Losartan versus gene therapy - Chronic control of high blood pressure in spontaneously hypertensive rats

Interruption of the renin-angiotensin system by pharmacological manipulations attenuates high blood pressure (BP) in the spontaneously hypertensive rat (SHR). However, these agents, such as losartan, need to be administered daily to maintain effective BP control. Therefore, we have hypothesized that a genetic intervention in the expression of angiotensin type 1 receptor (AT(1)R) should attenuate development of hypertension on a long-term basis in SHR. A retroviral-mediated AT(1)R antisense cDNA gene delivery system (LNSV-AT(1)R-AS) was used to test this hypothesis and to compare its BP-lowering effects with those of losartan. Introduction of LNSV-AT(1)R-AS into 5-day-old Wistar-Kyoto rats and SHR resulted in a robust expression of AT(1)R antisense (AS) within 3 days and persisted for at least 30 days. This expression was associated with a selective attenuation of high BP in SHR by 25 to 30 mm Hg. Although basal lowering of BP was exclusive to SHR, the angiotensin II (Ang II) presser response was significantly reduced in all LNSV-AT(1)R-AS-treated rats. The decreased response to Ang II was associated with a similar attenuation of Ang II-induced dipsogenic responses in both strains of rats. The BP-lowering effects of LNSV-AT(1)R-AS treatment and losartan treatment were similar and primarily observed in SHR. However, the antihypertensive effect lasted less than 24 hours in losartan-treated SHR compared with 90 days in LNSV-AT(1)R-AS-treated SHR. In addition, losartan was unable to further lower BP in LNSV-AT(1)R-AS-treated SHR. Collectively, these results suggest that both losartan and LNSV-AT,R-AS treatment produces an antihypertensive response selectively in SHR that is mediated by interruption of AT(1)R function. However, a single, acute genetic treatment with LNSV-AT(1)R-AS can result in long-term control of high BP at a similar level of effectiveness as losartan, without altering plasma Ang II levels.