Abstract 441: Aldosterone-salt Hypertension Depends on the SFO, Central Aldosterone Synthase and MR Specifically in the PVN

Central blockade of mineralocorticoid receptor (MR) prevents aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats with telemetry probes were treated with chronic intra-cerebroventricular infusion of aldo synthase (AS) inhibitor FAD286 (25 μg/day), MR blocker eplerenone (5 μg/day) or vehicle. After 2 days, subcutaneous (sc) aldo infusion (1 μg/h) was started and saline was provided as drinking water. In a second set of rats with telemetry, electrolytic or sham lesions of the SFO, or bilateral intra-PVN infusion of AAV-MR-siRNA or AAV-SCM-siRNA (1 μl of 5x10 10 genomic particles/ml) at 100ng/min were performed, and sc aldo infusion started 1 week later. AAV-MR-siRNA decreased MR mRNA and protein expression in the PVN by ~60 and 30%, but had no effects on MR expression in other nuclei such as the SFO and SON. SFO lesion, blockade of brain AS or MR, or knockdown of MR in the PVN attenuated aldo-salt hypertension by ~60%. Data=means± SE (n=5-9/group). *p These results suggest that an increase in circulating aldosterone may via MR and AT 1 R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR in the PVN activate a central aldosterone-MR-AT 1 R neuro-modulatory pathway, which plays a major role in the progressive hypertension. (Supported by grant # FRN:MOP-74432 from the Canadian Institutes of Health Research)