RESUMEN

Considering that the retrotrapezoid nucleus/respiratory parafacial region (RTN/pFRG) would be an important center in the central nervous system involved in the maintenance and modulation of respiratory activity, we hypothesized that neurons in this nucleus would also be involved in the postinspiratory (post-I) phase of the respiratory cycle through a connection with the pontine Kölliker-Fuse (KF) region. Here, we performed pharmacogenetic manipulation (AAV-hM3D(Gq)-mCherry or AAV-hM4D(Gi)-mCherry) in VGlut2-cre, Ai6 conscious mice to evaluate breathing parameters through whole body plethysmography under baseline conditions (normoxia: [Formula: see text] = 0.21) or under hypercapnia or hypoxia challenges ([Formula: see text] = 0.07 or [Formula: see text] = 0.08). Under normoxia, selective stimulation of RTN/pFRG resulted in a smaller increase in V̇e (1,272 ± 102.5, vs. RTN/pFRG stimulation: 1,878 ± 122.1 mL/kg/min), due to a smaller increase in VT (5.4 ± 0.35, vs. RTN/pFRG stimulation: 7.77 ± 0.21 mL/kg) without changing fR in a condition of KF inhibition. However, inhibition of the VGlut2 neurons in the KF did affect the TE1 produced by selective activation of RTN/pFRG (119.9 ± 2.53, vs. RTN/pFRG stimulation: 104 ± 2.46 ms). Both the hypercapnia and hypoxia ventilatory response were reduced after inhibition of VGlut2-expressing KF neurons. Therefore, consistent with anatomical projections RTN/pFRG neurons regulate lung ventilation by controlling all aspects of breathing, i.e., breathing frequency, inspiration, postinspiration, and active expiration. All the modulation seems to be dependent on the integrity of the glutamatergic neurons in the KF region.NEW & NOTEWORTHY Our research reveals specific roles and interactions between the retrotrapezoid nucleus/respiratory parafacial region (RTN/pFRG) and the pontine Kölliker-Fuse (KF) region in controlling respiratory phases. RTN/pFRG neurons are key in regulating all aspects of breathing, including frequency, inspiration, postinspiration, and active expiration. This regulation depends on the functional integrity of glutamatergic neurons in the KF region, aligning with anatomical projections.

Asunto(s)

Hipoxia , Núcleo de Kölliker-Fuse , Animales , Núcleo de Kölliker-Fuse/metabolismo , Ratones , Masculino , Hipoxia/fisiopatología , Hipoxia/metabolismo , Respiración , Neuronas/metabolismo , Neuronas/fisiología , Hipercapnia/fisiopatología , Hipercapnia/metabolismo

RESUMEN

Aging invariably decreases sensory and motor stimuli and affects several neuronal systems and their connectivity to key brain regions, including those involved in breathing. Nevertheless, further investigation is needed to fully comprehend the link between senescence and respiratory function. Here, we investigate whether a mouse model of accelerated senescence could develop central and peripheral respiratory abnormalities. Adult male Senescence Accelerated Mouse Prone 8 (SAMP8) and the control SAMR1 mice (10 months old) were used. Ventilatory parameters were assessed by whole-body plethysmography, and measurements of respiratory input impedance were performed. SAMP8 mice exhibited a reduction in the density of neurokinin-1 receptor immunoreactivity in the entire ventral respiratory column. Physiological experiments showed that SAMP8 mice exhibited a decreased tachypneic response to hypoxia (FiO2 = 0.08; 10 min) or hypercapnia (FiCO2 = 0.07; 10 min). Additionally, the ventilatory response to hypercapnia increased further due to higher tidal volume. Measurements of respiratory mechanics in SAMP8 mice showed decreased static compliance (Cstat), inspiratory capacity (IC), resistance (Rn), and elastance (H) at different ages (3, 6, and 10 months old). SAMP8 mice also have a decrease in contractile response to methacholine compared to SAMR1. In conclusion, our findings indicate that SAMP8 mice display a loss of the NK1-expressing neurons in the respiratory brainstem centers, along with impairments in both central and peripheral respiratory mechanisms. These observations suggest a potential impact on breathing in a senescence animal model.

Asunto(s)

Envejecimiento , Hipercapnia , Receptores de Neuroquinina-1 , Animales , Ratones , Masculino , Envejecimiento/fisiología , Receptores de Neuroquinina-1/metabolismo , Hipercapnia/fisiopatología , Hipercapnia/metabolismo , Hipoxia/metabolismo , Hipoxia/fisiopatología , Mecánica Respiratoria/fisiología , Modelos Animales de Enfermedad , Respiración

RESUMEN

Exercise elicits physiological adaptations, including hyperpnea. However, the mechanisms underlying exercise-induced hyperpnea remain unresolved. Skeletal muscle acts as a secretory organ, releasing irisin (IR) during exercise. Irisin can cross the blood-brain barrier, influencing muscle and tissue metabolism, as well as signaling in the central nervous system (CNS). We evaluated the effect of intracerebroventricular or intraperitoneal injection of IR in adult male rats on the cardiorespiratory and metabolic function during sleep-wake cycle under room air, hypercapnia and hypoxia. Central IR injection caused an inhibition on ventilation (VE) during wakefulness under normoxia, while peripheral IR reduced VE during sleep. Additionally, central IR exacerbates hypercapnic hyperventilation by increasing VE and reducing oxygen consumption. As to cardiovascular regulation, central IR caused an increase in heart rate (HR) across all conditions, while no change was observed following peripheral administration. Finally, central IR attenuated the hypoxia-induced regulated hypothermia and increase sleep episodes, while peripheral IR augmented CO2-induced hypothermia, during wakefulness. Overall, our results suggest that IR act mostly on CNS exerting an inhibitory effect on breathing under resting conditions, while stimulating the hypercapnic ventilatory response and increasing HR. Therefore, IR seems not to be responsible for the exercise-induced hyperpnea, but contributes to the increase in HR.

Asunto(s)

Fibronectinas , Condicionamiento Físico Animal , Animales , Masculino , Ratas , Fibronectinas/metabolismo , Hipercapnia/metabolismo , Hipercapnia/fisiopatología , Hipoxia/metabolismo , Hipoxia/fisiopatología , Frecuencia Cardíaca , Sueño/fisiología , Vigilia/fisiología , Consumo de Oxígeno , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Respiración , Mioquinas

RESUMEN

The management of acute respiratory failure may require, among other measures, airway control, mechanical ventilation, and hemodynamic stabilization. About 60% of critically ill patients will require some type of respiratory support. For these reasons, an understanding of respiratory pathophysiology is important. The aim of this review is to establish an up-to-date of the concepts and fundamentals for acute respiratory failure.

---

El manejo de la falla respiratoria aguda puede requerir, entre otras medidas, control de la vía aérea, ventilación mecánica y estabilización hemodinámica. Alrededor del 60% de los pacientes graves requerirán de algún tipo de soporte respiratorio. Por estas razones es importante el entendimiento de la fisiopatología respiratoria. El objetivo de esta revisión es establecer conceptos y fundamentos actualizados sobre la falla respiratoria aguda.

Asunto(s)

Humanos , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/fisiopatología , Insuficiencia Respiratoria/terapia , Respiración Artificial , Insuficiencia Respiratoria/clasificación , Intercambio Gaseoso Pulmonar , Enfermedad Aguda , Hipercapnia/diagnóstico , Hipercapnia/fisiopatología , Hipercapnia/terapia , Hipoxia/diagnóstico , Hipoxia/fisiopatología , Hipoxia/terapia

RESUMEN

Ventilation and gas exchange have been studied in relatively few species of snakes, especially regarding their response to environmental hypoxia or hypercarbia. We exposed Crotalus durissus (N = 6) and Boa constrictor (N = 6) to decreasing levels of oxygen (12, 9, 6, 3 % O2) and increasing levels of carbon dioxide (1.5, 3.0, 4.5, 6.0 % CO2) and analyzed the effect of the different gas mixtures on ventilation and gas exchange using open-flow respirometry. Neither hypoxia nor hypercarbia significantly altered the duration of expiration or inspiration, nor their proportions. Both hypoxia and hypercarbia increased minute ventilation, but the decrease in oxygen had a less pronounced effect on ventilation. Gas exchange under normoxic conditions was low and was not significantly affected by hypoxia, but hypercarbia decreased gas exchange significantly in both species. While B. constrictor maintained its respiratory exchange ratio (RER) under hypercarbia between 0.5 and 1.0, C. durissus showed a RER above 1.0 during hypercarbia, due to a significantly greater CO2 excretion. The overall responses of both species to hypercarbia and especially to hypoxia were very similar, which could be associated to similar lifestyles as ambush hunting sit-and-wait predators that are able to ingest large prey items. The observed differences in gas exchange could be related to respiratory systems with macroscopically different structures, possessing only a tracheal lung in C. durissus, but two functional lungs in B. constrictor.

Asunto(s)

Dióxido de Carbono/metabolismo , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Consumo de Oxígeno/fisiología , Intercambio Gaseoso Pulmonar/fisiología , Ventilación Pulmonar/fisiología , Mecánica Respiratoria/fisiología , Animales , Boidae , Crotalus , Modelos Animales de Enfermedad

RESUMEN

Early ethanol exposure affects respiratory neuroplasticity; a risk factor associated with the Sudden Infant Death Syndrome. High and chronic ethanol doses exert long-lasting effects upon respiratory rates, apneic episodes and ventilatory processes triggered by hypoxia. The present study was performed in 3-9-day-old rat pups. Respiratory processes under normoxic and hypoxic conditions were analyzed in pups intoxicated with different ethanol doses which were pre-exposed or not to the drug. A second major goal was to examine if acute and/or chronic early ethanol exposure affects blood parameters related with hypercapnic or hypoxic states. In Experiment 1, at postnatal day 9, animals previously treated with ethanol (2.0 g/kg) or vehicle (0.0 g/kg) were tested sober or intoxicated with 0.75, 1.37 or 2.00 g/kg ethanol. The test involved sequential air conditions defined as initial normoxia, hypoxia and recovery normoxia. Motor activity was also evaluated. In Experiment 2, blood parameters indicative of possible hypoxic and hypercapnic states were assessed as a function of early chronic or acute experiences with the drug. The main results of Experiment 1 were as follows: i) ethanol's depressant effects upon respiratory rates increased as a function of sequential treatment with the drug (sensitization); ii) ethanol inhibited apneic episodes even when employing the lowest dose at test (0.75 g/kg); iii) the hyperventilatory response caused by hypoxia negatively correlated with the ethanol dose administered at test; iv) ventilatory long-term facilitation (LTF) during recovery normoxia was observed in pups pre-exposed to the drug and in pups that received the different ethanol doses at test; v) self-grooming increased in pups treated with either 1.37 or 2.00 g/kg ethanol. The main result of Experiment 2 indicated that acute as well as chronic ethanol exposure results in acidosis-hypercapnia. The results indicate that early and brief experiences with ethanol are sufficient to affect different respiratory plasticity processes as well as blood biomarkers indicative of acidosis-hypercapnia. An association between the LTF process and the acidosis-hypercapnic state caused by ethanol seems to exist. The mentioned experiences with the drug are sufficient to result in an anomalous programming of respiratory patterns and metabolic conditions.

Asunto(s)

Depresores del Sistema Nervioso Central/toxicidad , Etanol/toxicidad , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Respiración/efectos de los fármacos , Animales , Animales Recién Nacidos , Femenino , Hipercapnia/sangre , Hipoxia/sangre , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Ratas , Ratas Wistar

RESUMEN

The pontine A5 noradrenergic group contributes to the maturation of the respiratory system before birth in rats. These neurons are connected to the neural network responsible for respiratory rhythmogenesis. In the present study, we investigated the participation of A5 noradrenergic neurons in neonates (P7-8 and P14-15) in the control of ventilation during hypoxia and hypercapnia in in vivo experiments using conjugated saporin anti-dopamine beta-hydroxylase (DßH-SAP) to specifically ablate noradrenergic neurons. Thus, DßH-SAP (420 ng/µL) or saporin (SAP, control) was injected into the A5 region of neonatal male Wistar rats. Hypoxia reduced respiratory variability in control animals; however, A5 lesion prevented this effect in P7-8 rats. Our data suggest that noradrenergic neurons of the A5 region in neonate rats do not participate in the control of ventilation under baseline and hypercapnic conditions, but exert an inhibitory modulation on breathing variability under hypoxic challenge in early life (P7-8).

Asunto(s)

Neuronas Adrenérgicas/metabolismo , Tronco Encefálico/citología , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Respiración , Neuronas Adrenérgicas/efectos de los fármacos , Neuronas Adrenérgicas/fisiología , Animales , Animales Recién Nacidos , Tronco Encefálico/crecimiento & desarrollo , Tronco Encefálico/fisiopatología , Dopamina beta-Hidroxilasa/farmacología , Masculino , Ratas , Ratas Wistar , Saporinas/farmacología

RESUMEN

Active expiration represents an important mechanism to improve ventilation in conditions of augmented ventilatory demand, such as hypercapnia. While a rostral ventromedullary region, the parafacial respiratory group (pFRG), has been identified as a conditional expiratory oscillator, little is known about how central chemosensitive sites contribute to modulate active expiration under hypercapnia. In this study, we investigated the influence of the medullary raphe in the emergence of phasic expiratory abdominal activity during hypercapnia in unanesthetized adult male rats, in a state-dependent manner. To do so, reverse microdialysis of muscimol (GABAA receptor agonist, 1 mM) or 8-OH-DPAT (5-HT1A agonist, 1 mM) was applied in the MR during sleep and wakefulness periods, both in normocapnic (room air) and hypercapnic conditions (7% CO2). Electromyography (EMG) of diaphragm and abdominal muscles was performed to measure inspiratory and expiratory motor outputs. We found that active expiration did not occur in room air exposure during wakefulness or sleep. However, hypercapnia did recruit active expiration, and differential effects were observed with the drug dialyses in the medullary raphe. Muscimol increased the diaphragm inspiratory motor output and also increased the amplitude and frequency of abdominal expiratory rhythmic activity during hypercapnia in wakefulness periods. On the other hand, the microdialysis of 8-OH-DPAT attenuated hypercapnia-induced active expiration in a state-dependent manner. Our data suggest that the medullary raphe can either inhibit or potentiate respiratory motor activity during hypercapnia, and the balance of these inhibitory or excitatory outputs may determine the expression of active expiration.

Asunto(s)

Diafragma/fisiopatología , Espiración , Hipercapnia/fisiopatología , Núcleos del Rafe/fisiopatología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Músculos Abdominales/inervación , Músculos Abdominales/fisiopatología , Animales , Diafragma/inervación , Agonistas de Receptores de GABA-A/farmacología , Masculino , Muscimol/farmacología , Contracción Muscular , Núcleos del Rafe/efectos de los fármacos , Ratas , Ratas Wistar , Agonistas de Receptores de Serotonina/farmacología , Sueño , Vigilia

RESUMEN

Many diseases of the respiratory system occur differently in males and females, indicating a possible role of gonadal hormones in respiratory control. We hypothesized that testosterone (T) is important for the ventilatory chemosensitivity responses in males. To test this hypothesis, we evaluated ventilation (V̇ E), metabolic rate and body temperature (Tb) under normoxia/normocapnia, hypercapnia and hypoxia in orchiectomized (ORX), ORX with testosterone replacement (ORX + T) or flutamide (FL, androgen receptor blocker)-treated rats. We also performed immunohistochemistry to evaluate the presence of androgen receptor (AR) in the carotid body (CB) of intact males. Orchiectomy promoted a reduction V̇ E and ventilatory equivalent (V̇ E /V̇ O2) under room-air conditions, which was restored with testosterone treatment. Moreover, during hypoxia or hypercapnia, animals that received testosterone replacement had a higher V̇ E and V̇ E /V̇ O2 than control and ORX, without changes in metabolic and thermal variables. Flutamide decreased the hypoxic ventilatory response without changing the CO2-drive to breathe, suggesting that the testosterone effect on hypercapnic hyperventilation does not appear to involve the AR. We also determined the presence of AR in the CB of intact animals. Our findings demonstrate that testosterone seems to be important for maintaining resting V̇ E in males. In addition, the influence of testosterone on V̇ E, either during resting conditions or under hypoxia and hypercapnia, seems to be a direct and specific effect, as no changes in metabolic rate or Tb were observed during any treatment. Finally, a putative site of testosterone action during hypoxia is the CB, since we detected the presence of AR in this structure.

Asunto(s)

Regulación de la Temperatura Corporal/fisiología , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Fenómenos Fisiológicos Respiratorios , Testosterona/fisiología , Antagonistas de Receptores Androgénicos/farmacocinética , Animales , Cuerpo Carotídeo/química , Flutamida/farmacología , Masculino , Orquiectomía , Consumo de Oxígeno/fisiología , Ratas , Ratas Wistar , Receptores Androgénicos/análisis , Receptores Androgénicos/fisiología , Testosterona/administración & dosificación

RESUMEN

One of the possible causes of death in epilepsy is breathing disorders, especially apneas, which lead to an increase in CO2 levels (hypercapnia) and/or a decrease in O2 levels in arterial blood (hypoxemia). The respiratory neurons located in the ventral brainstem respiratory column are the main groups responsible for controlling breathing. Recent data from our group demonstrated respiratory changes in two experimental models of epilepsy, i.e. audiogenic epilepsy, and amygdala rapid kindling. Here, we aimed to evaluate respiratory changes in the classic model of temporal lobe epilepsy induced by intra-hippocampal injection of pilocarpine. Adult Wistar rats with stainless-steel cannulas implanted in the hippocampus region were used. The animals were submitted to pilocarpine injection (2.4 mg/µL, N = 12-15) or saline (N = 9) into the hippocampus. The respiratory parameters analyzed by whole-body plethysmography were respiratory rate (fR), tidal volume (VT) and ventilation (VE). Respiratory mechanics such as Newtonian airway resistance (Rn), viscance of the pulmonary parenchyma (G) and the elastance of the pulmonary parenchyma (H) were also investigated. No changes in baseline breathing were detected 15 or 30 days after pilocarpine-induced status epilepticus (SE). However, 30 days after pilocarpine-induced SE, a significant reduction in VE was observed during hypercapnic (7% CO2) stimulation, without affecting the hypoxia (8% O2) ventilatory response. We also did not observe changes in respiratory mechanics. The present results suggest that the impairment of the hypercapnia ventilatory response in pilocarpine-induced SE could be related to a presumable degeneration of brainstem respiratory neurons but not to peripheral mechanisms.

Asunto(s)

Células Quimiorreceptoras/efectos de los fármacos , Pilocarpina/toxicidad , Respiración/efectos de los fármacos , Estado Epiléptico/inducido químicamente , Estado Epiléptico/fisiopatología , Volumen de Ventilación Pulmonar/efectos de los fármacos , Animales , Células Quimiorreceptoras/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Hipercapnia/inducido químicamente , Hipercapnia/fisiopatología , Inyecciones Intraventriculares , Masculino , Agonistas Muscarínicos/administración & dosificación , Agonistas Muscarínicos/toxicidad , Pilocarpina/administración & dosificación , Ratas , Ratas Wistar , Mecánica Respiratoria/efectos de los fármacos , Mecánica Respiratoria/fisiología , Volumen de Ventilación Pulmonar/fisiología

RESUMEN

The parafacial respiratory group (pFRG), located in the lateral aspect of the rostroventral lateral medulla, has been described as a conditional expiratory oscillator that emerges mainly in conditions of high metabolic challenges to increase breathing. The convergence of inhibitory and excitatory inputs to pFRG and the generation of active expiration may be more complex than previously thought. We hypothesized that the medullary raphe, a region that has long been described to be involved in breathing activity, is also responsible for the expiratory activity under hypercapnic condition. To test this hypothesis, we performed anatomical and physiological experiments in urethane-anesthetized adult male Wistar rats. Our data showed anatomical projections from serotonergic (5-HT-ergic) and GABAergic neurons of raphe magnus (RMg) and obscurus (ROb) to the pFRG region. Pharmacological inhibition of RMg or ROb with muscimol (60 pmol/30 nL) did not change the frequency or amplitude of diaphragm activity and did not generate active expiration. However, under hypercapnia (9-10% CO2), the inhibition of RMg or ROb increased the amplitude of abdominal activity, without changing the increased amplitude of diaphragm activity. Depletion of serotonergic neurons with saporin anti-SERT injections into ROb and RMg did not increase the amplitude of abdominal activity during hypercapnia. These results show that the presumably GABAergic neurons within the RMg and ROb may be the inhibitory source to modulate the activity of pFRG during hypercapnia condition.NEW & NOTEWORTHY Medullary raphe has been involved in the inspiratory response to central chemoreflex; however, these reports have never addressed the role of raphe neurons on active expiration induced by hypercapnia. Here, we showed that a subset of GABA cells within the medullary raphe directly project to the parafacial respiratory region, modulating active expiration under high levels of CO2.

Asunto(s)

Espiración/fisiología , Neuronas GABAérgicas/fisiología , Hipercapnia/fisiopatología , Bulbo Raquídeo/fisiología , Red Nerviosa/fisiología , Núcleos del Rafe/fisiología , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Neuronas Serotoninérgicas/fisiología

RESUMEN

The locus coeruleus (LC) is a pontine nucleus important for respiratory control and central chemoreception. It is affected in Alzheimer's disease (AD) and alteration of LC cell function may account for respiratory problems observed in AD patients. In the current study, we tested the electrophysiological properties and CO2/pH sensitivity of LC neurons in a model for AD. Sporadic AD was induced in rats by intracerebroventricular injection of 2 mg/kg streptozotocin (STZ), which induces behavioral and molecular impairments found in AD. LC neurons were recorded using the patch clamp technique and tested for responses to CO2 (10% CO2, pH = 7.0). The majority (~60%) of noradrenergic LC neurons in adult rats were inhibited by CO2 exposure as indicated by a significant decrease in action potential (AP) discharge to step depolarizations. The STZ-AD rat model had a greater sensitivity to CO2 than controls. The increased CO2-sensitivity was demonstrated by a significantly stronger inhibition of activity during hypercapnia that was in part due to hyperpolarization of the resting membrane potential. Reduction of AP discharge in both groups was generally accompanied by lower LC network activity, depolarized AP threshold, increased AP repolarization, and increased current through a subpopulation of voltage-gated K+ channels (KV). The latter was indicated by enhanced transient KV currents particularly in the STZ-AD group. Interestingly, steady-state KV currents were reduced under hypercapnia, a change that would favor enhanced AP discharge. However, the collective response of most LC neurons in adult rats, and particularly those in the STZ-AD group, was inhibited by CO2.

Asunto(s)

Enfermedad de Alzheimer/fisiopatología , Hipercapnia/fisiopatología , Locus Coeruleus/fisiopatología , Neuronas/fisiología , Enfermedad de Alzheimer/inducido químicamente , Animales , Dióxido de Carbono/farmacología , Modelos Animales de Enfermedad , Locus Coeruleus/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estreptozocina/toxicidad

RESUMEN

The concentration of CO2 in the environment surrounding the embryo impacts development and may also influence the cardiorespiratory responses after hatching. Therefore, we aimed to evaluate the cardiorespiratory and thermal responses to hypercapnia in chicks that were exposed to CO2 during embryonic development, i.e., incubation. Embryos were incubated without and with a gradual increase in CO2 concentration up to 1 % during the first ten days of incubation. Ten-day-old chicks (males and females) were again acutely exposed to hypercapnia (7 % CO2), or to room air (normocapnia) and pulmonary ventilation, arterial pH and blood gases, arterial blood pressure and heart rate, body temperature (Tb) and oxygen consumption (V⋅O2) were measured. Compared to control animals, male chicks incubated with 1 % CO2 presented an attenuated ventilatory response to hypercapnia (P < 0.05), whereas no difference was found in the hypercapnic ventilatory response in both female chick groups (0 % vs 1 % CO2 incubation). Hypercapnia induced bradycardia in all groups (P < 0.001). The CO2 exposure during incubation did not alter the cardiovascular responses to hypercapnia in post-hatch animals. There were no significant effects of incubation treatment (0 % vs 1 % CO2) or sex in the mean arterial pressure, Tb, and V⋅O2 of animals in normocapnia and hypercapnia. As for the V⋅E/V⋅O2, hypercapnia caused an increase in both groups (P < 0.05), regardless of incubation treatment. In conclusion, among cardiorespiratory and metabolic variables, the ventilatory response to hypercapnia can be attenuated by pre-exposure to 1 % CO2 during embryonic development, especially in male chicks up to 10 days.

Asunto(s)

Presión Arterial/fisiología , Temperatura Corporal/fisiología , Dióxido de Carbono/administración & dosificación , Frecuencia Cardíaca/fisiología , Hipercapnia/fisiopatología , Ventilación Pulmonar/fisiología , Animales , Embrión de Pollo , Pollos , Desarrollo Embrionario , Femenino , Masculino , Factores Sexuales , Factores de Tiempo

RESUMEN

Enhanced central chemoreflex (CC) gain is observed in volume overload heart failure (HF) and is correlated with autonomic dysfunction and breathing disorders. The aim of this study was to determine the role of the CC in the development of respiratory and autonomic dysfunction in HF. Volume overload was surgically created to induce HF in male Sprague-Dawley rats. Radiotelemetry transmitters were implanted for continuous monitoring of blood pressure and heart rate. After recovering from surgery, conscious unrestrained rats were exposed to episodic hypercapnic stimulation [EHS; 10 cycles/5 min, inspiratory fraction of carbon dioxide (FICO2) 7%] in a whole body plethysmograph for recording of cardiorespiratory function. To determine the contribution of CC to cardiorespiratory variables, selective ablation of chemoreceptor neurons within the retrotrapezoid nucleus (RTN) was performed via injection of saporin toxin conjugated to substance P (SSP-SAP). Vehicle-treated rats (HF+Veh and Sham+Veh) were used as controls for SSP-SAP experiments. Sixty minutes post-EHS, minute ventilation was depressed in sham animals relative to HF animals (ΔV̇e: -5.55 ± 2.10 vs. 1.24 ± 1.35 mL/min 100 g, P < 0.05; Sham+Veh vs. HF+Veh). Furthermore, EHS resulted in autonomic imbalance, cardiorespiratory entrainment, and ventilatory disturbances in HF+Veh but not Sham+Veh rats, and these effects were significantly attenuated by SSP-SAP treatment. Also, the apnea-hypopnea index (AHI) was significantly lower in HF+SSP-SAP rats compared with HF+Veh rats (AHI: 5.5 ± 0.8 vs. 14.4 ± 1.3 events/h, HF+SSP-SAP vs. HF+Veh, respectively, P < 0.05). Finally, EHS-induced respiratory-cardiovascular coupling in HF rats depends on RTN chemoreceptor neurons because it was reduced by SSP-SAP treatment. Overall, EHS triggers ventilatory plasticity and elicits cardiorespiratory abnormalities in HF that are largely dependent on RTN chemoreceptor neurons.

Asunto(s)

Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Sistema Nervioso Central/fisiopatología , Células Quimiorreceptoras/metabolismo , Insuficiencia Cardíaca/fisiopatología , Neuronas/fisiología , Trastornos Respiratorios/fisiopatología , Animales , Enfermedades del Sistema Nervioso Autónomo/metabolismo , Presión Sanguínea/fisiología , Sistema Nervioso Central/metabolismo , Insuficiencia Cardíaca/metabolismo , Frecuencia Cardíaca/fisiología , Hipercapnia/metabolismo , Hipercapnia/fisiopatología , Masculino , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Respiración , Trastornos Respiratorios/metabolismo

RESUMEN

NEW FINDINGS: What is the central question of this study? Do A6 neurons modulate active expiratory and airway responses evoked by hypercapnia/acidosis? What is the main finding and its importance? Acute inhibition of A6 neurons reduced active expiratory, inspiratory and the associated oropharyngeal and laryngeal motor responses to hypercapnia/acidosis. A6 neurons provide excitatory synaptic drive contributing to the central generation of inspiratory and expiratory motor activity as well as the control of upper airway resistance. ABSTRACT: During rest, inspiration is an active phenomenon, whereas expiration is passive. Under conditions of high chemical drive, such as hypercapnia/acidosis, there is an increase in inspiratory activity, expiration becomes active and upper airway resistance is reduced. The locus coeruleus noradrenergic neurons (A6 neurons) are activated when exposed to elevated CO2 /[H+ ] levels and modulate respiratory brainstem neurons regulating ventilation. However, the role of A6 neurons in the control of upper airway resistance is not fully understood. We tested the hypothesis that A6 neurons contribute to the central generation of active inspiratory and expiratory responses and the associated changes in the motor nerves controlling upper airway resistance during hypercapnia/acidosis in rats. Using a perfused brainstem-spinal cord preparation, we inhibited A6 neurons using pharmacogenetics and evaluated the active expiratory (abdominal nerve), laryngeal (cervical vagus nerve), oropharyngeal (hypoglossal nerve) and inspiratory (phrenic nerve) motor nerve responses to hypercapnia/acidosis. Acute inhibition of A6 neurons did not produce significant changes in the respiratory pattern in normocapnia. However, the hypercapnia/acidosis-induced active expiratory response and the associated changes in the motor nerves responsible for control of oropharyngeal and laryngeal resistance, as well as the inspiratory response were all reduced after inhibition of A6 neurons. Our data demonstrate that A6 neurons exert an important excitatory synaptic drive to the central generation of both active inspiratory and expiratory activities and modulate the control of upper airway resistance during hypercapnia/acidosis.

Asunto(s)

Acidosis/fisiopatología , Resistencia de las Vías Respiratorias , Espiración , Hipercapnia/fisiopatología , Neuronas/fisiología , Animales , Tronco Encefálico/citología , Nervio Hipogloso/fisiología , Masculino , Nervio Frénico/fisiología , Ratas , Ratas Wistar , Médula Espinal/citología , Transfección , Nervio Vago/fisiología

RESUMEN

The nucleus of the solitary tract (NTS) is an important area of the brainstem that receives and integrates afferent cardiorespiratory sensorial information, including those from arterial chemoreceptors and baroreceptors. It was described that acetylcholine (ACh) in the commissural subnucleus of the NTS (cNTS) promotes an increase in the phrenic nerve activity (PNA) and antagonism of nicotinic receptors in the same region reduces the magnitude of tachypneic response to peripheral chemoreceptor stimulation, suggesting a functional role of cholinergic transmission within the cNTS in the chemosensory control of respiratory activity. In the present study, we investigated whether cholinergic receptor antagonism in the cNTS modifies the sympathetic and respiratory reflex responses to hypercapnia. Using an arterially perfused in situ preparation of juvenile male Holtzman rats, we found that the nicotinic antagonist (mecamylamine, 5 mM), but not the muscarinic antagonist (atropine, 5 mM), into the cNTS attenuated the hypercapnia-induced increase of hypoglossal activity. Furthermore, mecamylamine in the cNTS potentiated the generation of late-expiratory (late-E) activity in abdominal nerve induced by hypercapnia. None of the cholinergic antagonists microinjected in the cNTS changed either the sympathetic or the phrenic nerve responses to hypercapnia. Our data provide evidence for the role of cholinergic transmission in the cNTS, acting on nicotinic receptors, modulating the hypoglossal and abdominal responses to hypercapnia.

Asunto(s)

Neuronas Colinérgicas/fisiología , Hipercapnia/metabolismo , Respiración , Transmisión Sináptica , Comisuras Telencefálicas/fisiología , Animales , Atropina/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Hipercapnia/fisiopatología , Nervio Hipogloso/fisiología , Masculino , Mecamilamina/farmacología , Agonistas Muscarínicos/farmacología , Antagonistas Nicotínicos/farmacología , Nervio Frénico/fisiología , Ratas , Receptores Colinérgicos/metabolismo , Reflejo , Núcleo Solitario/fisiología , Núcleo Solitario/fisiopatología , Comisuras Telencefálicas/fisiopatología

RESUMEN

Active expiration (AE) is part of the breathing phase; it is conditional and occurs when we increase our metabolic demand, such as during hypercapnia, hypoxia, or exercise. The parafacial respiratory group (pFRG) is involved in AE. Data from the literature suggest that excitatory and the absence of inhibitory inputs to the pFRG are necessary to determine AE. However, the source of the inputs to the pFRG that trigger AE remains unclear. We show in adult urethane-anesthetized Wistar rats that the pharmacological inhibition of the medial aspect of the nucleus of the solitary tract (mNTS) or the rostral aspect of the pedunculopontine tegmental nucleus (rPPTg) is able to generate AE. In addition, direct inhibitory projection from the mNTS or indirect cholinergic projection from the rPPTg is able to contact pFRG to trigger AE. The inhibition of the mNTS or the rPPTg under conditions of high metabolic demand, such as hypercapnia (9-10% CO2), did not affect the AE. The present results suggest for the first time that inhibitory sources from the mNTS and a cholinergic pathway from the rPPTg, involving M2/M4 muscarinic receptors, could be important sources to modulate and sustain AE.

Asunto(s)

Espiración/fisiología , Hipercapnia/metabolismo , Bulbo Raquídeo/metabolismo , Neuronas/metabolismo , Animales , Hipercapnia/fisiopatología , Masculino , Ratas Wistar , Respiración

RESUMEN

Hydrogen sulfide (H2S) is classically known for its toxic effects. More recently H2S has been documented as a neuromodulator. Here we investigated the central effects of aminooxyacetate (AOA; inhibitor of the H2S-synthesizing enzyme cystathionine ß-synthase, CBS) on cardiovascular, respiratory and thermoregulatory responses to hypercapnia in spontaneously hypertensive rats (SHR). To attain this goal we measured mean arterial pressure (MAP), heart rate (HR), ventilation (VE), and deep body temperature (Tb) of SHR and (normotensive) Wistar Kyoto (WKY) rats before and after microinjection of AOA (9 nmol/µL) or saline into the fourth ventricle immediately followed by 30-min hypercapnia exposure (7% inspired CO2). In saline-treated WKY rats, hypercapnia caused an increase in MAP accompanied by bradycardia, an increase in VE, and a drop in Tb. In AOA-treated WKY rats exposed to hypercapnia, the drug did not affect the increased MAP, potentiated the bradycardic response, attenuated the increased VE, and potentiated the drop in Tb. In saline-treated SHR, in comparison to the saline-treated WKY rats, hypercapnia elicited a minor, shorter-lasting increase in MAP with no changes in HR, evoked a greater increase in VE, and did not induce a drop in Tb. In AOA-treated SHR exposed to hypercapnia, the drug did not change the hypercapnia-induced cardiovascular and ventilatory responses while permitted a drop in Tb. Our findings indicate that AOA, an inhibitor of H2S production, modulates cardiorespiratory and thermoregulatory responses to hypercapnia in normotensive rats, whereas hypertension development in SHR is accompanied by suppression of the AOA effect on the cardiovascular and respiratory responses.

Asunto(s)

Ácido Aminooxiacético/farmacología , Presión Arterial , Regulación de la Temperatura Corporal , Temperatura Corporal , Inhibidores Enzimáticos/farmacología , Frecuencia Cardíaca , Sulfuro de Hidrógeno/antagonistas & inhibidores , Hipercapnia/fisiopatología , Frecuencia Respiratoria , Ácido Aminooxiacético/administración & dosificación , Animales , Presión Arterial/efectos de los fármacos , Presión Arterial/fisiología , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Regulación de la Temperatura Corporal/efectos de los fármacos , Regulación de la Temperatura Corporal/fisiología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Frecuencia Respiratoria/efectos de los fármacos , Frecuencia Respiratoria/fisiología

RESUMEN

NEW FINDINGS: What is the central question of this study? Clinical reports have described and suggested central and peripheral respiratory abnormalities in Parkinson's disease (PD) patients; however, these reports have never addressed the occurrence of these abnormalities in an animal model. What is the main finding and its importance? A mouse model of PD has reduced neurokinin-1 receptor immunoreactivity in the pre-BÓ§tzinger complex and Phox2b-expressing neurons in the retrotrapezoid nucleus. The PD mouse has impairments of respiratory frequency and the hypercapnic ventilatory response. Lung collagen deposition and ribcage stiffness appear in PD mice. ABSTRACT: Parkinson's disease (PD) is a neurodegenerative motor disorder characterized by dopaminergic deficits in the brain. Parkinson's disease patients may experience shortness of breath, dyspnoea, breathing difficulties and pneumonia, which can be linked as a cause of morbidity and mortality of those patients. The aim of the present study was to clarify whether a mouse model of PD could develop central brainstem and lung respiratory abnormalities. Adult male C57BL/6 mice received bilateral injections of 6-hydroxydopamine (10 µg µl-1 ; 0.5 µl) or vehicle into the striatum. Ventilatory parameters were assessed in the 40 days after induction of PD, by whole-body plethysmography. In addition, measurements of respiratory input impedance (closed and opened thorax) were performed. 6-Hydroxydopamine reduced the number of tyrosine hydroxylase neurons in the substantia nigra pars compacta, the density of neurokinin-1 receptor immunoreactivity in the pre-BÓ§tzinger complex and the number of Phox2b neurons in the retrotrapezoid nucleus. Physiological experiments revealed a reduction in resting respiratory frequency in PD animals, owing to an increase in expiratory time and a blunted hypercapnic ventilatory response. Measurements of respiratory input impedance showed that only PD animals with the thorax preserved had increased viscance, indicating that the ribcage could be stiff in this animal model of PD. Consistent with stiffened ribcage mechanics, abnormal collagen deposits in alveolar septa and airways were observed in PD animals. Our data showed that our mouse model of PD presented with neurodegeneration in respiratory brainstem centres and disruption of lung mechanical properties, suggesting that both central and peripheral deficiencies contribute to PD-related respiratory pathologies.

Asunto(s)

Enfermedad de Parkinson Secundaria/fisiopatología , Trastornos Respiratorios/etiología , Trastornos Respiratorios/fisiopatología , Animales , Fenómenos Biomecánicos , Colágeno/metabolismo , Hipercapnia/fisiopatología , Pulmón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Microinyecciones , Neostriado , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Pletismografía , Alveolos Pulmonares/metabolismo , Frecuencia Respiratoria , Costillas/fisiopatología

RESUMEN

The carotid body (CB) chemoreceptors sense changes in arterial blood gases. Upon stimulation CB chemoreceptors cells release one or more transmitters to excite sensory nerve fibers of the carotid sinus nerve. While several neurotransmitters have been described to contribute to the CB chemosensory process less is known about modulatory molecules. Recent data suggest that erythropoietin (Epo) is involved in the control of ventilation, and it has been shown that Epo receptor is constitutively expressed in the CB chemoreceptors, suggesting a possible role for Epo in regulation of CB function. Therefore, in the present study we aimed to determine whether exogenous applications of Epo modulate the hypoxic and hypercapnic CB chemosensory responses. Carotid sinus nerve discharge was recorded in-situ from anesthetized adult male and female Sprague Dawley rats (350 g, n = 8) before and after systemic administration of Epo (2000 UI/kg). CB-chemosensitivity to hypoxia and hypercapnia was calculated by exposing the rat to FiO2 5-15% and FiCO2 10% gas mixtures, respectively. During baseline recordings at normoxia, we found no effects of Epo on CB activity both in male and female rats. In addition, Epo had no effect on maximal CB response to hypoxia in both male and female rats. Epo injections enhanced the maximum CB chemosensory response to hypercapnia in female rats (before vs. after Epo, 72.5 ± 7.1 Hz vs. 108.3 ± 6.9 Hz, p < 0.05). In contrast, Epo had no effect on maximum CB chemosensory response to hypercapnia in male rats but significantly increased the response recovery times (time required to return to baseline discharge following hypercapnic stimulus) from 2.1 ± 0.1 s to 8.2 ± 2.3 s (p < 0.05). Taken together, our results suggest that Epo has some modulatory effect on the CB chemosensory response to hypercapnia.

Asunto(s)

Cuerpo Carotídeo/fisiología , Células Quimiorreceptoras/fisiología , Eritropoyetina/farmacología , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Animales , Femenino , Masculino , Ratas , Ratas Sprague-Dawley