Activation of Brain Angiotensin Type‐2 Receptors Reverses DOCA‐salt Hypertension in Mice

Abstract

These studies assess the impact of activating brain angiotensin type‐2 receptors (AT2R) on blood pressure in a mouse model of hypertension. Experiments combine the use of a transgenic AT2R green fluorescent protein reporter mouse with in situ hybridization (ISH) to reveal that AT2R‐containing cells are localized to brain regions that regulate cardiovascular function. In particular, the nucleus of the solitary tract (NTS) densely expresses AT2R, primarily in glutamic acid decarboxylase‐1 (Gad1)‐containing (i.e., GABAergic) neurons. Based on this localization and the known hypertensive actions of GABA in the NTS, we hypothesized that brain AT2R activation would reverse hypertension in mice via the inhibition of NTS GABA signaling. Mice were initially rendered hypertensive via administration of deoxycorticosterone acetate and consumption of isotonic saline (DOCA‐salt) or served as normotensive controls. Subsequently, the impact of the chronic administration of the selective AT2R agonist, compound 21 (C21; 7.5 ng/h into the lateral cerebral ventricle [icv]) on blood pressure and gene expression within the NTS were assessed. Chronic icv C21 reduced baseline blood pressure relative to control mice and reversed DOCA‐salt hypertension. Gene expression studies revealed that DOCA‐salt hypertension was associated with elevated Gad1 and AT2R mRNAs within the NTS. The antihypertensive actions of C21 were associated with decreased Gad1 mRNA in the NTS, suggestive of reduced GABAergic signaling. Collectively, the present results indicate that AT2R activation using C21 reverses DOCA‐salt hypertension and that this is accompanied by alterations in NTS gene expression that are consistent with NTS GABAergic signaling playing a role in these effects.