Abstract 051: Exploiting Angiotensin Sensitive Vagal Afferents To Understand And Alleviate Hypertension: A Closed Loop System For Blood Pressure Control

Abstract

Cardiovascular homeostasis is maintained by neural signals arising from arterial baroreceptors (BRs) that apprise the brain of vascular stretch. Here, we test the overall hypothesis that angiotensin-II (AngII) type 1a receptor expressing neurons within the nodose ganglia (NDG AT1aR ) serve as BR that undergo plasticity during chronic elevations in BP. We found that NDG AT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (cNTS), and synthesize Piezo-1/-2. AT1aR-GCaMP6s mice were used to determine whether NDG AT1aR couple their firing to elevated BP. Two-photon intravital imaging revealed that phenylephrine (PE; i.v.) increased GCaMP6s fluorescence within NDG AT1aR (ΔF/F max = 0.65±0.05*, Time ΔF/Fmax = 92s) and this response was delayed in mice given DOCA-salt (Time ΔF/Fmax = 124s) or chronic AngII (Time ΔF/Fmax = 155s). To determine if optical perturbation of NDG AT1aR affects the baroreflex, expression of excitatory channelrhodpsin2 (ChR2) or inhibitory halorhodopsin (Halo) was directed to AT1aR cells. Optical excitation of NDG AT1aR at their axon terminals in the cNTS elicited frequency-dependent decreases in BP (ΔSBP @ 0.5, 1, 2, 3 Hz = -6.74±3.42 # , -9.75±2.33 # , -23.24±4.39 # , -25.27±4.38 # ) and HR (ΔHR @ 0.5, 1, 2, 3 Hz = -7.81±3.14 # , -14.86±3.22 # , -23.39±5.02 # , -23.66±4.13 # ). Conversely, optical inhibition of NDG AT1aR at axon terminals in the cNTS blunted pressor responses to PE (ΔHR PE(Min) = -36.15±5.31, ΔHR PE+Light(Min) = -23.11±3.33 + ). ChR2-expressing mice were then subjected to DOCA-salt. Optical excitation elicited hypotensive (ΔSBP Min = -21.11±4.05 + ) and bradycardic (ΔHR Min = -235.6±46.69 + ) responses; however, the duration of these effects was altered. We developed a closed loop system to target NDG AT1aR at axon terminals in the cNTS of ChR2-expressing mice to determine if these neurons can be exploited to alleviate hypertension. Mice were subjected to acute and chronic stimuli to elevate BP and stimulated by the system until BP returned below threshold. Collectively, these studies reveal the structure and function of NDG AT1aR and suggest that such neurons may be exploited to discern and relieve hypertension. ( p < 0.05, * time by treatment, # time by frequency, or + time by light interaction)