Angiotensin Type 1a Receptors in the Subfornical Organ Are Required for Deoxycorticosterone Acetate-Salt HypertensionNovelty and Significance
Although elevated renin–angiotensin system activity and angiotensinergic signaling within the brain are required for hypertension, polydipsia, and increased metabolic rate induced by deoxycorticosterone acetate (DOCA)-salt, the contribution of specific receptor subtypes and brain nuclei mediating these responses remains poorly defined. We hypothesized that angiotensin type 1a receptors (AT1aR) within the subfornical organ (SFO) mediate these responses. Transgenic mice carrying a conditional allele of the endogenous AT1aR (AT1aRflox) were administered an adenovirus encoding Cre-recombinase and enhanced green fluorescent protein (eGFP) or adenovirus encoding eGFP alone into the lateral cerebral ventricle. Adenovirus encoding Cre-recombinase reduced AT1aR mRNA and induced recombination in AT1aRflox genomic DNA specifically in the SFO, without significant effect in the paraventricular or arcuate nuclei, and also induced SFO-specific recombination in ROSATdTomato reporter mice. The effect of SFO-targeted ablation of endogenous AT1aR was evaluated in AT1aRflox mice at 3 time points: (1) baseline, (2) 1 week after virus injection but before DOCA-salt, and (3) after 3 weeks of DOCA-salt. DOCA-salt–treated mice with deletion of AT1aR in SFO exhibited a blunted increase in arterial pressure. Increased sympathetic cardiac modulation and urine copeptin, a marker of vasopressin release, were both significantly reduced in DOCA-salt mice when AT1aR was deleted in the SFO. Additionally, deletion of AT1aR in the SFO significantly attenuated the polydipsia, polyuria, and sodium intake in response to DOCA-salt. Together, these data highlight the contribution of AT1aR in the SFO to arterial pressure regulation potentially through changes on sympathetic cardiac modulation, vasopressin release, and hydromineral balance in the DOCA-salt model of hypertension.
- circumventricular organs
- fluid balance
- site-specific receptor deletion
- Received October 12, 2012.
- Revision received November 29, 2012.
- Accepted December 1, 2012.
- © 2013 American Heart Association, Inc.