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At least 577 records · Page 32Linked to original sources
PubMed1993

Oxygen sensing in airway chemoreceptors.

Pulmonary neuroepithelial bodies, composed of innervated clusters of amine- and peptide-containing cells, are widely distributed throughout the airway mucosa of human and animal lungs. Structurally, neuroepithelial bodies resemble chemoreceptors (such as carotid body, taste buds) and are thought to function as hypoxia sensitive airway sensors. Evidence for this is indirect, however, and the mechanism of oxygen sensing by these cells is unknown. Here we culture neuroepithelial bodies isolated from rabbit fetal lungs and identify voltage-activated potassium, calcium and sodium currents using the whole-cell patch clamp technique. Upon exposure to hypoxia there is a reversible reduction (25-30%) in the outward potassium current, with no change in inward currents. In addition, we demonstrate the expression of an oxygen-binding protein (b-cytochrome, NADPH oxidase) on the plasma membrane of these cells. The identification of an oxygen-sensing mechanism (namely the presence of an O2-sensitive potassium channel coupled to an O2 sensor protein) in the cells of pulmonary neuroepithelial bodies indicates that they are transducers of the hypoxia stimulus and hence may function as airway chemoreceptors in the regulation of respiration.

Animals↗
PubMed2004

Respiratory control by ventral surface chemoreceptor neurons in rats.

A long-standing theory posits that central chemoreception, the CNS mechanism for CO(2) detection and regulation of breathing, involves neurons located at the ventral surface of the medulla oblongata (VMS). Using in vivo and in vitro electrophysiological recordings, we identify VMS neurons within the rat retrotrapezoid nucleus (RTN) that have characteristics befitting these elusive chemoreceptors. These glutamatergic neurons are vigorously activated by CO(2) in vivo, whereas serotonergic neurons are not. Their CO(2) sensitivity is unaffected by pharmacological blockade of the respiratory pattern generator and persists without carotid body input. RTN CO(2)-sensitive neurons have extensive dendrites along the VMS and they innervate key pontomedullary respiratory centers. In brainstem slices, a subset of RTN neurons with markedly similar morphology is robustly activated by acidification and CO(2). Their pH sensitivity is intrinsic and involves a background K(+) current. In short, the CO(2)-sensitive neurons of the RTN are good candidates for the long sought-after VMS chemoreceptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2001

Heterogeneity of neuronal nicotinic acetylcholine receptors in 5-HT-containing chemoreceptor cells of the chicken aorta.

The effects of nicotinic agonists and antagonists on whole-cell currents and 5-hydroxytryptamine (5-HT) release were studied in order to characterize nicotinic ACh receptors on the 5-HT-containing chemoreceptor cells of the chicken aorta. ACh, nicotine and dimethylphenylpiperazinium (DMPP) evoked concentration-dependent inward currents accompanied by increases in current noise at a holding potential of -70 mV. The peak amplitude of the current response to DMPP was 50% larger than that to either nicotine or ACH: Hexamethonium, alpha - bungarotoxin (alpha - BTX) and methyllycaconitine decreased nicotine-induced inward currents in a concentration-dependent manner. Although hexamethonium (0.1 mM) abolished the current response to nicotine (30 microM), a high concentration (1 microM) of alpha - BTX decreased it only by about 30% of the control response. Methyllycaconitine (0.1 microM) decreased the current response to nicotine to the same extent as did alpha - BTX whilst a high concentration (10 microM) abolished the response. ACh, nicotine and DMPP caused concentration-dependent increases in 5-HT output from the thoracic aorta which effect was blocked by hexamethonium (0.1 mM). Pre-treatment with alpha - BTX (1 microM) for 30 min reduced the output of 5-HT induced by ACh to 70% of the control response. It is suggested that neuronal nicotinic ACh receptors, sensitive and insensitive to alpha - BTX, are present on the chemoreceptor cells of the chicken aorta, the activation of which causes the release of 5-HT.

Acetylcholine↗
PubMed1999

Activation of renal pelvic chemoreceptors in rats: role of calcitonin gene-related peptide receptors.

Substance P and calcitonin gene-related peptide (CGRP) increase afferent renal nerve activity (ARNA). A substance P receptor antagonist but not a CGRP receptor antagonist, h-CGRP (8-37), blocks the ARNA response to renal mechanoreceptor (MR) stimulation. We have examined whether calcitonin gene-related peptide activates renal pelvic sensory receptors and whether such activation contributes to renal chemoreceptor stimulation. The calcitonin gene-related peptide receptor antagonist, h-CGRP (8-37) [0.01-10 micromol L-1] dose-dependently decreased (29 +/- 4-86 +/- 13%, P < 0.01) the ipsilateral afferent renal nerve activity in response to the renal pelvic administration of calcitonin gene-related peptide (0.26 micromol L-1). Renal pelvic perfusion with 900 mM NaCl also increased ipsilateral ARNA (23 +/- 3% increase, P < 0.02) and contralateral urinary sodium excretion (13 +/- 4% increase, P < 0. 05). However, these responses to hypertonic NaCl were unaltered by h-CGRP (8-37). Renal pelvic perfusion with 1 or 10 microM h-CGRP (8-37) also failed to alter the ARNA responses to KCl (31.25, 62.5 and 125 mM). These results indicate that there are sensory receptors in the renal pelvic area that are responsive to calcitonin gene-related peptide. The activation of these receptors elicits a contralateral natriuretic response. In contrast, the activation of renal calcitonin gene-related peptide receptors does not contribute to renal chemoreceptor activation.

Animals↗
PubMed2003

Solitary chemoreceptor cells in the nasal cavity serve as sentinels of respiration.

Inhalation of irritating substances leads to activation of the trigeminal nerve, triggering protective reflexes that include apnea or sneezing. Receptors for trigeminal irritants are generally assumed to be located exclusively on free nerve endings within the nasal epithelium, requiring that trigeminal irritants diffuse through the junctional barrier at the epithelial surface to activate receptors. We find, in both rats and mice, an extensive population of chemosensory cells that reach the surface of the nasal epithelium and form synaptic contacts with trigeminal afferent nerve fibers. These chemosensory cells express T2R "bitter-taste" receptors and alpha-gustducin, a G protein involved in chemosensory transduction. Functional studies indicate that bitter substances applied to the nasal epithelium activate the trigeminal nerve and evoke changes in respiratory rate. By extending to the surface of the nasal epithelium, these chemosensory cells serve to expand the repertoire of compounds that can activate trigeminal protective reflexes. The trigeminal chemoreceptor cells are likely to be remnants of the phylogenetically ancient population of solitary chemoreceptor cells found in the epithelium of all anamniote aquatic vertebrates.

Animals↗
PubMed2003

Molecular evolution of the insect chemoreceptor gene superfamily in Drosophila melanogaster.

The insect chemoreceptor superfamily in Drosophila melanogaster is predicted to consist of 62 odorant receptor (Or) and 68 gustatory receptor (Gr) proteins, encoded by families of 60 Or and 60 Gr genes through alternative splicing. We include two previously undescribed Or genes and two previously undescribed Gr genes; two previously predicted Or genes are shown to be alternative splice forms. Three polymorphic pseudogenes and one highly defective pseudogene are recognized. Phylogenetic analysis reveals deep branches connecting multiple highly divergent clades within the Gr family, and the Or family appears to be a single highly expanded lineage within the superfamily. The genes are spread throughout the Drosophila genome, with some relatively recently diverged genes still clustered in the genome. The Gr5a gene on the X chromosome, which encodes a receptor for the sugar trehalose, has transposed from one such tandem cluster of six genes at cytological location 64, as has Gr61a, and all eight of these receptors might bind sugars. Analysis of intron evolution suggests that the common ancestor consisted of a long N-terminal exon encoding transmembrane domains 1-5 followed by three exons encoding transmembrane domains 6-7. As many as 57 additional introns have been acquired idiosyncratically during the evolution of the superfamily, whereas the ancestral introns and some of the older idiosyncratic introns have been lost at least 48 times independently. Altogether, these patterns of molecular evolution suggest that this is an ancient superfamily of chemoreceptors, probably dating back at least to the origin of the arthropods.

Alternative Splicing↗
PubMed1996

NADPH-oxidase and a hydrogen peroxide-sensitive K+ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines.

Pulmonary neuroepithelial bodies (NEB) are widely distributed throughout the airway mucosa of human and animal lungs. Based on the observation that NEB cells have a candidate oxygen sensor enzyme complex (NADPH oxidase) and an oxygen-sensitive K+ current, it has been suggested that NEB may function as airway chemoreceptors. Here we report that mRNAs for both the hydrogen peroxide sensitive voltage gated potassium channel subunit (KH2O2) KV3.3a and membrane components of NADPH oxidase (gp91phox and p22phox) are coexpressed in the NEB cells of fetal rabbit and neonatal human lungs. Using a microfluorometry and dihydrorhodamine 123 as a probe to assess H2O2 generation, NEB cells exhibited oxidase activity under basal conditions. The oxidase in NEB cells was significantly stimulated by exposure to phorbol esther (0.1 microM) and inhibited by diphenyliodonium (5 microM). Studies using whole-cell voltage clamp showed that the K+ current of cultured fetal rabbit NEB cells exhibited inactivating properties similar to KV3.3a transcripts expressed in Xenopus oocyte model. Exposure of NEB cells to hydrogen peroxide (H2O2, the dismuted by-product of the oxidase) under normoxia resulted in an increase of the outward K+ current indicating that H2O2 could be the transmitter modulating the O2-sensitive K+ channel. Expressed mRNAs or corresponding protein products for the NADPH oxidase membrane cytochrome b as well as mRNA encoding KV3.3a were identified in small cell lung carcinoma cell lines. The studies presented here provide strong evidence for an oxidase-O2 sensitive potassium channel molecular complex operating as an O2 sensor in NEB cells, which function as chemoreceptors in airways and in NEB related tumors. Such a complex may represent an evolutionary conserved biochemical link for a membrane bound O2-signaling mechanism proposed for other cells and life forms.

Animals↗
PubMed2000

NADPH oxidase is an O2 sensor in airway chemoreceptors: evidence from K+ current modulation in wild-type and oxidase-deficient mice.

Pulmonary neuroepithelial bodies (NEBs) are presumed airway chemoreceptors that express the putative O(2) sensor protein NADPH oxidase and O(2)-sensitive K(+) channels K(+)(O(2)). Although there is a consensus that redox modulation of K(+)(O(2)) may be a common O(2)-sensing mechanism, the identity of the O(2) sensor and related coupling pathways are still controversial. To test whether NADPH oxidase is the O(2) sensor in NEB cells, we performed patch-clamp experiments on intact NEBs identified by neutral red staining in fresh lung slices from wild-type (WT) and oxidase-deficient (OD) mice. In OD mice, cytochrome b(558) and oxidase function was disrupted in the gp91(phox) subunit coding region by insertion of a neomycin phosphotransferase (neo) gene. Expression in NEB cells of neo mRNA, a marker for nonfunctional gp91(phox), was confirmed by nonisotopic in situ hybridization. In WT cells, hypoxia (pO(2) = 15-20 mmHg; 1 mmHg = 133 Pa) caused a reversible inhibition ( approximately 46%) of both Ca(2+)-independent and Ca(2+)-dependent K(+) currents. In contrast, hypoxia had no effect on K(+) current in OD cells, even though both K(+) current components were expressed. Diphenylene iodonium (1 microM), an inhibitor of the oxidase, reduced K(+) current by approximately 30% in WT cells but had no effect in OD cells. Hydrogen peroxide (H(2)O(2); 0.25 mM), a reactive oxygen species generated by functional NADPH oxidase, augmented K(+) current by >30% in both WT and OD cells; further, in WT cells, H(2)O(2) restored K(+) current amplitude in the presence of diphenylene iodonium. We conclude that NADPH oxidase acts as the O(2) sensor in pulmonary airway chemoreceptors.

4-Aminopyridine↗
PubMed1999

A method of assessing ventilatory responses to chemoreceptor stimulation in infants.

Various methods of assessing infant chemoreceptor responses have been reported in the literature. However, equipment dead space, trigeminal stimulation and inherent respiratory variability may have affected the results. A method is presented which attempts to reduce the effect of these factors and thereby isolate the chemoreceptor response. Inspiratory gas was delivered into a lightweight face mask with a pliable rim, minimal dead space and a connected pneumotachograph. Ventilatory data were computed breath by breath. Computer-controlled electromagnetic valves allowed instantaneous switching between air and different gas mixtures, repeated in a randomized sequence. In 18 healthy term neonates, the mask increased ventilation by 12% (95% confidence interval 6-18%), measured by calibrated strain-gauge bands. The effect on respiratory frequency and tidal volume differed significantly between sleep states. Neonates were challenged with short-lasting hyperoxia, mild hypoxia, rebreathing and mild hypercapnia. Coherent averaging of several ventilatory responses from each sleep state reduced the variability while maintaining a high time-resolution.

Analysis of Variance↗
PubMed1992

Potassium channel types in arterial chemoreceptor cells and their selective modulation by oxygen.

Single K+ channel currents were recorded in excised membrane patches from dispersed chemoreceptor cells of the rabbit carotid body under conditions that abolish current flow through Na+ and Ca2+ channels. We have found three classes of voltage-gated K+ channels that differ in their single-channel conductance (gamma), dependence on internal Ca2+ (Ca2+i), and sensitivity to changes in O2 tension (PO2). Ca(2+)-activated K+ channels (KCa channels) with gamma approximately 210 pS in symmetrical K+ solutions were observed when [Ca2+]i was greater than 0.1 microM. Small conductance channels with gamma = 16 pS were not affected by [Ca2+]i and they exhibited slow activation and inactivation time courses. In these two channel types open probability (P(open)) was unaffected when exposed to normoxic (PO2 = 140 mmHg) or hypoxic (PO2 approximately 5-10 mmHg) external solutions. A third channel type (referred to as KO2 channel), having an intermediate gamma(approximately 40 pS), was the most frequently recorded. KO2 channels are steeply voltage dependent and not affected by [Ca2+]i, they inactivate almost completely in less than 500 ms, and their P(open) reversibly decreases upon exposure to low PO2. The effect of low PO2 is voltage dependent, being more pronounced at moderately depolarized voltages. At 0 mV, for example, P(open) diminishes to approximately 40% of the control value. The time course of ensemble current averages of KO2 channels is remarkably similar to that of the O2-sensitive K+ current. In addition, ensemble average and macroscopic K+ currents are affected similarly by low PO2. These observations strongly suggest that KO2 channels are the main contributors to the macroscopic K+ current of glomus cells. The reversible inhibition of KO2 channel activity by low PO2 does not desensitize and is not related to the presence of F-, ATP, and GTP-gamma-S at the internal face of the membrane. These results indicate that KO2 channels confer upon glomus cells their unique chemoreceptor properties and that the O2-K+ channel interaction occurs either directly or through an O2 sensor intrinsic to the plasma membrane closely associated with the channel molecule.

Adenosine Triphosphate↗
PubMed1989

Effect of halothane, enflurane and isoflurane on carotid body chemoreceptor activity in the rabbit and the cat.

The response of the carotid body chemoreceptors to administration of halothane, enflurane and isoflurane was tested in the rabbit and cat. In the steady-state all three volatile anaesthetics, in doses up to 1%, were mildly chemodepressant. The oxygen response curves were shifted downwards, but hypoxic stimuli below 5.3 kPa overcame this chemodepression. Two-point carbon dioxide response curves were also shifted downwards, but with no change in slope. Possible mechanisms involved in the chemoreceptor response to transient and steady-state anaesthetic administration are discussed.

Action Potentials↗
PubMed2001

Updating the str and srj (stl) families of chemoreceptors in Caenorhabditis nematodes reveals frequent gene movement within and between chromosomes.

The seven transmembrane receptor (str) and srj (renamed from stl) families of chemoreceptors have been updated and the genes formally named following completion of the Caenorhabditis elegans genome sequencing project. Analysis of gene locations revealed that 84% of the 320 genes and pseudogenes in these two families reside on the large chromosome V. Movements to other chromosomes, especially chromosome IV, have nevertheless been relatively common, but only one has led to further gene family diversification. Comparisons with homologs in C. briggsae indicated that 22.5% of these genes have been newly formed by gene duplication since the species split, while also showing that four have been lost by large deletions. These patterns of gene evolution are similar to those revealed by analysis of the equally large srh family of chemoreceptors, and are likely to reflect general features of nematode genome dynamics. Thus large random deletions presumably balance the rapid proliferation of genes and their degeneration into pseudogenes, while gene movement within and between chromosomes keeps these nematode genomes in flux.

Animals↗
PubMed1996

The effect of halothane on phrenic and chemoreceptor responses to hypoxia in anesthetized kittens.

We examined the effect of halothane on phrenic never and carotid sinus discharge during hypoxia in anesthetized kittens. In 12 animals, phrenic amplitude was measured during normoxia, during isocapnic hypoxia, and after a return to normoxia, both with and without halothane. Without halothane, all animals had an increase in phrenic amplitude during hypoxia. With halothane, half the animals showed an increase in phrenic amplitude followed by a decline. In a second group of animals, recordings were obtained from single or a few fiber strands of carotid sinus nerve. Without halothane, an increase in chemoreceptor discharge frequency during hypoxia was seen. With 1.0% halothane, frequency was decreased during normoxia and did not increase during hypoxia. Thus, halothane's effect on the ventilatory response to hypoxia, as measured by phrenic discharge, is at least partially explained by an effect on peripheral chemoreceptors.

Action Potentials↗
PubMed1996

Sympathetic and mesenteric venous responses to baroreceptor or chemoreceptor stimulation during epidural anesthesia in rabbits.

BACKGROUND: Baroreceptor and chemoreceptor reflexes maintain homeostasis through mechanisms that involve sympathetic activation. Because sympathetic control of the mesenteric veins plays a central role in hemodynamic responses to stress, the effects of epidural blockade on reflex responses to hypoxia and bilateral carotid occlusion (BCO) were examined by monitoring direct measures of splanchnic sympathetic neural traffic and mesenteric venous capacitance. METHODS: Rabbits were studied during alpha-chloralose anesthesia and mechanical ventilation. Sympathetic efferent nerve activity to the mesenteric vessels was measured by surgically placed electrodes, and mesenteric venous diameter was measured by videomicroscopy. Heart rate and mean arterial pressure were monitored by intraarterial cannulation. Intraluminal venous pressure was monitored by a servo-null micropressure technique. Responses were recorded during repeated administration of three different stresses, F1O2 = 0% for 40 s, F1O2 = 11% for 2.5 min, and BCO for 60 s. Animals received either thoracolumbar epidural blockade (0.4 ml/kg lidocaine 1.5%; n = 7) or 15 mg/kg intramuscular lidocaine (n = 7). RESULTS: Hypoxia and BCO produced sympathetic stimulation and active constriction of mesenteric veins. Epidural anesthesia accentuated the mean arterial pressure decrease from F1O2 of 0%, caused the 11% response to F1O2 to become depressor instead of pressor, and decreased the pressor effect BCO. Sympathetic efferent nerve activity and venous diameter responses to hypoxia and BCO were attenuated or eliminated. CONCLUSIONS: The hemodynamic effects of hypoxia result from a combination of direct depression and reflex activation. Thoracolumbar epidural anesthesia in rabbits impairs compensatory reflexes invoked by chemoreceptor stimulation and eliminates response to baroreceptor stimulation. Loss of splanchnic control of mesenteric capacitance contributes to the inhibition of the hemodynamic response to hypoxia or BCO during epidural anesthesia in rabbits.

Anesthesia, Epidural↗
PubMed1995

Medullary responses to chemoreceptor activation are inhibited by locus coeruleus and nucleus raphe magnus.

The effect of electrical and L-glutamate stimulation of the nucleus locus coeruleus (LC) and nucleus raphe magnus (NRM) on multiunit activity evoked in the nucleus tractus solitarius (NTS) by activation of arterial chemoreceptors (15-25 micrograms kg-1 of sodium cyanoborohydride, i.v.) was studied in rats anaesthetized with urethane (1.1 g kg-1 i.p.). Multiunit discharge of NTS neurones in response to cyanide injection was composed by spikes higher than 200 microV and about 10 Hz frequency. Electrical and L-glutamate stimulation of the LC and the NRM significantly reduced the frequency of the cyanide-induced multiunit discharge. The results show that neurones of the NTS with input from arterial chemoreceptors can be inhibited by LC and and NRM cells, suggesting that these nuclei play a role in controlling chemosensory input at the NTS.

Animals↗
PubMed1996

Nitric oxide synthase isoforms and peripheral chemoreceptor stimulation in conscious rats.

To test the effect of nitric oxide synthase (NOS) blockade on the ventilatory responses to carotid body chemoreceptor stimulation in freely behaving animals, chronically instrumented adult Sprague-Dawley rats received increasing intravenous doses of sodium cyanide (NaCN; 0-300 micrograms kg-1) before and after i.v. administration of either 100 mg kg-1 N-nitro-L-arginine methyl ester (L-NAME), a non-specific NOS blocker, or 10 mg kg-1 S-methyl-L-thiocitrulline (SMTC), a selective neuronal NOS inhibitor. SMTC did not modify the NaCN dose-response curve. In contrast, L-NAME significantly enhanced the ventilatory responses to NaCN. Western blots of equivalent amounts of protein from carotid body tissue homogenates revealed higher levels of endothelial NOS than of neuronal NOS. We conclude that endothelial NOS provides the major source for NO within the carotid body, and exerts a down-regulatory effect upon peripheral chemoreceptor responsivity.

Animals↗
PubMed1997

Hypertension caused by chronic intermittent hypoxia--influence of chemoreceptors and sympathetic nervous system.

BACKGROUND: The sleep apnea syndrome (SAS) is a common health problem with a 30% prevalence among patients with so-called essential hypertension. OBJECTIVE: Prompted by this epidemiologic link we tried to find out whether there is a cause-effect relationship between SAS and systemic hypertension. DESIGN: We developed an animal model to simulate defined aspects of the SAS. Rats were exposed to chronic repetitive hypoxia for 7 h per day and their blood pressure was measured by invasive methods. RESULTS: We found that 30 days of intermittent hypoxia sufficed for the development of a significant elevation of blood pressure. The co-exposure to hypoxia and hypercapnia had no additional effect. Surgical denervation of peripheral chemoreceptors prevented the increase in arterial blood pressure. Adrenal demedullation and chemical denervation of the peripheral sympathetic nervous system by 6-hydroxy dopamine also prevented the increase. CONCLUSIONS: Our data imply that repetitive hypoxemia in SAS is probably the cause of the high prevalence of systemic hypertension in this population and that peripheral chemoreceptors and the sympathetic nervous system play important roles in this pathophysiologic process.

Adrenal Medulla↗
PubMed2002

Intragenic suppressors of a mutation in the aspartate chemoreceptor gene that abolishes binding of the receptor to methyltransferase.

In the chemotaxis of Escherichia coli, receptor methylation is the key process of adaptation. The methyltransferase CheR binds to the carboxy-terminal NWETF sequence of major chemoreceptors. The substitution of Ala for Trp of this sequence (W550A) of the aspartate chemoreceptor (Tar) abolishes its CheR-binding ability. In this study, six independent intragenic suppressors of the mutation were isolated. They were divided into two classes. Tar carrying the class I suppressors (G278A-L488M, T334A, G278A, G278C and A398T) showed signal biases toward tumbling, corresponding to increased activities of the receptor-associated histidine kinase CheA. These suppressors further reduced the unstimulated methylation level of Tar-W550A, but allowed slight but significant stimulation of methylation by aspartate. Some other CheA-activating mutations were also found to serve as class I suppressors. These results suggest that the class I suppressors compensate for the signal bias of Tar-W550A caused by its low methylation level and that the NWETF sequence is required primarily to maintain an appropriate level of methylation by increasing the local concentration of CheR around the receptor. The class II suppressor was a mutation in the termination codon (Op554W) resulting in the addition of 11 residues containing an xWxxF motif. This revertant Tar supported chemotaxis and was methylated almost as effectively as wild-type Tar. This effect was reversed by introducing a mutation in the xWxxF motif. These results reinforce the importance of the xWxxF motif and suggest that the motif does not have to be located at the extreme carboxy terminus.

Bacterial Proteins↗