Abstract 054: Prorenin Stimulates Firing Activity in Hypothalamic Neurons via Angiotensin II-Dependent and -Independent Mechanisms
The brain RAS plays a central role in cardiovascular homeostasis by modulating sympathetic nerve activity and hormone secretion. Still, the relevance of intrinsic brain RAS function is questioned because renin levels are too low to have an impact on angiotensin II (AngII) formation. The discovery of the prorenin receptor (PRR) brought new support to the brain RAS involvement in neurohumoral regulation. However, the mechanisms underlying PRR-mediated actions remain unknown. We used whole cell patch-clamp electrophysiology in hypothalamic slices to examine the effects of prorenin (PR) on the excitability of magnocellular neurosecretory neurons (MCNs) of the supraoptic nucleus and parvocellular RVLM-projecting presympathetic neurons of the paraventricular nucleus (PVN-RVLM), which play integral roles in cardiovascular control, and have been implicated in the pathophysiology of neurogenic hypertension.
PR application (2.5nM) increased the firing activity of both MCNs (basal 1.3±0.4 Hz vs PR 3.3±0.7 Hz; p=0.0086) and parvocellular neurons (basal 0.5±0.1 Hz vs PR 2.1±0.4 Hz; p=0.0006), including a subset of PVN-RVLM neurons (basal 0.5±0.1 Hz vs PR 1.4±0.4 Hz; p=0.048). In MCNs, this effect was blocked by a PRR antagonist (PRO20; 250nM; basal 1.9±0.6 Hz vs PRO20 1.3±0.5 Hz; p=0.017), but persisted in the presence of the AT1 receptor blocker, losartan (50μM; basal 0.8±0.2 Hz vs losartan 2.3±0.5 Hz; p=0.0018). Conversely, PR effects on PVN neurons persisted with PRO20 (basal 0.9±0.2 Hz vs PRO20 1.6±0.3 Hz; p=0.013), but were largely (~75%) blunted with losartan (basal 0.2±0.04 Hz vs losartan 0.6±0.1 Hz; p=0.0193; Δ basal 1.6±0.4 Hz vs Δ losartan 0.4±0.1 Hz; p=0.0175). These results suggest that while PR actions are primarily PRR-mediated in MCNs, they are predominantly AngII-dependent in PVN cells. Lastly, PR effects were abolished in both cell types by dialyzing neurons with the Ca2+ chelator BAPTA (10mM; MCNs: basal 0.6 ± 0.1 Hz vs BAPTA 0.3 ± 0.1 Hz; p=0.0277; PVN: basal 0.4±0.05 Hz vs BAPTA 0.5±0.2 Hz; p=0.6468).
Our results show for the first time that PR stimulates firing activity in both hypothalamic neurosecretory and presympathetic neurons, and support distinct AngII-independent and dependent signaling mechanisms in each neuronal population.
Author Disclosures: M.S. Pitra: None. Y. Feng: None. J.E. Stern: None.
- © 2015 by American Heart Association, Inc.