Background: Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation. Methods: Using a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo. Results: We discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose. Conclusions: We show GLP1 (glucagon-like peptide-1) to modulate the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition.

The motivation for this review comes from the emerging complexity of the autonomic innervation of the carotid body and its putative role in regulating chemoreceptor sensitivity. With the carotid bodies as a potential therapeutic target for numerous cardiorespiratory and metabolic diseases, an understanding of the neural control of its circulation is most relevant. Since nerve fibres track blood vessels and receive autonomic innervation, we initiate our review by describing the origins of arterial feed to the carotid body and its unique vascular architecture and blood flow. Arterial feed(s) vary amongst species and, unequivocally, the arterial blood supply is relatively high to this organ. The vasculature appears to form separate circuits inside the carotid body with one having an arterial venous anastomoses. Both sympathetic and parasympathetic nerves are present with postganglionic neurons located within the carotid body or close to it in the form of paraganglia. Their role in arterial vascular resistance control is described as is how carotid blood flow relates to carotid sinus afferent activity. We discuss non-vascular targets of autonomic nerves, their possible role in controlling glomus cell activity, and how certain transmitters may relate to function. We propose that the autonomic nerves sub-serving the carotid body provide a rapid mechanism to tune the gain of peripheral chemoreflex sensitivity based on alterations in blood flow and oxygen delivery, and might provide future therapeutic targets. However, there remain a number of unknowns regarding these mechanisms that require further research that is discussed.

Aims The carotid bodies (CB) of spontaneously hypertensive (SH) rats exhibit hypertonicity and hyperreflexia contributing to heightened peripheral sympathetic outflow. We hypothesized that CB hyperexcitability is driven by its own sympathetic innervation. Methods and results To test this, the chemoreflex was activated (NaCN 50-100 µL, 0.04%) in SH and Wistar rats in situ before and after: 1) electrical stimulation (ES; 30 Hz, 2 ms, 10 V) of the superior cervical ganglion (SCG), which innervates the CB; 2) unilateral resection of the SCG (SCGx); 3) CB injections of an α1-adrenergic receptor agonist (phenylephrine, 50 µL, 1 mmol/L), and 4) α1-adrenergic receptor antagonist prazosin (30 µL, 1 mmol/L) or tamsulosin (50 µL, 1 mmol/l). ES of the SCG enhanced CB-evoked sympathoexcitation by 40-50% (P < 0.05) with no difference between rat strains. Unilateral SCGx attenuated the CB-evoked sympathoexcitation in SH (62%; P < 0.01) but was without effect in Wistar rats; it also abolished the ongoing firing of chemoreceptive petrosal neurones of SH rats, which became hyperpolarized. In Wistar rats, CB injections of phenylephrine enhanced CB-evoked sympathoexcitation (33%; P < 0.05), which was prevented by prazosin (26%; P < 0.05) in SH rats. Tamsulosin alone reproduced the effects of prazosin in SH rats and prevented the sensitizing effect of the SCG following ES. Within the CB, α1A- and α1B-adrenoreceptors were co-localized on both glomus cells and blood vessels. In conscious SH rats instrumented for recording blood pressure, the CB-evoked pressor response was attenuated after SCGx, and systolic BP fell by 16 ± 4.85 mmHg. Conclusions The sympathetic innervation of the CB is tonically activated and sensitizes the CB of SH but not Wistar rats. Furthermore, sensitization of CB-evoked reflex sympathoexcitation appears to be mediated by α1-adrenoceptors located either on the vasculature and/or glomus cells. The SCG is novel target for controlling CB pathophysiology in hypertension. Translational perspective Severing the main connection between the SCG and CB (i.e., the ganglioglomerular nerve) is a potential translational approach for normalizing CB sensitivity and as a treatment for hypertension. Selective denervation of the ganglioglomerular nerve in humans would mean that both the CB and SCG maintain their physiological function thereby minimizing any side-effects.

Twenty‐five years ago, a new physiological preparation called the working heart–brainstem preparation (WHBP) was introduced with the claim it would provide a new platform allowing studies not possible before in cardiovascular, neuroendocrine, autonomic and respiratory research. Herein, we review some of the progress made with the WHBP, some advantages and disadvantages along with potential future applications, and provide photographs and technical drawings of all the customised equipment used for the preparation. Using mice or rats, the WHBP is an in situ experimental model that is perfused via an extracorporeal circuit benefitting from unprecedented surgical access, mechanical stability of the brain for whole cell recording and an uncompromised use of pharmacological agents akin to in vitro approaches. The preparation has revealed novel mechanistic insights into, for example, the generation of distinct respiratory rhythms, the neurogenesis of sympathetic activity, coupling between respiration and the heart and circulation, hypothalamic and spinal control mechanisms, and peripheral and central chemoreceptor mechanisms. Insights have been gleaned into diseases such as hypertension, heart failure and sleep apnoea. Findings from the in situ preparation have been ratified in conscious in vivo animals and when tested have translated to humans. We conclude by discussing potential future applications of the WHBP including two‐photon imaging of peripheral and central nervous systems and adoption of pharmacogenetic tools that will improve our understanding of physiological mechanisms and reveal novel mechanisms that may guide new treatment strategies for cardiorespiratory diseases.

Although it is well-established that severe poisoning by organophosphorus (OP) compounds strongly affects the cardiorespiratory system, the effects of sub-lethal exposure to these compounds on the neural control of cardiovascular function are poorly explored. The aim of this study was to evaluate the effects of acute sub-lethal exposure to chlorpyrifos (CPF), a commonly used OP insecticide, on three basic reflex mechanisms involved in blood pressure regulation, the peripheral chemoreflex, the baroreflex and the Bezold-Jarisch reflex. Adult male Wistar rats were injected intraperitoneally with a single dose of CPF (30 mg/kg) or saline (0.9%). 24 h after injections, cardiovascular reflexes were tested in awake rats. Potassium cyanide (KCN) and phenylbiguanide (PBG) were injected intravenously to activate the chemoreflex and the Bezold-Jarisch reflex, respectively. The baroreflex was activated by phenylephrine and sodium nitroprusside infusions. Blood samples were taken for measurements of butyrylcholinesterase (BChE) activity while acetylcholinesterase (AChE) activity was measured in brainstem samples. Animals treated with CPF presented signs of intoxication such as ataxia, tremor, lacrimation, salivation, tetany, urination and defecation. The hypertensive and the bradycardic responses of the chemoreflex as well as the hypotensive and bradycardic responses of the Bezold-Jarisch reflex were attenuated in CPF treated animals (P < 0.05). Concerning the baroreflex responses, CPF treatment reduced the bradycardia plateau, the range and the gain of the reflex (P < 0.05). Plasma BChE and brainstem AChE were both reduced significantly after CPF treatment (P < 0.05). Our results showed that acute sub-lethal exposure to CPF impairs the cardiovascular responses of homeostatic and defensive cardiovascular reflexes. These effects are associated with a marked inhibition of plasma BChE and brainstem AChE.