Chemoreceptor Stimulation Research Articles

The control of breathing in goldfish (Carassius auratus) experiencing thermally induced gill remodelling

At temperatures below 15°C the gill lamellae of goldfish (Carassius auratus) are largely covered by an interlamellar cell mass (ILCM) which decreases the functional surface area of the gill. The presence of the ILCM in goldfish acclimated to cold water conceivably could lead to a covering of the neuroepithelial cells (NECs), which are believed to be important for sensing ambient O₂ and CO₂ levels. In this study we tested the hypothesis that goldfish with covered lamellae (and presumably fewer NECs exposed to the water) exhibit a decreased capacity to hyperventilate in response to hypoxic stimuli. Measurements of ventilation amplitude and frequency were performed during exposure to acute hypoxia (P(w(O₂))=30 mmHg) or following injections of the O₂ chemoreceptor stimulant NaCN into the buccal cavity or caudal vein of fish acclimated to 25°C (uncovered lamellae) or 7°C (covered lamellae) to stimulate predominantly the externally or internally oriented NECs, respectively. The results demonstrated no significant differences in the response to hypoxia, with each group exhibiting similar percentage increases in ventilation amplitude (90-91%) and frequency (34-43%). Similarly, with the exception of a rightward shift of the ventilation frequency dose-response in the fish acclimated to 7°C, there were no significant differences between the two groups of fish in the ED(50) values. These findings suggest that goldfish with covered lamellae retain the capacity to sense external hypoxic stimuli. Using immunohistochemistry to identify serotonin-enriched NECs, it was demonstrated that the presence of the ILCM results in the NECs being redistributed towards the distal regions of the lamellae. In 25°C-acclimated fish, the NECs were distributed evenly along the length of the lamellae with 53±3% of them in the distal half, whereas in fish acclimated to 7°C, 83±5% of the NECs were confined to the distal half. Using the neuronal marker antibody ZN-12, it was demonstrated that the NECs at the distal edges of the lamellae are innervated by nerve fibres. Thus, it is hypothesised that the capacity to sense external hypoxic stimuli in goldfish acclimated to cold water is maintained despite the increasing coverage of the gill epithelial surfaces because of a redistribution of innervated NECs to the exposed distal regions of the lamellae.

Concomitant Effects of Nitric Oxide and Carotid Chemoreceptor Stimulation on Brain Glucose in Normoglycemic and Hyperglycemic Rats

Carotid body (CB) sinus perfusion with different glucose concentrations modifies arterial glucose concentration and brain glucose retention, thereby changing the brain's threshold to hypoxia. Because nitric oxide (NO) modulates hypoxic chemoreception, we investigated the relationship between NO- and CB-receptor pathways on arterial glucose and brain arteriovenous (a-v) glucose difference after hypoxic stimulation under hyperglycemic conditions. Normoglycemic and streptozotocin (STZ, 50 mg/kg i.p.)-induced hyperglycemic Sprague Dawley rats were infused with the NO donor, sodium nitroprusside (SNP), or the NOS inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) into the circulatory isolated carotid sinus after (30 sec) local anoxic CB chemoreceptor stimulation with sodium cyanide (NaCN). L-NAME abolished the hyperglycemia and the increase in brain a-v glucose concentration difference induced by CB chemoreceptor stimulation in normoglycemic rats, whereas the same treatment in hyperglycemic rats did not change the glucose variables studied. However, SNP infused under the same conditions induced a bigger rise in arterial glucose and brain a-v glucose concentration difference only in normoglycemic rats, when compared with the results obtained in sham-2-control rats. CB stimulation plus SNP treatment also resulted in an increase in nitrite levels in cephalic venous blood in normoglycemic, but not in hyperglycemic, rats. We showed a clear concomitant effect of SNP infusion into local CB circulation and anoxic cyanide stimulation, enhancing hyperglycemia and brain a-v glucose concentration difference. Importantly, at high glucose levels, nitrergic drugs did not modify glucose variables when compared with the corresponding sham controls.

Quimiossensibilidade durante exercício na insuficiência cardíaca: respostas ventilatórias, cronotrópicas e neurohormonais

FUNDAMENTO: Insuficiência cardíaca (IC) está associada com aumento da quimio-sensibilidade periférica e central em repouso, que pode estar correlacionada com um aumento na resposta ventilatória durante exercício. Entretanto, SUS sensibilidade na IC durante o exercício ainda não foi reportada. OBJETIVO: Testar se o estímulo dos quimiorreceptores centrais e periféricos em pacientes com IC pode modular respostas ventilatórias, cronotrópicas e neurohormonais durante exercício submáximo. MÉTODOS: Investigamos a quimio-sensibilidade central e periférica em 15 pacientes com insuficiência cardíaca (IC) e 7 controles normais (C), comparando a resposta durante 3 testes de caminhada de 6 minutos (TC6M), realizado em esteira ergométrica com: ar ambiente, em hipóxia e em hipercapnia (em ordem randômica). RESULTADOS: FR em ar ambiente nos grupos C e IC foi 17±2 e 22±2 (p<,0001); em hipóxia, foi 17±1 e 23±2 (p<,02); com CO25% foi 20±2 e 22±5 (p<,02). Volume tidal (VT) ou corrente em ar ambiente foi 1,25±0,17 e 1,08±0,19 (p<,01); em hipóxia 1,65±0,34 e 1,2±0,2(p<,0001); com CO25% 1,55±0,46 e 1,29±0,39 (p<,0001). Em repouso, o aumento na IC foi maior para VE (C 33±40%, IC 62±94%, p<,01), FC(C 7±10%, IC 10±10%, p<0,05) em repouso. Durante a hipóxia, o aumento durante o exercício na IC foi maior para FR (C 1±4, IC 11±6,p<,05), FC (C 12±2, IC 14±3, p<,05), VE/VO2 (C -4±18%, IC 24±21%, p<,01), FC/VO2 (C -26±11%, IC 11±5%, p<,01), VE/DC (C 36±10%, 46±14, p<,05% ) and FC/DC (C 18±8%, HF 29±11, p<,01). Durante exercício em hipóxia no grupo IC, o NO diminuiu e os níveis de IL-6 e aldosterona aumentaram. Os níveis neurohormonais permaneceram inalterados no grupo C. CONCLUSÃO: A quimio-sensibilidade central e a periférica durante o exercício estão aumentadas na IC e podem modular padrões respiratórios, cronotrópicos cardíacos e atividade neurohormonal durante exercício.

Early potential impairment of renal sensory nerves in streptozotocin-induced diabetic rats: role of neurokinin receptors

Electrophysiological studies in the mammalian kidney have identified two major classes of sensory receptors of the afferent renal nerves; chemoreceptors (CR) and mechanoreceptors (MR). The localization of calcitonin gene-related peptide (CGRP) and substance P (SP) in these renal pelvic sensory neurons provides an anatomical basis for a possible functional interaction between the two neuropeptides and SP receptor. The present study was performed to examine the possible changes in the responsiveness of renal sensory SP and CGRP receptors in rats with streptozotocin (STZ)-induced diabetes mellitus. Due to the crucial role of renal pelvic SP and CGRP receptors in the activation of renal sensory neurons by various stimuli, we examined whether the responsiveness of MR or CR activation and the dorsal root ganglia content of neuropeptides and neurokinin 1 receptors (NK(1)R) were altered in diabetic rats compared with non-diabetic rats. Afferent renal nerve activity (ARNA) was recorded from the peripheral portion of the cut end of one renal nerve branch placed on a bipolar silver wire electrode. T(13) dorsal root ganglia (DRG) immunoreactivity was performed to NK(1)R, SP and CGRP. The results of the current study confirmed that the stimulation of renal MR and CR elicited a renorenal reflex response, and that the renal pelvic administration of SP and CGRP increased ipsilateral ARNA and contralateral urinary sodium excretion with no changes in arterial pressure. We also found a decrease in NK(1)R expression followed by an increase in SP and CGRP levels in the DRG of diabetic rats. The ARNA response, produced by renal pelvic MR and CR stimulation, was found to be significantly attenuated in the STZ-induced diabetic model. Conclusions. These data may indicate a compensatory synthesis and/or abnormal axonal delivery of neurokinins from the cell body to synaptic portions of the neuron as the underlying reason for attenuated ARNA in renal sensory neurons of diabetic rats.

Influence of increased plasma osmolality on sympathetic outflow during apnea.

Animal models have shown that peripheral chemoreceptors alter their firing patterns in response to changes in plasma osmolality, which, in turn, may modulate sympathetic outflow. The purpose of this study was to test the hypothesis that increases in plasma osmolality augment muscle sympathetic nerve activity (MSNA) responses to chemoreceptor activation. MSNA was recorded from the peroneal nerve (microneurography) during a 23-min intravenous hypertonic saline infusion (3% NaCl; HSI). Chemoreceptor activation was elicited by voluntary end-expiratory apnea. MSNA responses to end-expiratory apnea were calculated as the absolute increase from the preceding baseline period. Plasma osmolality significantly increased from pre- to post-HSI (284 ± 1 to 290 ± 1 mOsm/kg H(2)O; P < 0.01). There was a significant overall effect of osmolality on sympathetic activity (P < 0.01). Duration of the voluntary end-expiratory apnea was not different after HSI (pre = 40 ± 5 s; post = 41 ± 4 s). MSNA responses to end-expiratory apnea were not different after HSI, expressed as an absolute change in burst frequency (n = 11; pre = 8 ± 2; post = 11 ± 1 burst/min) and as a percent increase in total activity (pre = 51 ± 4% AU; post = 53 ± 4% AU). A second group of subjects (n = 8) participated in 23-min volume/time-control intravenous isotonic saline infusions (0.9% NaCl). Isotonic saline volume-control infusions yielded no change in plasma osmolality or MSNA at rest. Furthermore, MSNA responses to apnea following isotonic saline infusion were not different. In summary, elevated plasma osmolality increased MSNA at rest and during apnea, but contrary to the hypothesis, MSNA responsiveness to apnea was not augmented. Therefore, this study does not support a neural interaction between plasma osmolality and chemoreceptor stimulation.

Photostimulation of Phox2b Medullary Neurons Activates Cardiorespiratory Function in Conscious Rats

Hypoventilation is typically treated with positive pressure ventilation or, in extreme cases, by phrenic nerve stimulation. This preclinical study explores whether direct stimulation of central chemoreceptors could be used as an alternative method to stimulate breathing. To determine whether activation of the retrotrapezoid nucleus (RTN), which is located in the rostral ventrolateral medulla (RVLM), stimulates breathing with appropriate selectivity. A lentivirus was used to induce expression of the photoactivatable cationic channel channelrhodopsin-2 (ChR2) by RVLM Phox2b-containing neurons, a population that consists of central chemoreceptors (the ccRTN neurons) and blood pressure (BP)-regulating neurons (the C1 cells). The transfected neurons were activated with pulses of laser light. Respiratory effects were measured by plethysmography or diaphragmatic EMG recording and cardiovascular effects by monitoring BP, renal sympathetic nerve discharge, and the baroreflex. The RVLM contained 600 to 900 ChR2-transfected neurons (63% C1, 37% ccRTN). RVLM photostimulation significantly increased breathing rate (+42%), tidal volume (21%), minute volume (68%), and peak expiratory flow (48%). Photostimulation increased diaphragm EMG amplitude (19%) and frequency (21%). Photostimulation increased BP (4 mmHg) and renal sympathetic nerve discharge (43%) while decreasing heart rate (15 bpm). Photostimulation of ChR2-transfected RVLM Phox2b neurons produces a vigorous stimulation of breathing accompanied by a small sympathetically mediated increase in BP. These results demonstrate that breathing can be relatively selectively activated in resting unanesthetized mammals via optogenetic manipulation of RVLM neurons presumed to be central chemoreceptors. This methodology could perhaps be used in the future to enhance respiration in humans.

Evidence for distributed processing during hypoxic stimulation by the brainstem cardiorespiratory network

Brainstem neural networks play an important integrative role in the regulation of respiratory and cardiovascular responses to hypoxia, but their organization remains poorly understood. We addressed the hypothesis that a distributed brainstem network, including rostral medullary neurons (RMNs) in the region of the retrotrapezoid nucleus, dorsolateral pons, raphé, and ventrolateral cardiorespiratory column (VRC), integrate central and peripheral chemoreceptor inputs. Data were obtained from decerebrate adult cats. We used multi‐electrode arrays to record from up to 118 neurons simultaneously. Firing rate responses were measured during hypoxia and stimulation of central chemoreceptors. Spike trains were also analyzed with respiratory and cardiac cycle triggered histograms and cross correlation. Results include: 1. Multiple cardiorespiratory rhythms in neurons responsive to hypoxic stimulation. 2. Co‐expression of distributed eupneic network activity present together with gasp patterns during recovery from severe brain hypoxia. 3. Reciprocal effective RMN‐VRC connectivity of neurons responsive to both hypoxia and hypercapnia. The results suggest a brainstem network architecture with connectivity that shapes the respiratory motor pattern via overlapping circuits that modulate central and peripheral chemoreceptor‐mediated influences on breathing.Supported by NS19814, NS46062

Central CO2chemoreception in cardiorespiratory control

Central CO₂chemoreception in cardiorespiratory control

Effects of bilateral inhibition of retrotrapezoid nucleus on breathing in conscious rats

The last five years many studies suggested the retrotrapezoid nucleus (RTN) as the central respiratory chemoreceptors, however all experiments were performed in anesthetized animals. In the present study we sought to investigate a possible role of RTN neurons in the normal breathing in conscious rats. Male Holtzman rats (280–300 g) with bilateral stainless steel cannulas implanted into the RTN were used. In conscious rats, bilateral inhibition of RTN neurons with the GABA‐A agonist muscimol (100 pmol/50 nl) reduced resting ventilation (120±62, vs. saline: 928±77 ml/min/kg) and the increase in ventilation produced by hyperoxic hypercapnia (10% CO2) (962±174, vs. saline: 2654±231 ml/min/kg). However, muscimol into the RTN did not change the increase in ventilation produced by activation of peripheral chemoreceptors with hypoxia (8% O2) (1294±116, vs. saline: 1552±108 ml/min/kg). Bilateral injections of muscimol into the RTN slightly reduced resting MAP (Δ = −13±7, vs. saline: +3±2 mmHg), but did not affect the changes in MAP and HR produced by hyperoxia hypercapnia and peripheral chemoreceptor stimulation. In conclusion, RTN neurons activated by pCO2 presumably via their intrinsic chemosensitivity, provide chemical drive to breathe during resting or hypercapnia.Financial support: FAPESP and CNPq.

Hypoxic cardiorespiratory reflexes in the facultative air-breathing fish jeju (Hoplerythrinus unitaeniatus): role of branchial O2 chemoreceptors

In one series of experiments, heart frequency (f (H)), blood pressure (P (a)), gill ventilation frequency (f ( R )), ventilation amplitude (V (AMP)) and total gill ventilation (V (TOT)) were measured in intact jeju (Hoplerythrinus unitaeniatus) and jeju with progressive denervation of the branchial branches of cranial nerves IX (glossopharyngeal) and X (vagus) without access to air. When these fish were submitted to graded hypoxia (water PO(2) approximately 140, normoxia to 17 mmHg, severe hypoxia), they increased f ( R ), V (AMP), V (TOT) and P (a) and decreased f (H). In a second series of experiments, air-breathing frequency (f (RA)), measured in fish with access to the surface, increased with graded hypoxia. In both series, bilateral denervation of all gill arches eliminated the responses to graded hypoxia. Based on the effects of internal (caudal vein, 150 microg NaCN in 0.2 mL saline) and external (buccal) injections of NaCN (500 microg NaCN in 1.0 mL water) on f (R), V (AMP), V (TOT), P (a) and f (H) we conclude that the O(2) receptors involved in eliciting changes in gill ventilation and associated cardiovascular responses are present on all gill arches and monitor the O(2) levels of both inspired water and blood perfusing the gills. We also conclude that air breathing arises solely from stimulation of branchial chemoreceptors and support the hypothesis that internal hypoxaemia is the primary drive to air breathing.

The effect of oxygen administration on serum concentration of potassium during exercise

Recently, there have been many reports on the role of serum concentration of potassium as a potential limiting factor during exercise. K+ is known to induce muscle fatigue and to increase ventilation by direct stimulation of peripheral chemoreceptors. These two K(+)-mediated effects are considered to be the factors that limit exercise capacity. This effect seems to be exacerbated in hypoxemic states. The occurrence of hypoxemia in chronic pulmonary disease patients during exercise is believed to cause the excessive efflux of potassium to the extracellular space from skeletal muscles. The present study evaluated the relationship between the changes in arterial concentration of K+ and hypoxemia during exercise in 37 chronic pulmonary patients and 9 healthy controls. The study was carried out after obtaining formal and written consent of the patients in accordance with the stipulations of the Helsinki Declaration. Patients were divided into two groups according to PaO2 level at maximum exercise capacity; group I: PaO2 less than 55 torr, group II: PaO2 greater than or equal to 55 torr. The arterial concentration of K+ in group I patients tended to be higher than that in group II and controls. In group II, K+ concentration was significantly elevated (p less than 0.05) compared to controls. In group II, PaO2 values were inversely correlated with K+ (r = 0.3026; p less than 0.025), whereas in controls and group II they were unrelated. These results suggest that the augmented serum level of potassium in patients with chronic pulmonary disease is an important limiting factor during exercise.

Nitric oxide in the hypothalamus–pituitary axis mediates increases in brain glucose retention induced by carotid chemoreceptor stimulation with cyanide in rats

Neuronal nitric oxide synthase (nNOS), which catalyzes the generation of nitric oxide (NO), is expressed by neuron subpopulations in the CNS. Nitric oxide is involved in neurotransmission and central glucose homeostasis. Our prior studies have shown that carotid body receptors participate in brain glucose regulation in vivo, and suggest the presence of a NO tonic mechanism in the solitary tract nucleus (STn). However, the role of NO within STn in glucose control remains unknown. In this study, we explored the potential regulatory role of NO on brain glucose retention induced by carotid body chemoreceptor anoxic stimulation with sodium cyanide (NaCN) which inhibits oxidative metabolism. Intracisternal infusions of nitroxidergic drugs before carotid chemoreceptor stimulation in anesthetized rats, elicited changes in nitrite concentration in plasma and hypothalamus–pituitary (H–P) tissue, as well as in gene expression of neuronal and inducible isoforms (nNOS and iNOS) in H–P tissue. The changes observed in above variables modified brain glucose retention in an opposite direction. When the NO donor, sodium nitroprusside (SNP), was given before carotid stimulation, nitrite concentration in plasma and H–P tissue, and gene expression of nNOS and iNOS in H–P tissue increased, whereas brain glucose retention decreased. In contrast, when the NOS inhibitor, Nω-nitro- l-arginine methyl ester ( l-NAME) was infused immediately before carotid chemoreceptor stimulation, nitrite levels and nNOS expression decreased in plasma and H–P tissue, whereas brain glucose retention increased. Anoxic stimulation by itself induced an increase in the expression of both genes studied. All these results indicate that de novo expression of the nNOS gene in H–P tissue may be critically involved in central glucose changes observed after anoxic carotid chemoreceptor stimulation in conjunction with NO.

Serotonin neurons of the caudal raphe nuclei contribute to sympathetic recovery following hypotensive hemorrhage

Serotonin is thought to contribute to the syncopal-like response that develops during severe blood loss by inhibiting presympathetic neurons of the rostroventrolateral medulla (RVLM). Here, we tested whether serotonin cells activated during hypotensive hemorrhage, i.e., express the protein product of the immediate early gene c-Fos, are critical for the normal sympathetic response to blood loss in unanesthetized rats. Serotonin-immunoreactive cells of the raphe obscurus and raphe magnus, parapyramidal cells of the B3 region, subependymal cells of the ventral parapyramidal region, and cells of the ventrolateral periaqueductal gray region were activated by hypotensive hemorrhage, but not by hypotension alone. In contrast to findings in anesthetized animals, lesion of hindbrain serotonergic cells sufficient to produce >80% loss of serotonin nerve terminal immunoreactivity in the RVLM accelerated the sympatholytic response to blood loss, attenuated recovery of sympathetic activity after termination of hemorrhage, and exaggerated metabolic acidosis. Hindbrain serotonin lesion also attenuated ventilatory and sympathetic responses to stimulation of central chemoreceptors but increased spontaneous arterial baroreflex sensitivity and decreased blood pressure variability. A more global neurotoxic lesion that also eliminated tryptophan hydroxylase-immunoreactive cells of the ventrolateral periaqueductal gray region had no further effect on the sympatholytic response to blood loss. Together, the data indicate that serotonin cells of the caudal hindbrain contribute to compensatory responses following blood loss that help maintain oxygenation of peripheral tissue in the unanesthetized rat. This effect may be related to facilitation of chemoreflex responses to acidosis.

Contributions of central and peripheral chemoreceptors to the ventilatory response to CO2/H+

The major objective of this review is to evaluate existing information and reach conclusions regarding whether there is interaction between P(CO(2))/H(+) stimulation of carotid (peripheral) and intracranial (central) chemoreceptors. Interaction is defined as a ventilatory response to simultaneous changes in the degree of Pco2/H(+) stimulation of both chemoreceptors that is greater (hyperadditive) or less (hypoadditive) than the sum of the responses when stimulation of each set of chemoreceptors is individually altered. Simple summation of the simultaneous changes in stimuli results in no interaction (i.e., additive interaction). Knowledge of the nature of central/peripheral interaction is crucial for determining the physiological significance of newer models of ventilatory control based on recent neuroanatomic observations of the circuitry of key elements of the ventilatory control system. In this review, we will propose that these two sets of receptors are not functionally separate but rather that they are dependent on one another such that the sensitivity of the medullary chemoreceptors is critically determined by input from the peripheral chemoreceptors and possibly other breathing-related reflex afferents as well. The short format of this minireview demands that we be somewhat selective in developing our ideas. We will briefly discuss the limitations of experiments used to study CO(2)/H(+) sensitivity and interaction to date, traditional views of the relative contributions of peripheral and central chemoreceptors to CO(2)/H(+) sensitivity, the evidence for and against different types of interaction, and the effect of tonic carotid chemoreceptor afferent activity on central control mechanisms.

Central CO2 chemoreception and integrated neural mechanisms of cardiovascular and respiratory control

In this review, we examine why blood pressure (BP) and sympathetic nerve activity (SNA) increase during a rise in central nervous system (CNS) P(CO(2)) (central chemoreceptor stimulation). CNS acidification modifies SNA by two classes of mechanisms. The first one depends on the activation of the central respiratory controller (CRG) and causes the much-emphasized respiratory modulation of the SNA. The CRG probably modulates SNA at several brain stem or spinal locations, but the most important site of interaction seems to be the caudal ventrolateral medulla (CVLM), where unidentified components of the CRG periodically gate the baroreflex. CNS P(CO(2)) also influences sympathetic tone in a CRG-independent manner, and we propose that this process operates differently according to the level of CNS P(CO(2)). In normocapnia and indeed even below the ventilatory recruitment threshold, CNS P(CO(2)) exerts a tonic concentration-dependent excitatory effect on SNA that is plausibly mediated by specialized brain stem chemoreceptors such as the retrotrapezoid nucleus. Abnormally high levels of P(CO(2)) cause an aversive interoceptive awareness in awake individuals and trigger arousal from sleep. These alerting responses presumably activate wake-promoting and/or stress-related pathways such as the orexinergic, noradrenergic, and serotonergic neurons. These neuronal groups, which may also be directly activated by brain acidification, have brainwide projections that contribute to the CO(2)-induced rise in breathing and SNA by facilitating neuronal activity at innumerable CNS locations. In the case of SNA, these sites include the nucleus of the solitary tract, the ventrolateral medulla, and the preganglionic neurons.

Tonically Discharging Genioglossus Motor Units Show No Evidence of Rate Coding With Hypercapnia

The genioglossus (GG) is considered the principle protrudor muscle of the human tongue. Unlike most skeletal muscles, GG electromyographic (EMG) activities are robustly preserved in sleep and thus may fulfill a critical role in preserving airway patency. Previous studies in human subjects also confirm that the GG EMG increases in response to chemoreceptor and mechanoreceptor stimulation. This increase occurs secondary to the recruitment of previously inactive motor units (MUs) and/or an increase in firing rate of already active MUs. Which strategy the nervous system uses when the synaptic drive onto GG motoneurons increases is not known. Here we report on GG whole muscle and tonic MU activities under conditions that mimic sleep, i.e., mild-moderate elevations in CO(2) (3% inspired CO(2) or the addition of a 1.0 l dead space) and elevated airway resistance. Based on previous work in rat, we hypothesized that mild hypercapnia would increase the firing rates of tonic MUs and that these effects would be further potentiated by a modest increase in airway resistance. Fine wire and tungsten microelectrodes were inserted into the GG to record whole muscle and single MU activities in 21 subjects (13 women, 8 men; 20-55 yr). Either 3% inspired CO(2) or added dead space resulted in a 200-300% increase in the amplitude of both tonic and phasic components of the whole muscle GG EMG and a doubling of minute ventilation. Despite these changes, recordings obtained from a total of 84 tonically discharging GG single MUs provide no evidence of a change in firing rate under any of the conditions. On this basis we conclude that in healthy adults, the increase in the tonic component of the whole muscle GG EMG secondary to mild hypercapnia is due almost exclusively to the recruitment of previously inactive MUs.

Cardiovascular and respiratory reflexes of the gulf toadfish (Opsanus beta) during acute hypoxia

The acute cardiovascular and respiratory responses of the gulf toadfish, Opsanus beta, to acute hypoxia or exposure to the O(2) chemoreceptor stimulant, sodium cyanide (NaCN) were characterized and the role of serotonin type 2 (5-HT(2)) receptors in mediating these responses was investigated. Toadfish responded to hypoxia or NaCN exposure with a decrease in heart rate (fH) and an increase in breathing amplitude (V(AMP)) but no change in breathing frequency (fR). The bradycardia appeared to be mediated to some extent by 5-HT(2) receptors, as methysergide, a non-selective 5-HT(1/2) receptor antagonist, and ketanserin, a 5-HT(2) receptor antagonist, attenuated the response. Injection of alpha-methyl-5-HT, a 5-HT(2) agonist, also resulted in bradycardia that was inhibited by ketanserin, lending further support for 5-HT(2) receptor involvement, possibly 5-HT(2A) or 5-HT(2C), in the regulation of fH. External NaCN exposure resulted in a significant decrease in caudal arterial blood pressure (P(CA)) that was attenuated by methysergide. In contrast, injection with alpha-methyl-5-HT resulted in a substantial increase in P(CA) that was not affected by ketanserin, suggesting the possible involvement of 5-HT(2B) or 5-HT(2C) receptors. These data are the first to suggest a unique distribution of 5-HT(2B/2C) receptors may be involved in mediating vasoconstriction of the systemic vasculature of toadfish. These data also provide mechanistic support for why pulsatile urea excretion, believed to be regulated by 5-HT via the toadfish 5-HT(2A) receptor, is not triggered by hypoxia or external chemoreceptor activation.

Chemoreceptor Hypersensitivity, Sympathetic Excitation, and Overexpression of ASIC and TASK Channels Before the Onset of Hypertension in SHR

Increased sympathetic nerve activity has been linked to the pathogenesis of hypertension in humans and animal models. Enhanced peripheral chemoreceptor sensitivity which increases sympathetic nerve activity has been observed in established hypertension but has not been identified as a possible mechanism for initiating an increase in sympathetic nerve activity before the onset of hypertension. We tested this hypothesis by measuring the pH sensitivity of isolated carotid body glomus cells from young spontaneously hypertensive rats (SHR) before the onset of hypertension and their control normotensive Wistar-Kyoto (WKY) rats. We found a significant increase in the depolarizing effect of low pH in SHR versus WKY glomus cells which was caused by overexpression of 2 acid-sensing non-voltage-gated channels. One is the amiloride-sensitive acid-sensing sodium channel (ASIC3), which is activated by low pH and the other is the 2-pore domain acid-sensing K(+) channel (TASK1), which is inhibited by low pH and blocked by quinidine. Moreover, we found that the increase in sympathetic nerve activity in response to stimulation of chemoreceptors with sodium cyanide was markedly enhanced in the still normotensive young SHR compared to control WKY rats. Our results establish a novel molecular basis for increased chemotransduction that contributes to excessive sympathetic activity before the onset of hypertension.

Central and peripheral chemoreceptors evoke distinct responses in simultaneously recorded neurons of the raphé-pontomedullary respiratory network.

The brainstem network for generating and modulating the respiratory motor pattern includes neurons of the medullary ventrolateral respiratory column (VRC), dorsolateral pons (PRG) and raphé nuclei. Midline raphé neurons are proposed to be elements of a distributed brainstem system of central chemoreceptors, as well as modulators of central chemoreceptors at other sites, including the retrotrapezoid nucleus. Stimulation of the raphé system or peripheral chemoreceptors can induce a long-term facilitation of phrenic nerve activity; central chemoreceptor stimulation does not. The network mechanisms through which each class of chemoreceptor differentially influences breathing are poorly understood. Microelectrode arrays were used to monitor sets of spike trains from 114 PRG, 198 VRC and 166 midline neurons in six decerebrate vagotomized cats; 356 were recorded during sequential stimulation of both receptor classes via brief CO(2)-saturated saline injections in vertebral (central) and carotid arteries (peripheral). Seventy neurons responded to both stimuli. More neurons were responsive only to peripheral challenges than those responsive only to central chemoreceptor stimulation (PRG, 20 : 4; VRC, 41 : 10; midline, 25 : 13). Of 16 474 pairs of neurons evaluated for short-time scale correlations, similar percentages of reference neurons in each brain region had correlation features indicative of a specific interaction with at least one target neuron: PRG (59.6%), VRC (51.0%) and raphé nuclei (45.8%). The results suggest a brainstem network architecture with connectivity that shapes the respiratory motor pattern via overlapping circuits that modulate central and peripheral chemoreceptor-mediated influences on breathing.

Patient-Ventilator Dyssynchrony: Clinical Significance and Implications for Practice

The cost of providing care to critically ill patients in the United States consumes roughly 15% of all health care dollars, or 1% of the gross national product.1 Contributing to this economic burden are patients admitted to the intensive care unit (ICU) who require mechanical ventilation and patients with complications from their dependence on this technology.2,3 In fact, 50% of ICU patients receive mechanical ventilation.4 Often, sedation is required to increase patients’ tolerance of the endotracheal tube, reduce anxiety, and facilitate sleep. In particular, sedation is used frequently to reduce patient-ventilator dyssynchrony (PVD).5–9 Sassoon and Foster10 define PVD as a mismatching between the patient’s breaths (neural) and ventilator-assisted breaths (phase asynchrony), as well as the inability of the ventilator’s flow delivery to match the patient’s flow demand (flow asynchrony). This definition suggests a faulty interaction between the patient and ventilator that is commonly managed by sedation and advanced ventilator modes and adjustments. The correction of PVD is complex and multifaceted given the current capabilities of traditional ventilators. An imperfect solution exists because the sensitivity and responsiveness of both the patient and the ventilator during the interaction is confounded by factors related to the patient and the ventilator. However, in light of the most serious complications (hypoxemia, barotrauma, prolonged mechanical ventilation, and discomfort) of PVD, and an imperfect solution for the resolution of PVD at the current time, nurses continue to face the challenge of preventing the consequences of PVD as well as complications due to oversedation or undersedation. In this article, we discuss the factors contributing to PVD; the manifestations, measurement, types, and causes of PVD; nursing implications; and future directions for improvement, with nursing research questions proposed for consideration.