血压降低，而在Wistar Kyoto正常血压对照大鼠中则无此现象。观察到最大降压反应为33±5 mmHg，在整个发育过程中均保持，并且在给予LNSV-AT1R-AS 3个月后仍持续存在。血压降低与AT1R-AS转录本的表达以及许多外周血管紧张素II靶组织（如肠系膜动脉、肾上腺、心脏和肾脏）中AT1受体的减少有关。在LNSV-AT1R-AS处理的SH大鼠中还观察到血管紧张素II刺激的生理作用减弱，如主动脉环收缩和血压升高。这些观察结果表明，单次注射LNSV-AT1R-AS可使SH大鼠的血压长期恢复正常。它们表明这种基因转移策略可成功用于长期控制高血压的发展。
