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1.
Am J Physiol Regul Integr Comp Physiol ; 327(4): R423-R441, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39102465

RESUMO

There is evidence that astrocytes modulate synaptic transmission in the nucleus tractus solitarius (NTS) interacting with glutamatergic and purinergic mechanisms. Here, using in situ working heart-brainstem preparations, we evaluated the involvement of astrocyte and glutamatergic/purinergic neurotransmission in the processing of autonomic and respiratory pathways in the NTS of control and rats exposed to sustained hypoxia (SH). Baseline autonomic and respiratory activities and the responses to chemoreflex activation (KCN) were evaluated before and after microinjections of fluorocitrate (FCt, an astrocyte metabolic inhibitor), kynurenic acid, and pyridoxalphosphate-6-azophenyl-2',4'-disulfonate (PPADS) (nonselective antagonists of glutamatergic and purinergic receptors) into the rostral aspect of the caudal commissural NTS. FCt had no effects on the baseline parameters evaluated but reduced the bradycardic response to chemoreflex activation in SH rats. FCt combined with kynurenic acid and PPADS in control rats reduced the baseline duration of expiration, which was attenuated after SH. FCt produced a large increase in PN frequency discharge in control rats, which was reduced after SH, indicating a reduction in the astrocyte modulation after SH. The data show that 1) the bradycardic component of the peripheral chemoreflex is reduced in SH rats after astrocytes inhibition, 2) the inhibition of astrocytes in the presence of double antagonists in the NTS affects the modulation of baseline duration of expiration in control but not in SH rats, and 3) the autonomic and respiratory responses to chemoreflex activation are mediated by glutamatergic and purinergic receptors in the rostral aspect of the caudal commissural NTS.NEW & NOTEWORTHY Our findings indicate that the neurotransmission of autonomic and respiratory components of the peripheral chemoreflex in the nucleus tractus solitarius (NTS) is mediated by glutamatergic and purinergic mechanisms and reveal a selective involvement of NTS astrocytes in controlling the chemoreflex parasympathetic response in rats exposed to sustained hypoxia (SH) and the baseline duration of expiration mainly in control rats, indicating a selective role for astrocytes modulation in the NTS of control and SH rats.


Assuntos
Astrócitos , Ácido Glutâmico , Hipóxia , Receptores Purinérgicos , Núcleo Solitário , Transmissão Sináptica , Animais , Núcleo Solitário/metabolismo , Núcleo Solitário/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Hipóxia/fisiopatologia , Hipóxia/metabolismo , Masculino , Ácido Glutâmico/metabolismo , Receptores Purinérgicos/metabolismo , Ratos , Ratos Wistar , Ácido Cinurênico/farmacologia , Células Quimiorreceptoras/metabolismo , Células Quimiorreceptoras/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Citratos/farmacologia , Fatores de Tempo
2.
J Physiol ; 601(24): 5527-5551, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37747109

RESUMO

Carotid body pathophysiology is associated with many cardiovascular-respiratory-metabolic diseases. This pathophysiology reflects both hyper-sensitivity and hyper-tonicity. From both animal models and human patients, evidence indicates that amelioration of this pathophysiological signalling improves disease states such as a lowering of blood pressure in hypertension, a reduction of breathing disturbances with improved cardiac function in heart failure (HF) and a re-balancing of autonomic activity with lowered sympathetic discharge. Given this, we have reviewed the mechanisms of carotid body hyper-sensitivity and hyper-tonicity across disease models asking whether there is uniqueness related to specific disease states. Our analysis indicates some commonalities and some potential differences, although not all mechanisms have been fully explored across all disease models. One potential commonality is that of hypoperfusion of the carotid body across hypertension and HF, where the excessive sympathetic drive may reduce blood flow in both models and, in addition, lowered cardiac output in HF may potentiate the hypoperfusion state of the carotid body. Other mechanisms are explored that focus on neurotransmitter and signalling pathways intrinsic to the carotid body (e.g. ATP, carbon monoxide) as well as extrinsic molecules carried in the blood (e.g. leptin); there are also transcription factors found in the carotid body endothelium that modulate its activity (Krüppel-like factor 2). The evidence to date fully supports that a better understanding of the mechanisms of carotid body pathophysiology is a fruitful strategy for informing potential new treatment strategies for many cardiovascular, respiratory and metabolic diseases, and this is highly relevant clinically.


Assuntos
Corpo Carotídeo , Insuficiência Cardíaca , Hipertensão , Doenças Metabólicas , Animais , Humanos , Corpo Carotídeo/fisiologia , Coração
3.
Exp Physiol ; 108(11): 1434-1445, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37632713

RESUMO

Sustained hypoxia (SH) in mice induces changes in the respiratory pattern and increase in the parasympathetic tone to the heart. Among adenosine G-protein-coupled receptors (GPCRs), the A2A receptors are especially important in mediating adenosine actions during hypoxia due to their expression in neurons involved with the generation and modulation of the autonomic and respiratory functions. Herein, we performed an in vivo evaluation of the baseline cardiovascular and respiratory parameters and their changes in response to SH in knockout mice for A2A receptors (A2A KO). SH produced similar and significant reductions in mean arterial pressure and heart rate in both wild-type (WT) and A2A KO mice when compared to their respective normoxic controls. Mice from WT and A2A KO groups submitted to normoxia or SH presented similar cardiovascular responses to peripheral chemoreflex activation (KCN). Under normoxic conditions A2A KO mice presented a respiratory frequency (fR ) significantly higher in relation to the WT group, which was reduced in response to SH. These data show that the lack of adenosine A2A receptors in mice does not affect the cardiovascular parameters and the autonomic responses to chemoreflex activation in control (normoxia) and SH mice. We conclude that the A2A receptors play a major role in the control of respiratory frequency and in the tachypnoeic response to SH in mice. NEW FINDINGS: What is the central question of this study? Are cardiovascular and respiratory parameters and their changes in response to sustained hypoxia (SH) altered in adenosine A2A receptor knockout mice? What is the main finding and its importance? Cardiovascular parameters and their changes in response to SH were not altered in A2A KO mice. The respiratory frequency in A2A KO was higher than in WT mice. In response to SH the respiratory frequency increased in WT, while it was reduced in A2A KO mice. A2A receptors play a major role in the modulation of respiratory frequency and in the tachypnoeic response to SH in mice.


Assuntos
Adenosina , Sistema Cardiovascular , Animais , Camundongos , Hipóxia , Camundongos Knockout , Receptor A2A de Adenosina/metabolismo
4.
Adv Exp Med Biol ; 1427: 23-33, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37322332

RESUMO

The main question of this chapter is as follows: What is the contribution of changes in the sympathetic-respiratory coupling to the hypertension observed in some experimental models of hypoxia? Although there is evidence supporting the concept that sympathetic-respiratory coupling is increased in different models of experimental hypoxia [chronic intermittent hypoxia (CIH) and sustained hypoxia (SH)], it was also observed that in some strains of rats and in mice, these experimental models of hypoxia do not affect the sympathetic-respiratory coupling and the baseline arterial pressure. The data from studies performed in rats (different strains, male and female, and in the natural sleep cycle) and mice submitted to chronic CIH or SH are critically discussed. The main message from these studies performed in freely moving rodents and in the in situ working heart-brainstem preparation is that experimental hypoxia changes the respiratory pattern, which correlates with increased sympathetic activity and may explain the hypertension observed in male and female rats previously submitted to CIH or SH.


Assuntos
Hipertensão , Roedores , Ratos , Masculino , Feminino , Camundongos , Animais , Ratos Wistar , Sistema Nervoso Simpático , Hipertensão/etiologia , Hipóxia/complicações
5.
J Physiol ; 600(9): 2049-2075, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35294064

RESUMO

Twenty-five years ago, a new physiological preparation called the working heart-brainstem preparation (WHBP) was introduced with the claim it would provide a new platform allowing studies not possible before in cardiovascular, neuroendocrine, autonomic and respiratory research. Herein, we review some of the progress made with the WHBP, some advantages and disadvantages along with potential future applications, and provide photographs and technical drawings of all the customised equipment used for the preparation. Using mice or rats, the WHBP is an in situ experimental model that is perfused via an extracorporeal circuit benefitting from unprecedented surgical access, mechanical stability of the brain for whole cell recording and an uncompromised use of pharmacological agents akin to in vitro approaches. The preparation has revealed novel mechanistic insights into, for example, the generation of distinct respiratory rhythms, the neurogenesis of sympathetic activity, coupling between respiration and the heart and circulation, hypothalamic and spinal control mechanisms, and peripheral and central chemoreceptor mechanisms. Insights have been gleaned into diseases such as hypertension, heart failure and sleep apnoea. Findings from the in situ preparation have been ratified in conscious in vivo animals and when tested have translated to humans. We conclude by discussing potential future applications of the WHBP including two-photon imaging of peripheral and central nervous systems and adoption of pharmacogenetic tools that will improve our understanding of physiological mechanisms and reveal novel mechanisms that may guide new treatment strategies for cardiorespiratory diseases.


Assuntos
Tronco Encefálico , Coração , Animais , Tronco Encefálico/fisiologia , Fenômenos Fisiológicos Cardiovasculares , Coração/fisiologia , Pulmão , Camundongos , Ratos , Respiração
6.
J Physiol ; 599(21): 4925-4948, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34510468

RESUMO

Active expiration is essential for increasing pulmonary ventilation during high chemical drive (hypercapnia). The lateral parafacial (pFL ) region, which contains expiratory neurones, drives abdominal muscles during active expiration in response to hypercapnia. However, the electrophysiological properties and synaptic mechanisms determining the activity of pFL expiratory neurones, as well as the specific conditions for their emergence, are not fully understood. Using whole cell electrophysiology and single cell quantitative RT-PCR techniques, we describe the intrinsic electrophysiological properties, the phenotype and the respiratory-related synaptic inputs to the pFL expiratory neurones, as well as the mechanisms for the expression of their expiratory activity under conditions of hypercapnia-induced active expiration, using in situ preparations of juvenile rats. We also evaluated whether these neurones possess intrinsic CO2 /[H+ ] sensitivity and burst generating properties. GABAergic and glycinergic inhibition during inspiration and expiration suppressed the activity of glutamatergic pFL expiratory neurones in normocapnia. In hypercapnia, these neurones escape glycinergic inhibition and generate burst discharges at the end of expiration. Evidence for the contribution of post-inhibitory rebound, CaV 3.2 isoform of T-type Ca2+ channels and intracellular [Ca2+ ] is presented. Neither intrinsic bursting properties, mediated by persistent Na+ current, nor CO2 /[H+ ] sensitivity or expression of CO2 /[H+ ] sensitive ion channels/receptors (TASK or GPR4) were observed. On the other hand, hyperpolarisation-activated cyclic nucleotide-gated and twik-related K+ leak channels were recorded. Post-synaptic disinhibition and the intrinsic electrophysiological properties of glutamatergic neurones play important roles in the generation of the expiratory oscillations in the pFL region during hypercapnia in rats. KEY POINTS: Hypercapnia induces active expiration in rats and the recruitment of a specific population of expiratory neurones in the lateral parafacial (pFL ) region. Post-synaptic GABAergic and glycinergic inhibition both suppress the activity of glutamatergic pFL neurones during inspiratory and expiratory phases in normocapnia. Hypercapnia reduces glycinergic inhibition during expiration leading to burst generation by pFL neurones; evidence for a contribution of post-inhibitory rebound, voltage-gated Ca2+ channels and intracellular [Ca2+ ] is presented. pFL glutamatergic expiratory neurones are neither intrinsic burster neurones, nor CO2 /[H+ ] sensors, and do not express CO2 /[H+ ] sensitive ion channels or receptors. Post-synaptic disinhibition and the intrinsic electrophysiological properties of glutamatergic neurones both play important roles in the generation of the expiratory oscillations in the pFL region during hypercapnia in rats.


Assuntos
Expiração , Neurônios , Animais , Hipercapnia , Ratos
7.
Exp Physiol ; 106(3): 759-770, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33501717

RESUMO

NEW FINDINGS: What is the central question of this study? Do mice submitted to sustained hypoxia present autonomic and respiratory changes similarly to rats? What is the main finding and its importance? Arterial pressure in the normal range, reduced baseline heart rate and tachypnoea were observed in behaving sustained hypoxia mice. Recordings in the in situ preparation of mice submitted to sustained hypoxia show an increase in cervical vagus nerve activity and a simultaneous reduction in thoracic sympathetic nerve activity correlated with changes in the respiratory cycle. Therefore, mice are an important model for studies on the modulation of sympathetic activity to the cardiovascular system and the vagus innervation of the upper airways due to changes in the respiratory network induced by sustained hypoxia. ABSTRACT: Short-term sustained hypoxia (SH) in rats induces sympathetic overactivity and hypertension due to changes in sympathetic-respiratory coupling. However, there are no consistent data about the effect of SH on mice due to the different protocols of hypoxia and difficulties associated with the handling of these rodents under different experimental conditions. In situ recordings of autonomic and respiratory nerves in SH mice have not been performed yet. Herein, we evaluated the effects of SH ( FiO2  = 0.1 for 24 h) on baseline mean arterial pressure (MAP), heart rate (HR), respiratory frequency (fR ) and responses to chemoreflex activation in behaving SH mice. A characterization of changes in cervical vagus (cVN), thoracic sympathetic (tSN), phrenic (PN) and abdominal (AbN) nerves in SH mice using the in situ working heart-brainstem preparation was also performed. SH mice presented normal MAP, significant reduction in baseline HR, increase in baseline fR , as well as increase in the magnitude of bradycardic response to chemoreflex activation. In in situ preparations, SH mice presented a reduction in PN discharge frequency, and increases in the time of expiration and incidence of late-expiratory bursts in AbN activity. Nerve recordings also indicated a significant increase in cVN activity and a significant reduction in tSN activity during expiration in SH mice. These findings make SH mice an important experimental model for better understanding how changes in the respiratory network may impact on the modulation of vagal control to the upper airways, as well as in the sympathetic activity to the cardiovascular system.


Assuntos
Hipóxia , Sistema Nervoso Simpático , Animais , Expiração/fisiologia , Camundongos , Ratos , Ratos Wistar , Respiração , Sistema Nervoso Simpático/fisiologia
8.
J Physiol ; 597(7): 1935-1956, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30747446

RESUMO

KEY POINTS: Acute hypoxia induces active expiration in rectus abdominis (RA) muscles in conscious freely moving rats, although its overall contribution is smaller than in internal oblique (IO) muscles. Tonically active and silent RA motoneurons were identified in in vitro preparations of rat spinal cords. Sustained hypoxia (SH) increased the synaptic strength and induced morphological changes in tonically active RA motoneurons. Expiratory RA motoneurons were recorded in the in situ preparation and SH enhanced both the excitability and the synaptic transmission in those firing during the stage 2 expiration. The present study contributes to a better understanding of the mechanisms involved in SH recruitment of RA motoneurons to induce active expiration in rats. ABSTRACT: Rectus abdominis (RA) motoneurons translate the complex respiratory brainstem inputs into effective muscle contractions. Despite their fundamental role in respiration, their functional and morphological properties are not fully understood. In the present study, we investigated for the first time the contribution of RA muscle to active expiration and characterized RA motoneurons regarding their electrical, molecular and morphological profiles in control rats and in rats submitted to sustained hypoxia (SH), which induces chronic recruitment of abdominal muscles. Electromyographic experiments in conscious freely moving control rats and SH rats showed that RA contributes to active expiration induced by acute hypoxia, although its contribution is smaller than in internal oblique muscles. in vitro whole-cell patch clamp recordings from RA motoneurons revealed two populations of cells: tonically active and silent. SH induced hyperexcitability in the tonically active cells by changing their action potential properties, and EPSCs. Three-dimensional morphological reconstructions of these cells showed that SH increased the dendritic complexity, stimulated the appearance of dendrite spines, and increased the somatic area and volume. Physiologically identified RA motoneurons, firing in two distinct phases of expiration, were recorded in the brainstem-spinal cord in situ preparation of rats. SH increased the firing frequency and EPSCs of neurons firing during stage 2 expiration. Taken together, our results show that RA motoneurons reconfigure their biophysical properties, morphology and synaptic strength to produce an appropriate expiratory drive in response to SH in rats.


Assuntos
Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia , Músculo Esquelético/inervação , Oxigênio/administração & dosagem , Animais , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/fisiologia , Fenômenos Eletrofisiológicos , Masculino , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Fenômenos Fisiológicos Respiratórios , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia
9.
J Physiol ; 597(11): 2903-2923, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30993693

RESUMO

KEY POINTS: Rats subjected to sustained hypoxia (SH) present increases in arterial pressure (AP) and in glutamatergic transmission in the nucleus tractus solitarius (NTS) neurons sending projections to ventrolateral medulla (VLM). Treatment with minocycline, a microglial inhibitor, attenuated the increase in AP in response to SH. The increase in the amplitude of glutamatergic postsynaptic currents in the NTS-VLM neurons, induced by postsynaptic mechanisms, was blunted by minocycline treatment. The number of microglial cells was increased in the NTS of vehicle-treated SH rats but not in the NTS of minocycline-treated rats. The data show that microglial recruitment/proliferation induced by SH is associated with the enhancement of excitatory neurotransmission in NTS-VLM neurons, which may contribute to the observed increase in AP. ABSTRACT: Short-term sustained hypoxia (SH) produces significant autonomic and respiratory adjustments and triggers activation of microglia, the resident immune cells in the brain. SH also enhances glutamatergic neurotransmission in the NTS. Here we evaluated the role of microglial activation induced by SH on the cardiovascular changes and mainly on glutamatergic neurotransmission in NTS neurons sending projections to the ventrolateral medulla (NTS-VLM), using a microglia inhibitor (minocycline). Direct measurement of arterial pressure (AP) in freely moving rats showed that SH (24 h, fraction of inspired oxygen ( FI,O2 ) 0.1) in vehicle and minocycline (30 mg/kg i.p. for 3 days)-treated groups produced a significant increase in AP in relation to control groups under normoxic conditions, but this increase was significantly lower in minocycline-treated rats. Whole-cell patch-clamp recordings revealed that the active properties of the membrane were comparable among the groups. Nevertheless, the amplitudes of glutamatergic postsynaptic currents, evoked by tractus solitarius stimulation, were increased in NTS-VLM neurons of SH rats. Changes in asynchronous glutamatergic currents indicated that the observed increase in amplitude was due to postsynaptic mechanisms. These changes were blunted in the SH group previously treated with minocycline. Using immunofluorescence, we found that the number of microglial cells was increased in the NTS of vehicle-treated SH rats but not in the NTS neurons of minocycline-treated rats. Our data support the concept that microglial activation induced by SH is associated with the enhancement of excitatory neurotransmission in NTS-VLM neurons, which may contribute to the increase in AP observed in this experimental model.


Assuntos
Hipóxia/fisiopatologia , Minociclina/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Animais , Pressão Arterial/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores , Masculino , Microglia/fisiologia , Neurônios/fisiologia , Ratos Wistar , Núcleo Solitário/fisiologia
10.
J Neurophysiol ; 121(5): 1822-1830, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30892977

RESUMO

Sustained hypoxia (SH) activates chemoreceptors to produce cardiovascular and respiratory responses to bring the arterial partial pressure of O2 back to the physiological range. We evaluated the effect of SH (fraction of inspired O2 = 0.10, 24 h) on glutamatergic synaptic transmission and the interaction neuron-astrocyte in neurons of the nucleus tractus solitarii (NTS). Tractus solitarius (TS) fiber stimulation induced glutamatergic currents in neurons and astrocytes. SH increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/kainate) [-183 ± 122 pA (n = 10) vs. -353 ± 101 pA (n = 10)] and N-methyl-d-aspartate (NMDA) current amplitude [61 ± 10 pA (n = 7) vs. 102 ± 37 pA (n = 10)]. To investigate the effects of SH, we used fluoroacetate (FAC), an astrocytic inhibitor, which revealed an excitatory modulation on AMPA/kainate current and an inhibitory modulation of NMDA current in control rats. SH blunted the astrocytic modulation of AMPA [artificial cerebrospinal fluid (aCSF): -353 ± 101 pA vs. aCSF + FAC: -369 ± 76 pA (n = 10)] and NMDA currents [aCSF: 102 ± 37 pA vs. aCSF + FAC: 108 ± 32 pA (n = 10)]. SH increased AMPA current density [control: -6 ± 3.5 pA/pF (n = 6) vs. SH: -20 ± 12 pA/pF (n = 7)], suggesting changes in density, conductance, or affinity of AMPA receptors. SH produced no effect on astrocytic resting membrane potential, input resistance, and AMPA/kainate current. We conclude that SH decreased the neuron-astrocyte interaction at the NTS level, facilitating the glutamatergic transmission, which may contribute to the enhancement of cardiovascular and respiratory responses to baro- and chemoreflexes activation in SH rats. NEW & NOTEWORTHY Using an electrophysiological approach, we have shown that in nucleus tractus solitarii (NTS) from control rats, astrocytes modulate the AMPA and NMDA currents in NTS neurons, changing their excitability. Sustained hypoxia (SH) increased both glutamatergic currents in NTS neurons due to 1) a reduction in the astrocytic modulation and 2) an increase in the density of AMPA receptors. These new findings show the importance of neuron-astrocyte modulation in the excitatory synaptic transmission in NTS of control and SH rats.


Assuntos
Astrócitos/metabolismo , Ácido Glutâmico/farmacologia , Hipóxia/fisiopatologia , Núcleo Solitário/fisiopatologia , Transmissão Sináptica , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fluoracetatos/farmacologia , Hipóxia/metabolismo , Ácido Caínico/farmacologia , Masculino , Potenciais da Membrana , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Wistar , Núcleo Solitário/metabolismo
11.
Exp Physiol ; 104(9): 1408-1419, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31099915

RESUMO

NEW FINDINGS: What is the central question of this study? Chronic intermittent hypoxia (CIH) causes increased arterial pressure (AP), sympathetic overactivity and changes in expiratory modulation of sympathetic activity. However, changes in the short-term sleep-wake cycle pattern after CIH and their potential impact on cardiorespiratory parameters have not been reported previously. What is the main finding and its importance? Exposure to CIH for 10 days elevates AP in wakefulness and sleep but does not cause major changes in short-term sleep-wake cycle pattern. A higher incidence of muscular expiratory activity was observed in rats exposed to CIH only during wakefulness, indicating that active expiration is not required for the increase in AP in rats submitted to CIH. ABSTRACT: Chronic intermittent hypoxia (CIH) increases arterial pressure (AP) and changes sympathetic-respiratory coupling. However, the alterations in the sleep-wake cycle after CIH and their potential impact on cardiorespiratory parameters remain unknown. Here, we evaluated whether CIH-exposed rats present changes in their short-term sleep-wake cycle pattern and in cardiorespiratory parameters. Male Wistar rats (∼250 g) were divided into CIH and control groups. The CIH rats were exposed to 8 h day-1 of cycles of normoxia (fraction of inspired O2  = 0.208, 5 min) followed by hypoxia (fraction of inspired O2  = 0.06, 30-40 s) for 10 days. One day after CIH, electrocorticographic activity, cervical EMG, AP and heart rate were recorded for 3 h. Plethysmographic recordings were collected for 2 h. A subgroup of control and CIH rats also had the diaphragm and oblique abdominal muscle activities recorded. Chronic intermittent hypoxia did not alter the time for sleep onset, total time awake, durations of rapid eye movement (REM) and non-REM (NREM) sleep and number of REM episodes in the 3 h recordings. However, a significant increase in the duration of REM episodes was observed. The AP and heart rate were increased in all phases of the cycle in rats exposed to CIH. Respiratory frequency and ventilation were similar between groups in all phases, but tidal volume was increased during NREM and REM sleep in rats exposed to CIH. An increase in the incidence of active expiration during wakefulness was observed in rats exposed to CIH. The data show that CIH-related hypertension is not caused by changes in the sleep-wake cycle and suggest that active expiration is not required for the increase in AP in freely moving rats exposed to CIH.


Assuntos
Sistema Cardiovascular/fisiopatologia , Expiração/fisiologia , Hipóxia/fisiopatologia , Sono/fisiologia , Vigília/fisiologia , Animais , Pressão Arterial/fisiologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Wistar , Respiração , Sistema Nervoso Simpático/fisiopatologia
12.
Exp Physiol ; 104(1): 39-49, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30427561

RESUMO

NEW FINDINGS: What is the central question of this study? After sino-aortic denervation (SAD), rats present normal levels of mean arterial pressure (MAP), high MAP variability and changes in breathing. However, mechanisms involved in SAD-induced respiratory changes and their impact on the modulation of sympathetic activity remain unclear. Herein, we characterized the firing frequency of medullary respiratory neurons after SAD. What is the main finding and its importance? Sino-aortic denervation-induced prolonged inspiration was associated with a reduced interburst frequency of pre-inspiratory/inspiratory neurons and an increased long-term variability of late inspiratory neurons, but no changes were observed in the ramp-inspiratory and post-inspiratory neurons. This imbalance in the respiratory network might contribute to the modulation of sympathetic activity after SAD. ABSTRACT: In previous studies, we documented that after sino-aortic denervation (SAD) in rats there are significant changes in the breathing pattern, but no significant changes in sympathetic activity and mean arterial pressure compared with sham-operated rats. However, the neural mechanisms involved in the respiratory changes after SAD and the extent to which they might contribute to the observed normal sympathetic activity and mean arterial pressure remain unclear. Here, we hypothesized that after SAD, rats present with changes in the firing frequency of the ventral medullary inspiratory and post-inspiratory neurons. To test this hypothesis, male Wistar rats underwent SAD or sham surgery and 3 days later were surgically prepared for an in situ experiment. The duration of inspiration significantly increased in SAD rats. During inspiration, the total firing frequency of ramp-inspiratory, pre-inspiratory/inspiratory and late-inspiratory neurons was not different between groups. During post-inspiration, the total firing frequency of post-inspiratory neurons was also not different between groups. Furthermore, the data demonstrate a reduced interburst frequency of pre-inspiratory/inspiratory neurons and an increased long-term variability of late-inspiratory neurons in SAD compared with sham-operated rats. These findings indicate that the SAD-induced prolongation of inspiration was not accompanied by alterations in the total firing frequency of the ventral medullary respiratory neurons, but it was associated with changes in the long-term variability of late-inspiratory neurons. We suggest that the timing imbalance in the respiratory network in SAD rats might contribute to the modulation of presympathetic neurons after removal of baroreceptor afferents.


Assuntos
Pressão Arterial/fisiologia , Neurônios/fisiologia , Pressorreceptores/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Aorta/fisiologia , Hipertensão/fisiopatologia , Masculino , Ratos Wistar , Respiração
13.
Exp Physiol ; 104(9): 1371-1383, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31328309

RESUMO

NEW FINDINGS: What is the central question of this study? Adrenomedullin in the rostral ventrolateral medulla (RVLM) increases sympathetic activity; given that adrenomedullin is released during hypoxia, what are the effects of its agonism and antagonism in the RVLM after chronic intermitent hypoxia (CIH) exposure? What is the main finding and its importance? CIH exposure sensitizes adrenomedullin-dependent mechanisms in the RVLM, supporting its role as a sympathoexcitatory neuromodulator. A novel mechanism was identified for the generation of sympathetic overdrive and hypertension associated with hypoxia, providing potential guidance on new therapeutic approaches for controlling sympathetic hyperactivity in diseases such as sleep apnoea and neurogenic hypertension. ABSTRACT: Adrenomedullin in the rostral ventrolateral medulla (RVLM) has been shown to increase sympathetic activity whereas the antagonism of its receptors inhibited this autonomic activity lowering blood pressure in conditions of hypertension. Given that hypoxia is a stimulant for releasing adrenomedullin, we hypothesized that the presence of this peptide in the RVLM associated with chronic intermittent hypoxia (CIH) would cause sympathetic overdrive. Juvenile male rats (50-55 g) submitted to CIH (6% oxygen every 9 min, 8 h day-1 for 10 days) were studied in an arterially perfused in situ preparation where sympathetic activity was recorded. In control rats (n = 6), exogenously applied adrenomedullin in the RVLM raised baseline sympathetic activity when combined with episodic activation of peripheral chemoreceptors (KCN 0.05%, 5 times every 5 min). This sympathoexcitatory response was markedly amplified in rats previously exposed to CIH (n = 6). The antagonism of adrenomedullin receptors in the RVLM caused a significant reduction in sympathetic activity in the CIH group (n = 7), but not in controls (n = 8). The transient reflex-evoked sympathoexcitatory response to peripheral chemoreceptor stimulation was not affected by either adrenomedullin or adrenomedullin receptor antagonism in the RVLM of control and CIH rats. Our findings indicate that CIH sensitizes the sympathoexcitatory networks within the RVLM to adrenomedullin, supporting its role as an excitatory neuromodulator when intermittent hypoxia is present. These data reveal novel state-dependent mechanistic insights into the generation of sympathetic overdrive and provide potential guidance on possible unique approaches for controlling sympathetic discharge in diseases such as sleep apnoea and neurogenic hypertension.


Assuntos
Adrenomedulina/farmacologia , Hipóxia/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Bulbo/efeitos dos fármacos , Bulbo/fisiopatologia , Ratos , Síndromes da Apneia do Sono/fisiopatologia
14.
Am J Physiol Regul Integr Comp Physiol ; 315(5): R963-R971, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29949411

RESUMO

The carotid bodies are peripheral chemoreceptors and contribute to the homeostatic maintenance of arterial levels of O2, CO2, and [H+]. They have attracted much clinical interest recently because of the realization that aberrant signaling in these organs is associated with several pathologies including hypertension. Herein, we describe data suggesting that sympathetic overactivity in neurogenic hypertension is, at least in part, dependent on carotid body tonicity and hyperreflexia that is related to changes in the electrophysiological properties of chemoreceptive petrosal neurons. We present results showing critical roles for both ATP levels in the carotid bodies and expression of P2X3 receptors in petrosal chemoreceptive, but not baroreceptive, terminals in the etiology of carotid body tonicity and hyperreflexia. We discuss mechanisms that may underlie the changes in electrophysiological properties and P2X3 receptor expression in chemoreceptive petrosal neurons, as well as factors affecting ATP release by cells within the carotid bodies. Our findings support the notion of targeting the carotid bodies to reduce sympathetic outflow and arterial pressure, emphasizing the potential clinical importance of modulating purinergic transmission to treat pathologies associated with carotid body dysfunction but, importantly, sparing physiological chemoreflex function.


Assuntos
Corpo Carotídeo/fisiologia , Células Quimiorreceptoras/citologia , Hipertensão/fisiopatologia , Neurônios/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Plasticidade Celular , Humanos , Hipóxia/fisiopatologia
15.
Exp Physiol ; 103(4): 473-482, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29359403

RESUMO

NEW FINDINGS: What is the central question of this study? Chronic intermittent hypoxia (CIH) and one-kidney, one-clip experimental models lead to sympathetic overactivity and hypertension. The present study explored the impact of previous exposure to CIH on one-kidney, one-clip renal hypertension; we hypothesized that CIH potentiates its development. What is the main finding and its importance? The development of one-kidney, one-clip renal hypertension was attenuated by previous exposure to CIH, and this protective effect was eliminated by carotid body denervation. These findings indicate that inputs from peripheral chemoreceptors in CIH-preconditioned rats play a role in preventing the increase in sympathetic activity and arterial pressure induced by one-kidney, one-clip renal hypertension. ABSTRACT: Chronic intermittent hypoxia (CIH) and one-kidney, one-clip (1K, 1C) experimental models lead to sympathetic overactivity and hypertension. We hypothesized that previous exposure to CIH potentiates the development of 1K, 1C renal hypertension. Male rats were divided into the following four groups: Control-1K, 1C, maintained under normoxia followed by 1K, 1C surgery (n = 19); Control-Sham, maintained under normoxia, followed by sham surgery (n = 19); CIH-1K, 1C, exposed to CIH (10 days) and 1K, 1C surgery (n = 19); and CIH-Sham, exposed to CIH and sham surgery (n = 18). Animals were catheterized 8 days after 1K, 1C or Sham surgeries and cardiovascular and respiratory parameters recorded on the following day. Baseline mean arterial pressure was higher in Control-1K, 1C than in Control-Sham rats (P < 0.05) and was higher in CIH-1K, 1C than in CIH-Sham rats (P < 0.05). However, the increase in mean arterial pressure in CIH-1K, 1C animals was significantly blunted in comparison to Con-1K, 1C rats (P < 0.05), indicating that previous exposure to CIH attenuates the development of renal hypertension. Systemic administration of hexamethonium, a ganglionic blocker, promoted a larger hypotensive response in Con-1K, 1C compared with CIH-1K, 1C rats (P < 0.05), suggesting that sympathetic activity was attenuated in rats previously exposed to the CIH protocol. In addition, removal of the carotid bodies before 1K, 1C renal hypertension eliminated the protective effect of CIH preconditioning on the development of the 1K, 1C hypertension. We conclude that previous exposure to CIH attenuates the development of renal hypertension via a carotid body-dependent mechanism.


Assuntos
Hipertensão Renal/fisiopatologia , Hipóxia/fisiopatologia , Rim/fisiopatologia , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/fisiopatologia , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/fisiopatologia , Bloqueadores Ganglionares/farmacologia , Hexametônio/farmacologia , Hipertensão Renal/induzido quimicamente , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia
16.
Curr Hypertens Rep ; 20(1): 2, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29356918

RESUMO

PURPOSE OF REVIEW: Surgical removal of the baroreceptor afferents [sino-aortic denervation (SAD)] leads to a lack of inhibitory feedback to sympathetic outflow, which in turn is expected to result in a large increase in mean arterial pressure (MAP). However, few days after surgery, the sympathetic nerve activity (SNA) and MAP of SAD rats return to a range similar to that observed in control rats. In this review, we present experimental evidence suggesting that breathing contributes to control of SNA and MAP following SAD.The purpose of this review was to discuss studies exploring SNA and MAP regulation in SAD rats, highlighting the possible role of breathing in the neural mechanisms of this modulation of SNA. RECENT FINDINGS: Recent studies show that baroreceptor afferent stimulation or removal (SAD) results in changes in the respiratory pattern. Changes in the neural respiratory network and in the respiratory pattern must be considered among mechanisms involved in the modulation of the MAP after SAD.


Assuntos
Aorta/inervação , Pressão Arterial/fisiologia , Pressão Sanguínea/fisiologia , Seio Carotídeo/inervação , Pressorreceptores/fisiologia , Respiração , Animais , Aorta/fisiologia , Seio Carotídeo/fisiologia , Denervação/métodos , Hipertensão/fisiopatologia , Masculino , Rede Nervosa/fisiologia , Ratos , Sistema Nervoso Simpático/fisiologia
17.
Am J Physiol Regul Integr Comp Physiol ; 312(6): R864-R872, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28438764

RESUMO

Despite recent advances in the knowledge of the neural control of cardiovascular function, the cause of sympathetic overactivity in neurogenic hypertension remains unknown. Studies from our laboratory point out that rats submitted to chronic intermittent hypoxia (CIH), an experimental model of neurogenic hypertension, present changes in the central respiratory network that impact the pattern of sympathetic discharge and the levels of arterial pressure. In addition to the fine coordination of respiratory muscle contraction and relaxation, which is essential for O2 and CO2 pulmonary exchanges, neurons of the respiratory network are connected precisely to the neurons controlling the sympathetic activity in the brain stem. This respiratory-sympathetic neuronal interaction provides adjustments in the sympathetic outflow to the heart and vasculature during each respiratory phase according to the metabolic demands. Herein, we report that CIH-induced sympathetic over activity and mild hypertension are associated with increased frequency discharge of ventral medullary presympathetic neurons. We also describe that their increased frequency discharge is dependent on synaptic inputs, mostly from neurons of the brain stem respiratory network, rather than changes in their intrinsic electrophysiological properties. In perspective, we are taking into consideration the possibility that changes in the central respiratory rhythm/pattern generator contribute to increased sympathetic outflow and the development of neurogenic hypertension. Our experimental evidence provides support for the hypothesis that changes in the coupling of respiratory and sympathetic networks might be one of the unrevealed secrets of neurogenic hypertension in rats.


Assuntos
Pressão Arterial , Sistema Cardiovascular/inervação , Hipertensão/fisiopatologia , Pulmão/inervação , Respiração , Centro Respiratório/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Hipertensão/etiologia , Hipóxia/complicações , Hipóxia/fisiopatologia , Modelos Cardiovasculares , Vias Neurais/fisiopatologia
18.
Exp Physiol ; 102(9): 1100-1117, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28639723

RESUMO

NEW FINDINGS: What is the central question of this study? Sino-aortic denervated (SAD) rats present normal levels of sympathetic activity and mean arterial pressure. However, neural mechanisms regulating the sympathetic activity in the absence of arterial baroreceptors remain unclear. Considering that respiration modulates the sympathetic activity, we hypothesize that changes in the respiratory network contribute to keep the sympathetic outflow in the normal range after removal of arterial baroreceptors. What is the main finding and its importance? Despite longer inspiration observed in SAD rats, the respiratory-sympathetic coupling is working within a normal range of variation. These findings suggest that in the absence of arterial baroreceptors the respiratory modulation of sympathetic activity is maintained within the normal range. The activity of presympathetic neurons is under respiratory modulation, and changes in the central respiratory network may impact on the baseline sympathetic activity and mean arterial pressure. It is well known that after removal of baroreceptor afferents [sino-aortic denervation (SAD)], rats present an unexpected normal level of mean arterial pressure. We hypothesized that changes in the respiratory pattern and in the respiratory modulation of the sympathetic activity contribute to keep the sympathetic outflow within a normal range of variation in the absence of arterial baroreceptors in rats. To study these mechanisms, we recorded perfusion pressure and the activities of phrenic and thoracic sympathetic nerves in male juvenile rats using the working heart-brainstem preparation. The time of inspiration significantly increased in SAD rats, and this change was not dependent on the carotid bodies or on the vagal afferents. However, no changes were observed in the perfusion pressure or in the baseline thoracic sympathetic nerves in all phases of the respiratory cycle in SAD rats. Our data show that despite longer inspiratory activity, the baseline sympathetic activity is maintained at a normal level in SAD rats. These findings indicate that the respiratory-sympathetic coupling is normal after SAD and suggest that the respiratory modulation of sympathetic activity is maintained within the normal range after the removal of arterial baroreceptors.


Assuntos
Aorta/fisiologia , Inalação/fisiologia , Sistema Nervoso Simpático/fisiologia , Nervo Vago/fisiologia , Animais , Pressão Arterial/fisiologia , Artérias/fisiologia , Corpo Carotídeo/fisiologia , Denervação/métodos , Masculino , Neurônios/fisiologia , Pressorreceptores/fisiologia , Ratos , Ratos Wistar
19.
J Neurosci ; 35(17): 6903-17, 2015 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-25926465

RESUMO

Humans ascending to high altitudes are submitted to sustained hypoxia (SH), activating peripheral chemoreflex with several autonomic and respiratory responses. Here we analyzed the effect of short-term SH (24 h, FIO210%) on the processing of cardiovascular and respiratory reflexes using an in situ preparation of rats. SH increased both the sympatho-inhibitory and bradycardiac components of baroreflex and the sympathetic and respiratory responses of peripheral chemoreflex. Electrophysiological properties and synaptic transmission in the nucleus tractus solitarius (NTS) neurons, the first synaptic station of afferents of baroreflexes and chemoreflexes, were evaluated using brainstem slices and whole-cell patch-clamp. The second-order NTS neurons were identified by previous application of fluorescent tracer onto carotid body for chemoreceptor afferents or onto aortic depressor nerve for baroreceptor afferents. SH increased the intrinsic excitability of NTS neurons. Delayed excitation, caused by A-type potassium current (IKA), was observed in most of NTS neurons from control rats. The IKA amplitude was higher in identified second-order NTS neurons from control than in SH rats. SH also blunted the astrocytic inhibition of IKA in NTS neurons and increased the synaptic transmission in response to afferent fibers stimulation. The frequency of spontaneous excitatory currents was also increased in neurons from SH rats, indicating that SH increased the neurotransmission by presynaptic mechanisms. Therefore, short-term SH changed the glia-neuron interaction, increasing the excitability and excitatory transmission of NTS neurons, which may contribute to the observed increase in the reflex sensitivity of baroreflex and chemoreflex in in situ preparation.


Assuntos
Potenciais de Ação/fisiologia , Células Quimiorreceptoras/fisiologia , Hipóxia/patologia , Neuroglia/fisiologia , Núcleo Solitário/patologia , 4-Aminopiridina/farmacologia , Vias Aferentes/fisiologia , Aminoácidos , Animais , Barorreflexo/efeitos dos fármacos , Bicuculina/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Frequência Cardíaca/fisiologia , Técnicas In Vitro , Masculino , Bloqueadores dos Canais de Potássio/farmacologia , Pressorreceptores/efeitos dos fármacos , Ratos , Ratos Wistar , Sistema Nervoso Simpático/fisiopatologia
20.
Exp Physiol ; 101(11): 1359-1370, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27615272

RESUMO

NEW FINDINGS: What is the central question of this study? The arterial baroreflex regulates arterial pressure within a narrow range of variation. After sino-aortic denervation (SAD), rats show a large increase in arterial pressure variability, but mean arterial pressure levels remain similar to those of control rats. Considering that breathing influences the control of arterial pressure, the question is: to what extent does SAD cause changes in breathing? What is the main finding and its importance? Removal of arterial baroreceptors produced changes in breathing in rats, marked by a reduction in respiratory frequency, but not hypertension. These findings are indicative of a possible interaction of respiratory and autonomic neural mechanisms in the regulation of arterial pressure after SAD. Sino-aortic denervated (SAD) rats exhibit a mean arterial pressure (MAP) similar to that of control rats. Given that respiration modulates MAP, we hypothesized that conscious SAD rats show respiratory changes associated with the normal MAP. In this study, we evaluated the cardiovascular and respiratory activities and arterial blood gases in control and SAD rats. Male juvenile Wistar rats (postnatal day 19-21) were submitted to SAD, sham surgery or selective removal of the carotid bodies (CBX), and the three groups were evaluated 10 days after the surgery (SAD, n = 21; Sham, n = 18; and CBX, n = 13). The MAP in Sham, SAD and CBX groups was similar (P > 0.05), but the variability of MAP was significantly higher in SAD than in Sham and CBX rats (P < 0.0001). The duration of expiration and inspiration increased in SAD rats compared with Sham and CBX rats, which resulted in a reduced respiratory frequency and minute ventilation (P < 0.05). The arterial partial pressure of O2 and the haemoglobin saturation were reduced in SAD and CBX compared with Sham rats, whereas the arterial partial pressure of CO2 was increased in SAD compared with Sham rats. The short- and long-term respiratory variability were significantly higher in SAD than in Sham and CBX rats (P < 0.05). In addition, the reductions in MAP during deep breaths were greater in SAD than in Sham and CBX rats (P < 0.0001). The data show that SAD rats exhibit respiratory changes, which may be one of the compensatory mechanisms associated with the maintenance of normal levels of MAP in the absence of arterial baroreceptors.


Assuntos
Aorta/fisiologia , Pressão Arterial/fisiologia , Expiração/fisiologia , Inalação/fisiologia , Animais , Aorta/metabolismo , Artérias/metabolismo , Artérias/fisiologia , Barorreflexo/fisiologia , Dióxido de Carbono/metabolismo , Corpo Carotídeo/metabolismo , Corpo Carotídeo/fisiologia , Denervação/métodos , Masculino , Oxigênio/metabolismo , Pressorreceptores/metabolismo , Pressorreceptores/fisiologia , Ratos , Ratos Wistar , Nó Sinoatrial/metabolismo , Nó Sinoatrial/fisiologia
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