Abstract 104: DOCA Induced Natriorexigenic and Hypertensive Effects are Blunted by Central Infusion of AT1 Receptor Biased Agonist TRV120027

Abstract

TRV120027 (TRV) is biased agonist at the angiotensin AT1 receptor that activates the β-arrestin pathway, causing receptor internalization. AT1 signaling within the hypothalamus is required for the blood pressure, polydipsia, and sodium appetite phenotypes in the deoxycorticosterone acetate (DOCA)-salt model of salt-sensitive hypertension (HTN). We hypothesized that TRV action within the hypothalamus would antagonize the effects of DOCA-salt. Using a novel luciferase-based HiBit tagging assay, we confirmed that TRV decreased AT1 surface density in immortalized mouse hypothalamic N43/5 cells by 35±4% compared to vehicle (n=4, p<0.05), and this was prevented by pretreatment with losartan. TRV (0.05 μg/h, icv n=5-10) or aCSF (n=4-8) were chronically infused into C57BL/6J mice implanted with DOCA (50 mg, sc) pellets, compared with mice undergoing sham surgeries (CTL, n=5-8), and animals were offered chow, water and NaCl ad libitum . DOCA increased fluid intake at baseline (CTL 4±0 vs 15±1 mL/day DOCA+aCSF, p<0.05), 0.15 mol/L NaCl (3.8±0 vs 20±2, p<0.05), 0.3 mol/L (4±0 vs 26±2, p<0.05), and 0.45 mol/L (4±0 vs 28±3, p<0.05). DOCA-induced polydipsia was not affected by TRV at baseline (DOCA+aCSF 19±1 vs 15±0 mL/day, p>0.05), 0.15 mol/L NaCl (27±4 vs 20±2 mL/day, p>0.05), 0.3 mol/L (25±4 vs 26±2 mL/day, p>0.05), or 0.45 mol/L (25±3 vs 28±3 mL/day, p>0.05). However, TRV prevented DOCA-induced increase of NaCl preference at NaCl 0.15 mol/L (DOCA+aCSF 29±1 vs 14±2% DOCA+TRV, p<0.05), 0.30 mol/L (29±3 vs 5±1%, p<0.05), and 0.45 mol/L (29±3 vs 5±1%, p<0.05). DOCA+aCSF exhibited increased heart weight / tibia length (CTL 8±0 vs 10±0 g/m DOCA+aCSF, p<0.05), which was prevented by TRV (8±0, p<0.05). In a separate cohort, DOCA-implanted mice were provided only 0.9% NaCl drink for one week, and mean arterial pressure (MAP) was recorded after acute injection of TRV (2 μg icv n=5) or aCSF (n=5). MAP was elevated with DOCA-salt (141±5 mmHg), and at 40 minutes post injection, TRV decreased MAP by 17±4 mmHg (p<0.05). These data underscore the potential for AT1 receptor-biased agonists as tools to treat subtypes of HTN characterized by salt sensitivity and low circulating renin activity.