Abstract 627: Antisense Inhibition Of Angiotensinogen Reduces BP In Normotensive Sprague-Dawley Rats And Effectively Eliminates RAS-dependent BP Control In Hypertensive SHR Rats
Uncontrolled hypertension is an important contributor to stroke, myocardial infarction, heart failure and renal failure. Despite the armamentarium of antihypertensive therapeutics, there still exists a need for a novel agent effective in individuals with Resistant Hypertension (RHTN). Second generation antisense oligonucleotides (ASOs) are a novel therapeutic class of inhibitors that cause RNase H-mediated target mRNA degradation in organs such as the liver and kidneys. Experiments were conducted to determine the efficacy of ASO treatment targeting angiotensinogen (Agt). Normotensive Sprague-Dawley rats were given 10 - 80 mg/kg/wk of an Agt ASO for 4 weeks via subcutaneous injections. Dose-responsive reductions of liver Agt mRNA (20 - 96%), kidney Agt mRNA (40 - 75%) and plasma Agt (25 - 90%) were observed. BP, measured by tail-cuff volume-pressure recordings, was dose-dependently reduced by Agt ASO treatments as well. At the maximal ASO dose SBP, MAP and DBP were reduced by 39, 43 and 45 mm Hg, respectively. Studies comparing Agt ASO to captopril treatments were conducted in SHR rats. Agt ASO administered at 50, 75 or 100 mg/kg/wk for 2 weeks resulted in dose-dependent reductions of BP of 35 - 57 mm Hg (SBP), 32 - 52 mm Hg (MAP) and 31 - 49 mm Hg (DBP). Addition of 50 mg/kg/day of captopril did not result in further BP reductions in rats receiving 100 mg/kg/wk Agt ASO, suggesting maximal inhibition of RAS signaling was already achieved via Agt ASO treatment in this group. However, captopril treatment in the 50 and 75 mg/kg/wk Agt ASO treated groups did result in further reductions of 17 & 27 mm Hg (SBP), 17 & 25 mm Hg (MAP) and 17 & 24 mm Hg (DBP). These data demonstrate robust and predictive reductions of BP with long term Agt ASO treatment in normo- or hypertensive rats. Additionally, complete inhibition of RAS-dependent BP control could be achieved within 2 wks of ASO treatment. Finally, additive BP lowering was achieved with the combination treatment of Agt ASO and captopril, suggesting improvements in efficacy are possible when ASOs are added to existing RAS inhibitor therapeutics. Such improvements could be desirable in RHTN individuals and/or individuals not at their BP goal with existing RAS inhibitors.
- © 2012 by American Heart Association, Inc.