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Interoception entails perceiving or being aware of the internal state of the body, playing a pivotal role in regulating processes such as heartbeat, digestion, glucose metabolism, and respiration. The carotid body (CB) serves as an interoceptive organ, transmitting information to the brain via its sensitive nerve, the carotid sinus nerve, to maintain homeostasis. While traditionally known for sensing oxygen, carbon dioxide, and pH levels, the CB is now recognized to possess additional interoceptive properties, detecting various mediators involved in blood pressure regulation, inflammation, and glucose homeostasis, among other physiological functions. Furthermore, in the last decades CB dysfunction has been linked to diseases like sleep apnea, essential hypertension, and diabetes. In this review manuscript, we make a concise overview of the traditional interoceptive functions of the CB, acting as a sensor for oxygen levels, carbon dioxide levels, and pH, and introduce the novel interoceptive properties of the CB related to vascular, glucose and energy regulation. Additionally, we revise the contribution of the CB to the onset and progression of metabolic diseases, delving into the potential dysfunction of its interoceptive metabolic functions as a contributing factor to pathophysiology. Finally, we postulate the use of therapeutic interventions targeting the metabolic interoceptive properties of the CB as a potential avenue for addressing metabolic diseases. • The carotid body is an interoceptive organ, transmitting information to the brain via the carotid sinus nerve to maintain homeostasis. • Classical sensitive properties of the carotid body include detection of alterations in blood O 2 , CO 2 and pH. • Novel interoceptive properties of the carotid body, include the sensing of blood hormones, cytokines, and vascular factors. • Disturbances in the novel interoceptive properties of the carotid body could contribute to metabolic diseases. [ABSTRACT FROM AUTHOR]

The present study investigated the localization of the adenosine 5′-diphosphate (ADP)-selective P2Y12 purinoceptors in the rat carotid body using multilabeling immunofluorescence. Punctate immunoreactive products for P2Y12 were distributed in chemoreceptive type I cells immunoreactive to vesicular nucleotide transporter (VNUT) or dopamine beta-hydroxylase, but not in S100B-immunoreactive glial-like type II cells. P2Y12 immunoreactivity was localized in cell clusters containing VNUT-immunoreactive type I cells surrounded by the perinuclear cytoplasm and cytoplasmic processes of type II cells immunoreactive for ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) and NTPDase3, which hydrolyze extracellular nucleotide tri- and/or di-phosphates. In ATP bioluminescence assays using carotid bodies, the degradation of extracellular ATP was attenuated in the presence of the selective NTPDases inhibitor ARL67156, suggesting ATP-degrading activity by NTPDases in the tissue. These results suggest that ATP released from type I cells is degraded into ADP and adenosine 5′-monophosphate by NTPDases expressed in type II cells, and that ADP modulates type I cells via P2Y12 purinoceptors. [ABSTRACT FROM AUTHOR]

The sensitization and hypertonicity of visceral afferents are highly relevant to the development and progression of cardiovascular and respiratory disease states. In this review, we described the evidence that the inflammatory process regulates visceral afferent sensitivity and tonicity, affecting the control of the cardiovascular and respiratory system. Some inflammatory mediators like nitric oxide, angiotensin II, endothelin-1, and arginine vasopressin may inhibit baroreceptor afferents and contribute to the baroreflex impairment observed in cardiovascular diseases. Cytokines may act directly on peripheral afferent terminals that transmit information to the central nervous system (CNS). TLR-4 receptors, which recognize lipopolysaccharide, were identified in the nodose and petrosal ganglion and have been implicated in disrupting the blood-brain barrier, which can potentiate the inflammatory process. For example, cytokines may cross the blood-brain barrier to access the CNS. Additionally, pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α and some of their receptors have been identified in the nodose ganglion and carotid body. These pro-inflammatory cytokines also sensitize the dorsal root ganglion or are released in the nucleus of the solitary tract. In cardiovascular disease, pro-inflammatory mediators increase in the brain, heart, vessels, and plasma and may act locally or systemically to activate/sensitize afferent nervous terminals. Recent evidence demonstrated that the carotid body chemoreceptor cells might sense systemic pro-inflammatory molecules, supporting the novel proposal that the carotid body is part of the afferent pathway in the central anti-inflammatory reflexes. The exact mechanisms of how pro-inflammatory mediators affects visceral afferent signals and contribute to the pathophysiology of cardiovascular diseases awaits future research. [ABSTRACT FROM AUTHOR]

Although cardiovascular responses may be altered by respiratory changes under prolonged hypoxia, the relationship between respiratory and cardiovascular changes remains unknown. The aim of the present study is to clarify cardiorespiratory changes in anesthetized rats during and after hypoxic conditions using simultaneous recordings of cardiorespiratory variables with 20-sec recording intervals. After air breathing for 20 min (pre-exposure period), rats were subjected to 10% O 2 for 2 h (hypoxic exposure period) and then air for 30 min (recovery period). Minute ventilation (V E ), respiratory frequency, tidal volume, arterial blood pressure (BP), and heart rate (HR) were continuously monitored during the experimental period. Just after hypoxic exposure, V E , BP, and HR exhibited an overshoot, undershoot, and overshoot followed by a decrease, respectively. During the remaining hypoxic exposure period, continuous high V E and low BP were observed, whereas HR re-increased. In the recovery period, V E , BP, and HR showed an undershoot, increase, and decrease followed by an increase, respectively. These results suggest that the continuation of enhanced V E and re-increased HR, probably, due to carotid body excitation and accompanying sympathetic activation, during the late period of hypoxic exposure are protective responses to avoid worsening hypoxemia and further circulatory insufficiencies under sustained hypoxia. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate immunoreactivity for dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in carotid body (CB) glomus cells in spontaneously hypertensive rats (SHR/Izm) at 4 (prehypertensive stage), 8 (early stage of developmental hypertension), 12 (later stage of developmental hypertension), and 16 weeks of age (established hypertensive stage). Age-matched Wistar Kyoto rats (WKY/Izm) were used as controls. Staining properties for TH were similar between both strains at each age. Regarding DBH immunostaining, although some glomus cells showed intense DBH immunoreactivity at 4 weeks of age, these cells were rarely observed at 8, 12, and 16 weeks of age in WKY/Izm. In SHR/Izm, intense DBH immunoreactivity was observed in some glomus cells at 4 weeks of age, these cells were also observed at 8 and 12 weeks of age, and their number increased at 16 weeks of age. An image analysis showed that the percentage of DBH-immunopositive glomus cells in WKY/Izm was approximately 30% at 4 weeks of age and significantly decreased to approximately 10% at 8, 12, and 16 weeks of age ( p < 0.05). This percentage in SHR/Izm was approximately 40% at each age. The gray scale intensity for DBH immunoreactivity in DBH-immunopositive glomus cells was similar in both strains at 4 weeks of age, but became significantly lower in WKY/Izm and higher in SHR/Izm with increase in age ( p < 0.05). These results suggest that noradrenaline in glomus cells plays an important role in the regulation of neurotransmission between CB and afferent nerves during developmental hypertension. [ABSTRACT FROM AUTHOR]

Despite the plethora of current treatment options, hypertension remains a difficult condition to adequately control, and there is a pressing need for novel therapeutic strategies. The carotid body has recently become the focus of considerable interest as a potential novel treatment target in essential hypertension. Herein, we appraise the current literature suggesting that the carotid body plays an important causative role to generate sympathetic overactivity and drive increases in arterial pressure, in animal models of hypertension. We also review evidence from human studies showing cardiovascular benefits to the transient inactivation, or surgical removal of carotid bodies, and evaluate the potential benefits of pre-screening to identify patients likely to respond to carotid body-targeted therapy. Finally, given that a high proportion of patients who have undergone renal nerve ablation procedures remain hypertensive, we examine whether the renal nerves are necessary for the drop in blood pressure seen with carotid body removal. [ABSTRACT FROM AUTHOR]

Purpose Determination of the relationship between the estimated total volume of the carotid bodies (V rCB + lCB ), assessed by computed tomography angiography (CTA), and the autonomic cardiac function in patients with essential hypertension (EH). Materials and methods The study included 69 patients with diagnosed and pharmacologically treated EH. The estimated volume of each carotid body (CB) was evaluated on the basis of scans obtained in the CTA of carotid arteries, using the following formula: 4/3 × π × half of transverse dimension of CB in axial projection × half of longitudinal dimension of CB in the axial projection × half of craniocaudal dimension of CB in the sagittal/coronal projection. Cardiac autonomic function was assessed using time domain analysis of heart rate variability (HRV). Results The mean values of SDNNi, rMSSD and pNN50 at 24-h monitoring, during daily activity and during night rest, were significantly lower in patients with hypertension with the values of V rCB + lCB ≥ median compared to the group of hypertensive patients with the values of V rCB + lCB < median. Moreover, in patients with EH with the values of V rCB + lCB ≥ median, the mean values of SDNN were lower during daily activity. Based on the regression analysis, it was found out that the higher values of V rCB + lCB are an independent risk factor in HRV reduction (expressed as a reduction in the rMSSD). Conclusion In patients with EH, a relationship between the volume of CB, assessed by CTA of carotid arteries, and autonomic cardiac function seems to be probable. [ABSTRACT FROM AUTHOR]

Abstract: This study aimed to determine the roles played by the autonomic interoreceptors, the carotid bodies (cbs) and the aortic bodies (abs) in anesthetized, paralyzed, artificially ventilated cats'' response to systemic hypoxemia. Four 15min challenges stimulated each of 15 animals: (1) hypoxic hypoxia (10%O2 in N2; HH) in the intact (int) cat where both abs and cbs sent neural traffic to the nucleus tractus solitarius (NTS); (2) carbon monoxide hypoxia (30%O2 in N2 with the addition of CO; COH) in the intact cat where only the abs sent neural traffic to the NTS; (3) HH in the cat after transection of both aortic depressor nerves, resecting the aortic bodies (HHabr), where only the cbs sent neural traffic to the NTS; (4) COH to the abr cat where neither abs nor cbs sent neural traffic to the NTS. Cardiac output (C.O.), contractility (dP/dtMAX), systolic/diastolic pressures, aortic blood pressure, total peripheral resistance, pulmonary arterial pressure, and pulmonary vascular resistance (PVR) were measured. When both cbs and abs were active the maximum increases were observed except for PVR which decreased. Some variables showed the cbs to have a greater effect than the abs. The abs proved to be important during some challenges for maintaining blood pressure. The data support the critically important role for the chemoreceptor–sympathetic nervous system connection during hypoxemia for maintaining viable homeostasis, with some differences between the cbs and the abs. [Copyright &y& Elsevier]

Abstract: Under hypertension, it has been reported that the carotid body (CB) is enlarged and noradrenaline (NA) content in CB is increased. Therefore, it is hypothesized that morphological and neurochemical changes in CB are induced in hypertensive animal models. In the present study, we examined the morphological features and dopamine β-hydroxylase (DBH) immunoreactivity in CB of spontaneously hypertensive rats (SHR/Izm) and Wistar Kyoto rats (WKY/Izm). The CB of SHR/Izm was elongated in terms of the cross section of center and was enlarged in the reconstructed images compared with that of WKY/Izm, and the total volume of CB in SHR/Izm (0.048±0.004mm3) was significantly (p <0.05) increased compared with the value in WKY/Izm (0.032±0.006mm3). By immunohistochemistry, immunoreactivity for tyrosine hydroxylase in CB was mainly observed in glomus cells and the immunostaining properties were similar between WKY/Izm and SHR/Izm. On the other hand, DBH immunoreactivity was mainly observed in nerve fibers around blood vessels and observed in a few glomus cells in CB of WKY/Izm. The number of glomus cells with strong DBH immunoreactivity was increased in SHR/Izm compared with that in WKY/Izm. In conclusion, the present study exhibited the enlargement of CB as three-dimensional image and revealed the enhanced immunoreactivity for DBH of glomus cells in SHR/Izm. These results suggest that the morphology of CB is affected by the effect of sympathetic nerve and that the signal transduction from CB is regulated by NA in glomus cells under hypertensive conditions. [Copyright &y& Elsevier]

Abstract: The peripheral hyperosmolarity elicited by intravenous infusion of hypertonic saline brings potential benefits to the treatment of hemorrhage. The neural mechanisms involved in these beneficial effects remain unknown. The present study examines the role of carotid chemoreceptors in cardiovascular responses induced by hypertonic saline after hypovolemic hemorrhage in rats. Male Wistar rats (300–400g) were anesthetized with thiopental, and instrumented for recording of mean arterial pressure. Arterial pressure was reduced to 60mm Hg by withdrawal of arterial blood over 10min, and maintained at this level for 60min by withdrawal or infusion of blood. In control rats (n=8) with intact chemoreceptors, the subsequent intravenous infusion of hypertonic saline (3M NaCl, 1.8mlkg−1 body weight, in 2min) restored blood pressure (pressure increased from 61±4 to 118±5mm Hg). In experimental rats (n=8), the carotid body arteries were tied, 30min after the beginning of the hypotensive phase, leaving the carotid chemoreceptors ischemic. In these rats, hypertonic saline failed to restore blood pressure (pressure increased from 55±1 to 70±6mm Hg). These findings suggest that the restoration of blood pressure after hypovolemic hemorrhage induced by hypertonic saline depends on intact carotid chemoreceptors. [Copyright &y& Elsevier]

Abstract: The carotid body receptors participate in glucose regulation sensing glucose levels in blood entering the cephalic circulation. The carotid body receptors information, is initially processed within the nucleus tractus solitarius (NTS) and elicits changes in circulating glucose and brain glucose uptake. Previous work has shown that γ-aminobutyric acid (GABA) in NTS modulates respiratory reflexes, but the role of GABA within NTS in glucose regulation remains unknown. Here we show that GABAB receptor agonist (baclofen) or antagonists (phaclofen and CGP55845A) locally injected into NTS modified arterial glucose levels and brain glucose retention. Control injections outside NTS did not elicit these responses. In contrast, GABAA agonist and antagonist (muscimol or bicuculline) produced no significant changes in blood glucose levels. When these GABAergic drugs were applied before carotid body receptors stimulation, again, only GABAB agonist or antagonist significantly affected glycemic responses; baclofen microinjection significantly reduced the hyperglycemic response and brain glucose retention observed after carotid body receptors stimulation, while phaclofen produced the opposite effect, increasing significantly hyperglycemia and brain glucose retention. These results indicate that activation of GABAB, but not GABAA, receptors in the NTS modulates the glycemic responses after anoxic stimulation of the carotid body receptors, and suggest the presence of a tonic inhibitory mechanism in the NTS to avoid hyperglycemia. [Copyright &y& Elsevier]

The purpose of this study was to investigate the effects of electrical and chemical stimulation of the sub-lobule IX-b of the cerebellar uvula on the cardiorespiratory responses evoked on stimulation of the carotid chemoreceptors in the anaesthetised and paralysed rabbit. Recordings of arterial blood pressure, ECG, heart rate and phrenic nerve activity were evaluated. Sub-lobule IX-b was activated electrically (1 ms, 20 μA, 100 Hz, 4-s train) and stimulated chemically with sodium glutamate microinjections (2 mM, pH=7.4±0.1) using bipolar concentric or multibarrelled microelectrodes. Carotid body chemoreflexes were evoked by the retrograde injection of sodium cyanide (0.1%, 0.1 ml) into the blood supply of the carotid body through a cannula inserted in the external carotid artery. The interaction of uvula stimulation and the carotid chemoreceptor reflex was studied by following the chemoreceptor stimulus with a stimulus to the uvula. Electrical and chemical stimulation of the uvula evoked a characteristic bradycardia and a depressor response together with a decrease in phrenic nerve activity. Carotid body stimulation evoked a decrease in heart rate accompanied by an increase of both arterial blood pressure and phrenic nerve activity. However, simultaneous delivery of the two stimuli resulted in a depressor response together with a decrease of phrenic nerve activity and an increased bradycardia. These data suggest that stimulation of the cerebellar uvula exerts an inhibitory control of the chemoreflex efficacy as far as respiratory activity and blood pressure is concerned. [Copyright &y& Elsevier]

Atmospheric oxygen concentrations rose markedly at several points in evolutionary history. Each of these increases was followed by an evolutionary leap in organismal complexity, and thus the cellular adaptions we see today have been shaped by the levels of oxygen within our atmosphere. In eukaryotic cells, oxygen is essential for the production of adenosine 5′-triphosphate (ATP) which is the 'Universal Energy Currency' of life. Aerobic organisms survived by evolving precise mechanisms for converting oxygen within the environment into energy. Higher mammals developed specialised organs for detecting and responding to changes in oxygen content to maintain gaseous homeostasis for survival. Hypoxia is sensed by the carotid bodies, the primary chemoreceptor organs which utilise multiple neurotransmitters one of which is ATP to evoke compensatory reflexes. Yet, a paradox is presented in oxygen sensing cells of the carotid body when during periods of low oxygen, ATP is seemingly released in abundance to transmit this signal although the synthesis of ATP is theoretically halted because of its dependence on oxygen. We propose potential mechanisms to maintain ATP production in hypoxia and summarise recent data revealing elevated sensitivity of purinergic signalling within the carotid body during conditions of sympathetic overactivity and hypertension. We propose the carotid body is hypoxic in numerous chronic cardiovascular and respiratory diseases and highlight the therapeutic potential for modulating purinergic transmission. [ABSTRACT FROM AUTHOR]

We have considered some of the available evidence to account for the impact of SARS-CoV on the regulatory control of the autonomic nervous and respiratory systems. Apart from stimulating general interest in the subject, our hope was to provide putative explanations for some of the patients' symptoms based on described physiological and pathophysiological mechanisms seen in other diseases. Herein, we have focused on the carotid bodies. In this hypothetical viewpoint, we have discussed the plasticity of the carotid body chemoreflex and made a comparison between acute and chronic exposures to high altitude with COVID-19. From these discussions, we have postulated that the sensitivity of the hypoxic ventilatory response may well determine the outcome of disease severity and those that live at high altitude may be more resistant. We have provided insight into silent hypoxia and attempted to explain an absence of ventilatory drive and anxiety yet maintenance of consciousness. In an attempt to discover more about the mysteries of COVID-19, we conclude with questions and some hypothetical studies that may answer them. [ABSTRACT FROM AUTHOR]