Abstract 084: Neurons in the Nodose Ganglion that Express Angiotensin Type 1a Receptors Function as Primary Baroreceptor Afferents: An in vitro and in vivo Optogenetic Study

Abstract

The baroreflex is an essential regulator of blood pressure (BP); whereby, baroreceptors sense acute changes in BP and convey this information, via the nodose ganglia (NG), to the nucleus of the solitary tract (NTS). Manipulation of the baroreflex may provide a novel strategy in the treatment of hypertension. To that end, our neuroanatomical studies revealed a dense localization of angiotensin type 1a receptor (AT1a)-containing neuronal cell bodies in the NG and terminals in the NTS, thereby positioning them to play a role in the baroreflex. We, therefore, hypothesized that AT1a neurons residing in the NG potently influence cardiovascular function. Male and female mice expressing channelrhodopsin-2 (ChR2) and yellow fluorescent protein (eYFP) specifically in AT1a-expressing neurons (AT1aR-ChR2-eYFP) were used to determine the function of these neurons. In vitro patch clamp electrophysiological recordings from neurons in the NTS receiving axons expressing ChR2-eYFP revealed that optogenetic stimulation (473nm) reliably evoked excitatory postsynaptic currents (EPSCs). In concurrence with studies demonstrating that baroreceptor afferents utilize glutamate in the NTS, these EPSCs were eliminated by the presence of glutamate receptor antagonists. Next, the NG of anesthetized mice were subjected to optogenetic stimulation of varying frequencies (1, 15, 30Hz) for 1 min, and BP and HR responses were assessed. Optogenetic stimulation of these AT1a-expressing neurons led to significant decreases in mean arterial pressure (ΔMAP= -16±3*, -36±4*, -44±7* mmHg) and HR (ΔHR= -13±7, -104±44*, -163±59* bpm) in AT1a-ChR2-eYFP mice (n=6), but there was no effect on control mice harboring only the stop-FLOX-ChR2-eYFP gene (n=5; ΔMAP= 0±2, -2±1, 5±5 mmHg; ΔHR= 4±4, 3±4, -13±21 bpm). Additionally, AT1a-ChR2-eYFP mice rendered hypertensive via DOCA-salt (n=7) exhibited a dampened response to optogenetic stimulation (ΔMAP= -7±1#, -14±3*#, -30±6*# mmHg; ΔHR= -29±34, -71±37*, -178±50* bpm). Collectively, these data suggest that AT1a neurons in the NG are key regulators of the baroreflex, and may serve as a target for antihypertensive therapeutics. (p<0.05, *significantly different from control, #significantly different from normotensive AT1a-ChR2-eYFP)