Assessment of Vagus Nerve Stimulation Effects on Autonomic Regulation and Cardiac Variability in a Rodent Model of Stress-Induced Hypertension

Project Abstract

Vagus nerve stimulation (VNS) was evaluated for its effects on autonomic regulation and cardiac variability in a rodent model of stress-induced hypertension to elucidate mechanisms by which parasympathetic modulation influences cardiovascular risk under chronic stress. Male Sprague-Dawley rats were subjected to a validated chronic variable stress (CVS) paradigm for six weeks to induce sustained hypertensive states and autonomic imbalance, confirmed by elevated systolic blood pressure, heart rate, and altered baroreflex sensitivity. Animals were randomized to receive cuff-based VNS, sham stimulation, or no intervention, with the VNS protocol tuned to subthreshold intensities to minimize motor side effects while delivering high-frequency conditioning to vagal afferents and efferents. Hemodynamic parameters were monitored continuously via radiotelemetry, while autonomic tone was assessed through spectral analysis of heart rate variability (HRV) and systolic blood pressure variability, including low-frequency (LF) and high-frequency (HF) components and their LF/HF ratio as indices of sympathetic–parasympathetic balance. Baroreflex sensitivity was quantified using modified sequences and transfer function techniques across resting and stress-exposed periods. Additionally, plasma catecholamines (norepinephrine and epinephrine) and cortisol were measured as indices of sympathetic-adrenal axis activation. The study integrated immunometabolic readouts by quantifying inflammatory cytokines (TNF-?, IL-6) and nitric oxide metabolites to explore downstream vascular effects of autonomic modulation. VNS was hypothesized to restore autonomic equilibrium, reduce sympathetic dominance, and normalize HRV indices, thereby mitigating hypertension progression and improving baroreflex function under stress. Behavioral assays, including elevated plus-maze and open-field tests, were conducted to assess anxiety-like behavior and its relationship to autonomic changes. Data were analyzed using mixed-model ANOVA to account for repeated measures, with post hoc comparisons to identify time- and treatment-dependent effects. Mechanistic exploration involved gene expression analysis of adrenergic receptor signaling and inflammatory pathways in cardiac and vascular tissues, complemented by histopathological evaluation of left ventricle fibrosis and endothelial integrity. Preliminary findings indicate that chronic CVS elevates LF power and LF/HF ratio, reduces HF power, and blunts baroreflex gain, consistent with increased sympathetic tone and impaired autonomic regulation. VNS substantially attenuated these alterations, restoring HRV parameters toward baseline, improving baroreflex sensitivity, and decreasing circulating catecholamines and cortisol levels. The anti-inflammatory and vasoprotective effects of VNS were evidenced by reduced pro-inflammatory cytokines and enhanced nitric oxide bioavailability, correlating with improved endothelial markers and reduced myocardial fibrosis in treated rats. In conclusion, targeted VNS demonstrates a multi-faceted role in modulating autonomic balance, stress hormone output, inflammatory status, and vascular remodeling in a rodent model of stress-induced hypertension, supporting its potential translational application as an adjunctive therapy to attenuate cardiovascular risk in stress-related hypertensive conditions. Further work will optimize stimulation parameters, assess long-term outcomes, and validate translational relevance to human pathophysiology.

Project Overview

What This Project Is About

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The project studies how stimulating the vagus nerve changes how the body controls automatic functions like heart rate, especially under stress that raises blood pressure in rats. It looks at whether this nerve stimulation can stabilize heart rhythms and the body’s stress responses.

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The Problem It Addresses

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Many conditions involve an overactive stress system and unstable heart rhythms, which can lead to heart disease. Current treatments may have limits or side effects. This project explores a potential non-drug approach to help regulate the autonomic nervous system and improve cardiovascular safety in a controlled animal model.

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Objectives of the Project

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1. Describe how vagus nerve stimulation (VNS) affects heart rate and variability under stress in rodents.
2. Evaluate changes in autonomic balance between sympathetic and parasympathetic activity.
3. Assess whether VNS reduces stress-induced blood pressure rises.
4. Identify any potential safety concerns or adverse effects in the model.

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What You Will Do Step by Step

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1. Perform baseline measurements of heart rate, blood pressure, and stress hormones in rodents.

2. Apply controlled stress to induce hypertension-like responses.

3. Deliver vagus nerve stimulation using standard parameters and monitor immediate effects.

4. Record heart rate variability and blood pressure over time after stimulation.

5. Analyze data to compare stressed vs. unstressed periods and stimulated vs. non-stimulated conditions.

6. Review possible mechanisms by which VNS influences autonomic control.

7. Summarize safety observations and limitations of the model.

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Expected Outcome

You can expect to show that VNS moderates autonomic balance and reduces abnormal heart rhythm patterns associated with stress-induced hypertension in rodents, with clear data on changes in heart rate variability and blood pressure. This could inform future research on non-pharmacological options for cardiovascular health.