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17 pages, 1775 KiB

Open AccessArticle

Expanding Role of Dopaminergic Inhibition in Hypercapnic Responses of Cultured Rat Carotid Body Cells: Involvement of Type II Glial Cells

by Erin M. Leonard and Colin A. Nurse

Int. J. Mol. Sci. 2020, 21(15), 5434; https://doi.org/10.3390/ijms21155434 - 30 Jul 2020

Cited by 8 | Viewed by 3530

Abstract

Dopamine (DA) is a well-studied neurochemical in the mammalian carotid body (CB), a chemosensory organ involved in O₂ and CO₂/H⁺ homeostasis. DA released from receptor (type I) cells during chemostimulation is predominantly inhibitory, acting via pre- and post-synaptic dopamine [...] Read more.

Dopamine (DA) is a well-studied neurochemical in the mammalian carotid body (CB), a chemosensory organ involved in O₂ and CO₂/H⁺ homeostasis. DA released from receptor (type I) cells during chemostimulation is predominantly inhibitory, acting via pre- and post-synaptic dopamine D2 receptors (D2R) on type I cells and afferent (petrosal) terminals respectively. By contrast, co-released ATP is excitatory at postsynaptic P2X2/3R, though paracrine P2Y2R activation of neighboring glial-like type II cells may boost further ATP release. Here, we tested the hypothesis that DA may also inhibit type II cell function. When applied alone, DA (10 μM) had negligible effects on basal [Ca²⁺]_i in isolated rat type II cells. However, DA strongly inhibited [Ca²⁺]_i elevations (Δ[Ca^2+]_i) evoked by the P2Y2R agonist UTP (100 μM), an effect opposed by the D2/3R antagonist, sulpiride (1–10 μM). As expected, acute hypercapnia (10% CO₂; pH 7.4), or high K⁺ (30 mM) caused Δ[Ca²⁺]_i in type I cells. However, these stimuli sometimes triggered a secondary, delayed Δ[Ca²⁺]_i in nearby type II cells, attributable to crosstalk involving ATP-P2Y2R interactions. Interestingly sulpiride, or DA store-depletion using reserpine, potentiated both the frequency and magnitude of the secondary Δ[Ca²⁺]_i in type II cells. In functional CB-petrosal neuron cocultures, sulpiride potentiated hypercapnia-induced Δ[Ca²⁺]_i in type I cells, type II cells, and petrosal neurons. Moreover, stimulation of type II cells with UTP could directly evoke Δ[Ca²⁺]_i in nearby petrosal neurons. Thus, dopaminergic inhibition of purinergic signalling in type II cells may help control the integrated sensory output of the CB during hypercapnia. Full article

(This article belongs to the Special Issue Neurotransmitters and Neuropeptides in the Modulation of the Carotid Body)

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13 pages, 1214 KiB

Open AccessArticle

Peripheral Dopamine 2-Receptor Antagonist Reverses Hypertension in a Chronic Intermittent Hypoxia Rat Model

by Elena Olea, Inmaculada Docio, Miguel Quintero, Asunción Rocher, Ana Obeso, Ricardo Rigual and Angela Gomez-Niño

Int. J. Mol. Sci. 2020, 21(14), 4893; https://doi.org/10.3390/ijms21144893 - 10 Jul 2020

Cited by 4 | Viewed by 2705

Abstract

The sleep apnea-hypopnea syndrome (SAHS) involves periods of intermittent hypoxia, experimentally reproduced by exposing animal models to oscillatory PO₂ patterns. In both situations, chronic intermittent hypoxia (CIH) exposure produces carotid body (CB) hyperactivation generating an increased input to the brainstem which originates [...] Read more.

The sleep apnea-hypopnea syndrome (SAHS) involves periods of intermittent hypoxia, experimentally reproduced by exposing animal models to oscillatory PO₂ patterns. In both situations, chronic intermittent hypoxia (CIH) exposure produces carotid body (CB) hyperactivation generating an increased input to the brainstem which originates sympathetic hyperactivity, followed by hypertension that is abolished by CB denervation. CB has dopamine (DA) receptors in chemoreceptor cells acting as DA-2 autoreceptors. The aim was to check if blocking DA-2 receptors could decrease the CB hypersensitivity produced by CIH, minimizing CIH-related effects. Domperidone (DOM), a selective peripheral DA-2 receptor antagonist that does not cross the blood-brain barrier, was used to examine its effect on CIH (30 days) exposed rats. Arterial pressure, CB secretory activity and whole-body plethysmography were measured. DOM, acute or chronically administered during the last 15 days of CIH, reversed the hypertension produced by CIH, an analogous effect to that obtained with CB denervation. DOM marginally decreased blood pressure in control animals and did not affect hypoxic ventilatory response in control or CIH animals. No adverse effects were observed. DOM, used as gastrokinetic and antiemetic drug, could be a therapeutic opportunity for hypertension in SAHS patients’ resistant to standard treatments. Full article

(This article belongs to the Special Issue Neurotransmitters and Neuropeptides in the Modulation of the Carotid Body)

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Review

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15 pages, 3427 KiB

Open AccessReview

Neurotransmitter Modulation of Carotid Body Germinal Niche

by Verónica Sobrino, Aida Platero-Luengo, Valentina Annese, Elena Navarro-Guerrero, Patricia González-Rodríguez, José López-Barneo and Ricardo Pardal

Int. J. Mol. Sci. 2020, 21(21), 8231; https://doi.org/10.3390/ijms21218231 - 3 Nov 2020

Cited by 5 | Viewed by 2916

Abstract

The carotid body (CB), a neural-crest-derived organ and the main arterial chemoreceptor in mammals, is composed of clusters of cells called glomeruli. Each glomerulus contains neuron-like, O₂-sensing glomus cells, which are innervated by sensory fibers of the petrosal ganglion and are [...] Read more.

The carotid body (CB), a neural-crest-derived organ and the main arterial chemoreceptor in mammals, is composed of clusters of cells called glomeruli. Each glomerulus contains neuron-like, O₂-sensing glomus cells, which are innervated by sensory fibers of the petrosal ganglion and are located in close contact with a dense network of fenestrated capillaries. In response to hypoxia, glomus cells release transmitters to activate afferent fibers impinging on the respiratory and autonomic centers to induce hyperventilation and sympathetic activation. Glomus cells are embraced by interdigitating processes of sustentacular, glia-like, type II cells. The CB has an extraordinary structural plasticity, unusual for a neural tissue, as it can grow several folds its size in subjects exposed to sustained hypoxia (as for example in high altitude dwellers or in patients with cardiopulmonary diseases). CB growth in hypoxia is mainly due to the generation of new glomeruli and blood vessels. In recent years it has been shown that the adult CB contains a collection of quiescent multipotent stem cells, as well as immature progenitors committed to the neurogenic or the angiogenic lineages. Herein, we review the main properties of the different cell types in the CB germinal niche. We also summarize experimental data suggesting that O₂-sensitive glomus cells are the master regulators of CB plasticity. Upon exposure to hypoxia, neurotransmitters and neuromodulators released by glomus cells act as paracrine signals that induce proliferation and differentiation of multipotent stem cells and progenitors, thus causing CB hypertrophy and an increased sensory output. Pharmacological modulation of glomus cell activity might constitute a useful clinical tool to fight pathologies associated with exaggerated sympathetic outflow due to CB overactivation. Full article

(This article belongs to the Special Issue Neurotransmitters and Neuropeptides in the Modulation of the Carotid Body)

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28 pages, 759 KiB

Open AccessReview

Growth Factors in the Carotid Body—An Update

by Elena Stocco, Silvia Barbon, Cinzia Tortorella, Veronica Macchi, Raffaele De Caro and Andrea Porzionato

Int. J. Mol. Sci. 2020, 21(19), 7267; https://doi.org/10.3390/ijms21197267 - 1 Oct 2020

Cited by 18 | Viewed by 3750

Abstract

The carotid body may undergo plasticity changes during development/ageing and in response to environmental (hypoxia and hyperoxia), metabolic, and inflammatory stimuli. The different cell types of the carotid body express a wide series of growth factors and corresponding receptors, which play a role [...] Read more.

The carotid body may undergo plasticity changes during development/ageing and in response to environmental (hypoxia and hyperoxia), metabolic, and inflammatory stimuli. The different cell types of the carotid body express a wide series of growth factors and corresponding receptors, which play a role in the modulation of carotid body function and plasticity. In particular, type I cells express nerve growth factor, brain-derived neurotrophic factor, neurotrophin 3, glial cell line-derived neurotrophic factor, ciliary neurotrophic factor, insulin-like-growth factor-I and -II, basic fibroblast growth factor, epidermal growth factor, transforming growth factor-α and -β, interleukin-1β and -6, tumor necrosis factor-α, vascular endothelial growth factor, and endothelin-1. Many specific growth factor receptors have been identified in type I cells, indicating autocrine/paracrine effects. Type II cells may also produce growth factors and express corresponding receptors. Future research will have to consider growth factors in further experimental models of cardiovascular, metabolic, and inflammatory diseases and in human (normal and pathologic) samples. From a methodological point of view, microarray and/or proteomic approaches would permit contemporary analyses of large groups of growth factors. The eventual identification of physical interactions between receptors of different growth factors and/or neuromodulators could also add insights regarding functional interactions between different trophic mechanisms. Full article

(This article belongs to the Special Issue Neurotransmitters and Neuropeptides in the Modulation of the Carotid Body)

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20 pages, 2099 KiB

Open AccessReview

G-Protein-Coupled Receptor (GPCR) Signaling in the Carotid Body: Roles in Hypoxia and Cardiovascular and Respiratory Disease

by Hayyaf S. Aldossary, Abdulaziz A. Alzahrani, Demitris Nathanael, Eyas A. Alhuthail, Clare J. Ray, Nikolaos Batis, Prem Kumar, Andrew M. Coney and Andrew P. Holmes

Int. J. Mol. Sci. 2020, 21(17), 6012; https://doi.org/10.3390/ijms21176012 - 20 Aug 2020

Cited by 15 | Viewed by 5810

Abstract

The carotid body (CB) is an important organ located at the carotid bifurcation that constantly monitors the blood supplying the brain. During hypoxia, the CB immediately triggers an alarm in the form of nerve impulses sent to the brain. This activates protective reflexes [...] Read more.

The carotid body (CB) is an important organ located at the carotid bifurcation that constantly monitors the blood supplying the brain. During hypoxia, the CB immediately triggers an alarm in the form of nerve impulses sent to the brain. This activates protective reflexes including hyperventilation, tachycardia and vasoconstriction, to ensure blood and oxygen delivery to the brain and vital organs. However, in certain conditions, including obstructive sleep apnea, heart failure and essential/spontaneous hypertension, the CB becomes hyperactive, promoting neurogenic hypertension and arrhythmia. G-protein-coupled receptors (GPCRs) are very highly expressed in the CB and have key roles in mediating baseline CB activity and hypoxic sensitivity. Here, we provide a brief overview of the numerous GPCRs that are expressed in the CB, their mechanism of action and downstream effects. Furthermore, we will address how these GPCRs and signaling pathways may contribute to CB hyperactivity and cardiovascular and respiratory disease. GPCRs are a major target for drug discovery development. This information highlights specific GPCRs that could be targeted by novel or existing drugs to enable more personalized treatment of CB-mediated cardiovascular and respiratory disease. Full article

(This article belongs to the Special Issue Neurotransmitters and Neuropeptides in the Modulation of the Carotid Body)

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21 pages, 1194 KiB

Open AccessReview

Exploring the Mediators that Promote Carotid Body Dysfunction in Type 2 Diabetes and Obesity Related Syndromes

by Joana F. Sacramento, Kryspin Andrzejewski, Bernardete F. Melo, Maria J. Ribeiro, Ana Obeso and Silvia V. Conde

Int. J. Mol. Sci. 2020, 21(15), 5545; https://doi.org/10.3390/ijms21155545 - 3 Aug 2020

Cited by 24 | Viewed by 3663

Abstract

Carotid bodies (CBs) are peripheral chemoreceptors that sense changes in blood O₂, CO₂, and pH levels. Apart from ventilatory control, these organs are deeply involved in the homeostatic regulation of carbohydrates and lipid metabolism and inflammation. It has been [...] Read more.

Carotid bodies (CBs) are peripheral chemoreceptors that sense changes in blood O₂, CO₂, and pH levels. Apart from ventilatory control, these organs are deeply involved in the homeostatic regulation of carbohydrates and lipid metabolism and inflammation. It has been described that CB dysfunction is involved in the genesis of metabolic diseases and that CB overactivation is present in animal models of metabolic disease and in prediabetes patients. Additionally, resection of the CB-sensitive nerve, the carotid sinus nerve (CSN), or CB ablation in animals prevents and reverses diet-induced insulin resistance and glucose intolerance as well as sympathoadrenal overactivity, meaning that the beneficial effects of decreasing CB activity on glucose homeostasis are modulated by target-related efferent sympathetic nerves, through a reflex initiated in the CBs. In agreement with our pre-clinical data, hyperbaric oxygen therapy, which reduces CB activity, improves glucose homeostasis in type 2 diabetes patients. Insulin, leptin, and pro-inflammatory cytokines activate the CB. In this manuscript, we review in a concise manner the putative pathways linking CB chemoreceptor deregulation with the pathogenesis of metabolic diseases and discuss and present new data that highlight the roles of hyperinsulinemia, hyperleptinemia, and chronic inflammation as major factors contributing to CB dysfunction in metabolic disorders. Full article

(This article belongs to the Special Issue Neurotransmitters and Neuropeptides in the Modulation of the Carotid Body)

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26 pages, 1114 KiB

Open AccessReview

Carotid Body and Metabolic Syndrome: Mechanisms and Potential Therapeutic Targets

by Lenise J. Kim and Vsevolod Y. Polotsky

Int. J. Mol. Sci. 2020, 21(14), 5117; https://doi.org/10.3390/ijms21145117 - 20 Jul 2020

Cited by 16 | Viewed by 9099

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Neurotransmitters and Neuropeptides in the Modulation of the Carotid Body)

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15 pages, 698 KiB

Open AccessReview

Vasoactive Intestinal Polypeptide in the Carotid Body—A History of Forty Years of Research. A Mini Review

by Slawomir Gonkowski

Int. J. Mol. Sci. 2020, 21(13), 4692; https://doi.org/10.3390/ijms21134692 - 30 Jun 2020

Cited by 9 | Viewed by 5244

Abstract

Vasoactive intestinal polypeptide (VIP) consists of 28 amino acid residues and is widespread
in many internal organs and systems. Its presence has also been found in the nervous structures
supplying the carotid body not only in mammals but also in birds and amphibians. [...] Read more.

Vasoactive intestinal polypeptide (VIP) consists of 28 amino acid residues and is widespread
in many internal organs and systems. Its presence has also been found in the nervous structures
supplying the carotid body not only in mammals but also in birds and amphibians. The number
and distribution of VIP in the carotid body clearly depends on the animal species studied;
however, among all the species, this neuropeptide is present in nerve fibers around blood vessels
and between glomus cell clusters. It is also known that the number of nerves containing VIP located
in the carotid body may change under various pathological and physiological factors. The knowledge
concerning the functioning of VIP in the carotid body is relatively limited. It is known that VIP may
impact the glomus type I cells, causing changes in their spontaneous discharge, but the main impact
of VIP on the carotid body is probably connected with the vasodilatory eects of this peptide and its
influence on blood flow and oxygen delivery. This review is a concise summary of forty years of
research concerning the distribution of VIP in the carotid body. Full article

(This article belongs to the Special Issue Neurotransmitters and Neuropeptides in the Modulation of the Carotid Body)

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