Reversal of hypertension by angiotensin II type 1 receptor antisense gene therapy in the adult SHR

Pharmacological blockade of the renin-angiotensin system in both hypertensi ve patients and animal models such as the spontaneously hypertensive rat (S HR) effectively reduces blood pressure (BP). Recent studies have establishe d that virally mediated delivery (vector LNSV) of antisense to the angioten sin II type 1 receptor (LNSV-AT(1)R-AS) will attenuate or abolish the devel opment of hypertension in the SHR. How; ever, the effectiveness of this gen e therapy approach to reduce high BP once it is established in the adult ha s 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 t he vascular reactivity associated with the hypertension. Intracardiac injec tion 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 com pared with SHR treated with virus alone (LNSV without antisense). Measureme nt of renal resistance arteriolar reactivity demonstrated a leftward shift in the KCI and phenylephrine concentration-response relationships and an im paired endothelium-dependent relaxation to ACh in LNSV-treated SHR compared with control Wistar-Kyoto rats. These vascular alterations were reversed i n 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 re verse renovascular pathophysiology associated with the hypertensive state w hen administered to the adult SHR.