# Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Post-traumatic stress disorder (PTSD) is a highly prevalent and debilitating mental health
disorder that is independently associated with an increased risk of cardiovascular (CV) disease
and hypertension. Given the large numbers of post-9/11 Veterans afflicted with PTSD,
addressing this under-recognized but highly significant consequence of PTSD is of paramount
importance to protect the future health of these young Veterans. We have shown that
post-9/11 Veterans with PTSD have overactivation of the sympathetic nervous system (SNS)
during mental stress and impaired arterial baroreflex sensitivity (BRS) that could contribute to
the pathogenesis of hypertension and CV disease in these patients. While we have now
established that central sympathetic output is augmented in PTSD, the downstream effects of
SNS output on blood pressure (BP) regulation in PTSD remain unknown and is a major goal of
this proposal. We hypothesize that augmented sympathetic nerve activity in PTSD leads to
augmented SNS-mediated vasoconstriction within the kidney, an organ with a critical role in BP
regulation. Exaggerated increases in sympathetically mediated renal vasoconstriction could
perpetuate sustained increases in BP over time via renal sodium reabsorption and activation of
the renin-angiotensin system (RAS). To test this hypothesis, we will measure renal blood flow
velocity using Doppler ultrasound, continuous hemodynamics, muscle sympathetic nerve
activity (MSNA) using microneurography, plasma renin activity and inflammatory biomarkers at
rest and during mental stress in post 9/11 Veterans and matched controls. We further
hypothesize that SNS activation leads to an exaggerated vasoconstrictive response (i.e.
heightened neurovascular transduction of SNS activity) mediated by abnormal vascular
adrenergic receptor sensitivity in PTSD. To test this hypothesis, we will determine vascular
alpha-1 adrenergic receptor (α1AR) sensitivity by measuring vasoconstriction in response to
exponentially increasing doses of the selective α1AR agonist phenylephrine using a linear
variable differential transformer in PTSD and controls. Finally, prior studies have shown that
transcutaneous vagus nerve stimulation (tVNS) reduces SNS activity, improves BRS, and
lowers inflammation in healthy humans and a number of chronic diseases; however, the
potential benefits of tVNS on SNS function and regulation in PTSD have never previously been
investigated. We hypothesize that tVNS acutely lowers SNS activity and improves sympathetic
and cardiovagal BRS in PTSD. To test this hypothesis, we will measure MSNA, EKG,
hemodynamics, inflammation, and BRS using pharmacologic manipulation of BP at rest and
during tVNS (versus sham stimulation) in PTSD patients. tVNS could be a novel
nonpharmacologic approach to reducing SNS activity and restoring BRS in these patients.
Improving SNS overactivity and BRS may have long term benefits on reducing CV risk in PTSD
patients.

## Key facts

- **NIH application ID:** 11115541
- **Project number:** 5I01CX001065-09
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Jeanie Park
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2015-07-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11115541

## Citation

> US National Institutes of Health, RePORTER application 11115541, Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder (5I01CX001065-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11115541. Licensed CC0.

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