Thirst and blood pressure regulation in a novel angiotensin II receptor type 1a knockout rat

Angiotensin II (AngII) plays a pivotal role in body fluid balance through AngII type 1 receptors (Agtr1) expressed in circumventricular organs to stimulate thirst. Blockade of central Agtr1 attenuates thirst to hypotension but not acute hypernatremia. Data in genetic knockout models are limited as systemic AngII does not stimulate thirst in mice, and Agtr1a^-/- mice are severely hypotensive. Therefore, we generated a novel Agtr1a^-/- rat using CRISPR-Cas9 to produce an 11-bp frame-shift deletion in exon 3. Baseline mean arterial blood pressure (ABP) was approximately 10 mmHg lower in Agtr1a^-/- vs. wild-type (WT) rats with no differences in heart rate. Depressor responses to ganglionic blockade, vasopressin receptor blockade, or angiotensin converting enzyme inhibition were not different between strains. Systemic AngII (40 ng/min, IV) significantly increased water intake and mean ABP in WT rats, but these responses were absent in Agtr1a^-/- rats. Hypotension-induced thirst produced by the vasodilator diazoxide (25 mg/kg, IV) stimulated water intake in WT but not in Agtr1a^-/- rats. In contrast, water intake stimulated by hypernatremia (2 M NaCl, IV) or overnight water deprivation was not different between strains. These findings support a critical role for Agtr1a in thirst induced by AngII and hypotension but not by hypernatremia or overnight water deprivation.