RESUMO
NEW FINDINGS: What is the central question of this study? Melanin-concentrating hormone (MCH) suppresses the hypercapnic chemoreflex: what is the mechanism by which this effect is produced? What is the main finding and its importance? MCH acting in the lateral hypothalamic area but not in the locus coeruleus in rats, in the light period, attenuates the hypercapnic chemoreflex. The data provide new insight into the role of MCH in the modulation of the hypercapnic ventilatory response. ABSTRACT: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide involved in a broad range of homeostatic functions including regulation of the hypercapnic chemoreflex. We evaluated whether MCH modulates the hypercapnic ventilatory response by acting in the lateral hypothalamic area (LHA) and/or in the locus coeruleus (LC). Here, we measured pulmonary ventilation ( V Ì E ${\dot V_{\rm{E}}}$ ), body temperature, electroencephalogram (EEG) and electromyogram (EMG) of unanaesthetized adult male Wistar rats before and after microinjection of MCH (0.4 mM) or MCH receptor 1 (MCH1-R) antagonist (SNAP-94847; 63 mM) into the LHA and LC, in room air and 7% CO2 conditions during wakefulness and sleep in the dark and light periods. MCH intra-LHA caused a decreased CO2 ventilatory response during wakefulness and sleep in the light period, while SNAP-94847 intra-LHA increased this response, during wakefulness in the light period. In the LC, MCH or the MCH1-R antagonist caused no change in the hypercapnic ventilatory response. Our results suggest that MCH, in the LHA, exerts an inhibitory modulation of the hypercapnic ventilatory response during the light-inactive period in rats.
Assuntos
Região Hipotalâmica Lateral , Hormônios Hipotalâmicos , Masculino , Ratos , Animais , Dióxido de Carbono , Ratos Wistar , Hormônios Hipotalâmicos/metabolismo , Hormônios Hipotalâmicos/farmacologia , HipercapniaRESUMO
Hypercapnia promotes an increase in pulmonary ventilation due to the stimulation of brainstem chemosensory cells that are connected to the respiratory network. Among these cells are the raphe serotonergic neurons which widely send projections to distinct central respiratory compartments. Nevertheless, the physiological role of specific raphe serotonergic projections to other chemosensitive sites on the emergence of hypercapnia ventilatory response in vivo still remains to be elucidated. Here we investigated whether the ventilatory response to hypercapnia requires serotonergic inputs to the chemosensitive cells of the retrotrapezoid nucleus (RTN) in the ventrolateral medulla. To test this, pulmonary ventilation was evaluated under baseline conditions and during hypercapnia (7% CO2) in unanesthetized juvenile Holtzman rats (60-90â¯g) that received bilateral microinjections of either vehicle (control) or anti-SERT-SAP (0.1â¯mM, 10â¯pmol/100â¯nl) toxin in the RTN to retrogradely destroy serotonergic afferents to this region. Fifteen days after microinjections, baseline ventilation was not different between anti-SERT-SAP (nâ¯=â¯8) and control animals (nâ¯=â¯9). In contrast, the ablation of RTN-projecting serotonergic neurons markedly attenuated the hypercapnia-induced increase in respiratory frequency which was correlated with reduced numbers of serotonergic neurons in the raphe obscurus and magnus, but not in the raphe pallidus. The increase in tidal volume during hypercapnia was not significantly affected by anti-SERT-SAP microinjections in the RTN. Our data indicate that serotoninergic neurons that send projections to the RTN region are required for the processing of ventilatory reflex response during exposure to high CO2 in unanesthetized conditions.
Assuntos
Hipercapnia , Núcleos da Rafe , Animais , Dióxido de Carbono , Bulbo , Ventilação Pulmonar , Ratos , Ratos Wistar , RespiraçãoRESUMO
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.
Assuntos
Diafragma/fisiopatologia , Expiração , Hipercapnia/fisiopatologia , Núcleos da Rafe/fisiopatologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Músculos Abdominais/inervação , Músculos Abdominais/fisiopatologia , Animais , Diafragma/inervação , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Muscimol/farmacologia , Contração Muscular , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/farmacologia , Sono , VigíliaRESUMO
The acid-base status is a tightly regulated physiological process, resulting from a balance of ions in the organism relevant to acid-base. The efficiency of the regulatory systems importantly determines the compensatory pH changes for a given disturb. Vertebrates minimize (or compensate) an acid-base disturb by general processes, which include ion transfer and/or PCO2 changes. Acid-base adjustment in fish is predominantly achieved by branchial exchange of acid-base relevant ions with correlated change in plasma HCO3- levels. Conversely, land vertebrates change blood PCO2 through ventilatory process and hence respiratory control of acid-base regulation plays an important role as a compensatory mechanism. Lungfishes (Dipnoi) have central position on vertebrate's evolution being considered as the sister group to the tetrapods. With an aquatic life mode, lungfish share similarities of respiratory function with tetrapods. This article reviews evidence showing that lungfish's respiratory system regulates acid-base status, like terrestrial ectothermic vertebrates. In the South American lungfish, Lepidosiren paradoxa, the presence of central CO2/pH chemoreceptors was unequivocally described. Also, the blood PCO2 and acid-base status are typical of a terrestrial vertebrate. These aspects are discussed under different environmental conditions that require respiratory acid-base adjustments, such as, exposure to hypercarbia, hypoxia, high temperature and aestivation. Interesting questions regarding the location and cell phenotype of CO2/pH central and peripheral chemoreceptors remain an open field to be explored in lungfish.
Assuntos
Equilíbrio Ácido-Base/fisiologia , Peixes/fisiologia , Pulmão/fisiologia , Vertebrados/fisiologia , Animais , Dióxido de Carbono/metabolismo , Hipóxia Celular/fisiologia , Células Quimiorreceptoras/metabolismo , Células Quimiorreceptoras/fisiologia , Peixes/sangue , Peixes/metabolismo , Brânquias/metabolismo , Brânquias/fisiologia , Temperatura Alta , Concentração de Íons de Hidrogênio , Transporte de Íons/fisiologia , Pulmão/metabolismo , Oxigênio/metabolismo , Respiração , Vertebrados/metabolismoRESUMO
NEW FINDINGS: What is the central question of this study? ATP is known to modulate the chemosensitivity of some brain areas. However, whether the ATP contributes specifically to the mechanism of chemoreception in the lateral hypothalamus/perifornical area (LH/PFA) remains to be determined. What is the main finding and its importance? ATP, acting on the LH/PFA, enhances the hypercapnic ventilatory response in rats during wakefulness, in the dark period. Our results highlight the importance of ATP as a modulator of central chemoreception and provide new insight regarding the mechanisms involved in LH/PFA chemosensitivity and the sleep-wake differences in the CO2 /H+ -dependent drive to breathe. ABSTRACT: The lateral hypothalamus/perifornical area (LH/PFA) is a central chemoreceptor site, which acts in an arousal state-dependent manner. It has been shown that purinergic signalling through ATP influences the CO2 /H+ responsiveness of other chemosensitive regions, but it is unknown whether ATP is also involved in the mechanisms that underlie LH/PFA chemoreception. Here, we studied the effects of microdialysis of a P2X-receptor agonist [α,ß-methylene ATP (α,ß-meATP), 10 mm] and a non-selective P2-receptor antagonist [pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS), 1 mm] into the LH/PFA of conscious rats on ventilation in room air and in 7% CO2 . In the dark (active) phase, but not in the light, microdialysis of α,ß-meATP caused an augmented hypercapnic ventilatory response during wakefulness, but not during non-REM sleep (P < 0.001). PPADS caused no change in CO2 ventilatory responses in either the dark period or the light period. Our data suggest that ATP in LH/PFA contributes to the hypercapnic ventilatory response in conscious rats during wakefulness in the dark phase of the diurnal cycle.
Assuntos
Trifosfato de Adenosina/metabolismo , Dióxido de Carbono/metabolismo , Células Quimiorreceptoras/metabolismo , Região Hipotalâmica Lateral/metabolismo , Ventilação Pulmonar/fisiologia , Trifosfato de Adenosina/análogos & derivados , Animais , Células Quimiorreceptoras/efeitos dos fármacos , Hipercapnia/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Ventilação Pulmonar/efeitos dos fármacos , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Ratos , Ratos Wistar , Respiração/efeitos dos fármacos , Sono/efeitos dos fármacos , Sono/fisiologia , Vigília/efeitos dos fármacos , Vigília/fisiologiaRESUMO
NEW FINDINGS: What is the central question of this study? What is the relationship between neuroanatomical and functional respiratory changes in an experimental model of Parkinson's disease? What is the main finding and its importance? Sixty days after induction of Parkinson's disease in a rat model, there are decreases in baseline breathing and in the number of neurons, density of the neurokinin-1 receptor and density of astrocytes in the ventrolateral respiratory region. These results provide the first evidence that neuroanatomical changes occur before functional respiratory deficits in a Parkinson's disease model and that there is a positive correlation between those sets of changes. The neuroanatomical changes impair respiratory activity and are presumably a major cause of the respiratory problems observed in Parkinson's disease. ABSTRACT: We showed previously that 60 days after the induction of Parkinson's disease (PD) in a rat model, there are decreases in baseline breathing and in the number of phox2b-expressing neurons of the retrotrapezoid nucleus (RTN) and nucleus of the solitary tract (NTS), as well as a reduction in the density of the neurokinin-1 receptor (NK1r) in the pre-Bötzinger complex (preBötC) and rostral ventrolateral respiratory group (rVRG). Here, our aim was to evaluate the correlation between neuroanatomical and functional respiratory changes in an experimental model of PD. Male Wistar rats with bilateral injections of 6-hydroxydopamine (6-OHDA, 24 µg µl-1 ) or vehicle into the striatum had respiratory parameters assessed by whole-body plethysmography 1 day before and 30, 40 or 60 days after the ablation. From the 30th day after the ablation, we observed a reduction in the number of phox2b neurons in the RTN and NTS and a reduction in the density of astrocytes in the rVRG. At 40 days after the ablation, we observed decreases in the density of NK1r in the preBötC and rVRG and of astrocytes in the RTN region. At 60 days, we observed a reduction in the density of astrocytes in the NTS and preBötC regions. The functional data showed changes in the resting and hypercapnia-induced respiratory rates and tidal volume from days 40-60 after injury. Our data suggest that the neuroanatomical changes impair respiratory activity and are presumably a major cause of the respiratory problems observed in PD.
Assuntos
Neurônios/patologia , Doença de Parkinson/fisiopatologia , Centro Respiratório/fisiopatologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Proteínas de Homeodomínio/metabolismo , Hipercapnia/metabolismo , Hipercapnia/fisiopatologia , Masculino , Modelos Teóricos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxidopamina/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Ratos , Ratos Wistar , Receptores da Neurocinina-1/metabolismo , Respiração/efeitos dos fármacos , Centro Respiratório/efeitos dos fármacos , Centro Respiratório/metabolismo , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Núcleo Solitário/fisiopatologia , Fatores de Transcrição/metabolismoRESUMO
The mechanisms responsible for the onset of respiratory activity during fetal life are unknown. The onset of respiratory rhythm may be a consequence of the genetic program of each of the constituents of the respiratory network, so they start to interact and generate respiratory cycles when reaching a certain degree of maturation. Alternatively, generation of cycles might require the contribution of recently formed sensory inputs that will trigger oscillatory activity in the nascent respiratory neural network. If this hypothesis is true, then sensory input to the respiratory generator must be already formed and become functional before the onset of fetal respiration. In this review, we evaluate the timing of the onset of the respiratory rhythm in comparison to the appearance of receptors, neurotransmitter machinery, and afferent projections provided by two central chemoreceptive nuclei, the raphe and locus coeruleus nuclei.
Assuntos
Desenvolvimento Fetal/fisiologia , Locus Cerúleo/fisiologia , Neurônios/fisiologia , Núcleos da Rafe/fisiologia , Respiração , Mecânica Respiratória/fisiologia , Potenciais de Ação/fisiologia , Animais , HumanosRESUMO
Astrocytes perform various homeostatic functions in the nervous system beyond that of a supportive or metabolic role for neurons. A growing body of evidence indicates that astrocytes are crucial for central respiratory chemoreception. This review presents a classical overview of respiratory central chemoreception and the new evidence for astrocytes as brainstem sensors in the respiratory response to hypercapnia. We review properties of astrocytes for chemosensory function and for modulation of the respiratory network. We propose that astrocytes not only mediate between CO2/H+ levels and motor responses, but they also allow for two emergent functions: (1) Amplifying the responses of intrinsic chemosensitive neurons through feedforward signaling via gliotransmitters and; (2) Recruiting non-intrinsically chemosensitive cells thanks to volume spreading of signals (calcium waves and gliotransmitters) to regions distant from the CO2/H+ sensitive domains. Thus, astrocytes may both increase the intensity of the neuron responses at the chemosensitive sites and recruit of a greater number of respiratory neurons to participate in the response to hypercapnia.