Key challenges in exploring the rat as a preclinical neurostimulation model for aortic baroreflex modulation in hypertension

Electrode-based electrophysiological interfaces with peripheral nerves have come a long way since the 1960s, with several neurostimulation applications witnessing widespread clinical implementation since then. In resistant hypertension, previous clinical trials have shown that "carotid" baroreflex stimulation using device-based baroreflex activation therapy (BAT) can effectively lower blood pressure (BP). However, device-based "aortic" baroreflex stimulation remains untouched for clinical translation. The rat is a remarkable animal model that facilitates exploration of mechanisms pertaining to the baroreceptor reflex and preclinical development of novel therapeutic strategies for BP modulation and hypertension treatment. Specifically, the aortic depressor nerve (ADN) in rats carries a relatively pure population of barosensitive afferent neurons, which enable selective investigation of the aortic baroreflex function. In a rat model of essential hypertension, the spontaneously hypertensive rat (SHR), we have recently investigated the aortic baroreceptor afferents as an alternate target for BP modulation, and showed that "low intensity" stimulation is able to evoke clinically meaningful reductions in BP. Deriving high quality short-term and long-term data on aortic baroreflex modulation in rats is currently hampered by a number of unresolved experimental challenges, including anatomical variations across rats which complicates identification of the ADN, the use of unrefined neurostimulation tools or paradigms, and issues arising from anesthetized and conscious surgical preparations. With the goal of refining existing experimental protocols designed for preclinical investigation of the baroreflex, this review seeks to outline current challenges hindering further progress in aortic baroreflex modulation studies in rats and present some practical considerations and recently emerging ideas to overcome them. Aortic baroreflex modulation.