Search

New Findings: What is the central question of this study?Are carotid bodies (CBs) modulated by the damage‐associated molecular patterns (DAMPs) and humoral factors of aseptic tissue injury?What are the main findings and their importance?DAMPs (HMGB1, S100 A8/A9) and blood plasma from rats subjected to tibia surgery, a model of aseptic injury, stimulate the release of neurotransmitters (ATP, dopamine) and TNF‐α from ex vivo rat CBs. All‐thiol HMGB1 mediates upregulation of immune‐related biological pathways. These data suggest regulation of CB function by endogenous mediators of innate immunity. The glomus cells of carotid bodies (CBs) are the primary sensors of arterial partial O2 and CO2 tensions and moreover serve as multimodal receptors responding also to other stimuli, such as pathogen‐associated molecular patterns (PAMPs) produced by acute infection. Modulation of CB function by excessive amounts of these immunomodulators is suggested to be associated with a detrimental hyperinflammatory state. We have hypothesized that yet another class of immunomodulators, endogenous danger‐associated molecular patterns (DAMPs), released upon aseptic tissue injury and recognized by the same pathogen recognition receptors as PAMPs, might modulate the CB activity in a fashion similar to PAMPs. We have tested this hypothesis by exposing rat CBs to various DAMPs, such as HMGB1 (all‐thiol and disulfide forms) and S100 A8/A9 in a series of ex vivo experiments that demonstrated the release of dopamine and ATP, neurotransmitters known to mediate CB homeostatic responses. We observed a similar response after incubating CBs with conditioned blood plasma obtained from the rats subjected to tibia surgery, a model of aseptic injury. In addition, we have investigated global gene expression in the rat CB using an RNA sequencing approach. Differential gene expression analysis showed all‐thiol HMGB1‐driven upregulation of a number of prominent pro‐inflammatory markers including Il1α and Il1β. Interestingly, conditioned plasma had a more profound effect on the CB transcriptome resulting in inhibition rather than activation of the immune‐related pathways. These data are the first to suggest potential modulation of CB function by endogenous mediators of innate immunity. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? Data on human carotid body (CB) function are limited. The aim of this study was therefore to investigate whether the human CB releases acetylcholine, ATP or cytokines during hypoxia., What is the main finding and its importance? Using human CBs, we demonstrate hypoxia-induced acetylcholine and ATP release, suggesting that these neurotransmitters, as in several experimental animal models, play a role in hypoxic signalling also in the human carotid body. Moreover, the human CB releases cytokines upon hypoxia and expresses cytokine receptors as well as hypoxia-inducible factor proteins HIF-1α and HIF-2α in glomus cells, indicating their role in immune signalling and oxygen sensing, respectively, in accordance with previous animal data., Studies on experimental animals established that the carotid bodies are sensory organs for detecting arterial blood O2 levels and that the ensuing chemosensory reflex is a major regulator of cardiorespiratory functions during hypoxia. However, little information is available on the human carotid body responses to hypoxia. The present study was performed on human carotid bodies obtained from surgical patients undergoing elective head and neck cancer surgery. Our results show that exposing carotid body slices to hypoxia for a period as brief as 5 min markedly facilitates the release of ACh and ATP. Furthermore, prolonged hypoxia for 1 h induces an increased release of interleukin (IL)-1β, IL-4, IL-6, IL-8 and IL-10. Immunohistochemical analysis revealed that type 1 cells of the human carotid body express an array of cytokine receptors as well as hypoxia-inducible factor-1α and hypoxia-inducible factor-2α. Taken together, these results demonstrate that ACh and ATP are released from the human carotid body in response to hypoxia, suggesting that these neurotransmitters, as in several experimental animal models, play a role in hypoxic signalling also in the human carotid body. The finding that the human carotid body releases cytokines in response to hypoxia adds to the growing body of information suggesting that the carotid body may play a role in detecting inflammation, providing a link between the immune system and the nervous system. [ABSTRACT FROM AUTHOR]

Abstract: We have characterized the mouse carotid body (CB) with special attention to nicotinic, purinergic and dopaminergic receptors as well as the TASK-1 K+-channel. Mouse CB sections were stained immunohistochemically and visualized using fluorescent and confocal microscopy. The CB type 1 cells contained the α3 (n =8), α4 (n =7), α7 (n =4) and β2 (n =3) nicotinic acetylcholine receptor (nAChR) subunits, the ATP-receptors P2X2 (n =15) and P2X3 (n =9), the dopamine D2 receptor (n =9) and the TASK-1 K+-channel (n =7). Here we report the presence of α3, α4, α7 and β2 nAChR subunits, the D2 receptor and the TASK-1 K+-channel in the mouse CB. Also, we confirm the presence of the P2X2 and P2X3 receptors in mouse CB. Thus, we have localized nicotinergic, purinergic and dopaminergic receptors and the TASK-1 K+-channel on a protein level in one species. Our data are in line with the theory that the CB chemoreceptor cell hosts an orchestra of receptor systems that ultimately modulate the response to hypoxia. [Copyright &y& Elsevier]

Background: Although the contribution of the gamma-aminobutyric acid (GABA) receptor system in peripheral chemosensation is unclear, immunohistochemistry has demonstrated the presence of GABA-ergic receptors in mammalian carotid bodies. We hypothesized that an activation of the carotid body GABA receptors would counteract the depolarizing effect of hypoxia. Methods: The carotid body with arterial supply and the carotid sinus nerve was removed en bloc from New Zealand White rabbits and placed in a perfusion chamber. The carotid body preparation was perfused via the cut common carotid artery with a modified Tyrode's solution at a rate of 3.5-4.5 ml/min with a constant pressure of 45 cmH2O. The carotid sinus nerve firing frequency (Hz) was recorded at two different oxygen tension levels during perfusion with midazolam of 1, 10 and 100 microg/l. Results: The frequency was decreased by midazolam in a dose-dependent manner (n = 8). Firing frequencies (mean +/- SEM) at the low oxygen tension level decreased from 643.13 +/- 67.2 Hz in the control to 554.5 +/- 67.7 Hz (P = 0.054 vs. control), 509.01 +/- 100.5 Hz (P < 0.012 vs. control) and 422.6 +/- 77.3 Hz (P < 0.001 vs. control) during perfusion with midazolam of 1, 10 and 100 microg/l, respectively. Conclusion: Midazolam depresses carotid body chemoreceptor activity in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Background: Vecuronium depresses carotid body chemosensitivity during hypoxia. We hypothesized that this is caused by inhibition of cholinergic transmission of the carotid body.Methods: The carotid body with its sinus nerve was removed en bloc from thiopentone-anaesthetized adult male New Zealand rabbits and perfused in vitro with modified Tyrodes buffer solution at constant perfusion pressure, temperature, a buffer pH of 7.4 and normocapnia. Chemoreceptor discharge and spike frequencies (fx) were recorded from the whole sinus nerve after administration of 500 microg nicotine, given as duplicated controls and thereafter following 30 min perfusion of equipotent concentrations of atracurium (28.1 microM) or vecuronium(10 microM), after 30 min of neostigmine perfusion (9.2 microM) and finally after 30 min wash-out with buffer solution only. A short-lasting hypoxic test was performed before and at the end of the experimental period to confirm the responsiveness and validity of the preparation.Results: Atracurium (n = 7) and vecuronium (n = 6) reduced chemoreceptor responses to nicotine by 70 +/- 30% and 66 +/- 19% (SEM) (P<0.05). Chemoreceptor discharges showed full recovery after neostigmine in the atracurium group and partial recovery in the vecuronium group (P<0.05). Finally, after wash-out the chemoreceptor responses to nicotine had fully recovered in both groups.Conclusion: Atracurium and vecuronium in equipotent concentrations block nicotine-induced chemoreceptor responses of the carotid body. [ABSTRACT FROM AUTHOR]

The carotid body (CB) is the key sensing organ for physiological oxygen levels in the body. Under conditions of low oxygen (hypoxia), the CB plays crucial roles in signaling to the cardiorespiratory center in the medulla oblongata for the restoration of oxygen homeostasis. How hypoxia regulates gene expression in the human CB remains poorly understood. While limited information on transcriptional regulation in animal CBs is available, the identity and impact of important post-transcriptional regulators such as non-coding RNAs, and in particular miRNAs are not known. Here we show using ex vivo experiments that indeed a number of miRNAs are differentially regulated in surgically removed human CB slices when acute hypoxic conditions were applied. Analysis of the hypoxia-regulated miRNAs shows that they target biological pathways with upregulation of functions related to cell proliferation and immune response and downregulation of cell differentiation and cell death functions. Comparative analysis of the human CB miRNAome with the global miRNA expression patterns of a large number of different human tissues showed that the CB miRNAome had a unique profile which reflects its highly specialized functional status. Nevertheless, the human CB miRNAome is most closely related to the miRNA expression pattern of brain tissues indicating that they may have the most similar developmental origins. [ABSTRACT FROM AUTHOR]

Abstract: Propofol is a commonly used anesthetic agent, and it attenuates hypoxic ventilatory response in humans. Propofol reduce in vivo and in vitro carotid body responses to hypoxia as well as to nicotine in experimental animals. In the present study we examined the effects of propofol on carotid body responses to hypercapnia and K+-induced carotid body activation and compared these effects with hypoxia in an in vitro rabbit carotid body preparation. Hypoxia, hypercapnia and potassium increased the carotid sinus nerve activity and propofol attenuated the chemoreceptor responses to all three stimuli. However, the magnitude of propofol-induced attenuation was greater for hypercapnic and K+-induced carotid body activation compared to the hypoxic response. These observations suggest that propofol-induced attenuation of the hypoxic response is partly secondary to depression of chemoreceptor response to hypercapnia inhibiting the synergistic interactions between O2 and CO2 and may involve CO2/H+ sensitive K+ channels. [Copyright &y& Elsevier]

Neuromuscular blocking agents predominantly block muscle type nicotinic acetylcholine receptors as opposed to the neuronal type. However, there is growing evidence that neuromuscular blocking agents have affinity to some neuronal nicotinic acetylcholine receptors. The carotid body chemoreceptor as the essential oxygen-sensing cell, relies on cholinergic signalling. Atracurium and vecuronium impair carotid body chemoreceptor activity during hypoxia. Here, we characterize atracurium and vecuronium as antagonists at nicotinic receptors of the carotid body chemoreceptor. Isolated rabbit carotid body preparations with carotid sinus nerve were used, and chemoreceptor activities were recorded. There was a concentration-dependent reduction in the chemoreceptor responses to nicotine, with an IC50 to 50 μg nicotine of 3.64 and 1.64 μM and to 500 μg nicotine of 27.00 μM and 7.29 μM for atracurium and vecuronium, respectively. It is concluded that atracurium and vecuronium depress nicotine-induced chemoreceptor responses of the carotid body in a dose-dependent fashion. [Copyright &y& Elsevier]