Reversal of hypertension by angiotensin II type 1 receptor antisense gene therapy in the adult SHR
Reversal of hypertension by angiotensin II type 1 receptor antisense gene therapy in the adult SHR
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DOI：
10.1152/ajpheart.1999.277.3.h1260
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发表时间：
1999-09-01
影响因子：
4.8
通讯作者：
Raizada, MK
中科院分区：
文献类型：
--
作者：
Katovich, MJ;Gelband, CH;Raizada, MK
在高血压患者和动物模型如自发性高血压大鼠（SHR）中，药物阻断肾素-血管紧张素系统可有效降低血压（BP）。最近的研究已经确定，病毒介导的递送（载体LNSV）血管紧张素II 1型受体（LNSV-AT（1）R-AS）的反义将减轻或消除SHR中高血压的发展。然而，这种基因治疗方法一旦在成人中建立，降低高血压的有效性尚未确定。在本研究中，我们研究了病毒递送AT（1）R-AS到成年SHR中将降低血压并逆转与高血压相关的血管反应性的假设。将含有LNSV-AT 1 R-AS的病毒颗粒心内注射到成年人中：与单独用病毒治疗的SHR（无反义LNSV）相比，SHR导致血压降低30- 60 mmHg，并维持长达36天。肾阻力小动脉反应性的测量表明，在KCl和苯肾上腺素的浓度-反应关系和受损的血管内皮依赖性舒张ACh在LNSV治疗的SHR与对照组相比，Wistar-Kyoto大鼠的一个显著变化。这些血管变化在LNSV-AT（1）R-AS治疗的SHR中被逆转。总的来说，这些数据表明，病毒介导的AT 1 R-AS基因传递可以有效地降低血压和逆转肾血管病理生理与高血压状态时，给药到成年SHR。
Pharmacological blockade of the renin-angiotensin system in both hypertensive patients and animal models such as the spontaneously hypertensive rat (SHR) effectively reduces blood pressure (BP). Recent studies have established that virally mediated delivery (vector LNSV) of antisense to the angiotensin II type 1 receptor (LNSV-AT(1)R-AS) will attenuate or abolish the development of hypertension in the SHR. How; ever, the effectiveness of this gene therapy approach to reduce high BP once it is established in the adult has not been ascertained. In this study, we investigated the hypothesis that viral delivery of AT(1)R-AS into the adult SHR will reduce BP and reverse the vascular reactivity associated with the hypertension. Intracardiac injection of virus particles containing LNSV-AT1R-AS into adult: SHR resulted in a 30- to 60-mmHg reduction in BP that was maintained for up to 36 days compared with SHR treated with virus alone (LNSV without antisense). Measurement of renal resistance arteriolar reactivity demonstrated a leftward shift in the KCI and phenylephrine concentration-response relationships and an impaired endothelium-dependent relaxation to ACh in LNSV-treated SHR compared with control Wistar-Kyoto rats. These vascular alterations were reversed in the LNSV-AT(1)R-AS-treated SHR. Collectively, these data demonstrate that virally mediated gene delivery of AT1R-AS can effectively reduce BP and reverse renovascular pathophysiology associated with the hypertensive state when administered to the adult SHR.