REVERSIR at 1 mg/kg fully restored mean arterial pressure to baseline (105 mm Hg) after a 12 mm Hg drop induced by AGT siRNA, with high salt diet providing an additive effect.
Does REVERSIR and/or high salt diet reverse the blood pressure-lowering effects of AGT siRNA in salt-depleted WKY rats?
REVERSIR technology fully restores blood pressure after AGT siRNA treatment in hypotensive rats, and high salt diet enhances this recovery.
Objective: One subcutaneous injection of angiotensinogen-targeting small-interfering RNA (AGT siRNA) is able to suppress hepatic AGT synthesis for >6 months, inducing prolonged blood pressure-lowering effects. Both REVERSIR (RVR)-reverse siRNA silencing technology 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. Design and method: 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 its combination showed the largest MAP rise, even 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 LSD 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. The effects of RVR and HSD were additive. These data imply that RVR but not high salt alone is capable of fully restoring blood pressure in this model, and that high salt enhances the RVR-induced recovery of blood pressure after AGT siRNA treatment under hypotensive conditions.
López et al. (Fri,) conducted a other in Hypotension induced by AGT siRNA. REVERSIR (RVR) and High Salt Diet (HSD) vs. Baseline / AGT siRNA alone was evaluated on Mean arterial pressure (MAP). REVERSIR at 1 mg/kg fully restored mean arterial pressure to baseline (105 mm Hg) after a 12 mm Hg drop induced by AGT siRNA, with high salt diet providing an additive effect.