Low intensity stimulation of aortic baroreceptor afferent fibers as a potential therapeutic alternative for hypertension treatment

Abstract

Carotid baroreceptor stimulation has been clinically explored for antihypertensive benefits, but neuromodulation of aortic baroreceptor afferents remains unexplored for potential translation into the clinic. Published studies have used supramaximal stimulations, which are unphysiological and energy inefficient. The objective of the present study was to identify optimal low-charge nerve stimulation parameters that would provide a clinically-relevant (20–30 mmHg) decrease in mean arterial pressure (MAP) in anesthetized spontaneously hypertensive rats. Stimulations of 20 s were delivered to the left aortic depressor nerve (ADN) of these rats using low ranges of pulse amplitudes (≤ 0.6 mA), widths (≤ 0.5 ms) and frequencies (≤ 5 Hz). We also assessed the effects of continuous (20 s) versus intermittent (5 s ON/3 s OFF and 5 s ON/3 s OFF for 20 s) stimulation on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance using low (5 Hz) and high (15 Hz) frequencies. Lower pulse amplitudes (0.2 mA) produced 9 ± 2 to 18 ± 2 mmHg decreases in MAP. Higher pulse amplitudes (0.4 mA) produced a median MAP reduction of 28 ± 4 mmHg at 0.2 ms and 5 Hz, with no added benefit seen above 0.4 mA. Continuous and intermittent low frequency stimulation at 0.4 mA and 0.2 ms produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation at 0.4 mA and 0.2 ms produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. We conclude from these findings that “low intensity intermittent” electrical stimulation is an effective alternate way for neuromodulation of the aortic baroreceptor afferents and to evoke a required restoration of MAP levels in spontaneously hypertensive rats. This approach enables low energy consumption and markedly lowers the excessive decreases in MAP and hemodynamic disturbances elicited by continuous high-charge injection protocols.

Functional symmetry of the aortic baroreflex in female spontaneously hypertensive rats

“…All raw data traces were smoothed over a 1 s time constant and subsequently converted into 5 s bins. Measures of vascular resistance were calculated by dividing MAP by the blood flow values recorded from the mesenteric and femoral vascular beds, as described previously [21,22,25,28]. Resting baseline levels were recorded over a 40 s period prior to starting the neurostimulation protocol.…”

“…Depth of anesthesia was confirmed throughout the experiment by absence of reflex response to tactile (corneal stroking) and noxious (hindpaw pinch) stimuli. The rationale for choice of anesthesia has been described in a previous study from our laboratory [25]. Core body temperature was maintained between 36.5 and 37 °C using a heating blanket (T/Pump warm water re-circulator, Stryker Medical, Michigan, USA).…”

“…The surgical approach used to instrument rats for unilateral and bilateral ADN stimulation whilst recording BP, HR, and regional blood flows have been described elsewhere [21,22,25]. Briefly, pentobarbital (Diamondback, Arizona, USA) anesthesia was delivered using an intraperitoneal injection of 50 mg/kg of the anesthetic followed by a continuous infusion (Harvard Apparatus Ltd., Massachusetts, USA) into the right femoral vein at a dose of 10 mg/kg/h and an infusion rate of 2 ml/h.…”

“…Optimal charge parameters were chosen in accordance with our previous studies [21,22,25,27]. Briefly, left, right and bilateral ADN stimulations were delivered continuously for 20 s, with the pulse intensity and width kept at 0.4 mA and 0.2 ms, respectively, and pulse frequency varied (1, 2.5, 5, 10, 20, and 40 Hz) and applied in a random sequence.…”

Differential central integration of left versus right baroreceptor afferent input in spontaneously hypertensive rats

“…In particular, direct electrical stimulation of the baroreceptor afferents in spontaneously hypertensive rats (SHR) carries a massive potential to functionally assess the baroreflex circuit in relation to hypertension, identify novel targets for BP modulation and discover new methods for enhancing and improving current BAT technology. Indeed, using the SHR model, we have recently identified the ‘aortic’ baroreceptor afferents as a viable alternative neuromodulation target to ‘carotid’ baroreceptor stimulation in lowering mean arterial pressure (MAP) [ 12 ]. We have further showed that ‘low intensity’ stimulation is an effective alternate way for neuromodulation of the aortic baroreceptor afferents, enabling low-energy consumption to induce a clinically relevant reduction in MAP levels in the SHRs [ 12 ].…”