Low-intensity focused ultrasound stimulation treatment decreases blood pressure in spontaneously hypertensive rats

Dapeng Li, Zhiwei Cui, Shanshan Xu, Tianqi Xu, Shan Wu, Ayache Bouakaz, Mingxi Wan, Siyuan Zhang

IEEE Transactions on Biomedical Engineering 2020 · 10.1109/tbme.2020.2975279

rodentotherautonomic physiologyhistology molecular

Abstract

Objective We applied low-intensity focused ultrasound (LIFU) stimulation of the ventrolateral periaqueductal gray (vlPAG) in spontaneously hypertensive rats (SHRs) model to demonstrate the feasibility of LIFU stimulation to decrease blood pressure (BP). Methods The rats were treated with LIFU stimulation for 20 min every day for one week. The change of BP and heart rate (HR) were recorded to evaluate the antihypertensive effect. Then the plasma levels of epinephrine (EPI), norepinephrine (NE), and angiotensin II (ANGII) were measured to evaluate the activity of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS). The c-fos immunofluorescence assay was performed to investigate the antihypertensive nerve pathway. Moreover, the biological safety of ultrasound sonication was examined. Results The LIFU stimulation induced a significant reduction of BP in 8 SHRs. The mean systolic blood pressure (SBP) was reduced from 170 ± 4 mmHg to 128 ± 4.5 mmHg after a one-week treatment, p Conclusion The results support that LIFU stimulation of the vlPAG could relieve hypertension in SHRs. Significance The LIFU stimulation of the vlPAG could potentially be a new alternative non-invasive device therapy for hypertension.

Abstract via europepmc.

Speciesrat (spontaneously hypertensive rat; Wistar-Kyoto)

Subjects8, 8swept animals

Sessions per subject7

Randomisedyes

Blindingnot reported

Sham / controlactive control site, no treatment control

Auditory controlnot reported

Readout timingoffline

Anaesthesiaanaesthetised

Readoutsautonomic physiology, histology molecular — tail-cuff blood pressure and heart rate; plasma EPI, NE, ANGII ELISA; c-fos immunofluorescence; HE and TUNEL staining; thermocouple brain temperature

Direction of effectexcitatoryUS stimulation of the vlPAG enhanced c-fos density in vlPAG and CVLM and reduced SBP, HR and plasma EPI, NE and ANGII in SHRs; sham site had no effect.

Adverse eventsnone observedHE and TUNEL staining showed no tissue damage or apoptosis after 1 h of stimulation; thermocouple temperature stayed 33.8-33.9 C at 0.4 MPa pulsed.

Exposures

Exposure 1: LIFU to vlPAG

Target: periaqueductal gray — “ventrolateral periaqueductal gray (vlPAG)”
Device: not reported

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	620	✓✓✓
Pulse duration (ms)	2	✓✓✓
Pulse repetition frequency (Hz)	250	✓✓✓
Duty cycle (%)	not reportedpulse duration × PRF gives 50%	⚑
Sonication duration (s)	0.2	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	not reported
Free-field Isppa (W/cm²)	not reported
Free-field Ispta (W/cm²)	not reported
In-situ estimate	measurementsingle value
In-situ pressure (kPa)	400	✓✓✓⚑
In-situ Isppa (W/cm²)	5.13	✓?
In-situ Ispta (W/cm²)	2.56	✓?

Protocol, in the paper’s words

2 ms burst duration at 250 Hz PRF, sonication duration 200 ms, inter-stimulation interval 5 s. Total treatment time 20 min every day for one week.

Flags from extraction

n_subjects — 32 rats in four groups of 8; only the LIFU and Sham groups (8 each) received ultrasound in the BP experiment, with separate smaller cohorts for c-fos and histology.
exposures[0].in_situ.pressure_kpa — Peak rarefactional pressure 0.4 MPa measured with a rat skull in degassed water; recorded as in_situ measurement.
exposures[0].timing.duty_cycle_pct — Duty cycle not stated.
sham_type — Sham SHRs sonicated below the motor cortex (real ultrasound, different site); Control SHRs and WKY rats unexposed.
exposures[0].device.family — No transducer maker named.
anaesthesia — Isoflurane during stimulation; BP measured in conscious rats.