# Regulation of neuro-cardiovascular function during stress

> **NIH VA I01** · JOHN D DINGELL VA MEDICAL CENTER · 2021 · —

## Abstract

Cardiovascular morbidity and mortality is higher among Veterans than the general population independent of
factors such as chronic illnesses or socio-econamic status. Depression is now recognized as a non-traditional
risk factor for cardiovascular disease. Nearly one-third of Veterans suffer from depression at some point,
regardless of whether they have been deployed in combat. Activation of vasopressin (AVP) receptors within
the central nervous system, specifically the paraventricular nucleus (PVN) has been implicated in depression.
Recent studies have shown that AVP is released from dendrites within the PVN and that central AVP mediates
the sympathoexcitation observed heart failure. Sympathoexcitation is also strongly associated with greater
cardiovascular risk. Notably, gamma-aminobutyric acid (GABA) typically suppresses sympathoexcitation. New
evidence indicates that GABA may exert a paradoxically stimulatory effect on AVP signaling due to plasticity
that occurs in the chloride ion concentration within neurons. The intracellular chloride concentration is
controlled by chloride transport via the sodium chloride co-transporter 1 (NKCC1) which transports chloride ion
into the cell or the potassium chloride co-transporter 2 (KCC2) which extrudes chloride ion. Thus, we
hypothesize that AVP activates V1a receptors (V1aR) and/or V1b receptors (V1bR) within the PVN to increase
arterial pressure, heart rate and sympathetic activity thereby contributing to the augmentation of these
responses to acute stress in an animal model of depression. Three specific aims will be addressed. In Specific
Aim 1, we will use pharmacologic inhibition and genetic knockdown with siRNA approaches to assess whether
exogenous AVP activation of V1aR or V1bR alone or in combination results in increased arterial pressure, heart
rate and RSNA and exaggerated responses to acute stress. In Specific Aim 2, we will test whether changes in
NKCC1 or KCC2 transport in PVN attenuate, or even reverse, GABAergic inhibition of hemodynamic and
RSNA responses to V1aR and/or V1bR activation in the basal state or during acute stress. In Specific Aim 3, we
will ascertain whether endogenous AVP within the PVN activates V1aR and/or V1bR thereby contributing to the
increased arterial pressure and RSNA in a rat model of chronic unpredictable stress (CMS), a validated model
of depression, and whether increased transport via NKCC1 or decreased transport via KCC2 prevents
GABAergic suppression of these responses. We will test this hypothesis in conscious, unrestrained Sprague
Dawley rats chronically-instrumented with telemetry transmitters for both hemodynamic and nerve activity
measurements. The ability to monitor not only arterial pressure but also RSNA by telemetry in conscious rats
has been mastered by only a few laboratories including our own and provides a powerful tool for assessment
of basal and stress conditions with minimal investigator interference. We will identify the contribution of the...

## Key facts

- **NIH application ID:** 10376718
- **Project number:** 5I01BX003480-05
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** Noreen F Rossi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376718

## Citation

> US National Institutes of Health, RePORTER application 10376718, Regulation of neuro-cardiovascular function during stress (5I01BX003480-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10376718. Licensed CC0.

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