Postnatal hypoxemia increases angiotensin II sensitivity and up-regulates AT1a angiotensin receptors in rat carotid body chemoreceptors

In the present study, the effects of postnatal hypoxemia on the AT1 angiotensin receptor-mediated activities in the rat carotid body were studied. Angiotensin II (Ang II) concentration-dependently increased the chemoreceptor afferent activity in the isolated carotid body. Single- or pauci-fiber recording of the sinus nerve revealed that the afferent response to Ang II was enhanced in the postnatally hypoxic carotid body. To determine whether the increased sensitivity to Ang II is mediated by changes in the functional expression of Ang II receptors in the carotid body chemoreceptors, cytosolic calcium ([Ca2+]i) was measured by spectrofluorimetry in fura-2 acetoxymethyl ester-loaded type I cells dissociated from carotid bodies. Ang II (25-100 nM) concentration-dependently increased [Ca2+]i in the type I cells. The proportion of clusters of type I cells responsive to Ang II was higher in the postnatally hypoxic group than in the normoxic control (89 vs 66%). In addition, the peak [Ca2+]i response to Ang II was enhanced 2- to 3-fold in the postnatally hypoxic group. The [Ca2+]i response to Ang II was abolished by pretreatment with losartan (1 microM), an AT1 receptor antagonist, but not by PD-123177 (1 microM), an AT(2) antagonist. Double-labeling immunohistochemistry confirmed that an enhanced immunoreactivity for AT1 receptor was co-localized to the lobules of type I cells in the hypoxic group. In addition, RT-PCR analysis of subtypes of AT1 receptors showed an up-regulation of AT1a but a down-regulation of AT1b receptors, indicating a differential regulation of the expression of AT1 receptor subtypes by postnatal hypoxia in the carotid body. These data suggest that postnatal hypoxemia is associated with an increased sensitivity of peripheral chemoreceptors in response to Ang II and an up-regulation of AT1a receptor-mediated [Ca2+]i activity of the chemoreceptors. This modulation may be important for adaptation of carotid body functions in the hypoxic ventilatory response and in electrolyte and water homeostasis during perinatal and postnatal hypoxia.

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Carotid Body Chemoreceptors: Physiology, Pathology, and Implications for Health and Disease

Physiological Reviews ◽

10.1152/physrev.00039.2019 ◽

2021 ◽

Author(s):

Rodrigo Iturriaga ◽

Julio Alcayaga ◽

Mark W. Chapleau ◽

Virend K Somers

Keyword(s):

Carotid Body ◽

Metabolic Diseases ◽

Ionic Channels ◽

Type I ◽

Peripheral Chemoreceptor ◽

Type I Cells ◽

Obstructive Sleep ◽

Carotid Body Chemoreceptors ◽

Respiratory Gases ◽

I Cells

The carotid body (CB) is the main peripheral chemoreceptor for arterial respiratory gases O2 and CO2, 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 physiologic responses, and its role in maintaining health and potentiating disease. Emphasis will be placed on: i) Transduction mechanisms in chemoreceptor (type I) cells, highlighting the role played by the hypoxic inhibition of O2-dependent K+ channels and mitochondrial oxidative metabolism, and their modification by intracellular molecules and other ionic channels; ii) 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; iii) 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 iv) 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.

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Functional expression of angiotensin II receptors in type-I cells of the rat carotid body

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s004240000445 ◽

2001 ◽

Vol 441 (4) ◽

pp. 474-480 ◽

Cited By ~ 40

Author(s):

Man-Lung Fung ◽

Siu-Yin Lam ◽

Yueping Chen ◽

Xiaoli Dong ◽

Po Sing Leung

Keyword(s):

Angiotensin Ii ◽

Carotid Body ◽

Functional Expression ◽

Angiotensin Ii Receptors ◽

Type I ◽

Type I Cells ◽

I Cells

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CO2/pH Chemosensory Signaling in Co-Cultures of Rat Carotid Body Receptors and Petrosal Neurons: Role of ATP and ACh

Journal of Neurophysiology ◽

10.1152/jn.01099.2003 ◽

2004 ◽

Vol 92 (6) ◽

pp. 3433-3445 ◽

Cited By ~ 69

Author(s):

Min Zhang ◽

Colin A. Nurse

Keyword(s):

Carotid Body ◽

Type I ◽

Type I Cells ◽

Confocal Immunofluorescence ◽

Culture Model ◽

Cell Current ◽

Receptor Blockers ◽

Increased Sensitivity ◽

Chemical Synapses ◽

I Cells

The neurotransmitter mechanisms that process acid hypercapnia in the mammalian carotid body (CB) are poorly understood. Using a co-culture model containing rat CB chemoreceptor (type 1 cell) clusters and petrosal neurons (PN), we tested the hypothesis that co-released ACh and ATP was an important mechanism. Sensory transmission from type I clusters to PN in co-culture occurred at chemical synapses via co-release of ATP and ACh because isohydric hypercapnia depolarized and/or increased firing in co-cultured PN, but not in PN cultured alone; PN chemoexcitatory responses were inhibited by decreasing the extracellular Ca2+: Mg2+ ratio; partial inhibition of these responses occurred during separate perfusion of cholinergic (hexamethonium or mecamylamine) and P2X (suramin) receptor blockers, although inhibition was often complete with both blockers present; and rapid chemoexcitatory responses to hypercapnia were inhibited by acetazolamide (10 μM), an inhibitor of carbonic anhydrase, localized in type I cells. Acidosis (pH = 7.0, 7.2) enhanced the ATP-induced whole cell current in functional PN relative to that at physiologic pH (7.4), suggesting that increased sensitivity of postsynaptic P2X receptors may contribute to acid chemotransmission. Type I cells in CB tissue sections expressed vesicular acetylcholine transporter (VAChT), a cholinergic marker, as revealed by confocal immunofluorescence. Thus co-release of ACh and ATP is an important neurotransmitter mechanism for processing isohydric and acidic hypercapnia in the rat carotid body.

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Characteristics of carotid body chemosensitivity in NADPH oxidase-deficient mice

AJP Cell Physiology ◽

10.1152/ajpcell.2002.282.1.c27 ◽

2002 ◽

Vol 282 (1) ◽

pp. C27-C33 ◽

Cited By ~ 58

Author(s):

L. He ◽

J. Chen ◽

B. Dinger ◽

K. Sanders ◽

K. Sundar ◽

...

Keyword(s):

Tyrosine Hydroxylase ◽

Nadph Oxidase ◽

Carotid Body ◽

Gene Knockout ◽

Type I ◽

Type I Cells ◽

Carotid Bodies ◽

Marker Antigen ◽

I Cells

Various heme-containing proteins have been proposed as primary molecular O2 sensors for hypoxia-sensitive type I cells in the mammalian carotid body. One set of data in particular supports the involvement of a cytochrome b NADPH oxidase that is commonly found in neutrophils. Subunits of this enzyme have been immunocytochemically localized in type I cells, and diphenyleneiodonium, an inhibitor of the oxidase, increases carotid body chemoreceptor activity. The present study evaluated immunocytochemical and functional properties of carotid bodies from normal mice and from mice with a disrupted gp91 phagocytic oxidase (gp91 phox ) DNA sequence gene knockout (KO), a gene that codes for a subunit of the neutrophilic form of NADPH oxidase. Immunostaining for tyrosine hydroxylase, a signature marker antigen for type I cells, was found in groups or lobules of cells displaying morphological features typical of the O2-sensitive cells in other species, and the incidence of tyrosine hydroxylase-immunopositive cells was similar in carotid bodies from both strains of mice. Studies of whole cell K+currents also revealed identical current-voltage relationships and current depression by hypoxia in type I cells dissociated from normal vs. KO animals. Likewise, hypoxia-evoked increases in intracellular Ca2+ concentration were not significantly different for normal and KO type I cells. The whole organ response to hypoxia was evaluated in recordings of carotid sinus nerve activity in vitro. In these experiments, responses elicited by hypoxia and by the classic chemoreceptor stimulant nicotine were also indistinguishable in normal vs. KO preparations. Our data demonstrate that carotid body function remains intact after sequence disruption of the gp91 phox gene. These findings are not in accord with the hypothesis that the phagocytic form of NADPH oxidase acts as a primary O2 sensor in arterial chemoreception.

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Immunohistochemical Characteristics of the Human Carotid Body in the Antenatal and Postnatal Periods of Development

International Journal of Molecular Sciences ◽

10.3390/ijms22158222 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8222

Author(s):

Dmitry Otlyga ◽

Ekaterina Tsvetkova ◽

Olga Junemann ◽

Sergey Saveliev

Keyword(s):

Tyrosine Hydroxylase ◽

Carotid Body ◽

Nerve Fibers ◽

Individual Development ◽

Endocrine Function ◽

Type I ◽

Type I Cells ◽

Carotid Bodies ◽

I Cells ◽

Human Carotid

The evolutionary and ontogenetic development of the carotid body is still understudied. Research aimed at studying the comparative morphology of the organ at different periods in the individual development of various animal species should play a crucial role in understanding the physiology of the carotid body. However, despite more than two centuries of study, the human carotid body remains poorly understood. There are many knowledge gaps in particular related to the antenatal development of this structure. The aim of our work is to study the morphological and immunohistochemical characteristics of the human carotid body in the antenatal and postnatal periods of development. We investigated the human carotid bodies from 1 embryo, 20 fetuses and 13 adults of different ages using samples obtained at autopsy. Immunohistochemistry revealed expression of βIII-tubulin and tyrosine hydroxylase in the type I cells and nerve fibers at all periods of ontogenesis; synaptophysin and PGP9.5 in the type I cells in some of the antenatal cases and all of the postnatal cases; 200 kDa neurofilaments in nerve fibers in some of the antenatal cases and all of the postnatal cases; and GFAP and S100 in the type II cells and Schwann cells in some of the antenatal cases and all of the postnatal cases. A high level of tyrosine hydroxylase in the type I cells was a distinctive feature of the antenatal carotid bodies. On the contrary, in the type I cells of adults, the expression of tyrosine hydroxylase was significantly lower. Our data suggest that the human carotid body may perform an endocrine function in the antenatal period, while in the postnatal period of development, it loses this function and becomes a chemosensory organ.

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