Poster Z13 - Deep Peroneal Nerve Neuromodulation Reduced Ambulatory Arterial Pressure in Spontaneously Hypertensive Rats

Introduction: Hypertension remains a major health problem characterized by mean arterial systolic blood pressure (MAP) >130 mmHg and diastolic blood pressure (DBP) >90 mmHg. This condition affects more than 103.3 million people in the USA and is a major contributing factor in the development of cardiovascular diseases such as stroke and heart failure, and kidney failure. Despite current advancements in medical treatments for hypertension a significant proportion of affected patients fail to adhere to their recommended treatments, or do not respond to first line medical therapy including combinations of several antihypertensive drugs. Drug-Resistant hypertension (DRH) affects 15% of hypertensive patients despite full adherence to three antihypertensive drugs of complementary mechanisms. Therapy options for DRH include the development of new pharmacological agents including a dual endothelin A and B receptor antagonist albeit with modest results. Alternatively, surgical renal denervation aimed at reducing the high sympathetic drive in DRH animals. Bilateral electrodes implanted near the aortic arch have been used to stimulate the baroreceptors, which exert an inhibitory influence on sympathetic nerve activity. This approach is currently FDA approved.
We have previously reported that stimulation of the common peroneal nerve induced an acute 15.8 % reduction in MAP values in anesthetized spontaneously hypertensive rats (SHR). This effect was reproducible and maximal with stimulation parameters that include 1 mA cathodic pulses at low frequency (2Hz). In this study we evaluate the effect of daily cPNS therapy for four weeks to evaluate the effect of this neuromodulation therapy on reducing ambulatory MAP in hypertensive rats.

Materials and

Methods: A total of 15 adult male rats were included in the study divided in Wistar Kyoto (WKY) control animals (n=7), and SHR (n=8). SHRs animals are a model of primary hypertension due to an overactive sympathetic drive. The animals were divided into four separate groups. WKY controls, WKY+ES (Electrical Stimulation), SHR control, SHR +ES.
wNClip neural stimulator fabrication: The device is fabricated using UV-sensitive, medical grade, Epo-TEK Epoxy 301, which is non-toxic and ISO 10993 biocompatible, and encapsulated in biocompatible BIO SLA material (USP Class VI). The nerve attachment feature was integrated into the 3D printed nerve-attachment device with a Z-shaped microchannel, leading to a stimulation chamber containing gold trace electrodes. This new design facilitates nerve implantation by placing it underneath the nerve and gently lifting it over the microchannel. wNClip implantation: A 2.0 cm incision on the hind-limb was done to expose the common peroneal nerve branch from the sciatic nerve and gently isolated from surrounding connective tissue using a glass rod and kept hydrated with warm physiological saline solution (pH 7.2). After isolating the CPN, the wNClip was implanted.
Sub-chronic Common Peroneal Nerve Stimulation (cPNS): Electrical stimulation was delivered in anesthetized animals every day 5-days a week and for 4 weeks. Each daily session was applied in the morning for 8-minutes and consisted of cathodic monophasic pulses of 1 mA in amplitude, and 1 ms pulse duration and at 2 Hz frequency. These stimulation parameters efficiently induced a cardiovascular depressor response as previously reported.

Results, Conclusions, and Discussions: The eleven implanted wNClips used in this study were successfully activated at 50-90% power level from the external antenna placed 4-8 cm from the implant. This power level has been shown to deliver 100-300 microamps to the nerve, which is above threshold and causes limb movement.
Daily cPNS consisting of 2Hz monophasic stimulation at threshold for 8 minutes every day for four weeks, consistently induced an immediate reduction MAP in SHR animals from -16 mm Hg after week 1, to -42 mmHg in week 4; a significant two-fold reduction over that observed in normotensive animals (p < 0.004).
Awake MAP lowered by cPNS in SHR. We observed a progressive reduction in MAP median values over time. A 2-way ANOVA indicated that the treatment effect was significant (F (1, 29) = 6.5; p< 0.02). During the first week of cPNs treatment MAP values were 21% higher in the SHR animals (p < 0.04). Fisher’s post hoc analysis revealed a significant reduction in ambulatory MAP by the 3rd week of treatment (131.4 ± 24.5 mmHg; p< 0.005) compared to week 1, and comparable to values in the WKY control group. However, a significant increase in week 4 was observed, with MAP values increasing to 159.5 ± 39.6.5 mmHg; p< 0.05), indicating either a loss of effect or an adaptation to the treatment. In contrast to the temporal changes to MAP, cPNS treatment did not modify the median HR ambulatory values over time with treated WKY animals showing a range of 282-300 BPM and SHR 284-302 over the four-week treatment period. Heart rate in WKY control averaged 353.1 ± 9.8 BPM (n=5) in the first week and did not change significantly during ES (350.1 ± 19.2). This was also observed in anesthetized SHR which HR averaged 348.2 ± 39.3 BPM during the first week, which tend to be mildly reduced but during ES (332.8 ± 52.7) although not statistically different, and comparable to those in WKY controls.
Electrical stimulation of the common peroneal nerve induced a reduction in MAP that is comparable to that reportedly achieved pharmacologically by ACE inhibitor Ramipril, or by renal denervation procedures.

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