CHRONIC CONTROL OF HIGH BLOOD-PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT BY DELIVERY OF ANGIOTENSIN TYPE-1 RECEPTOR ANTISENSE

The renin-angiotensin system plays a crucial role in the development a nd establishment of the hypertensive state in the spontaneously hypert ensive (SH) rat. Interruption of this system's activity by pharmacolog ical means results in the lowering of blood pressure (BP) and control of hypertension. However, such means are temporary and require the con tinuous use of drugs for the control of this pathophysiological state. Our objective in this investigation was to determine if a virally med iated gene-transfer approach using angiotensin type 1 receptor antisen se (AT(1)R-AS) could be used to control hypertension on a long-term ba sis in the SH rat model of human essential hypertension. Injection of viral particles containing AT(1)R-AS (LNSV-AT(1)R-AS) in 5-day-old rat s resulted in a lowering of BP exclusively in the SH rat and not in th e Wistar kyoto normotensive control. A maximal anti-hypertensive respo nse of 33 +/- 5 mmHg was observed, was maintained throughout developme nt, and still persisted 3 months after administration of LNSV-AT(1)R-A S. The lowering of BP was associated with the expression of AT(1)R-AS transcript and decreases in AT(1)-receptor in many peripheral angioten sin II target tissues such as mesenteric artery, adrenal gland, heart, and kidney. Attenuation of angiotensin II-stimulated physiological ac tions such as contraction of aortic rings and increase in BP was also observed in the LNSV-AT(1)R-AS-treated SH rat. These observations show that a single injection of LNSV-AT(1)R-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 o n a permanent basis.