RESUMO
BACKGROUND: Lipopolysaccharide (LPS)-induced systemic inflammation (SI) is associated with neuroinflammation in the brain, hypotension, tachycardia, and multiple organs dysfunctions. Considering that during SI these important cardiovascular and inflammatory changes take place, we measured the sensitivity of the cardiovascular reflexes baroreflex, chemoreflex, and Bezold-Jarisch that are key regulators of hemodynamic function. We also evaluated neuroinflammation in the nucleus tractus solitarius (NTS), the first synaptic station that integrates peripheral signals arising from the cardiovascular and inflammatory status. METHODS: We combined cardiovascular recordings, immunofluorescence, and assays of inflammatory markers in male Wistar rats that receive iv administration of LPS (1.5 or 2.5 mg kg-1) to investigate putative interactions of the neuroinflammation in the NTS and in the anteroventral preoptic region of the hypothalamus (AVPO) with the short-term regulation of blood pressure and heart rate. RESULTS: LPS induced hypotension, tachycardia, autonomic disbalance, hypothermia followed by fever, and reduction in spontaneous baroreflex gain. On the other hand, during SI, the bradycardic component of Bezold-Jarisch and chemoreflex activation was increased. These changes were associated with a higher number of activated microglia and interleukin (IL)-1ß levels in the NTS. CONCLUSIONS: The present data are consistent with the notion that during SI and neuroinflammation in the NTS, rats have a reduced baroreflex gain, combined with an enhancement of the bradycardic component of Bezold-Jarisch and chemoreflex despite the important cardiovascular impairments (hypotension and tachycardia). These changes in the cardiac component of Bezold-Jarisch and chemoreflex may be beneficial during SI and indicate that the improvement of theses reflexes responsiveness though specific nerve stimulations may be useful in the management of sepsis.
Assuntos
Hemodinâmica/fisiologia , Inflamação/fisiopatologia , Núcleo Solitário/fisiopatologia , Animais , Hemodinâmica/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Ratos Wistar , Núcleo Solitário/efeitos dos fármacosRESUMO
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/fisiologiaRESUMO
A high-fat diet (HFD) induces an increase in arterial pressure and a decrease in baroreflex function, which may be associated with increased expression of angiotensin type 1 receptor (AT1R) and pro-inflammatory cytokine genes and reduced expression of the angiotensin type 2 receptor (AT2R) gene within the nucleus of the solitary tract (NTS), a key area of the brainstem involved in cardiovascular control. Thus, in the present study, we evaluated the changes in arterial pressure and gene expression of components of the renin-angiotensin system (RAS) and neuroinflammatory markers in the NTS of rats fed a HFD and treated with either an AT1R blocker or with virus-mediated AT2R overexpression in the NTS. Male Holtzman rats (300-320 g) were fed either a standard rat chow diet (SD) or HFD for 6 weeks before commencing the tests. AT1R blockade in the NTS of HFD-fed rats attenuated the increase in arterial pressure and the impairment of reflex bradycardia, whereas AT2R overexpression in the NTS only improved the baroreflex function. The HFD also increased the hypertensive and decreased the protective axis of the RAS and was associated with neuroinflammation within the NTS. The expression of angiotensin-converting enzyme and neuroinflammatory components, but not AT1R, in the NTS was reduced by AT2R overexpression in this site. Based on these data, AT1R and AT2R in the NTS are differentially involved in the cardiovascular changes induced by a HFD. Chronic inflammation and changes in the RAS in the NTS may also account for the cardiovascular responses observed in HFD-fed rats.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Pressão Arterial/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Núcleo Solitário/metabolismo , Animais , Pressão Arterial/fisiologia , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Dieta Hiperlipídica , Masculino , Ratos , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/fisiologia , Núcleo Solitário/efeitos dos fármacosRESUMO
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 application of sodium cyanide (NaCN) to the carotid body receptors (CBR) (CBR stimulation) induces rapid blood hyperglycemia and an increase in brain glucose retention. The commissural nucleus tractus solitarius (cNTS) is an essential relay nucleus in this hyperglycemic reflex; it receives glutamatergic afferents (that also release brain derived neurotrophic factor, BDNF) from the nodose-petrosal ganglia that relays CBR information. Previous work showed that AMPA in NTS blocks hyperglycemia and brain glucose retention after CBR stimulation. In contrast, BDNF, which attenuates glutamatergic AMPA currents in NTS, enhances these glycemic responses. Here we investigated the combined effects of BDNF and AMPA (and their antagonists) in NTS on the glycemic responses to CBR stimulation. Microinjections of BDNF plus AMPA into the cNTS before CBR stimulation in anesthetized rats, induced blood hyperglycemia and an increase in brain arteriovenous (a-v) of blood glucose concentration difference, which we infer is due to increased brain glucose retention. By contrast, the microinjection of the TrkB antagonist K252a plus AMPA abolished the glycemic responses to CBR stimulation similar to what is observed after AMPA pretreatments. In BDNF plus AMPA microinjections preceding CBR stimulation, the number of c-fos immunoreactive cNTS neurons increased. In contrast, in the rats microinjected with K252a plus AMPA in NTS, before CBR stimulation, c-fos expression in cNTS decreased. The expression of AMPA receptors GluR2/3 did not change in any of the studied groups. These results indicate that BDNF in cNTS plays a key role in the modulation of the hyperglycemic reflex initiated by CBR stimulation.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/metabolismo , Hiperglicemia/metabolismo , Núcleo Solitário/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Glucose/metabolismo , Hiperglicemia/induzido quimicamente , Hiperglicemia/patologia , Imuno-Histoquímica , Masculino , Microinjeções , Neurotransmissores/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Distribuição Aleatória , Ratos Wistar , Receptor trkB/agonistas , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Receptores de AMPA/agonistas , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/metabolismo , Cianeto de Sódio/farmacologia , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/administração & dosagemRESUMO
Previously we have demonstrated that microinjection of acetylcholine (ACh) into the intermediate nucleus of the solitary tract (iNTS) induced sympatho-inhibition combined with a decrease in the phrenic nerve activity (PNA), whereas in the commissural NTS (cNTS), ACh did not change sympathetic nerve activity (SNA), but increased the PNA. In view of these demonstrated distinctive effects of ACh in different subnuclei of the NTS the current studies were undertaken to examine, using patch clamp techniques, the specific effects of ACh on the excitability of individual neurons in the NTS, as well as the neuropharmacology of these actions. Coronal slices of the brainstem containing either cNTS or iNTS subnuclei were used, and whole cell patch clamp recordings obtained from individual neurons in these two subnuclei. In cNTS, 58% of recorded neurons (n=12) demonstrated rapid reversible depolarizations in response to ACh (10mM), effects which were inhibited by the nicotinic antagonist mecamylamine (10µM), but unaffected by the muscarinic antagonist atropine (10µM). Similarly, bath application of ACh depolarized 76% of iNTS neurons (n=17), although in this case both atropine and mecamylamine reduced the ACh-induced depolarization. These data demonstrate that ACh depolarizes cNTS neurons through actions on nicotinic receptors, while depolarizing effects in iNTS are apparently mediated by both receptors.
Assuntos
Antagonistas Colinérgicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Neurônios/efeitos dos fármacos , Antagonistas Nicotínicos/farmacologia , Núcleo Solitário/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Atropina/farmacologia , Agonistas Colinérgicos/farmacologia , Masculino , Mecamilamina/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos Sprague-Dawley , Núcleo Solitário/metabolismo , Técnicas de Cultura de TecidosRESUMO
A single exposure to amphetamine induces neurochemical sensitization in striatal areas. The neuropeptide angiotensin II, through AT1 receptors (AT1-R) activation, is involved in these responses. However, amphetamine-induced alterations can be extended to extra-striatal areas involved in blood pressure control and their physiological outcomes. Our aim for the present study was to analyze the possible role for AT1-R in these events using a two-injection protocol and to further characterize the proposed AT1-R antagonism protocol. Central effect of orally administered AT1-R blocker (Candesartan, 3mg/kg p.o.×5days) in male Wistar rats was analyzed by spontaneous activity of neurons within locus coeruleus. In another group of animals pretreated with the AT1-R blocker or vehicle, sensitization was achieved by a single administration of amphetamine (5mg/kg i.p. - day 6) followed by a 3-week period off drug. On day 27, after receiving an amphetamine challenge (0.5mg/kg i.p.), we evaluated: (1) the sensitized c-Fos expression in locus coeruleus (LC), nucleus of the solitary tract (NTS), caudal ventrolateral medulla (A1) and central amygdala (CeAmy); and (2) the blood pressure response. AT1-R blockade decreased LC neurons' spontaneous firing rate. Moreover, sensitized c-Fos immunoreactivity in TH+neurons was found in LC and NTS; and both responses were blunted by the AT1-R blocker pretreatment. Meanwhile, no differences were found neither in CeAmy nor A1. Sensitized blood pressure response was observed as sustained changes in mean arterial pressure and was effectively prevented by AT1-R blockade. Our results extend AT1-R role in amphetamine-induced sensitization over noradrenergic nuclei and their cardiovascular output.
Assuntos
Anfetamina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Simpatomiméticos/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea/fisiologia , Núcleo Central da Amígdala/citologia , Núcleo Central da Amígdala/efeitos dos fármacos , Núcleo Central da Amígdala/metabolismo , Locus Cerúleo/citologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Bulbo/citologia , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Distribuição Aleatória , Ratos Wistar , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismoRESUMO
Previously we showed that activation of the Nucleus of the Solitary Tract (NTS)-Nucleus Paragigantocellularis (PGi)-Locus coeruleus (LC) pathway, which theoretically culminates with norepinephrine (NE) release in dorsal hippocampus (CA1 region) and basolateral amygdala (BLA) is necessary for the consolidation of object recognition (OR) memory. Here we show that, while the microinjection of the beta-noradrenergic receptor blocker timolol into CA1 impairs OR memory consolidation, the microinjection of norepinephrine (NE) promotes the persistence of this type of memory. Further, we show that OR consolidation is attended by an increase of norepinephrine (NE) levels and of the expression of brain derived neurotrophic factor (BDNF) in hippocampus, which are impaired by inactivation of the NTS-PGi-LC pathway by the infusion of muscimol into the NTS.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/fisiologia , Consolidação da Memória/fisiologia , Norepinefrina/fisiologia , Reconhecimento Psicológico/fisiologia , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Agonistas de Receptores de GABA-A/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Muscimol/administração & dosagem , N-Metilaspartato/administração & dosagem , Norepinefrina/administração & dosagem , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/fisiologia , Timolol/administração & dosagemRESUMO
The antihypertensive drugs moxonidine and clonidine are α2-adrenoceptor and imidazoline (I1) agonists. Previous results from our laboratory have shown that moxonidine can act in the commissural nucleus of the solitary tract (commNTS). In addition, some studies have shown that GABA or glutamate receptor blockade in the RVLM blunted the hypotension produced by these antihypertensive agents in spontaneously hypertensive rats. Therefore, in the present study we verify whether the cardiovascular and sympathetic effects produced by moxonidine in the commNTS are dependent on GABAergic or glutamatergic mechanisms. Mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (sSNA) were recorded in urethane-anesthetized, and artificially-ventilated male Wistar rats (250-350 g). Injection of the GABAA antagonist bicuculline (25 pmol/50 nL) into the commNTS reduced the hypotension as well as the sympathoinhibition elicited by moxonidine. Prior injection of the glutamate receptor antagonist kynurenic acid (2.5 nmol/50 nL) into the commNTS was not effective in reducing the hypotension and sympathoinhibition elicited by moxonidine. Therefore, we conclude that the hypotensive and sympathoinhibitory effects elicited by microinjection of moxonidine into the commNTS are dependent on GABA receptors, but not ionotropic glutamate receptors.
Assuntos
Anti-Hipertensivos/farmacologia , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Imidazóis/farmacologia , Núcleo Solitário/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Análise de Variância , Animais , Bicuculina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Ácido Cinurênico/farmacologia , Masculino , Ratos , Ratos Wistar , Nervos Esplâncnicos/efeitos dos fármacos , Nervos Esplâncnicos/fisiologia , Fatores de TempoRESUMO
Previous studies from our laboratory have shown that methysergide, a serotonergic antagonist, injected into the lateral parabrachial nucleus (LPBN) combined with a pre-load of 2 M NaCl, given by gavage, induces 0.3 M NaCl intake. The mechanisms involved in this paradoxical behavior are still unknown. In the present work, we investigated the effect of serotonergic blockade into the LPBN on hindbrain and hypothalamic activity, gastric emptying and arterial blood pressure in cell-dehydrated rats. Methysergide plus 2 M NaCl infused intragastrically or intravenously promoted 0.3 M NaCl intake in two-bottle tests. In cell-dehydrated rats with no access to fluids, methysergide compared to vehicle increased Fos immunoreactivity in the medial nucleus of the solitary tract, area postrema and non-oxytocinergic cells of the ventral portion of the hypothalamic paraventricular nucleus (PVN). There was no alteration in the number of neurons double-labeled for Fos-ir and oxytocin in the PVN and supraoptic nuclei. There was also no alteration in plasma oxytocin and vasopressin, or arterial pressure. In rats cell-dehydrated by i.v. 2 M NaCl, methysergide also did not change the amount of an intragastric load of 0.3 M NaCl retained in the stomach or intestine. The results suggest that methysergide injected into the LPBN of cell-dehydrated rat does not alter primary inhibitory signals that control sodium intake. The inhibitory signals blocked by methysergide in the LPBN possibly originated from activation of brain osmoreceptors, second order visceral/hormonal signals or a combination of both.