Hyperactivity of the brain renin-angiotensin system (RAS) is implicated in the development and maintenance of arterial hypertension (HTA). We previously showed that angiotensin III (AngIII) is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over blood pressure (BP) in alert hypertensive rats. Therefore, aminopeptidase A (APA) the enzyme generating brain AngIII, represents a new therapeutic target for the treatment of HTA. This led to the development of RB150 (also known as QGC001), a prodrug of the specific and selective APA inhibitor, EC33. When given orally, RB150 is able to cross the blood-brain-barrier, to inhibit brain APA activity and to decrease BP in two experimental models of HTA. We investigate here the effects of repeated oral administrations of RB150 (50 mg/kg/day) over 10 days on BP in conscious DOCA-salt rats to assess if a tolerance to the antihypertensive RB150 effect occurs after chronic treatment.
Design and method:
For this purpose, 5 hours after RB150 administration, we measured daily variations in systolic BP (sBP) by the tail-cuff method, plasma arginine-vasopressin (AVP) levels by radioimmunoassay and metabolic parameters
Chronic oral treatment with RB150 significantly decreased sBP compared with saline over the 10 days treatment period, without significantly altering heart rate. The maximal decrease in sBP (−29.6 ± 6 mmHg) was observed on the second day and the average RB150-induced decrease in sBP over 10 days was not significantly changed (−21 ± 5 mmHg), showing no tolerance to the antihypertensive effect of RB150 after repeated administrations. Chronic oral treatment with RB150 reduced by 59% the increase in plasma AVP levels observed in DOCA-salt rats compared with normotensive rats receiving saline. The administration of RB150 increased significantly diuresis by 39% and natriuresis by 34% without modification of plasma sodium and potassium levels when compared to DOCA-salt rats receiving saline over a 10 days analysis. This may participate to the blood pressure decrease by reducing the size of fluid compartment.
Our results further confirm the interest of developing RB150 as a novel centrally-acting agent for the treatment of HTA.