Abstract Body: Introduction: One subcutaneous injection of angiotensinogen-targeting small-interfering RNA (AGT siRNA) is able to suppress hepatic AGT synthesis for >6 months, thus inducing prolonged blood pressure-lowering effects.
Hypothesis: Both the reverse siRNA silencing technology (REVERSIR, RVR) and a high salt diet (HSD) can reverse the blood pressure drop in AGT siRNA-treated spontaneously hypertensive rats within several days. To also evaluate such reversal in hypotensive conditions, we treated salt-depleted, normotensive Wistar Kyoto (WKY) rats with AGT siRNA, and then exposed them to RVR, HSD or RVR + HSD.
Methods: Ten-week old WKY rats were placed on a low salt diet and treated with 10 mg/kg AGT siRNA. Three weeks later they were given RVR (0.1, 1, or 10 mg/kg), HSD or HSD + RVR 10 mg/kg. Mean arterial pressure (MAP) was monitored by radiotelemetry, and circulating AGT and renin were measured by enzyme-kinetic assay.
Results: Baseline MAP was 105±3 mm Hg. AGT siRNA lowered MAP by »12 mm Hg and suppressed AGT by >95%, while renin rose 5-fold. RVR 0.1 mg/kg was without effect. RVR 1 mg/kg restored AGT by 50% and partially normalized renin, allowing MAP to return to baseline. RVR 10 mg/kg fully normalized AGT and renin, and induced the same MAP return as RVR 1 mg/kg. HSD did not affect AGT, and partially normalized renin and MAP. RVR 10 mg/kg + HSD fully normalized AGT and renin, and this combination was accompanied by the largest MAP rise, allowing MAP to rise above baseline. The MAP rise after RVR + HSD equaled the sum of the separate effects of these treatments. All MAP rises were maximal within 2-3 days.
Conclusions: AGT siRNA (10 mg/kg) lowers MAP in WKY rats under low salt diet conditions. RVR at a dose of 1 mg/kg fully restored MAP, and this effect was not different at higher RVR doses. HSD partially restored MAP, and enhanced the RVR-induced recovery of blood pressure after AGT siRNA treatment under hypotensive conditions.