Recent studies demonstrated a critical functional connection between the autonomic (sympathetic and parasympathetic) nervous and the immune systems. The carotid sinus nerve (CSN) conveys electrical signals from the chemoreceptors of the carotid bifurcation to the central nervous system where the stimuli are processed to activate sympathetic and parasympathetic efferent signals. Here, we reported that chemoreflex activation via electrical CSN stimulation, in conscious rats, controls the innate immune response to lipopolysaccharide attenuating the plasma levels of inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1β (IL-1β) and interleukin 6 (IL-6). By contrast, the chemoreflex stimulation increases the plasma levels of anti-inflammatory cytokine interleukin 10 (IL-10). This chemoreflex anti-inflammatory network was abrogated by carotid chemoreceptor denervation and by pharmacological blockade of either sympathetic - propranolol - or parasympathetic - methylatropine – signals. The chemoreflex stimulation as well as the surgical and pharmacological procedures were confirmed by real-time recording of hemodynamic parameters [pulsatile arterial pressure (PAP) and heart rate (HR)]. These results reveal, in conscious animals, a novel mechanism of neuromodulation mediated by the carotid chemoreceptors and involving both the sympathetic and parasympathetic systems.

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A brief review of the effects of caffeine and energy drinks in combination with alcohol is provided in order to establish a landscape of the theme. Several studies have identified a range of negative physiological effects associated with this combination, including elevated blood pressure, decreased cerebral blood flow velocity, insomnia, nervousness, headache, tachycardia, gastrointestinal disorders, tremor, psychomotor agitation, and psycho physiological alteration of decision-making and impulsivity. However, more studies are needed to better understand the complexity of the damages resulting from this interaction, mainly experimental studies.

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)

It is accepted that activation of angiotensin type 1a receptors (AT1a) within the CNS elevates blood pressure by influencing sympathetic outflow and vasopressin (VP) secretion; however, the neuronal circuits mediating these effects are not completely understood. The present studies characterize the structure and function of AT1a neurons residing in the median preoptic nucleus (MnPO) and the organum vasculosum of the lamina terminalis (OVLT), thereby evaluating their potential role in blood pressure control. Using male mice that express Cre-recombinase prior to the STOP codon of the AT1a gene, initial studies combined genetic reporting with in situ hybridization to reveal that AT1a neurons in the MnPO and OVLT are largely excitatory (87±4% express vesicular glutamate transporter 2). Subsequently, AT1a-Cre mice were delivered a Cre-inducible adeno-associated virus to induce expression of channelrhodopsin-2 (ChR2) and enhanced yellow fluorescent protein (eYFP) specifically within AT1a neurons of the MnPO/OVLT (AAV-ChR2-eYFP; n = 4). Control mice were delivered AAV-eYFP (n = 4). Analysis of eYFP immunofluorescence revealed that neurons within the MnPO/OVLT that express AT1a send projections to the paraventricular nucleus of the hypothalamus (PVN; an area involved in sympathetic outflow and VP secretion) that appear to synapse onto VP synthesizing neurons. To evaluate the functionality of this connection, we optogenetically stimulated AT1a neurons in the region while recording cardiovascular parameters in anesthetized mice. Ten-minutes of optogenetic stimulation (473 nM;15 Hz; 20 ms pulse width; 60 s ON/OFF) robustly elevated systolic blood pressure in AAV-ChR2-eYFP mice relative to AAV-eYFP controls. This effect was rapid in its onset (34 ± 9 vs. -2 ± 4 mmHg at 5 min, p < 0.05) but persisted for the entire 50 min of cardiovascular recording (45 ± 11 vs. -3 ± 7 mmHg at 50 min, p < 0.05). Intriguingly, the optogenetic stimulation also resulted in 62% increase in Fos induction in AVP neurons within the PVN relative to AAV-eYFP controls (86 ± 5 vs. 52 ± 2 %; p<0.01). Collectively, these results suggest that excitation of AT1a neurons in the MnPO/OVLT recruits autonomic and neuroendocrine responses that promote robust and sustained increases in blood pressure.

Litte is known about correlation of cardiovascular and inflammatory reflex. Electric activation of the carotid sinus (CS), also known as baroreflex activation therapy (BAT), have been used as an effective technology for controlling AP in patients with resistant hypertension. Up to date, therapeutic efficacy of BAT has been evaluated mostly in humans and canine model. The lack of an appropriate animal model can be a limiting factor to understandingdetails of mechanisms involved with cardiovascular system and immune responses.Recent studies in awake rats have clearly demonstrated that BAT evokes hemodynamic and immunological responses; however, its mechanism is not known. Thus, further studies utilizing this animal model may offer an important tool to clarify the mechanisms involved in the responses evoked by recruitment of autonomic nervous system and immune system mediated by the cardiovascular and inflammatory reflex.