Abstract 079: Long-Lasting RNAi Therapeutics Targeting Angiotensinogen Induces a Robust and Durable Antihypertensive Effect

Abstract

All angiotensin stems from angiotensinogen (AGT). A single dose of small interfering ribonucleic acids (siRNA) targeting AGT may provide long-lasting blood pressure reductions, as it would abolish angiotensin generation. Here we assessed efficacy of AGT siRNA in spontaneously hypertensive rats (SHRs). SHRs were treated for 4 weeks with vehicle, siRNA (10 mg/kg; s.c. every 2 weeks), valsartan (31 mg/kg/day; oral), captopril (100 mg/kg/day; oral), valsartan+siRNA, or captopril+valsartan (all groups n=8). Mean arterial pressure (MAP) was measured via radiotelemetry. Baseline MAP was 137±2 mmHg. ΔMAP was largest after valsartan+siRNA (-67±3 mmHg; P<0.01 vs. captopril+valsartan), followed by captopril+valsartan, captopril, siRNA and valsartan (-55±4, -24±2, -14±1, and -9±2 mmHg, respectively). Valsartan+siRNA reduced cardiac hypertrophy the most (P<0.05 vs. captopril+valsartan). After 4 weeks, siRNA lowered AGT by 98.6%, which increased to 99.9% in combination with valsartan. All treatments increased renin, the highest rise occurring after valsartan+siRNA. Yet, only valsartan+siRNA lowered angiotensin II. No treatment altered aldosterone. Plasma K + tended to increase in all groups, significance being reached only in the valsartan+siRNA group. Both types of dual blockade attenuated normal growth from the second week of treatment onwards. In conclusion, due to renin upregulation, circulating angiotensin II remained intact even with only 1.4% of AGT left, relative to pretreatment. Consequently, AGT siRNA caused a similar antihypertensive effect as valsartan and captopril. Importantly, when combining siRNA+valsartan, angiotensin II collapsed, and blood pressure decreased synergistically. Given the potential for low dosing frequency suggested by this study, this novel treatment may address medication adherence problems in patients with resistant hypertension and further development is warranted.