Journal article
Angiotensin II Inhibits the A-type K + Current of Hypothalamic Paraventricular Nucleus Neurons in Rats with Heart Failure: Role of MAPK-ERK1/2 Signaling
American journal of physiology. Regulatory, integrative and comparative physiology, Vol.322(6), pp.R526-R534
03/23/2022
DOI: 10.1152/ajpregu.00308.2021
PMCID: PMC9076419
PMID: 35319903
Abstract
ANGII-mediated sympathohumoral activation constitutes a pathophysiological mechanism in heart failure (HF). While the hypothalamic paraventricular nucleus (PVN) is a major site mediating ANGII effects in HF, the precise mechanisms by which ANGII influences sympathohumoral outflow from the PVN remain unknown. ANGII activates the ubiquitous intracellular MAPK signaling cascades and recent studies revealed a key role for ERK1/2 MAPK signaling in ANGII-mediated sympathoexcitation in HF rats. Importantly, ERK1/2 was reported to inhibit the transient outward potassium current (I
) in hippocampal neurons. Given that I
is a critical determinant of the PVN neuronal excitability, and that downregulation of I
in the brain has been reported in cardiovascular disease states, including HF, we investigated here whether ANGII modulates I
in PVN neurons via the MAPK-ERK pathway, and, whether these effects are altered in HF rats. Patch-clamp recordings from identified magnocellular neurosecretory (MNNs) and presympathetic (PS) PVN neurons revealed that ANGII inhibited I
in both PVN neuronal types, both in sham and HF rats. Importantly, ANGII effects were blocked by inhibiting MAPK-ERK signaling as well as by inhibiting EGFR, a gateway to MAPK-ERK signaling. While no differences in basal I
magnitude were found between sham and HF rats under normal conditions, MAPK-ERK blockade resulted in significantly larger I
in both PVN neuronal types in HF rats. Taken together, our studies show that ANGII-induced ERK1/2 activity inhibits I
, an effect expected to increase the excitability of presympathetic and neuroendocrine PVN neurons, contributing in turn to the neurohumoral overactivity than promotes progression of the HF syndrome.
Details
- Title: Subtitle
- Angiotensin II Inhibits the A-type K + Current of Hypothalamic Paraventricular Nucleus Neurons in Rats with Heart Failure: Role of MAPK-ERK1/2 Signaling
- Creators
- Ranjan Kumer Roy - Georgia State UniversityHildebrando Candido Ferreira-Neto - Georgia State UniversityRobert B Felder - University of IowaJavier E Stern - Georgia State University
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Regulatory, integrative and comparative physiology, Vol.322(6), pp.R526-R534
- DOI
- 10.1152/ajpregu.00308.2021
- PMID
- 35319903
- PMCID
- PMC9076419
- eISSN
- 1522-1490
- Grant note
- HL136149 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) American Heart Association (AHA) HL090948 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) NS094640 / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
- Language
- English
- Date published
- 03/23/2022
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984230138402771
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