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PubMed2002

Gene expression in peripheral arterial chemoreceptors.

The peripheral arterial chemoreceptors of the carotid body participate in the ventilatory responses to hypoxia and hypercapnia, the arousal responses to asphyxial apnea, and the acclimatization to high altitude. In response to an excitatory stimuli, glomus cells in the carotid body depolarize, their intracellular calcium levels rise, and neurotransmitters are released from them. Neurotransmitters then bind to autoreceptors on glomus cells and postsynaptic receptors on chemoafferents of the carotid sinus nerve. Binding to inhibitory or excitatory receptors on chemoafferents control the electrical activity of the carotid sinus nerve, which provides the input to respiratory-related brainstem nuclei. We and others have used gene expression in the carotid body as a tool to determine what neurotransmitters mediate the response of peripheral arterial chemoreceptors to excitatory stimuli, specifically hypoxia. Data from physiological studies support the involvement of numerous putative neurotransmitters in hypoxic chemosensitivity. This article reviews how in situ hybridization histochemistry and other cellular localization techniques confirm, refute, or expand what is known about the role of dopamine, norepinephrine, substance P, acetylcholine, adenosine, and ATP in chemotransmission. In spite of some species differences, review of the available data support that 1). dopamine and norepinephrine are synthesized and released from glomus cells in all species and play an inhibitory role in hypoxic chemosensitivity; 2). substance P and acetylcholine are not synthesized in glomus cells of most species but may be made and released from nerve fibers innervating the carotid body in essentially all species; 3). adenosine and ATP are ubiquitous molecules that most likely play an excitatory role in hypoxic chemosensitivity.

Animals↗
PubMed1992

Suspected chemoreceptors in coelenterates and ctenophores.

Chemoreceptors in coelenterates and ctenophores have not been identified with certainty. Among prospective chemoreceptive cells are the sensory nerve cells, the cnidocyst-bearing cnidocytes, and the epitheliomuscular cells that are likely to be involved in feeding or aggression. Both behaviors are mediated by coordinated chemical and mechanical reception. This is reflected in the close apposition of putative chemo- and mechanoreceptors. Among the structures that have been designated as likely chemo- and/or mechanoreceptors are stereocilia, kinocilia, and/or microvilli which are universally present on all the putative chemoreceptor complexes, while gland cells and mucous secretions are prevalent. Evidence that the actin-containing stereocilia are chemically modulated mechanoreceptors is presented for several forms.

Animals↗
PubMed1995

Plasticity in cultured carotid body chemoreceptors: environmental modulation of GAP-43 and neurofilament.

In this study we use dissociated cell cultures of the rat carotid body to investigate the adaptive capabilities of endogenous oxygen chemoreceptors, following chronic stimulation by various environmental factors. These oxygen chemoreceptors are catecholamine-containing glomus cells, which derive from the neural crest and resemble adrenal medullary chromaffin cells. Using double-label immunofluorescence, we found that chronic exposure of carotid body cultures to hypoxia (2% to 10% oxygen) caused a significant fraction of tyrosine hydroxylase-positive (TH+) glomus cells to acquire detectable immunoreactivity for growth-associated protein GAP-43. The effect was dose-dependent and peaked around an oxygen tension of 6%, where approximately 30% of glomus cells were GAP-43 positive. Treatment with agents that elevate intracellular cyclic adenosine monophosphate (cAMP) (i.e., dibutyryl cAMP or forskolin) also markedly stimulated GAP-43 expression. Since hypoxia is known to increase cAMP levels in glomus cells, it is possible that the effect of hypoxia on GAP-43 expression was mediated, at least in part, by a cAMP-dependent pathway. Unlike hypoxia, however, cAMP analogs also stimulated neurofilament (NF 68 or NF 160 kD) expression and neurite outgrowth in glomus cells, and these properties were enhanced by retinoic acid. Nerve growth factor, which promotes neuronal differentiation in related crest-derived endocrine cells, and dibutyryl cGMP were ineffective. Thus, it appears that postnatal glomus cells are plastic and can express neuronal traits in vitro. However, since hypoxia stimulated GAP-43 expression, without promoting neurite outgrowth, it appears that the two processes can be uncoupled. We suggest that stimulation of GAP-43 by hypoxia may be important for other physiological processes, e.g., enhancing neurotransmitter release or sensitization of G-protein-coupled receptor transduction.

Animals↗
PubMed1997

Analysis of protein structure in intact cells: crosslinking in vivo between introduced cysteines in the transmembrane domain of a bacterial chemoreceptor.

Oxidative crosslinking of cysteines introduced by site-specific mutagenesis is a powerful tool for structural analysis of proteins, but the approach has been limited to studies in vitro. We recently reported that intact cells of Escherichia coli could be treated with Cu(II)-(o-phenanthroline)3 or molecular iodine in a way that left unperturbed flagellar function or general chemotactic response, yet crosslinks were quantitatively formed between select cysteines in adjoining transmembrane helices of chemoreceptor Trg. This suggested that oxidative crosslinking might be utilized for structural analysis in vivo. Thus, we used our comprehensive collection of Trg derivatives, each containing a single cysteine at one of the 54 positions in the two transmembrane segments of the receptor monomer to characterize patterns of crosslinking in vivo and in vitro for this homodimeric protein. We found that in vivo crosslinking compared favorably as a technique for structural analysis with the more conventional in vitro approach. Patterns of crosslinking generated by oxidation treatments of intact cells indicated extensive interaction of transmembrane segment 1 (TM1) with its homologous partner (TM1') in the other subunit and a more distant placement of TM2 and TM2', the same relationships identified by crosslinking in isolated membranes. In addition, the same helical faces for TM1-TM1' interaction and TM2-TM2' orientation were identified in vivo and in vitro. The correspondence of the patterns also indicates that structural features identified by analysis of in vitro crosslinking are relevant to the organization of the chemoreceptor in its native environment, the intact, functional cell. It appears that the different features of the two functionally benign treatments used for in vivo oxidations can provide insights into protein dynamics.

Bacterial Proteins↗
PubMed2002

Lack of contribution of mitochondrial electron transport to acute O(2) sensing in model airway chemoreceptors.

We have recently reported that the model airway chemoreceptors, H146 cells, exhibit a significant component of their oxygen-sensing transduction pathway which cannot be explained by activity of NADPH oxidase. Using patch-clamp, we have studied the transduction system linking reduced O(2) to k(+) channel inhibition and report that, in complete contrast to recent suggestions in pulmonary vasculature, O(2) sensing by the model airway chemoreceptors, H146 cells, does not require functional mitochondria. These data show, for the first time, that mitochondrial production of reactive O(2) species is not the unifying mechanism in O(2) sensing.

Antimycin A↗
PubMed2001

Activation of a latent respiratory motor pathway by stimulation of neurons in the medullary chemoreceptor area of the rat.

Previous studies have demonstrated that during respiratory stress (hypercapnia and hypoxia), a latent crossed respiratory pathway can be activated to produce hemidiaphragm recovery following an ipsilateral C2 spinal cord hemisection. The present study investigates the effects of ventral medullary chemoreceptor area stimulation by microinjection of (1S,3R)-aminocyclopentanedicarboxylic acid (ACPD), a glutamate metabotropic receptor agonist, on activating the latent pathway following left C2 spinal cord hemisection in rats in which end-tidal CO2 was maintained at a constant level. Experiments were conducted on anesthetized, vagotomized, paralyzed, and artificially ventilated rats in which phrenic nerve activity was recorded bilaterally. Before drug injection, the phrenic nerve contralateral to hemisection showed vigorous respiratory-related activity, but the phrenic nerve ipsilateral to hemisection showed no discernible respiratory-related activity. ACPD (1-100 nl, 1 mM) was injected directly into the region of the retrotrapezoid nucleus (RTN), a known medullary chemoreceptor area. Microinjection of ACPD into the right RTN increased respiratory-related activity in the right phrenic nerve (contralateral to hemisection). ACPD (>5 nl, 1 mM) microinjection also significantly induced respiratory recovery in the phrenic nerve ipsilateral to hemisection in a dose-dependent manner. The present study indicates that respiratory recovery can be achieved by stimulation of respiratory circuitry without increasing CO2 levels.

Animals↗
PubMed1993

Schistosoma mansoni: fatty acid-induced cercarial tail loss does not involve eicosanoid production and chemoreceptors.

Inhibitors of eicosanoid production had no effect on linoleic acid-induced Schistosoma mansoni cercarial tail loss. In addition, linoleic acid-induced cercarial tail loss was not inhibited by silver nitrate, which binds to putative chemoreceptors for fatty acids in cercariae. There was no correlation between molecular structures of fatty acids and their potencies to induce tail loss. Furthermore, transcompounds of fatty acids which cannot be precursors of eicosanoids elicited tail loss as potently as cis-compounds did. The present results suggest that fatty acid-induced cercarial tail loss is not mediated by eicosanoid production and chemoreceptors, which are involved in cercarial penetration behavior stimulated by fatty acids.

Animals↗
PubMed2000

The present status of the mechanical hypothesis for chemoreceptor stimulation.

Reasons are given to show why the transmitter based hypothesis for the stimulation of chemoreceptors needs to be reviewed. On the other hand evidence is presented to show that chemoreceptors can be stimulated by various mechanical stimuli and how the local PO2 can be sensed by the type II cell which by getting mechanically deformed causes this cell to shrink. This shrinkage is transmitted to the generator region of the nerve terminal thereby leading to the production of propagated impulses at the regenerative region thus making the whole process of generation of information about the local PO2, similar to the generation of sensory information by other sensory receptors.

Animals↗
PubMed2000

Chronic hypoxia induces changes in the central nervous system processing of arterial chemoreceptor input.

Chronic hypoxia increases the hypoxic ventilatory response (HVR) in awake rats and the phrenic nerve response to carotid sinus nerve stimulation in anesthetized rats. An increased O2 sensitivity of the arterial chemoreceptors contributes to the increase in the HVR, but changes in the CNS processing of afferent information from arterial chemoreceptors are also involved. Adult male Sprague-Dawley rats were exposed to 0-7 days of hypobaric hypoxia (PIO2 = 80 Torr). Ventilation was measured in rats exposed to 0, 2 and 7 days of hypoxia using whole-body plethysmography. Ventilation increased after 2 days and remained elevated after 7 days of hypoxia. Following dopamine D2 receptor (D2-R) blockade in the CNS, frequency significantly decreased after 0 and 7 days of hypoxia, but did not change significantly after 2 days of hypoxia. In anesthetized rats, the phrenic nerve response to carotid sinus nerve stimulation was reduced following systemic D2-R blockade in control rats and those exposed to 7 days of hypoxia. After 2 days of hypoxia, there was no effect of blocking systemic D2-R. To determine whether changes in D2-R mRNA precede physiological changes, competitive RT-PCR was used to quantify D2-R mRNA in micropunches from the nucleus tractus solitarius (NTS) in normoxic and chronically hypoxic rats. In hypoxia, D2-R mRNA in the caudal NTS initially increased (6-12 hours) and then decreased below control levels (24 hours-7 days). These results show that chronic hypoxia causes time-dependent changes in D2-R that could result in changes in the ventilatory response to hypoxia.

Acclimatization↗
PubMed1975

The ultrastructure of the sensory cells in the chemoreceptor of the ommatophore of Helix pomatia L.

Most of the sensory cells found in the chemoreceptor of the ommatophore of Helix pomatia are typical bipolar cells. The chemoreceptor is deveded by a furrow into two parts; within the ventral subdivision the layer of sensory cell bodiesis thicker than in the dorsal part. According to the differentiations of the apical surface of the dendrites, it is possible to distinguish six different classes: a) dendrites with one cilium and 75 nm thick cytofila (sometimes dendrites of identical appearance posses more than one cilium); b)dendrites with several cilial and 150 nm thick cytofila; c) dendrites with several cilia, 50 nm thick cytofila, and long, striated rootlets; d) dendrites with several cilia bur without cytofila; e) dendrites with 130 nm thick cytofila but without cilia; and f) dendrites with 65 nm thick cytofila but without cilia; dendrites of this class are the only ones with a cytoplasm more electron dense than that of the surrounding supporting cells. All these dendrites are connected to the surrounding supporting cells by terminal bars, each consisting of zonula adhaerens, aonula intermedia and zonula septata. The perikarya of the sensory cells measure approximately 15 mum by 8 mum and enclose 10 mum by 6 mum large nuclei. Axons, originating from these perikarya, extend to the branches of the digital ganglion. In the distal part of this gangloin the axons come into synaptic contact with interneurons, but in our electron micrography it was not possible to coordinate processes and synapses with the corresponding neurons.

Axons↗
PubMed1986

Chemoreceptor response to hypoxia and hypercapnia in catecholamine depleted rabbit and cat carotid bodies in vitro.

The response of single chemoafferent fibres to hypoxic and hypercapnic stimulation was studied in vitro under different experimental conditions: 1. control, 2. 24 h after reserpinization (5 mg/kg iv) and 3. 18 h after iv injection of alpha-methyl-p-tyrosine (100 mg/kg in the rabbit, and 1. control and 2. 24 h after reserpinization (5 mg/kg ip) in the cat. The spontaneous activity was decreased by monoamine depletion. The amplitude of the response to hypoxia and to hypercapnia was decreased by reserpinization in the rabbit and in the cat, the change being less marked in the latter species. Similarly, treatment with alpha-methyl-p-tyrosine decreased the ability of chemoreceptors to respond to hypoxia and hypercapnia and, in a few instances, these receptors could only be excited by superfusion of nitrogen-equilibrated medium. These results emphasize to possible role of monoamine, and particularly dopamine, in modifying the sensitivity of arterial chemoreceptors to their natural stimuli.

Animals↗
PubMed1988

Adaptation in chemoreceptor cells. I. Self-adapting backgrounds determine threshold and cause parallel shift of response function.

1. The self-adapting effects of chemical backgrounds on the response of primary chemoreceptor cells to superimposed stimuli were studied using lobster (Homarus americanus) NH4 receptor cells. 2. These receptors responded for several seconds to the onset of the backgrounds, and then returned to their initial level of spontaneous activity (usually zero). The strongest response always occurred only during the steepest concentration change; the response then decayed back to zero or to the earlier spontaneous firing level, while the background concentration was still rising, and remained silent during the entire time that the background was maintained constant (20-30 min) 3. Exposure to constant self-adapting backgrounds eliminated the response of NH4 receptor cells to stimuli of concentration lower than the background, and reduced the responses to all higher stimulus concentrations tested by a nearly equal amount. This resulted in a parallel shift of the stimulus-response function to the right along the abscissa. 4. Since the response threshold was completely re-set by adaptation to backgrounds, NH4 receptors seem to function mostly as detectors of relative rather than absolute stimulus intensity across their entire dynamic range: the response to a given stimulus-to-background ratio remained the same over 3 log step increases of background concentration. 5. As in other sensory modalities, a parallel shift of response functions appears to be an important property of chemoreceptor cells, allowing for this sensory system to function over a wider stimulus intensity range than the instantaneous dynamic range of individual receptor cells.

Action Potentials↗
PubMed1992

Normotensive normoxic men undergoing water diuresis fail to respond to stimulation of their peripheral arterial chemoreceptors by almitrine with an increase in plasma concentrations of atrial natriuretic factor.

The purpose of this study was to investigate the possible participation of atrial natriuretic factor (ANF) in the natriuretic and diuretic response occurring after stimulation of the peripheral arterial chemoreceptors by almitrine bismesylate in normoxic humans. The experiments were performed in 14 healthy male volunteers undergoing water diuresis. Each subject participated in two experiments. In one of them they ingested 100-mg almitrine at 12 p.m. The other study served as a control. Surprisingly, our subjects responded to almitrine with an elevation of urine flow only, whereas sodium excretion remained almost unchanged over the whole period of the experiments. As regards ANF plasma concentrations, no statistically significant differences between the control and the almitrine group could be observed. Moreover, no direct connection between ANF plasma concentrations and renal volume excretion was detectable. We conclude that a specific stimulation of peripheral arterial chemoreceptors by almitrine in humans undergoing water diuresis did not seem to raise ANF plasma concentrations as is the case at high altitude. Therefore we would suggest that there exists no specific reflex influence of these receptors on ANF release.

Administration, Oral↗
PubMed1985

Role of peripheral chemoreceptors in response to smoke-induced apnea vs tracheal occlusion.

Reflex autonomic changes which occur after cigarette smoke enters the upper airways are partially due to peripheral chemoreceptor stimulation. Chemoreceptor denervation attenuates but does not abolish smoke induced bradycardia. Denervation nearly abolishes bradycardia induced by tracheal occlusion. Hypertension accompanies smoke induced apnea but does not occur during tracheal occlusion.

Animals↗
PubMed1988

Carbon dioxide exchange across the walls of arterioles: implication for the location of the medullary chemoreceptors.

The location of the medullary chemoreceptors is not conclusively established. The original experiments, which were believed to suggest a shallow surface location in the ventrolateral medulla, have been questioned because substances, particularly CO2, applied on the surface of the medulla could diffuse into small arterioles. Because the whole tissue blood flow is supplied by surface arterioles, they could transport substances from the surface into the tissue to the respiratory centers. We studied simple transport equations describing movement of CO2 in arterioles bathed by rapidly flowing cerebrospinal fluid (CSF) and arterioles in tissue perfused by capillaries. Substantial exchange of CO2 could occur across the arteriole wall for all expected sizes of vessels when the partial pressure of CO2 at the outside wall was determined by CSF. When an arteriole is surrounded by tissue, only vessels with inside diameters (ID) less than or equal to 50 micron will exchange substantial amounts of CO2 but the smallest arterioles may be nearly in equilibrium with the tissue. The CO2 gradient in tissue around the arteriole will extend approximately 1 mm. Our simple theoretical description of CO2 transport in arterioles predicts substantial exchange in precapillary vessels. CO2 picked up by the smallest surface arterioles when the medulla is perfused at a high rate with CSF will not stay in the blood past the putative depth of the chemoreceptors. In arterioles greater than 30 micron, however, the CO2 could be carried to the respiratory centers.

Arterioles↗
PubMedDate not supplied

The relationship of breathing pattern to central chemoreceptor activity in infantile apnea.

In order to assess the relationship of breathing pattern to the central chemoreceptor activity in infantile apnea, we studied 18 infants referred to our regional apnea center with 12 hour nocturnal pneumocardiograms and ventilatory response to 2% and 4% carbon dioxide inhalation. 70% of the infants had normal pneumocardiograms and 60% of the infants had normal ventilatory response to CO2. Nine infants (45%) had normal results in both tests. Our results indicate that in infants with a normal breathing pattern as assessed by pneumocardiogram 75% had normal central chemoreceptor activity, while 37.5% of infants with abnormal breathing pattern had abnormal ventilatory response to CO2.

Apnea↗
PubMed1978

The effect of ethanol on the ventilatory responses mediated by the peripheral chemoreceptors in man.

The ventilatory responses mediated by the central and peripheral chemoreceptors were separately assessed in eight healthy volunteers before and after the oral ingestion of ethanol in a dose of 0.75 ml/kg. No significant depression of the central response was observed, but a significant depression of the peripheral response was observed at 25 and 95 minutes after the consumption of ethanol. The peripheral chemoreceptor stimulus was the simultaneous increase of hypoxia and hypercapnia and this novel method is described.

Administration, Oral↗
PubMed1997

Effects of vagal and carotid chemoreceptor afferents on the frequency and pattern of spontaneous augmented breaths in rabbits.

We investigated the effects of vagal afferents and carotid chemoreceptors on the frequency and pattern of spontaneous augmented breaths in anesthetized rabbits by analyzing the changes in the phrenic nerve discharge. Blockade of vagal C-fiber conduction by capsaicin treatment greatly reduced the frequency of spontaneous augmented breaths but had no significant effect on the pattern of the augmented breaths. Inhalation of sulfur dioxide, which abolished the Hering-Breuer inflation reflex, suppressed the frequency of spontaneous augmented breaths but did not significantly alter the pattern of the augmented breaths. Carotid sinus denervation diminished both the frequency and amplitude of spontaneous augmented breaths. The occurrence of spontaneous augmented breaths was not observed in rabbits after bilateral vagotomy. In other experiments we examined the relationship between rapidly adapting pulmonary stretch receptors (RARs) and dynamic lung compliance during the spontaneous augmented breath. The stimulation of RARs occurred at the first phase of spontaneous augmented breaths, and augmentation of transpulmonary pressure seen at the second phase coincided with vigorous stimulation of the receptor activity. These results suggest that spontaneous augmented breaths may be mediated by the summation of several facilitatory inputs from vagal and carotid chemoreceptor afferents.

Action Potentials↗