CONTROL OF ANTIHYPERTENSIVE EFFECT MEDIATED BY SMALL INTERFERING RNA TARGETING ANGIOTENSINOGEN

Abstract

Objective: A single dose of small interfering ribonucleic acids (siRNA) targeting angiotensinogen (AGT) provides a strong and durable antihypertensive effect, lasting weeks to months in preclinical models. Here, we investigated whether conventional vasopressors can elevate arterial pressure under conditions of AGT depletion and reverse RNAi-mediated blood pressure lowering. Design and method: Spontaneously hypertensive rats on a low-salt diet (<0.03% NaCl) were treated for 4 weeks with siRNA (10 mg/kg fortnightly; s.c.), supplemented with fludrocortisone (6 mg/kg/day; s.c.), midodrine (4 mg/kg/day; s.c.) or a high-salt diet (4% NaCl) during the final 2 weeks (n = 6–7 per group). Before and after 2 weeks of siRNA, blood pressure responses to intravenous bolus injections of angiotensin II (0.05; 0.5 and 5 mg/kg) and noradrenalin (0.1; 1.0 and 10 mg/kg) were recorded via radiotelemetry in anaesthetised rats. Results: Baseline mean arterial pressure (MAP; 136 ± 3 mmHg) was lowered by 19 ± 1 mmHg by AGT siRNA in combination with a low-salt diet. Acute pressor responses to angiotensin II and noradrenalin were identical before and after siRNA. Fludrocortisone restored MAP to baseline levels (137 ± 3 mmHg), as did replacing the low-salt diet with a high-salt diet (139 ± 4 mmHg). Midodrine had no effect. Under low salt conditions, siRNA virtually abolished plasma AGT by 99.2 ± 0.1% to 6 ± 1 nM, and increased active plasma renin concentrations. AGT was not altered by midodrine, only marginally raised by high sodium intake, but increased to 20 ± 5% of pre-siRNA treatment levels by fludrocortisone, paralleled by near-elimination of plasma renin levels by 98 ± 1% to 2.1 ± 0.9 ng angiotensin I/mL/h. Conclusions: The efficacy of angiotensin II and noradrenaline to raise blood pressure is not affected by RNAi-mediated AGT suppression. Increased sodium intake or fludrocortisone may represent chronic, less invasive alternatives for controlling blood pressure during AGT depletion, of which the latter seems to be facilitated by amplification of AGT production.