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Physiological Reviews Jul 2021The carotid body (CB) is the main peripheral chemoreceptor for arterial respiratory gases O and CO and pH, eliciting reflex ventilatory, cardiovascular, and humoral... (Review)
Review
The carotid body (CB) is the main peripheral chemoreceptor for arterial respiratory gases O and CO and pH, eliciting reflex ventilatory, cardiovascular, and humoral responses to maintain homeostasis. This review examines the fundamental biology underlying CB chemoreceptor function, its contribution to integrated physiological responses, and its role in maintaining health and potentiating disease. Emphasis is placed on ) transduction mechanisms in chemoreceptor (type I) cells, highlighting the role played by the hypoxic inhibition of O-dependent K channels and mitochondrial oxidative metabolism, and their modification by intracellular molecules and other ion channels; ) synaptic mechanisms linking type I cells and petrosal nerve terminals, focusing on the role played by the main proposed transmitters and modulatory gases, and the participation of glial cells in regulation of the chemosensory process; ) integrated reflex responses to CB activation, emphasizing that the responses differ dramatically depending on the nature of the physiological, pathological, or environmental challenges, and the interactions of the chemoreceptor reflex with other reflexes in optimizing oxygen delivery to the tissues; and ) the contribution of enhanced CB chemosensory discharge to autonomic and cardiorespiratory pathophysiology in obstructive sleep apnea, congestive heart failure, resistant hypertension, and metabolic diseases and how modulation of enhanced CB reactivity in disease conditions may attenuate pathophysiology.
Topics: Animals; Autonomic Nervous System; Cardiovascular System; Carotid Body; Chemoreceptor Cells; Humans; Hypoxia
PubMed: 33570461
DOI: 10.1152/physrev.00039.2019 -
International Journal of Molecular... Jul 2020The carotid body (CB) is responsible for the peripheral chemoreflex by sensing blood gases and pH. The CB also appears to act as a peripheral sensor of metabolites and... (Review)
Review
The carotid body (CB) is responsible for the peripheral chemoreflex by sensing blood gases and pH. The CB also appears to act as a peripheral sensor of metabolites and hormones, regulating the metabolism. CB malfunction induces aberrant chemosensory responses that culminate in the tonic overactivation of the sympathetic nervous system. The sympatho-excitation evoked by CB may contribute to the pathogenesis of metabolic syndrome, inducing systemic hypertension, insulin resistance and sleep-disordered breathing. Several molecular pathways are involved in the modulation of CB activity, and their pharmacological manipulation may lead to overall benefits for cardiometabolic diseases. In this review, we will discuss the role of the CB in the regulation of metabolism and in the pathogenesis of the metabolic dysfunction induced by CB overactivity. We will also explore the potential pharmacological targets in the CB for the treatment of metabolic syndrome.
Topics: Animals; Carotid Body; Drug Discovery; Glucose; Humans; Hypertension; Hypoxia; Insulin Resistance; Metabolic Syndrome; Molecular Targeted Therapy
PubMed: 32698380
DOI: 10.3390/ijms21145117 -
The Journal of Physiology Aug 2018The ageing process is characterized by a decline in several physiological functions resulting in a reduced capability to maintain homeostasis. The lowered homeostatic... (Review)
Review
The ageing process is characterized by a decline in several physiological functions resulting in a reduced capability to maintain homeostasis. The lowered homeostatic capacity seems to involve the carotid body (CB), whose role is to modulate ventilation and tissue oxygen supply. It thus plays a prime role in all ageing processes. Ageing causes marked changes in CB morphology. In older animals, it is enlarged and shows a concomitant decrease in the percentage of chemoreceptor tissue, as well as a proliferation of type II cells. The carotid glomitis is present with aggregates of lymphocytes and fibrosis of the lobules. Type I cells are dehydrated, with a profound vacuolization, a shrinking nucleus, and lipofuscin accumulation. With increased age, human CB shows a reduction in the number and volume of mitochondria, fewer synaptic junctions between glomi, along with a reduction in CB content of neurotransmitters, leading to a sort of 'physiological denervation'. Ageing could be interpreted as a cumulative result of oxidative damage to cells, which derives from aerobic metabolism. Moreover, metabolic rate is tightly correlated with life duration; thus a loss in mitochondrial function is one of the prime factors affecting CB ageing processes. The age-related reduction in synaptic junctions might be a self-protective mechanism through which cells buffer themselves against an accumulation of reactive oxygen species. The correlation between hypoxia and the life duration of CB cells remains an open question until how and why cells sense oxygen is understood.
Topics: Animals; Carotid Body; Cellular Senescence; Humans
PubMed: 29319194
DOI: 10.1113/JP275300 -
Advances in Experimental Medicine and... 2010The concept of a circulating RAS is well established and known to play an endocrine role in the regulation of fluid homeostasis (see Section 4.1, Chapter 4). However, it... (Review)
Review
The concept of a circulating RAS is well established and known to play an endocrine role in the regulation of fluid homeostasis (see Section 4.1, Chapter 4). However, it is more appropriate to view the RAS in the contemporary notion as an “angiotensin-generating system”, which consists of angiotensinogen, angiotensin-generating enzymes, and angiotensins, as well as their receptors. Some RASs can be termed as “complete”, having renin and ACE involved in the biosynthesis of angiotensin II peptide, i.e. in a renin and/or ACE-dependent manner which is exemplified in the circulating RAS. On the other hand, some RAS can be termed as “partial”, having alternate enzymes to renin and ACE, such as chymase and ACE2 (see Section 4.3, Chapter 4) available for the generation of angiotensin II and other bioactive angiotensin peptides in the biosynthetic cascade, i.e. in a renin and/or ACE-independent manner. Complete vs. partial RASs can be exemplified in the so-called intrinsic angiotensin-generating system or local RAS; for example, a local and functional RAS with renin and ACE-dependent but a renin-independent pathway have been indentified in the pancreas and carotid body, respectively. In the past two decades, local RASs have gained increasing recognition especially with regards to their clinical importance. Distinct from the circulating RAS, these functional local RASs exist in such diverse tissues and organs as the pancreas, liver, intestine, heart, kidney, vasculature, carotid body, and adipose, as well as the nervous, reproductive, and digestive systems. Taken into previous findings from our laboratory and others together, Table 5.1 is a summary of some recently identified local RASs in various levels of tissues and organs.
Topics: Animals; Carotid Body; Humans; Intestinal Mucosa; Liver; Renin-Angiotensin System
PubMed: 20700838
DOI: 10.1007/978-90-481-9060-7_5 -
Biological Research Feb 2016The carotid body (CB) is the main peripheral chemoreceptor that senses the arterial PO2, PCO2 and pH. In response to hypoxemia, hypercapnia and acidosis, carotid... (Review)
Review
The carotid body (CB) is the main peripheral chemoreceptor that senses the arterial PO2, PCO2 and pH. In response to hypoxemia, hypercapnia and acidosis, carotid chemosensory discharge elicits reflex respiratory, autonomic and cardiovascular adjustments. The classical construct considers the CB as the main peripheral oxygen sensor, triggering reflex physiological responses to acute hypoxemia and facilitating the ventilatory acclimation to chronic hypoxemia at high altitude. However, a growing body of experimental evidence supports the novel concept that an abnormally enhanced CB chemosensory input to the brainstem contributes to overactivation of the sympathetic nervous system, and consequent pathology. Indeed, the CB has been implicated in several diseases associated with increases in central sympathetic outflow. These include hypertension, heart failure, sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome. Indeed, ablation of the CB has been proposed for the treatment of severe and resistant hypertension in humans. In this review, we will analyze and discuss new evidence supporting an important role for the CB chemoreceptor in the progression of autonomic and cardiorespiratory alterations induced by heart failure, obstructive sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome.
Topics: Carotid Body; Heart Failure; Humans; Metabolic Diseases; Pulmonary Disease, Chronic Obstructive; Risk Factors; Sleep Apnea, Obstructive; Sympathetic Nervous System
PubMed: 26920146
DOI: 10.1186/s40659-016-0073-8 -
Current Hypertension Reports Aug 2016Hypertension continues to be a major contributor to global morbidity and mortality, fuelled by an abundance of patients with uncontrolled blood pressure despite the... (Review)
Review
Hypertension continues to be a major contributor to global morbidity and mortality, fuelled by an abundance of patients with uncontrolled blood pressure despite the multitude of pharmacological options available. This may occur as a consequence of true resistant hypertension, through an inability to tolerate current pharmacological therapies, or non-adherence to antihypertensive medication. In recent years, there has been a rapid expansion of device-based therapies proposed as novel non-pharmacological approaches to treating resistant hypertension. In this review, we discuss seven novel devices-renal nerve denervation, baroreflex activation therapy, carotid body ablation, central iliac arteriovenous anastomosis, deep brain stimulation, median nerve stimulation, and vagal nerve stimulation. We highlight how the devices differ, the varying degrees of evidence available to date and upcoming trials. This review also considers the possible factors that may enable appropriate device selection for different hypertension phenotypes.
Topics: Antihypertensive Agents; Arteriovenous Shunt, Surgical; Baroreflex; Blood Pressure; Carotid Body; Deep Brain Stimulation; Electric Stimulation Therapy; Humans; Hypertension; Iliac Artery; Iliac Vein; Median Nerve; Sympathectomy; Vagus Nerve Stimulation
PubMed: 27370788
DOI: 10.1007/s11906-016-0670-5 -
Physiological Genomics Jul 2018Known primarily for its oxygen-sensing capabilities, the carotid body chemoreceptors have recently been implicated, primarily by work in animal models, in the... (Review)
Review
Known primarily for its oxygen-sensing capabilities, the carotid body chemoreceptors have recently been implicated, primarily by work in animal models, in the pathophysiology of a number of metabolic conditions. The research presented in this brief review highlights translational work conducted at the Mayo Clinic between 2010 and 2017 in healthy humans and discusses key areas for future work in disease populations.
Topics: Animals; Carotid Body; Chemoreceptor Cells; Glucose; Humans; Hypoxia; Insulin; Oxygen; Translational Research, Biomedical
PubMed: 29652633
DOI: 10.1152/physiolgenomics.00032.2018 -
The Journal of Physiology Aug 2018The carotid body (CB) is considered the main O chemoreceptor, which contributes to cardiorespiratory homeostasis and ventilatory acclimatization. In clinical medicine,... (Review)
Review
The carotid body (CB) is considered the main O chemoreceptor, which contributes to cardiorespiratory homeostasis and ventilatory acclimatization. In clinical medicine, the most common pathologies associated with the CB are tumours. However, a growing body of evidence supports the novel idea that an enhanced CB chemosensory discharge contributes to the autonomic dysfunction and pathological consequences in obstructive sleep apnoea (OSA), hypertension, systolic heart failure (HF) and cardiometabolic diseases. Heightened CB chemosensory reactivity elicited by oxidative stress has been involved in sympathetic hyperactivity, cardiorespiratory instability, hypertension and insulin resistance. CB ablation, which reduces sympathetic hyperactivity, decreases hypertension in animal models of OSA and hypertension, eliminates breathing instability and improves animal survival in HF, and restores insulin tolerance in cardiometabolic models. Thus, data obtained from preclinical studies highlight the importance of the CB in the progression of sympathetic-related diseases, supporting the idea that appeasing the enhanced CB chemosensory drive may be useful in improving cardiovascular, respiratory and endocrine alterations. Accordingly, CB ablation has been proposed and used as a treatment for moderating resistant hypertension and HF-induced sympathetic hyperactivity in humans. First-in-human studies have shown that CB ablation reduces sympathetic overactivity, transiently reduces severe hypertension and improves quality of life in HF patients. Thus, CB ablation would be a useful therapy to reverse sympathetic overactivation in HF and severe hypertension, but caution is required before it is widely used due to the crucial physiological function played by the CB. Further studies in preclinical models are required to assess side-effects of CB ablation.
Topics: Animals; Carotid Body; Heart Failure; Humans; Hypertension; Hypoxia; Oxidative Stress; Sleep Apnea, Obstructive; Translational Research, Biomedical
PubMed: 29114876
DOI: 10.1113/JP275335 -
Respiratory Physiology & Neurobiology Jan 2013Arousal from sleep is a major defense mechanism in infants against hypoxia and/or hypercapnia. Arousal failure may be an important contributor to SIDS. Areas of the... (Review)
Review
Arousal from sleep is a major defense mechanism in infants against hypoxia and/or hypercapnia. Arousal failure may be an important contributor to SIDS. Areas of the brainstem that have been found to be abnormal in a majority of SIDS infants are involved in the arousal process. Arousal is sleep state dependent, being depressed during AS in most mammals, but depressed during QS in human infants. Repeated exposure to hypoxia causes a progressive blunting of arousal that may involve medullary raphe GABAergic mechanisms. Whereas CB chemoreceptors contribute heavily to arousal in response to hypoxia, serotonergic central chemoreceptors have been implicated in the arousal response to CO(2). Pulmonary or chest wall mechanoreceptors also contribute to arousal in proportion to the ventilatory response and decreases in their input may contribute to depressed arousal during AS. Little is known about specific arousal pathways beyond the NTS. Whether CB chemoreceptor stimulation directly stimulates arousal centers or whether this is done indirectly through respiratory networks remains unknown. This review will focus on arousal in response to hypoxia and CO(2) in the fetus and newborn and will outline what we know (and do not know) about the involvement of the carotid body in this process.
Topics: Arousal; Carotid Body; Fetus; Humans; Infant, Newborn; Sleep; Sudden Infant Death
PubMed: 22684039
DOI: 10.1016/j.resp.2012.06.005 -
Circulation Research Mar 2022Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve...
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 that GLP1 (glucagon-like peptide-1) modulates 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.
Topics: Animals; Blood Pressure; Carotid Body; Glucose; Hypertension; Rats; Rats, Inbred SHR
PubMed: 35100822
DOI: 10.1161/CIRCRESAHA.121.319874