| 期刊全称 | Arterial Chemoreceptors | | 期刊简称 | Arterial Chemorecept | | 影响因子2023 | Constancio Gonzalez,Colin A. Nurse,Chris Peers | | 视频video | | | 发行地址 | Concise reports of current chemoreceptor research.Authoritative reviews from internationally recognised experts.A unique collection of studies from all leading groups in the field: (1) FASEB Meeting; | | 学科分类 | Advances in Experimental Medicine and Biology | | 图书封面 |  | | Pindex | Book 2009 |
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Front Matter |
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Abstract
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,The Discovery of Sensory Nature of the Carotid Bodies – , , |
F. De Castro |
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Abstract
Although the carotid body (or .) was a structure familiar to anatomists in the XVIIIth century, it was not until the beginning of the XXth century that its role was revealed. It was then that the German physiologist Heinrich Hering described the respiratory reflex and he began to study the anatomical basis of this reflex focusing on the carotid region, and the carotid sinus in particular. At this time, the physiologists and pharmacologists associated with Jean-François Heymans and his son (Corneille) in Ghent (Belgium) adopted a different approach to resolve this issue, and they centred their efforts on the cardio-aortic reflexogenic region. However, at the . (Madrid, Spain), one of the youngest and more brilliant disciples of Santiago Ramón y Cajal, Fernando De Castro, took advantage of certain technical advances to study the fine structure of the carotid body (De Castro, 1925). In successive papers (1926, 1928, 1929), De Castro unravelled most of the histological secrets of this small structure and described the exact localisation of the “chemoreceptors” within the .. Indeed, his was the first description of cells specifically devoted to detect changes in the chemical composition
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,Fifty Years of Progress in Carotid Body Physiology – ,, |
R.S. Fitzgerald,C. Eyzaguirre,P. Zapata |
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Abstract
Research on arterial chemoreceptors, particularly on the carotid body, has been fruitful in the last fifty years, to which this review is addressed. The functional anatomy of the organ appears to be well established. The biophysical bases by which glomus cells transduce chemical changes in the . (hypoxia, hypercapnia, acidosis) into electrical and biochemical changes in glomus cells have received much attention. Physical changes (in temperature, flow and osmolarity) are also detected by the carotid body. Electrical coupling between glomus cells themselves appears as very extensive. Sustentacular cells classically considered as ensheathing glia for glomus cells and nerve endings now appear to behave as stem cells precursors for glomus cells under chronic hypoxic conditions. Many papers have been devoted to transmitters released from glomus cells (acetylcholine, dopamine, ATP) and well as to their effects upon chemosensory nerve activity. Chemosensory neurons have been explored from generation of action potentials at peripheral nerve endings, passing to properties of perikarya at petrosal ganglia and finally at characterization of synaptic transmission at solitary tract nuclei. There
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,Carotid Body: New Stimuli and New Preparations – ,, |
Colin A. Nurse |
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Abstract
Beginning with the pioneering work of Heymans and collaborators in the 1930’s, investigations into the role of the mammalian carotid body (CB) in the control of ventilation have attracted much attention. Progress for many years was restricted to the whole animal and organ level, resulting in characterization of the stimulus-response characteristics of the CB with its afferent nerve supply during exposure to chemostimuli such as low PO. (hypoxia), elevated PCO. (hypercapnia), and low pH (acidity). Major advances on the cellular and molecular mechanisms of chemotransduction occurred ˜20 years ago with the use of freshly-dissociated CB preparations and single cell studies using patch clamp and spectrofluorimetric techniques. This review will focus on more recent advances based on novel preparations including co-cultures of isolated CB receptor clusters and dispersed sensory or autonomic neurons, thin CB tissue slice preparations, and transgenic models. These preparations have contributed significantly, not only to our understanding of the transduction and neurotransmitter mechanisms that operate in the CB during sensory processing, but also to the identification and characterization o
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,Enzyme-Linked Acute Oxygen Sensing in Airway and Arterial Chemoreceptors – ,, |
J. Paul Kemp,C. Peers |
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Abstract
Researchers have speculated as to the molecular basis of O. sensing for decades. In more recent years, since the discovery of ion channels as identified effectors for O. sensing pathways, research has focussed on possible pathways coupling a reduction in hypoxia to altered ion channel activity. The most extensively studied systems are the K. channels which are inhibited by hypoxia in chemoreceptor tissues (carotid and neuroepithelial bodies). In this review, we consider the evidence supporting the involvement of well defined enzymes in mediating the regulation of K. channels by hypoxia. Specifically, we focus on the roles proposed for three enzyme systems; NADPH oxidase, heme oxygenase and AMP activated protein kinase. These systems differ in that the former two utilise O. directly (to form superoxide in the case of NADPH oxidase, and as a co-factor in the degradation of heme to carbon monoxide, bilirubin and ferrous iron in the case of heme oxygenase), but the third responds to shifts in the AMP:ATP ratio, so responds to changes in O. levels more indirectly. We consider the evidence in favour of each of these systems, and highlight their differential importance in different system
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,Cysteine Residues in the C-terminal Tail of the Human BKCaα Subunit Are Important for Channel Sensi |
S.P. Brazier,V. Telezhkin,R. Mears,C.T. Müller,D. Riccardi,P.J. Kemp |
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Abstract
Abstract.In the presence of oxygen (O.), carbon monoxide (CO) is synthesised from heme by endogenous hemeoxygenases, and is a powerful activator of BK. channels. This transduction pathway has been proposed to contribute to cellular O. sensing in rat carotid body. In the present study we have explored the role that four cysteine residues (C820, C911, C995 and C1028), located in the vicinity of the “calcium bowl” of C-terminal of human BK.-αsubunit, have on channel CO sensitivity. Mutant BK.-αsubunits were generated by site-directed mutagenesis (single, double and triple cysteine residue substitutions with glycine residues) and were transiently transfected into HEK 293 cells before subsequent analysis in inside-out membrane patches. Potassium cyanide (KCN) completely abolished activation of wild type BK. channels by the CO donor, tricarbonyldichlororuthenium (II) dimer, at 100μM. In the absence of KCN the CO donor increased wild-type channel activity in a concentration-dependent manner, with an EC. of ca. 50μM. Single cysteine point mutations of residues C820, C995 and C1028 affected neither channel characteristics nor CO EC. values. In contrast, the CO sensitivity of the C911G mutat
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,Modulation of O2 Sensitive K+ Channels by AMP-activated Protein Kinase, |
M.L. Dallas,J.L. Scragg,C.N. Wyatt,F. Ross,D.G. Hardie,A.M. Evans,C. Peers |
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Abstract
Hypoxic inhibition of K. channels in type I cells is believed to be of central importance in carotid body chemotransduction. We have recently suggested that hypoxic channel inhibition is mediated by AMP-activated protein kinase (AMPK). Here, we have further explored the modulation by AMPK of recombinant K. channels (expressed in HEK293 cells) whose native counterparts are considered O.-sensitive in the rat carotid body. Inhibition of maxiK channels by AMPK activation with AICAR was found to be independent of [Ca.]. and occurred regardless of whether the α subunit was co-expressed with an auxiliary β subunit. All effects of AICAR were fully reversed by the AMPK inhibitor compound C. MaxiK channels were also inhibited by the novel AMPK activator A-769662 and by intracellular dialysis with the constitutively active, truncated AMPK mutant, T172D. The molecular identity of the O.-sensitive leak K. conductance in rat type I cells remains unclear, but shares similarities with TASK-1 and TASK-3. Recombinant TASK-1 was insensitive to AICAR. However, TASK-3 was inhibited by either AICAR or A-769662 in a manner which was reversed by compound C. These data highlight a role for AMPK in the modu
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,Hydrogen Sulfide Inhibits Human BKCa Channels, |
V. Telezhkin,S.P. Brazier,S. Cayzac,C.T. Müller,D. Riccardi,P.J. Kemp |
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Abstract
abstract Hydrogen sulfide (H.S) is produced endogenously in many types of mammalian cells. Evidence is now accumulating to suggest that H.S is an endogenous signalling molecule, with a variety of molecular targets, including ion channels. Here, we describe the effects of H.S on the large conductance, calcium-sensitive potassium channel (BK.). This channel contributes to carotid body glomus cell excitability and oxygen-sensitivity. The experiments were performed on HEK 293 cells, stably expressing the human BK. channel α subunit, using patch-clamp in the inside-out configuration. The H.S donor, NaSH (100µM–10 mM), inhibited BK. channels in a concentration-dependent manner with an IC. of ca. 670μM. In contrast to the known effects of CO donors, the H.S donor maximally decreased the open state probability by over 50% and shifted the half activation voltage by more than +16mV. In addition, although 1 mM KCN completely suppressed CO-evoked channel activation, it was without effect on the H.S-induced channel inhibition, suggesting that the effects of CO and H.S were non-competitive. RT-PCR showed that mRNA for both of the H.S-producing enzymes, cystathionine-beta-synthase and cystathioni
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,DPPX Modifies TEA Sensitivity of the Kv4 Channels in Rabbit Carotid Body Chemoreceptor Cells, |
O. Colinas,F.D. Pérez-Carretero,E. Alonso,J.R. López-López,M.T. Pérez-García |
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Abstract
Chemoreceptor cells from rabbit carotid body (CB) exhibit transient outward currents reversibly inhibited by low P.. Molecular and functional dissection of the components of these outward currents indicates that at least two different channels (Kv4.3 and Kv3.4) contribute to this current. Furthermore, several lines of evidence support the conclusion that Kv4 channel subfamily members (either Kv4.3 alone or Kv4.3/Kv4.1 heteromultimers) are the oxygen sensitive K channels (K.) in rabbit CB chemoreceptor cells. However, the pharmacological characterization of these currents shows that they are almost completely blocked by high external TEA concentrations, while Kv4 channels have been shown to be TEA-insensitive. We hypothesized that the expression of regulatory subunits in chemoreceptor cells could modify TEA sensitivity of Kv4 channels. Here, we explore the presence and functional contribution of DPPX to K. currents in rabbit CB chemoreceptor cells by using DPPX functional knockdown with siRNA. Our data suggest that DPPX proteins are integral components of K. currents, and that their association with Kv4 subunits modulate the pharmacological profile of the heteromultimers.
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,Sustained Hypoxia Enhances TASK-like Current Inhibition by Acute Hypoxia in Rat Carotid Body Type-I |
F. Ortiz,R. Iturriaga,R. Varas |
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Abstract
Abstract.Carotid body type-I cells respond to acute hypoxia with membrane depolarization and calcium-dependent neurotransmitter release. The inhibition of a TASK-like background potassium channels plays a key role in initiating this response. Chronic hypoxia enhances the carotid body chemosensory responses evoked by acute hypoxia, however the accurate mechanism by which chronic hypoxia increases carotid body reactivity is not clear. Therefore, we investigated the effects of chronic hypoxia upon TASK-like currents in isolated type-I cells. Carotid bodies were excised from anaesthetized newborn Sprague-Dawley rats and dissociated by collagenase-trypsin digestion. Isolated cells were maintained under 5% CO. in normoxic (21% O.) or hypoxic (1–2% O.) environment for 24 and 48 hours. Channel activity (NPo) was recorded using the cell-attached configuration of the patch-clamp technique. In normoxic and 24 hours hypoxic cultured cells, acute hypoxic stimuli decreases NPo approximately 70% with no effects on current amplitude. On the other hand, in cultured cells subjected to 48 hours of hypoxia, NPo decreases near to 90% in response to acute hypoxia. We concluded that continuous hypoxic ex
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,Inhibition of L-Type Ca2+ Channels by Carbon Monoxide, |
M.L. Dallas,J.L. Scragg,C. Peers |
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Abstract
Inhibition of K. channels in glomus cells underlies excitation of the carotid body by hypoxia. It has recently been proposed that hypoxic inhibition involves either activation of AMP activated protein kinase (AMPK) or inhibition of carbon monoxide (CO) production by heme oxygenase 2 (HO-2). In the vasculature, L-type Ca. channels are also O. sensitive. Here, we have investigated the possible involvement of either AMPK or CO in the hypoxic inhibition of L-type Ca. channels. Using whole-cell patch clamp recordings from HEK293 cells stably expressing the human cardiac α1C.channel subunit, we found that pre-treatment of cells with AICAR (to activate AMPK) was without effect on Ca. currents. CO, applied via the donor molecule CORM-2 caused reversible, voltage-independent Ca. channel inhibition of up to . 50%, whereas its inactive form (iCORM) was without significant effect. Effects of CO were prevented by the antioxidant MnTMPyP, but not by inhibition of NADPH oxidase (with either apocynin or diphenyleneiodonium), or xanthine oxidase (with allopurinol). Instead, inhibitors of complex III of the mitochondrial electron transport chain and a mitochondrial-targeted antioxidant (Mito Q), pre
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,Effects of the Polyamine Spermine on Arterial Chemoreception, |
S. Cayzac,A. Rocher,A. Obeso,C. Gonzalez,P.J. Kemp,D. Riccardi |
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Abstract
Polyamines modulate many biological functions. Here we report a novel inhibitory modulation by spermine of catecholamine release by the rat carotid body and have identified the molecular mechanism underpinning it. We used molecular (RT-PCR and confocal microscopy) and functional (i.e., neurotransmitter release, patch clamp recording and calcium imaging) approaches to test the involvement of: (i) voltage-dependent calcium channels, and; (ii) the extracellular calcium-sensing receptor, CaR, a G protein-coupled receptor which is also activated by polyamines. RT-PCR and immunohistochemistry of isolated carotid bodies revealed that only Ca.1.2 and Ca.2.2 were expressed in type 1 cells while Ca.1.3, Ca.1.4, Ca.2.1, Ca.2.3 and Ca.3.1, Ca.3.2 and Ca.3.3, could not be detected. CaR expression was detected exclusively in the nerve endings. In isolated carotid bodies, the hypoxia-dependent (7% O. for 10 minutes) and depolarization-evoked catecholamine release were partially suppressed by pre- (and co)-incubation with 500µM spermine. In dissociated type 1 glomus cells intracellular calcium concentration did not change following spermine treatment, but this polyamine did inhibit the depolarisat
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,RT-PCR and Pharmacological Analysis of L-and T-Type Calcium Channels in Rat Carotid Body, |
A.I. Cáceres,E. Gonzalez-Obeso,C. Gonzalez,A. Rocher |
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Abstract
Mechanisms involved in carotid body (CB) chemoreceptor cells O.-sensing and responses are not fully understood. So far, it is known that hypoxia depolarizes chemoreceptor cells via O.-sensitive K.-channel inhibition; calcium influx via voltage-gated channels and neurotransmitter secretion follow. Presence of high voltage activated (HVA) calcium channels in rat CB chemoreceptor cells is well documented, but the presence of low voltage activated (LVH) or T-type calcium channels has not been reported to date. The fact that O.-sensitive PC12 cells express T-type channels and that they are inducible by chronic hypoxia (CH) lead us to hypothesize they could be present and play a role in the genesis of the hypoxic response in rat CB chemoreceptor cells. We have analyzed the expression of the three isoforms of T-type calcium channels (α1G, α1H and α1I) and the isoforms α1C and α1D of L-type calcium channels in rat CB by RT-PCR. We found that rat CB expresses α1G and α1C subunits. After chronic hypoxic treatment of adult rats (10° O., 8 days), expression of α1G seems to be down-regulated whereas α1C expression is up-regulated. Functionally, it was found that the release of catecholamine ind
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,Functional Characterization of Phosphodiesterases 4 in the Rat Carotid Body: Effect of Oxygen Conce |
A.R. Nunes,J.R. Batuce,E.C. Monterio |
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Abstract
The non-specific cAMP phosphodiesterase (PDE) inhibitor isobutyl- methylxanthine (IBMX) has been used to manipulate cAMP levels in carotid body (CB) preparations but the characterization of different PDE isoforms in CB has never been performed. PDE4 is one of the PDE families that uses cAMP as a specific substrate and changes its activity and affinity for drug inhibitors according to the degree of its phosphorylation. We investigated the effects of hypoxia on cAMP accumulation induced by different PDE4 inhibitors in the CB based on the hypothesis that acute changes in O. could interfere with their affinity..Concentration-response curves for the effects of the PDE4 selective inhibitors, rolipram and Ro 20-1724 and IBMX on cAMP were obtained in CBs, removed from rats and incubated in normoxia (20%O.) or hypoxia (5%O.)..No differences were found between cAMP concentrations in normoxic and hypoxic conditions in the absence of PDE inhibitors. In both conditions, the E. calculated for IBMX was similar to that of the specific PDE4 inhibitors. Hypoxia shifted the concentration response curves to the left with the following rank order of potency IBMX> RO 20-1724=rolipram and increased E. by
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,Calcium Sensitivity for Hypoxia in PGNs with PC-12 Cells in Co-Culture, |
G.P. Patel,S.M. Baby,A. Roy,S. Lahiri |
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Abstract
Calcium sensitivity of petrosal ganglion neurons (PGNs) to chemical stimuli with and without PC-12 cells in co-culture instead of glomus is not known– the idea being that two types of unusual cells could form synapse and provide a model for studies of chemotransduction. Calcium levels in the PGNs were measured in the presence of different chemical stimuli in the bath medium. Remarkably, the PGNs alone were not sensitive to hypoxia (10 torr), PCO (∼300 torr in normoxa) nor to ATP (100µM) but they developed the sensitivity to these stimuli in synaptic contact with PC-12 cells. The sharp rise in calcium level was suppressed (2/3) by suramin (100µM), a purinergic blocker, and the remaining 1/3 was blocked by hexomethonium, a cholinergic blocker. Taken together, these observations suggest that PGNs developed neurotransmission when in contact with PC-12 cells, as if the latter substituting for glomus cells, thus providing a model for chemotransduction studies. The reason for the insensitivity of PGNs alone to the chemical stimuli is unknown at this time.
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,Modification of Relative Gene Expression Ratio Obtained from Real Time qPCR with Whole Carotid Body |
J.H. Kim,I. Kim,J.L. Carroll |
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Abstract
Quantitative real time PCR (qPCR) is a common tool used to compare the relative gene expression between treated/untreated cells, different types of tissues, or immature/mature organs. When homogeneous cells are used for qPCR, the Ct number of a tested gene solely represents the quantity of gene expression in cells. However, when a heterogeneous tissue is used for qPCR, the Ct number of a tested gene should be modified depending on several factors: the percentage of each cell type in the sample tissue, the cell type where the target gene is expressed, and the cell type in which the target gene is regulated. The carotid body (CB) is mainly composed of three types of cells: type I (chemoreceptor) cells, type II cells, and other types of cells. Therefore, the relative gene expression ratio obtained from qPCR data using whole CB could be modified by applying one of the following 19 different cases: (1) the target gene is expressed in only one type of cell (3 cases), (2) the gene is expressed in two types of cells and increased in only one or both cell types (9 cases), and (3) the gene is expressed in all three types of cells and increased in only one, two, or all three cell types (7 cas
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,Neurotransmitters in Carotid Body Function: The Case of Dopamine – ,, |
R. Iturriaga,J. Alcayaga,C. Gonzalez |
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Abstract
The carotid body (CB) is the main peripheral chemoreceptor. The present model of CB chemoreception states that glomus (type I) cells are the primary receptors, which are synaptically connected to the nerve terminals of the petrosal ganglion neurons. In response to hypoxia, hypercapnia and acidosis, glomus cells release one (or more) transmitter(s) which, acting on the nerve terminals of chemosensory neurons, increases the afferent discharge. Among several molecules present in glomus cells, dopamine, acetylcholine and 5′-adenosine-triphosphate have been proposed to be the excitatory transmitters in the CB. Beside these putative excitatory transmitters, other molecules modulate the chemosensory process through direct actions on glomus cells and/or by producing tonic effects on CB blood vessels. In this review, we focus on the role played by dopamine in the CB chemoreception, with emphasis on the open question if the reported differences on its actions on the generation of afferent chemosensory activity reflect true species differences. The available data suggest that dopamine may play a modulatory role within the cat CB, while in the rabbit CB, dopamine is an excitatory transmitter.
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,Adenosine in Peripheral Chemoreception: New Insights into a Historically Overlooked Molecule – ,, |
S.V. Conde,E.C. Monteiro,A. Obeso,C. Gonzalez |
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Abstract
Abstract In the present article we review in a concise manner the literature on the general biology of adenosine signalling. In the first section we describe briefly the historical aspects of adenosine research. In the second section is presented the biochemical characteristics of this nucleoside, namely its metabolism and regulation, and its physiological actions. In the third section we have succinctly described the role of adenosine and its metabolism in hypoxia. The final section is devoted to the role of adenosine in chemoreception in the carotid body, providing a review of the literature on the presence of adenosine receptors in the carotid body; on the effects of adenosine at presynaptic level in carotid body chemoreceptor cells, as well as, its metabolism and regulation; and at postsynaptic level in carotid sinus nerve activity. Additionally, a review on the effects of adenosine in ventilation was done. This review discusses evidence for a key role of adenosine in the hypoxic response of carotid body and emphasizes new research likely to be important in the future.
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,The A2B-D2 Receptor Interaction that Controls Carotid Body Catecholamines Release Locates Between t |
S.V. Conde,A. Obeso,E.C. Monteiro,C. Gonzalez |
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Abstract
We have recently demonstrated that adenosine controls the release of catecholamines (CA) from carotid body (CB) acting on A. receptors. Here, we have investigated the hypothesis that this control is exerted via an interaction between adenosine A. and dopamine D. receptors present in chemoreceptor cells and if it is, the location of this interaction on the CB hypoxic transduction cascade. Experiments were performed . in CB from 3 months rats. The effect of adenosine A. and dopamine D. receptor agonists applied alone or conjunctly, was studied on the basal and evoked release (10% O. and ionomycin) of CA from CB. We have observed that the inhibitory action of propylnorapomorphine, a D. selective agonist, on the normoxic and 10%O.-evoked release of CA was abolished by NECA, an A. agonist, meaning that an interaction between the D. and A. receptors controls the release of CA from CB. Further, propylnorapomorphine inhibits the release of CA evoked by ionomycin, being this effect totally reversed by NECA. The present results provide direct pharmacological evidence that A. and D. receptors interact to modulate the release of CA from rat CB between the steps of Ca. entry and increase in int
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,Benzodiazepines and GABA-GABAA Receptor System in the Cat Carotid Body, |
A. Igarashi,N. Zadzilka,M. Shirahata |
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Abstract
Benzodiazepines (BZs) suppress ventilation possibly by augmenting the GABA. receptor activity in the respiratory control system, but precise sites of action are not well understood. The goals of this study were: (1) to identify GABA. receptor subunits in the carotid body (CB) and petrosal ganglion (PG); (2) to test if BZs exert their effects through the GABA. receptor in the CB chemosensory unit. Tissues were taken from euthanized adult cats. RNA was extracted from the brain, and cDNA sequences of several GABA. receptor subunits were determined. Subsequent RT-PCR analysis demonstrated the gene expression of α2, α3, β3, and γ2 subunits in the CB and the PG. Immunoreactivity for GABA and for GABA. receptor β3 and γ2 subunits was detected in chemosensory glomus cells (GCs) in the CB and neurons in the PG. The functional aspects of the GABA-GABA. receptor system in the CB was studied by measuring CB neural output using in vitro perfusion setup. Two BZs, midazolam and diazepam, decreased the CB neural response to hypoxia. With continuous application of bicuculline, a GABA. receptor antagonist, the effects of BZs were abolished. In conclusion, the GABA-GABA. receptor system is functionin
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发表于 2025-3-21 16:53:16
