Central Chemoreceptors Research Articles

Components to the acid–base related ventilatory drives in the South American lungfish Lepidosiren paradoxa

Lungfish are closely related to terrestrial vertebrates (tetrapoda). Like tetrapods, the South American lungfish (Lepidosiren paradoxa) has central chemoreceptors involved in regulation of acid-base status. However, no data were available on peripheral CO(2)/[H(+)] receptors. Therefore, we tested the hypothesis that such receptors exist by measuring the ventilatory responses during a 5h exposure to combined aquatic/gas phase hypercarbia 7% (approximately 49 mmHg). Normocarbic control ventilation was 22 ml BTPS kg(-1)h(-1), and hypercarbia increased ventilation to 175 ml BTPS kg(-1)h(-1) at 5h. This procedure was repeated with the modification that normocarbic mock CSF (pH 7.45; P(CO2) = 20.7 mmHg) was applied to superfuse the cerebral ventricular system during the last 2h of the experiment. This served to eliminate the hypercarbic stimulus to the central chemoreceptors, while possible responses from peripheral chemoreceptors would remain intact. Peripheral receptors were detected, since ventilation became reduced to 62 ml BTPS kg(-1)h(-1) (P<0.05), which exceeds the initial normocarbic control ventilation (P<0.05). Based on this, the peripheral contribution accounted for 20% of the total response to hypercarbia, similar to the contribution of these receptors in man.

Chronic hypercapnia modulates respiratory-related central pH/CO2 chemoreception in an amphibian,Bufo marinus

Anuran amphibians have multiple populations of pH/CO2-sensitive respiratory-related chemoreceptors. This study examined in cane toads (Bufo marinus) whether chronic hypercapnia (CHC) altered the pH/CO2 sensitivity of central respiratory-related chemoreceptors in vitro and whether CHC altered the acute hypercapnic ventilatory response (HCVR; 5% CO2) in vivo. Toads were exposed to CHC (3.5% CO2) for 9 days. In vitro brainstem-spinal cord preparations were used to examine central respiratory-related pH/CO2 chemosensitivity. CHC augmented in vitro fictive breathing as the pH of the superfusate was lowered from 8.2 to 7.4. Midbrain transection in vitro (at a level known to reduce the clustering of breaths) did not alter this augmentation. In vivo, CHC did not alter the acute HCVR but midbrain transection changed the breathing pattern and increased the overall level of ventilation. CHC did not alter the effect of olfactory CO2 chemoreceptor denervation on the acute HCVR in vivo but did alter the response when returned to normal air. The results indicate that CHC increases the response of central pH/CO2 chemoreceptors to changes in cerebrospinal fluid pH in vitro yet this increase is not manifest as an increase in the HCVR in vivo.

Locus coeruleus participates in amphibian central chemoreception

The locus coeruleus (LC) is a mesencephalic structure of the amphibian brain that has been considered to be homologous to the LC of mammals. However, there is no data about the role of LC in the central chemoreception in amphibians as it is in mammals. The present study was designed to investigate whether LC of toads (Bufo paracnemis) is activated by hypercarbia (5% CO2 in air) by using Fos immunoreactivity. Additionally, we investigated the role of noradrenergic LC neurons on cardio-respiratory responses to hypercarbia. To kill the noradrenergic neurons we administered 6-OHDA into the LC (n=8). Control animals had acid ascorbic acid (vehicle) injected into the LC (n=6) or had no surgery (n=7). A marked increase in c-Fos positive cells in the LC was observed after 3 h of breathing a hypercarbic gas mixture. Tyrosine hydroxylase immunoreactive noradrenergic neurons were reduced in the LC after 6-OHDA treatment. LC lesion did not affect room air ventilation and cardiovascular control. Hypercarbia caused hyperventilation in all 3 groups. However, chemical lesions in the LC attenuated the increase in the ventilatory response to hypercarbia (VE: control: 354.5 ± 69.9; vehicle: 358.2 ± 124.9 and 6-OHDA: 126.3 ± 26.8 mL BTPS kg−1min−1; One-way ANOVA), due to a lower tidal volume. We conclude that LC is activated by hypercarbia and that LC noradrenergic neurons of toads participate in the central chemoreception as in mammals. Financial support: FAPESP, CNPq.

PH i Regulation In Central CO 2 ‐Chemosensitive And Non‐Chemosensitive Cells: A Mathematical Model

Numerous studies have suggested that a decrease in intracellular pH (pHi) is the primary stimulus for CO2 sensing in central CO2 chemoreceptors. In CO2 chemosensitive neurons, an increase in CO2 (hypercapnia) leads to a maintained reduction in pHi while in non-chemosensitive neurons pHi recovery is observed. We developed a mathematical model to evaluate the roles of intrinsic buffering capacity, Na+/H+ exchange (NHE), and HCO3−/Cl− exchange (AE) on pHi regulation in response to simulated hypercapnic acidosis. The cell model incorporates conservation of mass and electroneutrality constraints, kinetic models of the Na+/K+-ATPase, AE, NHE3 isoform (believed to play a primary role in CO2 sensing), and passive permeation pathways for ions, nonelectrolytes, and H2O. H+ buffering (both inside and out) is handled by multiple buffer species all subject to the isohydric principle. In response to simulated hypercapnia, the model predicts pHi responses that are consistent with observations in non-chemosensitive cells, including a pHi recovery mechanism that is dependent on NHE (based on simulation of amiloride effects). The model also demonstrates that inhibition of NHE is sufficient to decrease pHi in the absence of increased CO2 and that the pHi fall during simulated hypercapnia is exacerbated. Additional H+ extrusion pathways need to be explored to identify other mechanisms involved in pHi regulation in CO2 chemosensitive neurons. Supported by DK66124

Hypoxia–sensitive glutamatergic neurons of solitary tract nucleus (NTS) innervate the retrotrapezoid nucleus (RTN) in rats

Central chemoreceptor neurons reside within the RTN. In this study, we tested whether RTN receives excitatory inputs from hypoxia-sensitive neurons located in commissuralis NTS (commNTS). After iontophoretic injection of the anterograde tracer biotinylated dextran amine (BDA) in commNTS, most (53%) BDA-labeled terminals in the RTN were immunoreactive for vesicular glutamate transporter-2 (VGLUT2) but very few (5%) were immunoreactive for glutamic acid decarboxylase (GAD67). Awake rats were exposed to hypoxia (n=6) or normoxia (control) (n=5) one week after iontophoretic injection of the retrograde tracer cholera toxin B (CTB) into the RTN. Hypoxia-activated neurons were identified by the presence of Fos-immunoreactive (Fos-ir) nuclei. Fos-ir commNTS neurons retrogradely labeled with CTB were detected only in hypoxia-treated rats. In commNTS, 51% of Fos-ir neurons with projections to RTN (CTB- immunoreactive) were glutamatergic and 2% were GABAergic. In conclusion, RTN chemoreceptors may receive an excitatory glutamatergic input from peripheral chemoreceptors via a single relay in commNTS. Supported by: HL 74011 (PGG); Capes-BEX 3495/04-3 (TSM).

Chemoreceptor and pulmonary stretch receptor interactions within amphibian respiratory control systems

The hypercapnic drive to breathe in amphibians is generally greater than hypoxic ventilatory drive and a variety of interdependent control systems function to regulate both the hypoxic and hypercapnic ventilatory responses. During exposure to hypercapnic conditions, breathing increases in response to input from central chemoreceptors (sensitive to CSF pH/CO(2) levels) and peripheral chemoreceptors (sensitive to arterial blood O(2) and CO(2)). On the other hand, olfactory CO(2) receptors in the nasal epithelium inhibit breathing during exposure to acute hypercapnia. Further complexity arises from the CO(2)-sensitive nature of the pulmonary stretch receptors (PSR) which provide both tonic (stimulates lung inflation at low lung volumes; deflation at higher volumes) and phasic (generally excitatory) feedback. This review focuses on interactions between the various populations of chemoreceptors and interactions between chemoreceptors and PSR. Differences between various levels of experimental reduction (i.e., in vitro; in situ; in vivo) are highlighted as are the effects of chronic respiratory challenges on acute hypoxic and hypercapnic chemoreflexes.

Increased Peripheral Chemoreceptors Sensitivity and Exercise Ventilation in Heart Transplant Recipients

Heart failure is characterized by increased ventilation during exercise, which is positively related to increased peripheral and central chemoreceptor sensitivity. Heart transplantation does not normalize the ventilatory response to exercise, and its effects on the chemoreflex control of ventilation remain unknown. We tested the hypothesis that chemoreceptor sensitivity is increased in heart transplant recipients (HTRs) and linked to exercise hyperpnea. We determined the ventilatory, muscle sympathetic nerve activity (MSNA), and circulatory responses to isocapnic hypoxia and hyperoxic hypercapnia 7+/-1 years after transplantation in 19 HTRs with a normal left ventricular ejection fraction of 60+/-2%. Results were compared with those of 11 closely matched referent subjects. Sixteen patients and 10 referent subjects also underwent cycle ergometer exercise tests. HTRs compared with referent subjects presented higher MSNA (52+/-4 versus 34+/-3 bursts/min; P<0.01) and heart rates (83+/-3 versus 68+/-3 bpm; P<0.01) during room air breathing. The ventilatory response to hypoxia was higher in HTRs than in referent subjects (P<0.01, ANOVA). The increase in MSNA also was more marked during hypoxia in the HTRs than in the referent group (P<0.05, ANOVA). Responses to hyperoxic hypercapnia did not differ between the HTRs and the referent group. The ventilatory response to exercise, characterized by the regression slope relating minute ventilation to CO2 output, was steeper in HTRs than in referent subjects (38+/-2 versus 29+/-1 L/mm Hg; P<0.01). Exercise ventilation in HTRs was related to the ventilatory response to isocapnic hypoxia (r=0.57; n=16; P<0.05) and to the ventilatory response to hyperoxic hypercapnia (r=0.50; n=16; P<0.05). Peripheral chemoreceptor sensitivity is increased in HTRs and is related to exercise hyperpnea after heart transplantation.

Catecholamine neurones in rats modulate sleep, breathing, central chemoreception and breathing variability

Brainstem catecholamine (CA) neurones have wide projections and an arousal-state-dependent activity pattern. They are thought to modulate the processing of sensory information and also participate in the control of breathing. Mice with lethal genetic defects that include CA neurones have abnormal respiratory control at birth. Also the A6 region (locus coeruleus), which contains CA neurones sensitive to CO(2) in vitro, is one of many putative central chemoreceptor sites. We studied the role of CA neurones in the control of breathing during sleep and wakefulness by specifically lesioning them with antidopamine beta-hydroxylase-saporin (DBH-SAP) injected via the 4th ventricle. After 3 weeks there was a 73-84% loss of A5, A6 and A7 tyrosine hydroxylase (TH) immunoreactive (ir) neurones along with 56-60% loss of C1 and C2 phenyl ethanolamine-N-methyltransferase (PNMT)-ir neurones. Over the 3 weeks, breathing frequency decreased significantly during air and 3 or 7% CO(2) breathing in both wakefulness and non-REM (NREM) sleep. The rats spent significantly less time awake and more time in NREM sleep. REM sleep time was unaffected. The ventilatory response to 7% CO(2) was reduced significantly in wakefulness at 7, 14 and 21 days (-28%) and in NREM sleep at 14 and 21 days (-26%). Breathing variability increased in REM sleep but not in wakefulness or NREM sleep. We conclude that CA neurones (1) promote wakefulness, (2) participate in central respiratory chemoreception, (3) stimulate breathing frequency, and (4) minimize breathing variability in REM sleep.

Serotonergic and glutamatergic neurons at the ventral medullary surface of the human infant: Observations relevant to central chemosensitivity in early human life

Central chemoreception is the mechanism by which the brain detects the level of carbon dioxide (CO 2) in the arterial blood and alters breathing accordingly in order to maintain it within physiological levels. The ventral surface of the medulla oblongata (VMS) of animals has long been recognized as a site of chemosensitivity, culminating in the recent identification of chemosensitive serotonergic (5-HT) and glutamatergic (Glut) neurons in this region. In this study, we analyzed the distribution of 5-HT and Glut neurons and their receptors in the arcuate nucleus (Arc) at the VMS of the human infant, using single-and double-label immunohistochemistry with specific antibodies. We also examined the expression of astrocytes, as experimental evidence suggests that astrocytes mediate, at least in part, central chemosensitivity via 5-HT and/or Glut receptors. We identified a small number of 5-HT neurons (approximately 5% of Arc neurons), distributed over the entire extent of the VMS, a large number of Glut neurons (approximately 95% of Arc neurons) that localized almost exclusively to the medial Arc, and a large number of astrocytes distributed across the entire extent of the VMS. The Arc also contained 5-HT 1A, kainate (GluR5), and 5-HT 2A receptors, which localized predominantly to 5-HT neurons, glutamate neurons and astrocytes, respectively. Astrocytes also expressed the vesicular glutamate transporter 2 and low levels of 5-HT 1A and kainate (GluR5) receptors, indicating that astrocytes may store and release glutamate, possibly in response to stimulation by 5-HT and/or Glut. These observations suggest that important functional interactions exist between 5-HT, glutamate, and astrocytes in the Arc. They also support the idea that the Arc is homologous to chemosensitive zones at the VMS in experimental animals. These data are important towards delineating the role of the human Arc in modulation of homeostasis, and its dysfunction in brainstem-associated pathologies such as the sudden infant death syndrome.

Why do we have both peripheral and central chemoreceptors?

The peripheral chemoreceptors, the carotid (and aortic) bodies, detect arterial hypoxemia and stimulate breathing. At normal arterial Po2 (PaO2) values, they provide a tonic excitatory input to the brain stem ([6][1]), and with hypoxia they respond dramatically as PaO2 falls below 70 Torr. Thus, for

Afferent and efferent connections of the rat retrotrapezoid nucleus

The rat retrotrapezoid nucleus (RTN) contains candidate central chemoreceptors that have extensive dendrites within the marginal layer (ML). This study describes the axonal projections of RTN neurons and their probable synaptic inputs. The ML showed a dense plexus of nerve terminals immunoreactive (ir) for markers of glutamatergic (vesicular glutamate transporters VGLUT1-3), gamma-aminobutyric acid (GABA)-ergic, adrenergic, serotonergic, cholinergic, and peptidergic transmission. The density of VGLUT3-ir terminals tracked the location of RTN chemoreceptors. The efferent and afferent projections of RTN were studied by placing small iontophoretic injections of anterograde (biotinylated dextran amine; BDA) and retrograde (cholera toxin B) tracers where RTN chemoreceptors have been previously recorded. BDA did not label the nearby C1 cells. BDA-ir varicosities were found in the solitary tract nucleus (NTS), all ventral respiratory column (VRC) subdivisions, A5 noradrenergic area, parabrachial complex, and spinal cord. In each target region, a large percentage of the BDA-ir varicosities was VGLUT2-ir (41-83%). Putative afferent input to RTN originated from spinal cord, caudal NTS, area postrema, VRC, dorsolateral pons, raphe nuclei, lateral hypothalamus, central amygdala, and insular cortex. The results suggest that 1) whether or not the ML is specialized for CO(2) sensing, its complex neuropil likely regulates the activity of RTN chemosensitive neurons; 2) the catecholaminergic, cholinergic, and serotonergic innervation of RTN represents a possible substrate for the known state-dependent control of RTN chemoreceptors; 3) VGLUT3-ir terminals are a probable marker of RTN; and 4) the chemosensitive neurons of RTN may provide a chemical drive to multiple respiratory outflows, insofar as RTN innervates the entire VRC.

Ventilatory effects of muscimol microdialysis into the rostral medullary raphé region of conscious rats

We hypothesized that inhibition of the rostral medullary raphe region (MRR), a putative central chemoreceptor location, with the GABA(A) receptor agonist muscimol would decrease ventilatory responses to hypercapnia and hypoxia in conscious rats, and that its known effect at this site on body temperature might alter its effect upon these ventilatory responses. At ambient temperatures of 24.5-26.5 degrees C (Cool), microdialysis of 1mM muscimol into the MRR significantly decreased body temperature by approximately 0.5 degrees C, increased the ventilatory response to 7% CO(2) and decreased the response to 10% O(2). At ambient temperatures of 29.5-30.5 degrees C (Warm), 1 mM muscimol microdialysis no longer decreased body temperature and increased the ventilatory response to hypercapnia and to hypoxia. Muscimol did not significantly affect the VE/VO2 ratio at either temperature. Muscimol significantly increased the hypercapnic ventilatory responses in Cool and Warm conditions and the hypoxic response in Warm conditions, which indicates the presence of an inhibitory effect of rostral MRR neurons sensitive to muscimol. In the Cool condition the ventilatory response to hypoxia is inhibited but appropriately so for the lower VO2 .

Control of arterial PCO2 by somatic afferents in sheep

The ventilatory response to electrically induced rhythmic muscle contractions (ERCs) was studied in six urethane-chloralose-anaesthetized sheep, while arterial oxygen and carbon dioxide pressure (P(a,O(2)) and P(a,CO2)) and perfusion pressure were maintained constant at the known chemoreception sites. With cephalic P(a,CO2) held constant, the response to inhaled CO2 was virtually abolished (0.03 +/- 0.04 l min(-1) Torr(-1)). During low-current ERC, which doubled the metabolic rate ( increased from 192 +/- 23 to 317 +/- 84 ml min(-1), P < 0.01), followed the change in closely (from 5.24 +/- 1.81 to -9.27 +/- 3.60 l min(-1), P < 0.01) in the absence of any chemical error signal occurring at carotid and central chemoreceptor level (Deltacephalic P(a,CO2)=-0.75 +/- 1 Torr). Systemic P(a,CO2) decreased by -2.47 +/- 1.9 Torr (P < 0.01). Both heart rate and systemic blood pressure increased significantly by 18.6 +/- 5.5 beats min(-1) and 7.0 +/- 9.3 mmHg, respectively. When the CO2 flow to the central circulation was reduced during ERC by blocking venous return ( decreased by 102 +/- 45 l min(-1), P < 0.01), ventilation was stimulated (from 11.99 +/- 4.11 to 13.01 +/- 4.63 l min(-1), P < 0.05). The opposite effect was observed when the arterial supply was blocked. Finally, raising the CO2 content and flow in the systemic blood did not significantly stimulate ventilation provided that the peripheral and central chemoreceptors were unaware of the changes in blood CO2/H+ composition. Our results support the existence of a system capable of controlling blood P(a,CO2) homeostasis when the metabolism increases independently of peripheral and central respiratory chemoreceptors. Information from the skeletal muscles related to the local vascular response provides the central nervous system with a respiratory stimulus proportional to the rate at which gases are exchanged in the muscles, thereby coupling ventilation to the metabolic rate.

Do muscle blood flow detectors link breathing to oxygen consumption in exercise?

One of the mysteries of physiology is how breathing is so closely linked to oxygen consumption in a wide variety of conditions such that arterial PO2 and PCO2 remain constant. This is especially true in mild to moderate aerobic muscular exercise where alveolar ventilation increases in direct proportion to oxygen consumption. How this occurs has been difficult to understand. There are two schools of thought. (1) ‘Central command’. The brain ‘decides’ to exercise and matches the motor activities of locomotion and breathing. This view arises from the observation that stimulation of specific brain regions increases both locomotor activity and breathing in a coordinated manner (Eldridge et al. 1985). The mystery here is how these neural events can be linked to metabolism in the distant tissue. (2) ‘Peripheral signals.’ Receptors in the periphery detect oxygen utilization (or its corollaries) and report to the brain, which then modifies breathing. Eligible receptors include the carotid body and the central chemoreceptors, which are quite sensitive to small changes in CO2, and an array of receptors in muscle that respond to mechanical and/or chemical signals including ATP (Kaufman & Hayes, 2002; Hanna & Kaufman, 2003). Haouzi and colleagues have been pursuing a particularly interesting subset of the ‘peripheral signals’ hypothesis, that sensory afferents detect the distension of small blood vessels (Haouzi et al. 2004). This distension could reflect muscle blood flow, which changes in proportion to tissue oxygen utilization. In this issue of The Journal of Physiology, Haouzi & Chenuel (2005) provide data that rule out any role for the carotid body and the central chemoreceptors in the exercise breathing response and indirectly support the vessel distension (blood flow) hypothesis. The experimental model is an anaesthetized sheep with exercise produced by electrically induced rhythmic muscle contractions (ERC). The induction of exercise by ERC eliminates ‘central command’ as a variable. By clever use of the vagaries of the cerebral circulation in this species, they perfuse vessels supplying both the carotid body and the central chemoreceptors with blood of constant arterial PO2 and PCO2 eliminating them as a source of the signal to breathe. During ERC under these conditions, ventilation still increases in direct proportion to muscle oxygen utilization. With block of venous return the appropriate match of ventilation to oxygen use remains unaltered suggesting that the signal for this match arises in the periphery. With block of arterial flow to the muscle, which decreases venous return without the vascular distension that occurs with venous block, ventilation is no longer linked to oxygen utilization. Thus in this model, the match of ventilation to muscle oxygen use involves distension of the small vessels (or accompanying tissue distortion), which the authors suggest represents a blood flow detector. Natural exercise differs remarkably from the experimental models used to examine the ‘central command’ and ‘peripheral signals’ hypotheses. With central stimulation (‘central command’) breathing does increase along with locomotion but the arterial PCO2 values decrease, and the match is imperfect. While the evidence from ERC experiments is intriguing, it seems unlikely that peripheral signals can be the single cause that links breathing to oxygen consumption in natural exercise given the powerful effects of central stimulation. In natural exercise perhaps ‘central command’ determines an initial match of locomotion and breathing that is modified by feedback from ‘peripheral signals’, an approach alluded to by most workers (Eldridge et al. 1985; Hanna & Kaufman, 2003; Haouzi & Chenuel, 2005). What is new here is the possibility that these ‘peripheral signals’ include a muscle blood flow detector, an intriguing suggestion that will doubtless promote discussion and experimentation.

Arterial acid–base status during digestion and following vascular infusion of NaHCO 3 and HCl in the South American rattlesnake, Crotalus durissus

Digestion is associated with gastric secretion that leads to an alkalinisation of the blood, termed the “alkaline tide”. Numerous studies on different reptiles and amphibians show that while plasma bicarbonate concentration ([HCO 3 −] pl) increases substantially during digestion, arterial pH (pHa) remains virtually unchanged, due to a concurrent rise in arterial PCO 2 (PaCO 2) caused by a relative hypoventilation. This has led to the suggestion that postprandial amphibians and reptiles regulate pHa rather than PaCO 2. Here we characterize blood gases in the South American rattlesnake ( Crotalus durissus) during digestion and following systemic infusions of NaHCO 3 and HCl in fasting animals to induce a metabolic alkalosis or acidosis in fasting animals. The magnitude of these acid–base disturbances were similar in magnitude to that mediated by digestion and exercise. Plasma [HCO 3 −] increased from 18.4 ± 1.5 to 23.7 ± 1.0 mmol L − 1 during digestion and was accompanied by a respiratory compensation where PaCO 2 increased from 13.0 ± 0.7 to 19.1 ± 1.4 mm Hg at 24 h. As a result, pHa decreased slightly, but were significantly below fasting levels 36 h into digestion. Infusion of NaHCO 3 (7 mmol kg − 1 ) resulted in a 10 mmol L − 1 increase in plasma [HCO 3 −] within 1 h and was accompanied by a rapid elevation of pHa (from 7.58 ± 0.01 to 7.78 ± 0.02). PaCO 2, however, did not change following HCO 3 − infusion, which indicates a lack of respiratory compensation. Following infusion of HCl (4 mmol kg − 1 ), plasma pHa decreased by 0.07 units and [HCO 3 −] pl was reduced by 4.6 mmol L − 1 within the first 3 h. PaCO 2, however, was not affected and there was no evidence for respiratory compensation. Our data show that digesting rattlesnakes exhibit respiratory compensations to the alkaline tide, whereas artificially induced metabolic acid–base disturbances of same magnitude remain uncompensated. It seems difficult to envision that the central and peripheral chemoreceptors would experience different stimuli during these conditions. One explanation for the different ventilatory responses could be that digestion induces a more relaxed state with low responsiveness to ventilatory stimuli.

On the peripheral and central chemoreception and control of breathing: an emerging role of ATP.

Peripheral and central respiratory chemoreceptors are ultimately responsible for maintenance of constant levels of arterial P(O2), P(CO2) and [H+], protecting the brain from hypoxia and ensuring that the breathing is always appropriate for metabolism. The aim of this discussion is to shed some light on the potential mechanisms of chemosensory transduction - the process which links chemosensory mechanisms to the central nervous mechanisms controlling breathing. Recent experimental data suggest that the purine nucleotide ATP acts as a common mediator of peripheral and central chemosensory transduction (within the carotid body and the medulla oblongata, respectively). In response to a decrease in P(O2) (hypoxia) oxygen-sensitive glomus cells of the carotid body release ATP to activate chemoafferent fibres of the carotid sinus nerve which transmit this information to the brainstem respiratory centres. In response to an increase in P(CO2)/[H+] (hypercapnia) chemosensitive structures located on the ventral surface of the medulla oblongata rapidly release ATP, which acts locally within the medullary respiratory network. The functional role of ATP released at both sites is similar--to evoke adaptive enhancement in breathing. Understanding the mechanisms of ATP release in response to chemosensory stimulation may prove to be essential for further detailed analysis of cellular and molecular mechanisms underlying respiratory chemosensitivity.

Interaction of chemoreceptor and baroreceptor reflexes by hypoxia and hypercapnia – a mechanism for promoting hypertension in obstructive sleep apnoea

Asphyxia, which occurs during obstructive sleep apnoeic events, alters the baroreceptor reflex and this may lead to hypertension. We have recently reported that breathing an asphyxic gas resets the baroreceptor-vascular resistance reflex towards higher pressures. The present study was designed to determine whether this effect was caused by the reduced oxygen tension, which affects mainly peripheral chemoreceptors, or by the increased carbon dioxide, which acts mainly on central chemoreceptors. We studied 11 healthy volunteer subjects aged between 20 and 55 years old (6 male). The stimulus to the carotid baroreceptors was changed using graded pressures of -40 to +60 mmHg applied to a neck chamber. Responses of vascular resistance were assessed in the forearm from changes in blood pressure (Finapres) divided by brachial blood flow velocity (Doppler) and cardiac responses from the changes in RR interval and heart rate. Stimulus-response curves were defined during (i) air breathing, (ii) hypoxia (12% O(2) in N(2)), and (iii) hypercapnia (5% CO(2) in 95% O(2)). Responses during air breathing were assessed both prior to and after either hypoxia or hypercapnia. We applied a sigmoid function or third order polynomial to the curves and determined the maximal differential (equivalent to peak sensitivity) and the corresponding carotid sinus pressure (equivalent to 'set point'). Hypoxia resulted in an increase in heart rate but no significant change in mean blood pressure or vascular resistance. However, there was an increase in vascular resistance in the post-stimulus period. Hypoxia had no significant effect on baroreflex sensitivity or 'set point' for the control of RR interval, heart rate or mean arterial pressure. Peak sensitivity of the vascular resistance response to baroreceptor stimulation was significantly reduced from -2.5 +/- 0.4 units to -1.4 +/- 0.1 units (P < 0.05) and this was restored in the post-stimulus period to -2.6 +/- 0.5 units. There was no effect on 'set point'. Hypercapnia, on the other hand, resulted in a decrease in heart rate, which remained reduced in the post-stimulus period and significantly increased mean blood pressure. Baseline vascular resistance was significantly increased and then further increased in the post-control period. Like hypoxia, hypercapnia had no effect on baroreflex control of RR interval, heart rate or mean arterial pressure. There was, also no significant change in the sensitivity of the vascular resistance responses, however, 'set point' was significantly increased from 74.7 +/- 4 to 87.0 +/- 2 mmHg (P < 0.02). This was not completely restored to pre-stimulus control levels in the post-stimulus control period (82.2 +/- 3 mmHg). These results suggest that the hypoxic component of asphyxia reduces baroreceptor-vascular resistance reflex sensitivity, whilst the hypercapnic component is responsible for increasing blood pressure and reflex 'set point'. Hypercapnia appears to have a lasting effect after the removal of the stimulus. Thus the effect of both peripheral and central chemoreceptors on baroreflex function may contribute to promoting hypertension in patients with obstructive sleep apnoea.

Central Neurogenic Hyperventilation

Central neurogenic hyperventilation is a rare condition with poorly understood pathophysiology. To describe a patient with central neurogenic hyperventilation caused by an infiltrative brainstem lymphoma. Based on analysis of this patient and other case reports, we propose that central neurogenic hyperventilation is uniquely the result of infiltrative tumors that stimulate pontine respiratory centers and central chemoreceptors.

Respiration: control of ventilation

Control of ventilation involves the basic cycle of inspiration and expiration and the chemoreceptor reflexes. The inspiration-expiration cycle is generated by the medulla, but it is smoothed by the combined actions of the pons and vagi. Inspiration is initiated by neurons that promote lung inflation via the intercostal and phrenic nerves; it is terminated by a combination of fatigue of these neurons and inhibitory actions from the pons, expiratory centre and increasing lung volume (via the vagus). As a result, expiration is initiated; this, in turn, is inhibited by fatigue of the expiratory neurons and by loss of inhibitory influences from the pons and the vagus as the lungs deflate. The physical work during respiration is against lung compliance and airway resistance. Too slow a frequency of very deep breaths would require excessive amounts of work against compliance forces; and rapid shallow breaths would greatly increase the work done against airway resistance. A balance between these extremes is achieved by the vagal afferents that help to terminate inspiration. Whole-body responses to gas changes indicate that rising carbon dioxide levels promote ventilation, a reflex that is increased by the simultaneous presence of acidaemia and, particularly, hypoxia (asphyxia). These reflex changes originate from peripheral chemoreceptors (aortic and carotid bodies) that monitor the oxygen, carbon dioxide and acid levels of the plasma, and from central chemoreceptors (floor of the IVth ventricle) that monitor the pH of the cerebrospinal fluid. Details of the integration between these reflexes and the basic inspiraton-expiration cycle remain to be elucidated.

Regulation of Ventral Surface Chemoreceptors by the Central Respiratory Pattern Generator

The rat retrotrapezoid nucleus (RTN) contains neurons described as central chemoreceptors in the adult and respiratory rhythm-generating pacemakers in neonates [parafacial respiratory group (pfRG)]. Here we test the hypothesis that both RTN and pfRG neurons are intrinsically chemosensitive and tonically firing neurons whose respiratory rhythmicity is caused by a synaptic feedback from the central respiratory pattern generator (CPG). In halothane-anesthetized adults, RTN neurons were silent below 4.5% end-expiratory (e-exp) CO2. Their activity increased linearly (3.2 Hz/1% CO2) up to 6.5% (CPG threshold) and then more slowly to peak approximately 10 Hz at 10% CO2. Respiratory modulation of RTN neurons was absent below CPG threshold, gradually stronger beyond, and, like pfRG neurons, typically (42%) characterized by twin periods of reduced activity near phrenic inspiration. After CPG inactivation with kynurenate (KYN), RTN neurons discharged linearly as a function of e-exp CO2 (slope, +1.7 Hz/1% CO2) and arterial pH (threshold, 7.48; slope, 39 Hz/pH unit). In coronal brain slices (postnatal days 7-12), RTN chemosensitive neurons were silent at pH 7.55. Their activity increased linearly with acidification up to pH 7.2 (17 Hz/pH unit at 35 degrees C) and was always tonic. In conclusion, consistent with their postulated central chemoreceptor role, RTN/pfRG neurons encode pH linearly and discharge tonically when disconnected from the rest of the respiratory centers in vivo (KYN treatment) and in vitro. In vivo, RTN neurons receive respiratory synchronous inhibitory inputs that may serve as feedback and impart these neurons with their characteristic respiratory modulation.