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. 2022 Jun 8:13:867705.
doi: 10.3389/fphys.2022.867705. eCollection 2022.

The Effects of Vagus Nerve Stimulation on Ventricular Electrophysiology and Nitric Oxide Release in the Rabbit Heart

Emily Allen  1   2 , Pott Pongpaopattanakul  1   2 , Reshma A Chauhan  1   2 , Kieran E Brack  1   2 , G André Ng  1   2
Affiliations

The Effects of Vagus Nerve Stimulation on Ventricular Electrophysiology and Nitric Oxide Release in the Rabbit Heart

Emily Allen et al. Front Physiol. .

Abstract

Background: Abnormal autonomic activity including impaired parasympathetic control is a known hallmark of heart failure (HF). Vagus nerve stimulation (VNS) has been shown to reduce the susceptibility of the heart to ventricular fibrillation, however the precise underlying mechanisms are not well understood and the detailed stimulation parameters needed to improve patient outcomes clinically are currently inconclusive. Objective: To investigate NO release and cardiac electrophysiological effects of electrical stimulation of the vagus nerve at varying parameters using the isolated innervated rabbit heart preparation. Methods: The right cervical vagus nerve was electrically stimulated in the innervated isolated rabbit heart preparation (n = 30). Heart rate (HR), effective refractory period (ERP), ventricular fibrillation threshold (VFT) and electrical restitution were measured as well as NO release from the left ventricle. Results: High voltage with low frequency VNS resulted in the most significant reduction in HR (by -20.6 ± 3.3%, -25.7 ± 3.0% and -30.5 ± 3.0% at 0.1, 1 and 2 ms pulse widths, with minimal increase in NO release. Low voltage and high frequency VNS significantly altered NO release in the left ventricle, whilst significantly flattening the slope of restitution and significantly increasing VFT. HR changes however using low voltage, high frequency VNS were minimal at 20Hz (to 138.5 ± 7.7 bpm (-7.3 ± 2.0%) at 1 ms pulse width and 141.1 ± 6.6 bpm (-4.4 ± 1.1%) at 2 ms pulse width). Conclusion: The protective effects of the VNS are independent of HR reductions demonstrating the likelihood of such effects being as a result of the modulation of more than one molecular pathway. Altering the parameters of VNS impacts neural fibre recruitment in the ventricle; influencing changes in ventricular electrophysiology, the protective effect of VNS against VF and the release of NO from the left ventricle.

Keywords: autonomic nervous system; electrophysiology; heart; nitric oxide; vagus nerve stimulation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The effects of varying VNS on the maximum slope of restitution. (A–C), plots of APD restitution curves from a typical experiment at baseline and during high voltage (A), low voltage (B) and low voltage-low frequency (C) VNS. The maximum slope of restitution at baseline (BL) and during high voltage (D–F), low voltage (G–I) and low voltage-low frequency (J–L) VNS at pulse widths of 0.1 m 1 and 2 ms. Data represent mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 vs. corresponding BL, n = 6.
FIGURE 2
FIGURE 2
Voltage and frequency dependent changes in NO fluorescence during VNS. Raw data illustrating DAF-2 fluorescence at a 490 nm (F490) excitation wavelength during high voltage-low frequency (3 Hz) stimulation (A), low voltage-high frequency (20 Hz) stimulation (B) and low voltage-low frequency (3 Hz) stimulation (C), at varying pulse widths.
FIGURE 3
FIGURE 3
The effects of VNS on NO release in the left ventricle. (A–C) Mean F490 levels during high voltage and low frequency stimulation at 1 (A), 2 (B) and 3 Hz (C) VNS at 0.1, 1, and 2 ms pulse widths. (D–F) Mean F490 levels during low voltage and high frequency stimulation at 5 (D), 10 (E) and 20Hz (F) VNS at 0.1, 1, and 2 ms pulse widths. (G–I) Mean F490 levels during low voltage and low frequency stimulation at 1 (G), 2 (H) and 3 Hz (I) VNS at 0.1, 1, and 2 ms pulse widths. Data represented as mean ± SEM. ****p < 0.0001 vs. corresponding BL n = 12.
FIGURE 4
FIGURE 4
The effects of VNS at varying stimulation parameters on (A) VFT (B) NO fluorescence and (C) HR change. Three-dimensional plots illustrating the effects of varying stimulation parameters on changes in VFT, NO fluorescence and heart rate, highlighting the important effect of VNS at high voltages and low frequencies (red) on heart rate (C), with low voltage and high frequency stimulation (blue) producing a more prominent effect on VFT (A) and NO release in the ventricle (B). Data in red represents high voltage stimulation. Data in blue represents low voltage stimulation.
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