Abstract 020: Physiological Significance of Angiotensin AT 1A Receptors in Vasopressin-producing Cells of the Supraoptic Nucleus

Abstract

Low-renin and salt-sensitive forms of hypertension are characterized by elevated activity of the brain renin-angiotensin system and secretion of arginine vasopressin (AVP). While angiotensin in the brain is a known stimulant of AVP secretion through its AT 1 receptor, the localization of relevant AT 1 receptors remains unclear. We tested whether AT 1A receptors localized to AVP-producing cells are important for AVP secretion. To examine AVP and AT 1A co-localization, mice expressing Cre-recombinase via the AVP gene (AVP-Cre) were bred with mice expressing a conditional red fluorescent ROSA-stop flox -tdTomato construct and GFP via an AT 1A BAC transgene. Dual-fluorescent cells were detected in supraoptic nuclei (SON) but not paraventricular nuclei. Mice lacking AT 1A specifically in AVP-producing cells (AT 1A AVP-KO ) were then generated by breeding AVP-Cre mice with mice harboring a conditional endogenous AT 1A gene. AT 1A AVP-KO mice exhibited normal serum (littermate n=13, 353±69 vs AT 1A AVP-KO n=7, 207±37 pg/mL, p=NS) and urine (n=26, 145±33 vs n=11, 170±54 pg/mL, p=NS) copeptin (the stable C-terminal fragment of AVP) as well as hematocrit (n=14, 46.3±0.7 vs n=7, 47.5±1.3 %, p=NS) despite increased serum osmolality (n=33, 324±1.3 vs n=19, 330±1.6 mOsm/kg, p<0.01), supporting a role for AT 1A in AVP-producing cells in modulating the osmotic control of AVP release. Systolic blood pressure (SBP) (n=18, 109±1.3 vs n=5, 107±1.2 mmHg), urine volume (n=27, 1.1±0.1 vs n=12, 0.9±0.2 mL/d), and fluid intake (n=27, 4.0±0.2 vs n=12, 3.9±0.2 mL/d) were all normal (p=NS) in AT 1A AVP-KO mice. Two-bottle choice between water and escalating concentrations of NaCl uncovered minor alterations in sodium intake behavior. Serum osmolality (n=22, 336±2 vs n=9, 333±3 mOsm/kg), SBP (n=23, +10.4±2.1 vs n=8, +12.9±2.0 mmHg), urine output (n=23, +12.7±0.8 vs n=9, +12.7±1.5 g/day), and fluid intake (n=23, +16.2±1.3 vs n=9, +14.8±2.5 mL/day) all increased normally (p=NS) in response to deoxycorticosterone acetate (DOCA)-salt treatment. Collectively these data support a role for AT 1A receptors, localized specifically to AVP-expressing cells of the SON, in the normal osmotic control of AVP secretion.