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Effects of domperidone on neonatal and adult carotid chemoreceptors in the cat
Abstract
It has been postulated that the weak carotid chemoreceptor responses of neonatal mammals may be due to inhibition produced by high levels of endogenous dopamine release or exaggerated sensitivity to dopaminergic inhibition. This was studied by measuring the effect of domperidone, a selective dopamine D2-receptor antagonist, on the carotid chemoreceptor response to O2 and CO2 in anesthetized neonatal and adult cats. The animals were exposed to four levels of isocapnic O2 (arterial PO2 of approximately 35-45, 55-65, 80-90, > 300 Torr) and four levels of isoxic CO2 (end-tidal PCO2 of approximately 21, 40, 58, and 78 Torr) before and after D2-receptor blockade. Whole nerve activity was recorded from the carotid sinus nerve (CSN). Both neonatal and adult cats increase CSN activity during hypoxia and hypercapnia (P < 0.001). Domperidone caused an increase in CSN activity at all O2 levels in adults (P < 0.01) but only during hypoxia in neonates (P < 0.001). Domperidone caused an increase in CSN activity during normo- and hypercapnia in adults but only during hypercapnia in neonates (P < 0.001). Domperidone approximately doubled an index of hypoxic sensitivity in the normoxia-hypoxia range (100 to 40 Torr) in the neonatal group but had little effect on sensitivity to hypoxia in adults. We conclude that the inhibitory role of endogenous dopamine in the carotid chemoreceptors changes with postnatal development.
... However, most studies show that DA inhibits carotid sinus nerve discharge (CSND) (Fidone et al., 1997) and numerous studies have reported that DA D 2 receptor antagonists such as domperidone increase CSND in response to hypoxia. Taken together, these findings strongly suggest that endogenous DA inhibits CSND (Iturriaga et al., 1994;Tomares et al., 1994;Fidone et al., 1997). ...
... Dopamine acts as an inhibitory modulator in the CB of newborn and its effects may change with age (Marchal et al., 1992b;Tomares et al., 1994). Tomares et al. (1994) reported that domperidone increased CB sensitivity to hypoxia in 1 week old but not in adult cats suggesting a greater degree of dopaminergic inhibition at this age. ...
... Dopamine acts as an inhibitory modulator in the CB of newborn and its effects may change with age (Marchal et al., 1992b;Tomares et al., 1994). Tomares et al. (1994) reported that domperidone increased CB sensitivity to hypoxia in 1 week old but not in adult cats suggesting a greater degree of dopaminergic inhibition at this age. Finally, studies of CB DA D 2 receptors show that mRNA level of these receptors is quantitatively lower in the newborn CB than in adult (Gauda et al., 1994;Bairam et al., 1996a). ...
Dopamine (DA) release (r) from the carotid body (CB) is thought to be modulated by feedback inhibition mediated by DA D2 autoreceptors. We tested the hypothesis that CB DAr is autoregulated in a concentration and age dependent manner. Using an in vitro CB infusion model [Bairam, A., Marchal, F., Cottet-Emard, J.M., Basson, H., Pequignot, J.M., Hascoet, J.M., Lahiri, S., 1996b. Effects of hypoxia on carotid body dopamine content and release in developing rabbits. J. Appl. Physiol. 80, 20–24.], we evaluated under unstimulated conditions the effects of 0.001, 0.01, 0.1, 1.0 and 10.0 μM of the specific DA D2 receptor antagonist domperidone on CB DAr in adult rabbits. In 10-day-old rabbit pups, concentrations of 0.01, 0.1, 1.0 μM were studied. In adult CBs, domperidone increased DAr in a concentration-dependent manner. DAr (pmol/h) was significantly greater compared to control (without domperidone) starting at a domperidone concentration of 0.1 μM (P<0.01). In 10-day-old pup CBs, 1.0 μM domperidone was required to produce a significant increase of DAr (pmol/h) compared to control (P<0.005). However, control DAr (as % of total catecholamine) was about 40%; significantly higher than 24% observed in adult CBs (P<0.001). We conclude that in rabbit CB, DAr is controlled by an autoreceptor mechanism in a concentration-dependent manner and this mechanism is less developed in pups than in adults.
... While dopamine appears to affect chemoreception in a complex manner, its ultimate effect is to inhibit CB discharge and thus ventilation (Shirahata, 2002). Conversely, the use of selective dopamine D 2 -receptor antagonist domperidone, which does not cross the blood–brain barrier (Laduron and Leysen, 1979; Kohli et al., 1983; Zapata et al., 1996 ), has been shown to increase ventilatory drive in animals (Lahiri et al., 1985; Kressin et al., 1986; Hsiao et al., 1989; Tomares et al., 1994) and in human adults (Delpierre et al., 1987; Bascom et al., 1991; Foo et al., 1995; Walsh et al., 1998) by enhancing the peripheral chemoreceptor response to O 2 and CO 2 . Accordingly, the present study used domperidone as a tool to increase CB sensitivity to O 2 and CO 2 with the purpose of investigating the influence of controller gain on the stability of breathing in the lamb. ...
... As a result, the firing rate of CB afferents increases (Prabhakar, 2000) with a consequential increase in baseline ventilation and fall in end-tidal and arterial CO 2 levels (Kressin et al., 1986; Hsiao et al., 1989). Interestingly, Tomares et al. (1994) found that domperidone had no effect under normoxic conditions in neonatal cats in contrast to adult cats, suggesting there is little tonic dopamine release in the newborn, a finding that is consistent with reports in the lamb (Blanco et al., 1984; Dawes et al., 1984). Despite such limited dopamine release in the CB of the newborn, we show for the first time that domperidone treatment increases the sensitivity of the peripheral chemoreceptors and promotes PB in a newborn animal. ...
Periodic breathing (PB) is an instability of the respiratory control system believed to be mediated principally by the peripheral chemoreceptors. We hypothesised that domperidone, a dopamine D(2)-receptor antagonist that increases carotid body sensitivity to O(2) and CO(2), would promote PB through an increase in the loop gain (LG) of the respiratory control system. Domperidone significantly increased controller gain for oxygen (p<0.05) and gave rise, following post-hyperventilation apnea, to an increased incidence of PB (14% vs. 86%), an increased PB epoch duration, and a decrease in duty ratio of PB (p<0.001); these changes are consistent with domperidone increasing LG. Although domperidone increased controller gain for CO(2) (p<0.05), the contribution of Pa(CO)(2) oscillations to the genesis of PB in the lamb remained small. We conclude that domperidone increases LG in the lamb via an increase in controller gain for oxygen. Our study demonstrates that a quantitative understanding of the factors that determine LG provides insight into the cause of PB.
... Thus, it appears that the low level of inhibitory autoregulatory function of these receptors in pups (Bairam et al., 2000a) leads to greater DA release in the immature CB. These significant developmental differences in the functional aspects of presynaptic D 2 autoreceptor control of DA release are very relevant since they likely explain, at least in part, why DA alters the CB chemosensitivity differently in adults versus newborns (Tomares et al., 1994;Hertzberg et al., 1990Hertzberg et al., , 1992. ...
... Despite reports that exogenous DA stimulates the CSN neural output depending on the dose, experimental design and on species studied, DA, in general, inhibits the CSN activity in both adults Gonzalez et al., 1994) and newborn animals (Marchal et al., 1992b). In newborn cats, administration of domperidone (D 2 receptor antagonist) increased CB CSN activity only in hypoxia and had little effect in normoxia or hyperoxia while, in adult cats domperidone increased CB CSN activity to a similar degree at all PO 2 levels (Tomares et al., 1994). ...
This review examines the possible role of neurotransmitters present in the carotid body on the functional expression of chemosensory activity during postnatal development. In particular, dopamine, acetylcholine, adenosine and neuropeptides are reviewed. Evidence to date shows involvement of these transmitters in signal transmission from the chemoreceptor cells to chemosensory afferent fibers of the sinus nerve, with clear age- or maturation-dependence of some aspects. However, it remains unresolved whether these neurotransmitters, some of which are expressed in the carotid body before birth, are directly involved in the maturation of the functional properties of the carotid chemoreceptors in sensing oxygen or other stimuli during postnatal development.
... For example, while dopamine blunts ventilatory responses originating at the carotid bodies, dopamine antagonists enhance carotid body output, albeit more pronounced at low oxygen levels. 56,57 More viable targets are the so-called background potassium channels of the K2P potassium channel family, i.e., hypoxia and acid-stimulated TASK-1, TASK-3, and heterodimer TASK-1/TASK-3 channels, which provide hypoxia-sensitive background potassium conductance in the carotid body type 1 cell. [58][59][60] In response to hypoxia, these channels mediate the depolarization of the type 1 carotid body cell. ...
Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.
... DA seems to have a well established inhibitory role for ventilation and its responses to acute hypoxia in the majority of species, such as the cat (Llados and Zapata 1978), the rabbit (Matsumoto et al. 1980), or the rat (Bee and Pallot 1995;Monteiro et al. 2011), but not in the dog where it has a stimulatory effect (Black et al. 1972). However, the notion of DA-mediated ventilatory inhibition has found support in the action of domperidone, a peripheral D2 antagonist, which increases ventilation (Bee and Pallot 1995), although in some reports the increase has only been found after birth and was lost with maturation (Tomares et al. 1994). The issue is further confounded by the postulate of the existence of the low affinity excitatory post-synaptic carotid body dopamine D2 receptor responding to high doses of DA, as opposed to the inhibitory effects on the hypoxic ventilator responses exerted by low doses of DA through high affinity D2 receptors in animals and man (Gonzales et al. 1994;Ward and Bellville 1982). ...
Dopamine (DA) is a putative neurotransmitter in the carotid body engaged in the generation of the hypoxic ventilatory response (HVR). However, the action of endogenous DA is unsettled. This study seeks to determine the ventilatory effects of increased availability of endogenous DA caused by inhibition of DA enzymatic breakdown. The peripheral inhibitor of MAO - debrisoquine, or COMT - entacapone, or both combined were injected to conscious rats. Ventilation and its responses to acute 8 % O2 in N2 were investigated in a whole body plethysmograph. We found that inhibition of MAO augmented the hyperventilatory response to hypoxia. Inhibition of COMT failed to influence the hypoxic response. However, simultaneous inhibition of both enzymes, the case in which endogenous availability of DA should increase the most, reversed the hypoxic augmentation of ventilation induced by MAO-inhibition. The inference is that when MAO alone is blocked, COMT takes over DA degradation in a compensatory way, which lowers the availability of DA, resulting in a higher intensity of the HVR. We conclude that MAO is the enzyme predominantly engaged in the chemoventilatory effects of DA. Furthermore, the findings imply that endogenous DA is inhibitory, rather than stimulatory, for hypoxic ventilation.
... It remains to be determined if the effects of DA on CSND depend on whether the activated receptors are located pre-and/or postsynaptically to chemoreceptor cells. As DA induces, in general, an inhibition of CSND and the DA D1-R gene seems to be expressed at low levels in the CB, DA D1-R receptors may not be important for chemoreceptor function under basal conditions (Mc-Queen, 1982;Tomares et al., 1994). We suggest that they might play a role under specific conditions such as development or chronic hypoxia. ...
Dopamine is a major neurotransmitter in the carotid body of several animal species and its functional role at the level of peripheral arterial chemoreflex pathway is attributed to the presence of the dopamine D2-receptors. We present evidence that the dopamine D1-receptor mRNA is also expressed in the carotid body of adult rabbits, cats and rats. A DNA fragment of 611 bp of this receptor was first isolated from rabbit. The nucleic acid sequence of this fragment was found to be 84.5% identical to that of rat. This specific 611 bp fragment was used as a probe to detect, either by Northern analysis or by the reverse transcription-polymerase chain reaction, the dopamine D1-receptor mRNA. The results revealed the presence of dopamine D1-receptor transcript in the carotid body as well as in the petrosal ganglion and the superior cervical ganglion from the three animal models studied here. The physiological significance of dopamine D1-receptor expression in the carotid body is discussed.
... Lahiri et al. (21) found augmented hypoxic excitation after blocking DA receptors, and Iturriaga et al. (17) found that intravenous domperidone (an antagonist of D 2 receptors) enhanced hypoxic responses. However, in another domperidone study, Tomares et al. (34) reported an increase in chemosensory activity in adult cats, but the researchers saw no noticeable effect on hypoxic sensitivity. There were much larger effects in neonatal cats. ...
It is hypothesized that carotid body chemosensory activity is coupled to neurosecretion. The purpose of this study was to examine whether there was a correspondence between carotid body tissue dopamine (DA) levels and neuronal discharge (ND) measured from the carotid sinus nerve of perfused cat carotid bodies and to characterize interaction between CO2 and O2 in these responses. ND and tissue DA were measured after changing from normoxic, normocapnic control bicarbonate buffer (PO2 >120 Torr, PCO2 25-30 Torr, pH approximately 7.4) to normoxic hypercapnia (PCO2 55-57 Torr, pH 7.1-7.2) or to hypoxic solutions (PO2 30-35 Torr) with normocapnia (PCO2 25-30 Torr, pH approximately 7.4) or hypocapnia (PCO2 10-15 Torr, pH 7.6-7.8). Similar temporal changes for ND and tissue DA were found for all of the stimuli, although there was a much different proportional relationship for normoxic hypercapnia. Both ND and DA increased above baseline values during flow interruption and normocapnic hypoxia, and both decreased below baseline values during hypoxic hypocapnia. In contrast, normoxic hypercapnia caused an initial increase in ND, from a baseline of 175 +/- 12 (SE) to a peak of 593 +/- 20 impulses/s within 4.6 +/- 0.9 s, followed by adaptation, whereas ND declined to 423 +/- 20 impulses/s after 1 min. Tissue DA initially increased from a baseline of 17.9 +/- 1.2 microM to a peak of 23.2 +/- 1.2 microM within 3.0 +/- 0.7 s, then declined to 2.6 +/- 1.0 microM. The substantial decrease in tissue DA during normoxic hypercapnia was not consistent with the parallel changes in DA with ND that were observed for hypoxic stimuli.
... One mechanism that has been proposed for the shift in chemoreceptor sensitivity range is the rapid change in carotid body dopamine content and turnover that takes place around birth [12,13]. Nicotine seems to modulate these changes in carotid body transmitters [13] as well as the postnatal development of ventilatory responses to altered inspiratory O level [13,14]. ...
To assess the effect of prenatal cigarette smoke exposure on the postnatal resetting of oxygen sensitivity in term infants.
15 healthy term infants of smoking mothers (median 10 cigarettes/day) and 16 controls were studied during quiet sleep 1, 3, and 10 days and 10 weeks postnatally. Strain-gauge respiratory trace was continuously recorded. Repeated 15-s challenges with 100% O2 and 15% O2 were presented in randomised order through a face mask. A median of six hyperoxic and six hypoxic challenges per recording were obtained. Breath-by-breath ventilation in a time-window from 20 s before onset of stimulus to 60 s after was extracted. For each infant at each age, the normalised coherently averaged response to hyperoxia and hypoxia was calculated. Mean ventilation at end of the 15-s stimulus was analysed with ANOVA, as were parameters describing a function fitted to each averaged response.
During air breathing, smoke-exposed infants had higher respiratory rates and lower tidal volumes than controls. Nicotine concentration in infant hair, measured by gas chromatography, was positively correlated with maternal level of smoking. A long-term development in oxygen sensitivity was demonstrated in both groups. However, neither the time-course nor the magnitude of O2 responses was affected by maternal smoking. Overall, hyperoxia reduced ventilation by 6.3% at day 1, 13.2% at day 3, 29.6% at day 10, and 40.0% at week 10. Transient hypoxia increased ventilation by 3.5%, 3.2%, 6.4%, and 8.8%, respectively, at the four ages studied.
Dopamine is a neurotransmitter involved in oxygen sensing and control of reflex hyperventilation. In aquatic vertebrates, oxygen sensing occurs in the gills via chemoreceptive neuroepithelial cells (NECs), but a mechanism for dopamine in autonomic control of ventilation has not been defined. We used immunohistochemistry and confocal microscopy to map the distribution of tyrosine hydroxylase (TH), an enzyme necessary for dopamine synthesis, in the gills of zebrafish. TH was found in nerve fibers of the gill filaments and respiratory lamellae. We further identified dopamine active transporter ( dat ) and vesicular monoamine transporter ( vmat2 ) expression in neurons of the gill filaments using transgenic lines. Moreover, TH‐ and dat ‐positive nerve fibers innervated NECs. In chemical screening assays, domperidone, a D 2 receptor antagonist, increased ventilation frequency in zebrafish larvae in a dose‐dependent manner. When larvae were confronted with acute hypoxia, the D 2 agonist, quinpirole, abolished the hyperventilatory response. Quantitative polymerase chain reaction confirmed expression of drd2a and drd2b (genes encoding D 2 receptors) in the gills, and their relative abundance decreased following acclimation to hypoxia for 48 h. We localized D 2 receptor immunoreactivity to NECs in the efferent gill filament epithelium, and a novel cell type in the afferent filament epithelium. We provide evidence for the synthesis and storage of dopamine by sensory nerve terminals that innervate NECs. We further suggest that D 2 receptors on presynaptic NECs provide a feedback mechanism that attenuates the chemoreceptor response to hypoxia. Our studies suggest that a fundamental, modulatory role for dopamine in oxygen sensing arose early in vertebrate evolution.
The fetus is living at low PO2 “Mount Everest in utero” and is at birth suddenly exposed to high PO2. This transition requires a change of setting of oxygen sensitivity. The carotid and aortic bodies are the main peripheral O2 sensors. While the carotid bodies seem to be the main peripheral chemoreceptors involved in respiratory control, the aortic bodies are more involved in cardiovascular homeostasis in the fetus (1). They have a low hypoxic sensitivity and their involvement in the hypoxic ventilatory response is controversial (2).
The maintenance of an adequate tissue oxygen supply requires coordination of a number of local and systemic responses to hypoxia. Hypoxemia can originate naturally with ascent to high altitude. It may also arise through a series of clinical disorders, which include inadequate respiration, as seen, for example, in sleep apnea or chronic obstructive diseases of the lung, but also through an inadequate O2 supply as might occur in heart failure or stroke or even through inadequate O2 extraction as in a number of metabolic myopathies or sepsis. The precise value for any tissue bed will depend upon the inspired O2 tension, the O2 carriage capacity of the blood, the vascular structure and blood flow of the tissue, as well as upon a specific set of circumstances including the local diffusion conditions and the O2 consumption of the tissue. While local responses can act to increase O2 delivery to a point, ultimate survival to systemic hypoxia usually depends primarily upon cardiorespiratory reflexes initiated by arterial hypoxemia. These have as their ultimate aim the establishment of a high, arterial driving pressure of O2 and have their origins at specialized chemical transducers. While oxygen sensing is increasingly beginning to appear to be a ubiquitous feature of cell physiology (1), with all cells responding in some way to falls in Po2 once severe enough to compromise cell activity, the systemic chemoreceptors are distinguished from other cell types by their relatively low threshold to arterial hypoxia, often beginning to respond at partial pressures of O2 just a few mmHg below normal arterial levels, as well as by the fact that the effect of their stimulation is observable at a systemic level. Classically, peripheral chemoreceptors, located in specialized cells within the carotid bodies, the aortic bodies, and the abdominal viscera, as well as pulmonary smooth muscle cells and erythropoeitin-secreting cells of the kidney, have fulfilled these criteria and to these should now perhaps be added the neuroepithelial bodies of the respiratory airways. In recent years, it is becoming clear that chemoreceptor cells can also exhibit a high degree of plasticity, adapting their stimulus response characteristics to match prevailing conditions, whether these occur naturally, pathologically or are artificially applied. This brief review will focus on the former and will discuss the postnatal maturational changes in O2 sensing observed in the peripheral chemoreceptors of the carotid body and speculate briefly on possible sites for the developmental process. Ultimately, any proposed mechanism of chemotransduction should be able to account for the findings at the level of chemoafferent discharge and for the maturational changes that occur postnatally.
In this study, we aimed to compare perioperative supplemental oxygen with dexamethasone and ondansetron to prevent postoperative nausea and vomiting (PONV) in patients undergoing middle ear surgery. Sixt two patients undergoing elective middle ear surgery, between]8 and 60 years (ASAI-II), were included in the study. Patients were randomly assigned to 4 groups: for Group K (control group) and Group AO (supplemental oxygen no antiemetic medication was used. After induction, 8 mg ondansetron for Group O (prophylactic ondansetron group) and 5 mg dexamethasone for Group D (prophylactic dexamethasone group) were administered for prophylaxis. In Group AO 25 % nitrous oxide and 75 % oxygen, in other groups 50% nitrous oxide and 50% oxygen were alpplied for maintenance. Postoperative nausea and vomiting, atiemetic drug usage and other complications were recorded. The incidence of postoperative nausea and vomiting for the first six hours aws 86% and 60% in Group K, 50% and 23% in group O, 53% and 26% in group D, 43% and 37% in group AO. Need for the antiemetic drugs in group 0, group D and group AO was significantly lower than group K. No side effect and pulmonary complication were observed in all groups. We concluded that the supplemental oxygen is as effective as dexamethasone and ondansetron for prevention of postoperative nause and vomiting and diminishes the need for rescue antiemetic.
Carotid body (CB) glomus cells respond to hypoxia by releasing neurotransmitters, such as ATP, which are believed to stimulate excitatory receptors on apposed nerve endings of the carotid sinus nerves as well as bind to autoreceptors on the glomus cell membrane to modulate response magnitude. The CB response to hypoxia is small at birth and increases during postnatal maturation in mammals. As ATP has been shown to inhibit the glomus cell response to hypoxia via an autoreceptor mechanism, we hypothesized that ATP-mediated inhibition may vary with age and play a role in postnatal development of the hypoxia response magnitude. The effects of ATP on CB glomus cell intracellular calcium ([Ca(2+)](i)) responses to hypoxia were studied at two ages, P0-1 and P14-18. The inhibitory effect of ATP or a stable ATP analog on the glomus cell response to hypoxia was greater in newborn rats compared to the more mature age group. Use of selective P2Y receptor agonists and antagonists suggests that the inhibitory effect of ATP on the glomus cell [Ca(2+)](i) response to hypoxia may be mediated by a P2Y12 receptor. Thus, developmental changes in ATP-mediated glomus cell inhibition may play a role in carotid chemoreceptor postnatal maturation.
In the carotid body (CB), it has been reported that the expressions of tyrosine hydroxylase (TH) mRNA and TH protein are enhanced by exposure to hypoxia. However, it is not known whether CO(2) affects the expression of TH in the CB. We examined the expression of TH mRNA and the immunoreactivity for TH in the CB of rats exposed to hypoxia (10% O(2)), hypercapnia (10% CO(2)) and hypercapnic hypoxia (10% O(2) and 10% CO(2)) for 2-24 h. The expression of TH mRNA in the CB was markedly enhanced in rats exposed to hypoxia for 4 h (6.6-fold), 6 h (6.0-fold) and 8 h (7.8-fold), and in rats exposed to hypercapnic hypoxia for 12 h (4.8-fold). The most intense TH immunoreactivity was observed in the CB from rats exposed to hypoxia for 12 and 24 h and to hypercapnic hypoxia for 24 h. The expressions of TH mRNA and the immunoreactivity for TH were not altered in the CB of rats exposed to hypercapnia. It is suggested that CO(2) does not affect TH expression in the CB, and that it inhibits hypoxia-enhanced TH expression.
Peripheral arterial chemoreceptors, particularly the carotid body chemoreceptors, are the primary sites for the detection of hypoxia and reflexly increase ventilatory drive and behavioral arousal during hypoxic or asphyxial events. Newborn infants are at risk for hypoxic and asphyxial events during sleep, yet, the strength of the chemoreceptor responses is low or absent at birth and then progressively increases with early postnatal development. This review summarizes the available data showing that even though the "oxygen sensor" in the glomus cells has not been unequivocally identified, it is clear that development affects many of the other properties of the chemoreceptor unit (glomus cell, afferent nerve fibers and neurotransmitter profile at the synapse) that are necessary and essential for the propagation of the "sensing" response, and exposure to hypoxia, hyperoxia and nicotine can modify normal development of each of the components leading to altered peripheral chemoreceptor responses.
The results of these studies are consistent with the hypothesis that carotid chemoreceptor type-I cell resetting occurs, at least in part, at the level of the type-I cell. Furthermore, we have developed an in vitro model of newborn type-I cell resetting, in which freshly isolated glomus cells from newborns exhibit small, immature [Ca2+]i response to anoxia, but-after 72 hours in culture-[Ca2+]i responses convert to adult magnitude and profile. Finally, work so far suggests that glomus cell resetting in this model is modulated by oxygen tension. The mechanisms of glomus cell resetting remain unknown. Resetting of O2 sensitivity could result from withdrawal of tonic inhibitory influences present in vivo, changes in the oxygen sensor itself, changes in ion channel expression, modulation, and function, or other mechanisms occurring around the time of birth. Additional work is needed to determine the mechanisms of glomus cell resetting at the cellular level, and the role of O2 tension and other potential modulators of resetting.
The hypothesis that dopamine (DA) overflow corresponds to carotid sinus nerve (CSN) discharge during hypercapnia and is dependent on [Ca2+]0 was tested. We simultaneously measured the time course of DA overflow and CSN discharge of the cat carotid body, perfused/superfused in vitro at 37 degrees C at decreasing [Ca2+]0, during transition from normocapnia (PCO2 approximately 30-35 Torr) to hypercapnia (PCO2 approximately 60-65 Torr). In the presence of normal [Ca2+]0, hypercapnia instantaneously increased nerve discharge to peak levels followed by a decrease to steady states which were above the basal rate of activity. CSN discharge rate did not differ at decreasing [Ca2+]0 between 2.2 and 1.0 mM, and it began to decline at 0.1 mM [Ca2+]0, culminating to zero level in most cases, at zero [Ca2+]0. DA overflow increased slightly during hypercapnic peak CSN activity. Thereafter it declined to steady state levels below those of normocapnic conditions. Decreases in steady state DA levels were significantly less at 0 mM [Ca2+]0 compared to the higher calcium concentrations (0.1, 1.0 and 2.2 mM). Overall, steady state CSN activity and DA overflow were inversely related. Thus, DA release cannot have excitatory implications for carotid chemoreceptors during hypercapnia in the cat.
Hypoxia, hypercapnia and acidosis stimulate the carotid body (CB) sending increased neural activity via a branch of the glossopharyngeal nerve to nucleus tractus solitarius; this precipitates an impressive array of cardiopulmonary, endocrine and renal reflex responses. However, the cellular mechanisms by which these stimuli generate the increased CB neural output are only poorly understood. Central to the understanding of these mechanisms is the determination of which agents are released within the CB in response to hypoxia, and serve as the stimulating transmitter(s) for chemosensory nerve endings. Acetylcholine (ACh) has been proposed as such an agent from the outset, but this proposal has been, and remains, controversial. The present study tests two hypotheses: (1) The CB releases ACh under normoxic/normocapnic conditions; and (2) The amount released increases during hypoxia and other conditions known to increase neural output from the CB. These hypotheses were tested in 12 experiments in which both CBs were removed from the anesthetized cat and incubated at 37 degrees C in a physiological salt solution while the solution was bubbled with four different concentrations of oxygen and carbon dioxide. The incubation medium was exchanged at 10 min intervals for 30 min (three periods of incubation). The medium was analyzed with high performance liquid chromatography-electrochemical detection for ACh content. Normoxic/normocapnic conditions (21% O2/6% CO2) produced a total of 0.639 +/- 0.106 pmol/150 microl (mean +/- S.E.M.; n = 12). All stimulating conditions produced larger total outputs: 4% O2/2% CO2 produced 1.773 +/- 0.46 pmol/150 microl; 0% O2/5% CO2, 0.868 +/- 0.13 pmol/150 microl; 4% O2/10% CO2, 1.077 +/- 0.21 pmol/150 microl. These three amounts were significantly greater than the normoxic/normocapnic condition, but indistinguishable among themselves. Further, the amount of ACh released did not diminish over the 30 min of stimulation. These data support the concept that during hypoxia ACh functions as a stimulating transmitter in the CB, and are consistent with the earlier reports of cholinergic enzymes and receptors found in the CB.
The sensitivity of peripheral arterial chemoreceptors in the carotid body to hypoxia increases with postnatal maturation. Carotid sinus nerve activity is augmented by adenosine binding to A(2a)-adenosine receptors and attenuated by dopamine binding to D(2)-dopamine receptors. In this study, we used in situ hybridization histochemistry to determine the change in the levels of mRNA expression for A(2a) and A(1)-adenosine receptors and D(2)-dopamine receptors in the rat carotid body. We also investigated the cellular distribution and possible colocalization of these receptor mRNAs and tyrosine hydroxylase (TH) mRNAs during the first 2 weeks of postnatal development. By using immunohistocytochemistry, we detected A(2a)-adenosine receptor protein in the carotid body and petrosal ganglion. We found that A(2a)-adenosine receptor mRNA and protein are expressed in the carotid body in animals at 0, 3, 6 and 14 postnatal days. The level of A(2a)-adenosine receptor mRNA expression significantly decreased by 14 postnatal days (P<0.02 vs. day 0) while D(2)-dopamine receptor mRNA levels significantly increased by day 3 and remained greater than D(2)-dopamine receptor mRNA levels at day 0 (P<0.001 all ages vs. day 0). TH mRNA was colocalized in cells in the carotid body with A(2a) adenosine receptor and D(2)-dopamine receptor mRNAs. A(1)-adenosine receptor mRNA was not expressed in the carotid body at any of the ages examined. In the petrosal ganglion, A(1)-adenosine receptor mRNA was abundantly expressed in numerous cells, A(2a)-adenosine receptor mRNA was expressed in a moderate number of cells while D(2)-dopamine receptor mRNA was seen in a few cells in the rostral petrosal ganglion. In conclusion, using in situ hybridization histochemistry, we have shown that mRNA for both the excitatory, A(2a)-adenosine receptor, and the inhibitory, D(2)-dopamine receptor, is developmentally regulated in presumably type I cells in the carotid body which may contribute to the maturation of hypoxic chemosensitivity. Furthermore, the presence A(1)-adenosine receptor mRNAs in cell bodies of the petrosal ganglion suggests that adenosine might also have an inhibitory role in hypoxic chemotransmission.
Progress on our understanding of the mechanisms by which ventilatory responses to hypoxia and hypercapnia mature following birth will be reviewed. New reports have broadened the current understanding of these mechanisms, especially those relating to maturation of the arterial chemoreceptors in the carotid body. However, a clear understanding of the physiologic, morphologic, neurochemical and molecular developmental events remains elusive. Of particular interest is the change in carotid body sensitivity to oxygen in the first days following birth. Further, perinatal hypoxia or hyperoxia results in blunted hypoxic chemosensitivity in premature infants with chronic lung disease and in various animal models. Hence, cellular and molecular mechanisms altering the normal maturational progression will also be discussed.
The aim of this study was to identify the mechanisms that regulate dopamine release (DA(r)) by the hypoxic carotid body (CB) during development. CBs sampled from adult (n = 58) and 10-day-old (n = 53) rabbits were incubated for 1 h in a medium equilibrated with 8% O(2) in N(2) without or in the presence of the specific DA D(2) receptor antagonist domperidone, 0.01, 0.1 and 1 microM. DA and its major metabolite DOPAC were measured in the CB (DA(CB)) and in the medium (DA(r)) by HPLC+ED. In adults, each concentration of domperidone significantly decreased DA(CB) and increased DA(r), compared with control (p < 0.01). In contrast, in 10-day old, only the 1 microM domperidone concentration decreased DA(CB) and increased DA(r) compared with control (p < 0.001). The data show that domperidone increases CB DA(r) in response to hypoxia in a concentration- and age-dependent manner and suggest this response depends, in part, on the functional maturation of CB DA D(2) receptors.
Chemotransduction of arterial hypoxemia by the cat carotid body is generally thought to begin with a hypoxia-induced depolarization of the glomus cells (GCs) of the carotid body (CB). This depolarization activates voltage-gated calcium channels with the subsequent entry of calcium, movement of transmitter-containing vesicles to the synaptic-like juncture between the GC and apposed sensory afferent neuron. The vesicles exocytotically release their transmitters which then proceed to the receptors on both the postsynaptic neuron and on the GCs themselves (autoreceptors). Action potentials and their modulation in the sensory fibers are the result, along with the modulation of further neurotransmitter release from the GCs. The purpose of the present study was to: (1) determine the parameters of an incubated cat CB preparation capable of releasing measurable amounts of catecholamines (CAs) in response to hypoxia; (2) determine the impact of muscarinic activities on CA release during the hypoxic challenge; (3) determine if the muscarinic activity preferentially modified the release of one CA more than another; (4) determine if there were any differences in the pattern of hypoxia-induced release of dopamine (DA) vs. norepinephrine (NE). CBs were harvested from deeply anesthetized cats. Cleaned of fat and connective tissue, they were incubated in Krebs Ringer bicarbonate solution at 37 degrees C, and bubbled with a hyperoxic mixture of gases (95% O(2)-5% CO(2)) for 30 min. The first series of experiments to address the CB's hypoxia-induced release of CAs explored the effects of incubating CBs for 2 h with hyperoxia vs. normoxia (21% O(2)-6% CO(2)) followed by a 30 min hypoxic challenge, with or without L-dihydroxyphenylalanine (L-DOPA). In the second series of experiments the CBs, after the first 30 min of hyperoxia, were next challenged with hypoxia (4% O(2)-5% CO(2)) for intervals of 3-20 min with intervening recovery periods of hyperoxia to determine the effect of the duration of the hypoxic exposure on CA release. In the third series of experiments the CBs, after the first 30 min of hyperoxia, were challenged with hypoxia for intervals of 10-40 min in the presence or absence of an M1 or M2 muscarinic receptor antagonist. CAs released into the incubation medium were analyzed by means of high performance liquid chromatography-electrochemical detection using standard procedures. Incubated cat CBs challenged for 2 h with hyperoxia followed by 30 min of hypoxia, released much more measurable amounts of CAs in the presence of 40 microM L-DOPA than without it. Moving from hyperoxia to hypoxia produced a better yield than moving from normoxia to hypoxia, and at least 10-20 min exposures were needed for measurable amounts of CAs. The M1 muscarinic receptor antagonist, pirenzepine, reduced the hypoxia-induced release of CAs during each exposure. Further, the reduction appeared to be dose-related. The M2 muscarinic receptor antagonist, methoctramine, enhanced the hypoxia-induced release of CAs during each exposure. These data support a role for acetylcholine (ACh) in the hypoxia-induced release of CAs, and suggest a significant, if modest, muscarinic dimension to it. And although hypoxia induced a greater release of DA than of NE, the muscarinic modulation of the release (both decreasing it and increasing it) may have had a greater impact on NE release than on DA release. Finally, the patterns of hypoxia-induced release of DA and NE from incubated cat carotid bodies are significantly different.
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.
Infants born to mothers who used cocaine during pregnancy are at increased risk for neonatal death and respiratory impairments. Confounding factors such as multiple substance abuse make it difficult to isolate the effects of cocaine. We used a murine model to test the hypothesis that prenatal cocaine exposure may impair ventilatory responses to chemical stimuli in newborns. Seventy-two pregnant mice were randomly assigned to three groups: cocaine (COC), saline (SAL), and untreated (UNT). COC and SAL mice received subcutaneous injections of either 20 mg/kg of cocaine or a saline solution twice a day from gestational days 8–17. Ventilation (V′E) and tidal volume (VT), both divided by body weight, and breath duration (TTOT) were measured using whole-body plethysmography in freely moving COC (n = 47), SAL (n = 123), and UNT (n = 93) pups on postnatal day 2.
The comparison between SAL and UNT pups showed significant differences in baseline breathing and in V′E responses to hypoxia, suggesting that maternal stress caused by injections affected the development of ventilatory control in pups. Baseline TTOT was significantly longer in COC than in SAL pups. V′E responses to hypoxia were significantly smaller in COC than in SAL pups (+27 ± 35% vs. +38 ± 25%), but V′E responses to hypercapnia were similar (29 ± 15% vs. 25 ± 23%).
Thus, breathing control was impaired by prenatal cocaine exposure, possibly because of abnormal development of neurotransmitter systems, such as the dopamine and serotonin systems. Pediatr Pulmonol. 2002; 34:434–441.
Peripheral arterial chemoreceptors are essential to respiratory and cardiac homeostasis. Although the components of these chemoreceptors lie within a tiny structure, the carotid body, the physiological affects resulting from activation of the peripheral arterial chemoreceptors have profound effects on arousal responses and cardiorespiratory responses to hypoxia and asphyxia (Gonzalez et αl., 1994). In response to hypoxia, hypercapnia and acidosis the glomus cell within the arterial chemoreceptor depolarizes; intracellular calcium levels rises, and neurotransmitters are released. These neurotransmitters bind to autoreceptors on the glomus cell and postsynaptic receptors on the carotid sinus nerve. Binding of neurotransmitters to autoreceptors on glomus cells regulates further neurotransmitter release, while binding to postsynaptic receptors on chemoafferent nerve fibers results in electrical output through the carotid sinus nerve (for reviews, see Gonzalezet al., 1994; Prabhakar 1994).
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