# Neurons expressing angiotensin type 2 receptors in the NTS as an access point for cardiovascular control.

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $564,976

## Abstract

Project Summary
Hypertension is the most important risk factor for the development of cardiovascular disease, the leading cause
of death in the U.S. Despite therapeutic advancements, nearly 20-30% of hypertensive patients have
uncontrolled high blood pressure. This resistant hypertension is associated with elevated sympathetic activity
and abnormal baroreflex reflex control and thus is termed neurogenic hypertension. Animal models of
neurogenic hypertension consistently implicate augmented release of GABA within the intermediate nucleus of
the solitary tract (intNTS) as a contributing pathophysiological mechanism. Correcting this pathophysiological
mechanism is a logical step towards decreasing high blood pressure of neurogenic origin. However, GABA and
its receptors are poor therapeutic targets because GABA is the predominant inhibitory neurotransmitter in the
CNS. To circumvent this impediment we began investigating whether neurons in the intNTS that express
angiotensin type 2 receptors (AT2R) may serve as an access point for therapeutic interventions that relieve
neurogenic hypertension. Using a novel transgenic mouse model (AT2R-eGFP reporter mouse) we discovered
that GABA neurons in the intNTS robustly express AT2R and optogenetic excitation of these neurons
significantly increases blood pressure. Intriguingly, DOCA-salt hypertension in mice increased indices of GABA
synthesis in the intNTS but central delivery of the AT2R agonist, Compound 21 (C21), abrogated this
hypertension and downregulated indices of GABA synthesis in the intNTS. Relevant to the proposed research,
the antihypertensive effects of brain AT2R activation were abolished by deleting AT2R from GABA neurons.
Based on these results we hypothesize that GABA neurons in the intNTS that express AT2R may be
manipulated to reverse the onset of neurogenic hypertension. Two Specific Aims are proposed to
substantiate or refute this hypothesis. Aim 1 combines genetic and pharmacological approaches to evaluate the
consequences of deleting or stimulating AT2R on GABAergic neurons in the intNTS. Aim 1 tests the hypothesis
that activation of AT2R expressed on GABAergic neurons in the intNTS alleviates DOCA-salt hypertension in
mice by decreasing GABA synthetic enzymes within these neurons, which consequently decreases sympatho-
excitation and improves baroreflex function. Aim 2 utilizes in vitro optogenetic and in vivo chemogenetic
approaches to evaluate how DOCA-salt hypertension with or without C21 affects GABA neurotransmission within
baroreflex circuits mediating cardiovascular function. Aim 2 tests the hypothesis that the activity of neurons
within the intNTS that express AT2R control baroreflex sensitivity and sympathetic outflow and their selective
inhibition mediates the reversal of hypertension. Execution of the proposed experiments will identify a discrete
population of neurons that can be targeted to control blood pressure and provide preclinical evidence for the
development of no...

## Key facts

- **NIH application ID:** 9840503
- **Project number:** 5R01HL136595-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Eric Gerald Krause
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $564,976
- **Award type:** 5
- **Project period:** 2017-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840503

## Citation

> US National Institutes of Health, RePORTER application 9840503, Neurons expressing angiotensin type 2 receptors in the NTS as an access point for cardiovascular control. (5R01HL136595-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9840503. Licensed CC0.

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