# Brain NaCl-sensing in salt-sensitive hypertension.

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $559,467

## Abstract

PROJECT SUMMARY
Excess dietary salt intake is strongly correlated with cardiovascular disease and is regarded as a major
contributing factor to the pathogenesis of hypertension. Time-controlled studies in both humans and
rodents suggest a high salt diet elevates plasma or cerebrospinal fluid (CSF) [NaCl] by 2-5mM to
activate specialized NaCl-sensing neurons located in hypothalamic circumventricular organs such as
the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ to increase sympathetic
nerve activity (SNA) and arterial blood pressure (ABP). Interestingly, central infusion of non-voltage
gated sodium channel antagonists attenuates every experimental model of salt-sensitive hypertension
tested to date. These antagonists target acid sensing ion channel, sodium hydrogen exchanger, sodium
calcium pump, and the epithelial sodium channel. In light of preliminary findings, our working hypothesis
is that a high salt diet elevates extracellular [NaCl] to activate NaCl-sensitive neurons of the OVLT
through a unique epithelial sodium channel (ENaC) expressing αβ subunits. The NaCl-sensitivity of
these ENaC neurons and sympathoexcitatory responses are enhanced by circulating factors such as
angiotensin II and aldosterone. Subsequent activation of descending pathways increases SNA and
ABP. This hypothesis will be tested through 3 specific aims: 1) determine the extent by which ENaC
subunits mediate the intrinsic NaCl-sensitivity of OVLT neurons and sympathoexcitatory responses to
an acute NaCl load, 2) determine whether angiotensin II enhances the NaCl-sensitivity of ENaC-positive
neurons in the OVLT and the extent by which these neurons contribute to angiotensin II-salt
hypertension, and 3) determine the extent by which aldosterone and deoxycorticosterone-salt
hypertension alter ENaC expression, enhance NaCl-sensitivity and depend on ENaC subunits of the
OVLT. Our rationale for this project is that identification of the cellular elements that underlie NaCl-
sensing in the brain will provide a framework for the development of novel therapeutic treatments of
salt-sensitive hypertension.

## Key facts

- **NIH application ID:** 9974567
- **Project number:** 5R01HL145875-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** SEAN D STOCKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $559,467
- **Award type:** 5
- **Project period:** 2019-07-10 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974567

## Citation

> US National Institutes of Health, RePORTER application 9974567, Brain NaCl-sensing in salt-sensitive hypertension. (5R01HL145875-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974567. Licensed CC0.

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