Abstract P060: Angiotensin AT1A Receptors on Vasopressin-Expressing Cells are Dispensable for DOCA-salt Hypertension

Abstract

Increased blood pressure in the deoxycorticosterone acetate (DOCA)-salt model of low-renin hypertension is correlated with increased vasopressin (AVP) secretion, and is sensitive to inhibition of the brain renin-angiotensin system (RAS). Further, AVP-deficient Brattleboro rats are largely resistant to DOCA-salt hypertension. These findings lead us to hypothesize a role for AT1A receptors localized to AVP-expressing neurons in the control of AVP secretion, specifically in low-renin hypertension. Blood pressure was assessed via tail-cuff plesthysmography and total daily AVP secretion assessed via urine copeptin in mice with specific disruption of the AT1A gene in AVP-expressing cells (AVP-Cre x AT1Aflox/flox mice, “KO”) under both baseline and DOCA-salt treatment conditions. Specific activity of Cre-recombinase within the paraventricular and supraoptic nuclei of AVP-Cre transgenic mice was confirmed by fluorescent microscopy in brain sections from mice expressing a conditional fluorescent reporter (AVP-Cre x ROSA-stopflox-tdTomato mice). At baseline, AVP secretion (via urine copeptin) trended downward with large variation (control n=17, 363±182 vs KO n=5, 33±11 pg/day; p>0.05) but there was no significant difference in blood pressure (control n=27, 107±1.3 vs KO n=12, 111±2.2 mmHg; p>0.05) compared to littermate controls. In response to DOCA-salt, blood pressure (control n=23, +10.35±2.1 vs KO n=8, +12.91±2.0; p>0.05), urine output (control n=23, +12.65±0.8 vs KO n=9, +12.73±1.5 g/day; p>0.05), and fluid intake (control n=23, +16.17±1.3 vs KO n=9, +14.83±2.5 mL/day; p>0.05) increased normally in KO mice. Preliminary findings indicate normal or possibly exaggerated urine copeptin levels in KO mice following DOCA-salt, and an exaggerated AVP release in response to increasing serum osmolality. Collectively, these data suggest that AT1A receptors on AVP expressing cells are required to mediate baseline secretion of AVP, but that these receptors are dispensable for DOCA-salt mediated increases in circulating AVP and blood pressure.