RESUMO
BACKGROUND AND AIM: High-fat (HF) diet consumption has been associated with gut dysbiosis and increased risk of dyslipidemia, type 2 diabetes mellitus and hypertension. Probiotic administration has been suggested as a safe therapeutic strategy for the treatment of cardiometabolic disorders. This study was designed to assess the effects of probiotic Lactobacillus (L.) fermentum 296, a fruit-derived bacteria strain, against cardiometabolic disorders induced by HF diet. METHODS AND RESULTS: Male Wistar rats were divided into control diet (CTL); HF diet; and HF diet treated with Lactobacillus fermentum 296 (HF + Lf 296). The L. fermentum 296 strain at 1 × 109 colony forming units (CFU)/ml were daily administered by oral gavage for 4 weeks. The results showed that rats fed with HF diet displayed insulin resistance, reduced Lactobacillus spp. counts in feces, serum lipids, and oxidative profile. Rats fed on HF diet also demonstrated augmented blood pressure associated with sympathetic hyperactivity and impaired baroreflex control. The administration of L. fermentum 296 for 4 weeks recovered fecal Lactobacillus sp. counts and alleviated hyperlipidemia, sympathetic hyperactivity, and reduced systolic blood pressure in HF rats without affecting baroreflex sensibility. CONCLUSION: Our results suggest the ability of L. fermentum 296 improve biochemical and cardiovascular parameters altered in cardiometabolic disorders.
Assuntos
Dieta Hiperlipídica , Dislipidemias/terapia , Microbioma Gastrointestinal , Hipertensão/terapia , Resistência à Insulina , Limosilactobacillus fermentum/crescimento & desenvolvimento , Síndrome Metabólica/terapia , Probióticos/farmacologia , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Pressão Sanguínea , Modelos Animais de Doenças , Disbiose , Dislipidemias/sangue , Dislipidemias/microbiologia , Hipertensão/microbiologia , Hipertensão/fisiopatologia , Insulina/sangue , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/microbiologia , Síndrome Metabólica/fisiopatologia , Ratos WistarRESUMO
TRV027 is a biased agonist for the Angiotensin (Ang)-II type 1 receptor (AT1R), able to recruit ß-arrestin 2 independently of G-proteins activation. ß-arrestin activation in the central nervous system (CNS) was suggested to oppose the effects of Ang-II. The present study evaluates the effect of central infusion of TRV027 on arterial pressure (AP), autonomic function, baroreflex sensitivity (BRS), and peripheral vascular reactivity. Spontaneously hypertensive (SH) and Wistar Kyoto (WKY) rats were treated with TRV027 for 14 days (20 ng/h) delivered to the lateral ventricle via osmotic minipumps. Mechanistic studies were performed in HEK293T cells co-transfected with AT1R and Ang converting enzyme type 2 (ACE2) treated with TRV027 (100 nM) or Ang-II (100 nM). TRV027 infusion in SH rats (SHR) reduced AP (~20 mmHg, P<0.05), sympathetic vasomotor activity (ΔMAP = -47.2 ± 2.8 compared with -64 ± 5.1 mmHg, P<0.05) and low-frequency (LF) oscillations of AP (1.7 ± 0.2 compared with 5.8 ± 0.4 mmHg, P<0.05) compared with the SHR control group. TRV027 also increased vagal tone, improved BRS, reduced the reactivity of mesenteric arteries to Ang-II and increased vascular sensitivity to phenylephrine (Phe), acetylcholine, (ACh), and sodium nitroprusside (SNP). In vitro, TRV027 prevented the Ang-II-induced up-regulation of ADAM17 and in contrast with Ang-II, had no effects on ACE2 activity and expression levels. Furthermore, TRV027 induced lesser interactions between AT1R and ACE2 compared with Ang-II. Together, these data suggest that due to its biased activity for the ß-arrestin pathway, TRV027 has beneficial effects within the CNS on hypertension, autonomic and vascular function, possibly through preserving ACE2 compensatory activity in neurones.
Assuntos
Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Oligopeptídeos/farmacologia , Angiotensina II/farmacologia , Enzima de Conversão de Angiotensina 2 , Animais , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Células HEK293 , Humanos , Hipertensão/fisiopatologia , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiologia , Peptidil Dipeptidase A/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptor Tipo 1 de Angiotensina/metabolismo , Vasoconstritores/farmacologiaRESUMO
Chemoreception is the classic mechanism by which the brain regulates breathing in response to changes in tissue CO2/H(+). A brainstem region called the retrotrapezoid nucleus (RTN) contains a population of Phox2b-expressing glutamatergic neurons that appear to function as important chemoreceptors. In the present study, we ask whether the destruction of a type of pH-sensitive interneuron that expresses the transcription factor Phox2b and is non-catecholaminergic (Phox2b(+)TH(-)) could affect breathing in conscious adult rats. The injection of substance P (1 nmol in a volume of 50 nl) into the RTN increased respiratory frequency, tidal volume, minute ventilation and mean arterial pressure. Bilateral injections of the toxin substance P conjugated with saporin (SSP-SAP) into the RTN destroyed Phox2b(+)TH(-) neurons but spared facial motoneurons, catecholaminergic and serotonergic neurons and the ventral respiratory column caudal to the facial motor nucleus. Bilateral inhibition of RTN neurons with SSP-SAP (0.6 ng in 30 nl) reduced resting ventilation and the increase in ventilation produced by hypercapnia (7% CO2) in conscious rats with or without peripheral chemoreceptors. In anaesthetized rats with bilateral lesions of around 90% of the Phox2b(+)TH(-) neurons, acute activation of the Bötzinger complex, the pre-Bötzinger complex or the rostral ventral respiratory group with NMDA (5 pmol in 50 nl) elicited normal cardiorespiratory output. In conclusion, the destruction of the Phox2b(+)TH(-) neurons is a plausible cause of the respiratory deficits observed after injection of SSP-SAP into the RTN. Our results also suggest that RTN neurons activate facilitatory mechanisms important to the control of breathing in resting or hypercapnic conditions in conscious adult rats.
Assuntos
Sistema Nervoso Central/fisiologia , Proteínas de Homeodomínio/fisiologia , Neurônios/fisiologia , Sistema Nervoso Periférico/fisiologia , Respiração , Células Receptoras Sensoriais/fisiologia , Fatores de Transcrição/fisiologia , Anestesia , Animais , Corpo Carotídeo/fisiologia , Denervação , Densitometria , Masculino , Ratos , Ratos Wistar , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/fisiologia , Reflexo/fisiologia , Centro Respiratório/fisiologia , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Saporinas , Substância P/farmacologiaRESUMO
Nitric oxide (NO) is one of the most important vasodilator molecules produced by the endothelium. It has already been established that NO/cGMP signaling pathway deficiencies are involved in the pathophysiological mechanisms of many cardiovascular diseases. In this context, the development of NO-releasing drugs for therapeutic use appears to be an effective alternative to replace the deficient endogenous NO and mimic the role of this molecule in the body. Organic nitrates represent the oldest class of NO donors that have been clinically used. Considering that tolerance can occur when these drugs are applied chronically, the search for new compounds of this class with lower tolerance potential is increasing. Here, we briefly discuss the mechanisms involved in nitrate tolerance and highlight some achievements from our group in the development of new organic nitrates and their preclinical application in cardiovascular disorders.
Assuntos
Nitratos/química , Doadores de Óxido Nítrico/química , Compostos Orgânicos/química , Humanos , Nitratos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Compostos Orgânicos/farmacologiaRESUMO
We showed previously that sino-aortic denervation prevented training-induced plasticity in pre-autonomic oxytocinergic neurons and blocked the beneficial effects of training. In this study, we investigate the combined effect of training and removal of specific chemoreceptor afferents on both cardiovascular parameters and oxytocin (OT) gene and protein expression within the hypothalamic paraventricular nucleus (PVN). Wistar rats and spontaneously hypertensive rats (SHRs) underwent carotid body denervation or sham surgery and were trained or kept sedentary for 3 months. After haemodynamic measurements at rest, rats were anaesthetized for brain perfusion. Fresh (perfused with PBS) and fixed brains (perfused with 4% paraformaldehyde) were processed for PVN OT mRNA (real-time PCR) and OT immunoreactivity within PVN subnuclei. In sham-operated rats, training improved treadmill performance and reduced resting heart rate (Wistar, -8%; SHRs, -10%), with a reduction in blood pressure only in SHRs (-8%). Training was accompanied by increased PVN OT mRNA expression (twofold increase in sham-operated SHRs) and peptide density in the posterior, ventromedial and dorsal cap PVN subnuclei (on average 70% increase in both strains), with significant correlations between OT content and training-induced resting bradycardia in sham-operated groups. Carotid body denervation did not interfere with the performance gain, abolished chemoreflex activation (without changing baroreflex control) and blocked training-induced cardiovascular adaptations and training-induced changes in PVN OT content in both strains. After carotid body denervation, there was no correlation between OT mRNA or OT immunoractivity and resting heart rate. The chronic absence of chemoreceptor inputs uncovers an unknown role of chemoreceptor signalling in driving the plasticity/activity of PVN oxytocinergic pre-autonomic neurons, thus mediating training-induced cardiovascular adaptive responses.
Assuntos
Corpo Carotídeo/metabolismo , Hipertensão/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Esforço Físico , Adaptação Fisiológica , Animais , Denervação Autônoma , Barorreflexo , Pressão Sanguínea , Modelos Animais de Doenças , Regulação da Expressão Gênica , Frequência Cardíaca , Hipertensão/genética , Hipertensão/fisiopatologia , Imuno-Histoquímica , Masculino , Ocitocina/genética , Núcleo Hipotalâmico Paraventricular/fisiopatologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Comportamento Sedentário , Transdução de Sinais , Fatores de TempoRESUMO
We hypothesize that a local ATP-NO-NMDA glutamate receptor interaction in the paraventricular nucleus (PVN) modulates the baseline mean arterial pressure and heart rate in unanaesthetized rats. The microinjection of α,ß-methylene ATP [methyl ATP; 0.06, 0.12 and 1.2 nmol (100 nl)(-1)] into the PVN caused pressor and tachycardiac responses. Cardiovascular responses evoked by methyl ATP [0.12 nmol (100 nl)(-1)] in the PVN were blocked by pretreatment with the ganglion blocker pentolinium (5 mg kg(-1) i.v.). Also, responses to the injection of methyl ATP [0.12 nmol (100 nl)(-1)] into the PVN were reduced by pretreatment with the selective P2 purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid [0.5 nmol (100 nl)(-1)], the neuronal NO synthase inhibitor N(ω)-propyl-l-arginine [0.04 nmol (100 nl)(-1)] or the selective NMDA glutamate receptor antagonist LY235959 [2 nmol (100 nl)(-1)]. In addition, an injection of the NO donor sodium nitroprusside [27 nmol (100 nl)(-1)] into the PVN caused similar cardiovascular responses to those observed after methyl ATP, which were blocked by local pretreatment with LY235959. Therefore, the present results suggest that cardiovascular responses evoked by methyl ATP in the PVN involve a local production of NO, which promotes local glutamate release and activation of NMDA receptors that are probably located in pre-autonomic parvocellular neurons, leading to sympathetic nervous system stimulation.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Óxido Nítrico/fisiologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Trifosfato de Adenosina/farmacologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores Ganglionares/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Microinjeções , Óxido Nítrico/biossíntese , Nitroprussiato/farmacologia , Antagonistas do Receptor Purinérgico P2/farmacologia , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Quinazolinonas , Ratos , Ratos Wistar , VigíliaRESUMO
Borneol is a bicyclic monoterpene that has long been used in traditional Chinese medicine to increase blood-brain barrier permeability and has shown promising cardiovascular effects. The present study aimed to evaluate the effect of borneol on vascular tone, blood pressure, autonomic function, and baroreflex sensitivity in normotensive and hypertensive rats. A combination of in vitro and in vivo assays was performed in 2-kidneys-1-clip hypertensive rats (2K1C) and their controls (sham). We assessed the in vivo effect of oral treatment with borneol on blood pressure, heart rate, autonomic function, and baroreflex sensitivity in sham and 2K1C rats. Additionally, the vasorelaxant effect of borneol in the superior mesenteric artery isolated from rats and its mechanism of action were evaluated. Oral administration of borneol (125 mg/kg/day) reduced blood pressure, sympathetic vasomotor hyperactivity, and serum oxidative stress and improved baroreflex sensitivity in 2K1C rats. In vessel preparations, borneol induced endothelium-independent vasodilatation after precontraction with phenylephrine or KCl (60 mM). There was no difference in the vascular effect induced by borneol in either the 2K1C or the sham group. In addition, borneol antagonized the contractions induced by CaCl2 and reversed (S)-(-)-Bay K 8644-induced contraction. These data suggest that borneol presents antihypertensive effects in 2K1C rats, which is associated with its ability to improve autonomic impairment and baroreflex dysfunction. The borneol-induced relaxation in the superior mesenteric artery involves L-type Ca2+ channel blockade. This vascular action associated with the antioxidant effect induced by borneol may be responsible, at least in part, for the in vivo effects induced by this monoterpene.
Assuntos
Hipertensão Renovascular , Hipertensão , Animais , Barorreflexo , Pressão Sanguínea/fisiologia , Canfanos/farmacologia , Canfanos/uso terapêutico , Feminino , Humanos , Hipertensão Renovascular/tratamento farmacológico , Masculino , RatosRESUMO
We showed previously that oxytocinergic (OTergic) projections from the hypothalamic paraventricular nucleus (PVN) to the dorsal brain stem mediate training-induced heart rate (HR) adjustments and that beneficial effects of training are blocked by sinoaortic denervation (SAD; Exp Physiol 94: 630-640; 1103-1113, 2009). We sought now to determine the combined effect of training and SAD on PVN OTergic neurons in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Rats underwent SAD or sham surgery and were trained (55% of maximal capacity) or kept sedentary for 3 mo. After hemodynamic measurements were taken at rest, rats were deeply anesthetized. Fresh brains were frozen and sliced to isolate the PVN; samples were processed for OT expression (real-time PCR) and fixed brains were processed for OT immunofluorescence. In sham rats, training improved treadmill performance and increased the gain of baroreflex control of HR. Training reduced resting HR (-8%) in both groups, with a fall in blood pressure (-10%) only in SHR rats. These changes were accompanied by marked increases in PVN OT mRNA expression (3.9- and 2.2-fold in WKY and SHR rats, respectively) and peptide density in PVN OTergic neurons (2.6-fold in both groups), with significant correlations between OT content and training-induced resting bradycardia. SAD abolished PVN OT mRNA expression and markedly reduced PVN OT density in WKY and SHR. Training had no effect on HR, PVN OT mRNA, or OT content following SAD. The chronic absence of inputs from baroreceptors and chemoreceptors uncovers the pivotal role of afferent signaling in driving both the plasticity and activity of PVN OTergic neurons, as well as the beneficial effects of training on cardiovascular control.
Assuntos
Vias Autônomas/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios Aferentes/fisiologia , Ocitocina/metabolismo , Condicionamento Físico Animal/fisiologia , Transdução de Sinais/fisiologia , Animais , Pressão Sanguínea/fisiologia , Denervação , Modelos Animais de Doenças , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Masculino , Modelos Animais , Núcleo Hipotalâmico Paraventricular/fisiologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Nó Sinoatrial/fisiologia , Nó Sinoatrial/cirurgia , Núcleo Supraóptico/fisiologiaRESUMO
Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated. In this study, we hypothesized that treatment with inorganic nitrate could prevent the increase in sympathetic nerve activity in an experimental model of Ang II (angiotensin II)-induced hypertension. Multiple in vivo approaches were combined, that is, Wistar rats orally treated with the nitric oxide synthase inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester, 0.5 g/L) and implanted with subcutaneous osmotic minipump for continuous delivery of Ang II (120 ng/kg per minute; 14 days). Simultaneously, rats were supplemented with sodium nitrate (10 mmol/L) or placebo (sodium chloride; 10 mmol/L) in the drinking water. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded. In placebo-treated rats, Ang II+L-NAME treatment-induced arterial hypertension, which was linked with reduced spontaneous baroreflex sensitivity and increased renal sympathetic nerve activity, as well as upregulation of AT1Rs (Ang II type-1 receptors) in the rostral ventrolateral medulla. Supplementation with nitrate normalized the expression of AT1Rs in rostral ventrolateral medulla and reduced sympathetic nerve activity, which was associated with attenuated development of hypertension. In conclusion, chronic dietary nitrate supplementation blunted the development of hypertension via mechanisms that involve reduction of sympathetic outflow.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/terapia , Nitratos/farmacologia , Sistema Nervoso Simpático/fisiopatologia , Angiotensina II/toxicidade , Animais , Barorreflexo/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos WistarRESUMO
Nitric oxide (NO) is a key signalling molecule in the regulation of cardiometabolic function and impaired bioactivity is considered to play an important role in the onset and progression of cardiovascular and metabolic disease. Research has revealed an alternative NO-generating pathway, independent of NO synthase (NOS), in which the inorganic anions nitrate (NO3-) and nitrite (NO2-) are serially reduced to form NO. This work specifically aimed at investigating the role of commensal bacteria in bioactivation of dietary nitrate and its protective effects in a model of cardiovascular and metabolic disease. In a two-hit model, germ-free and conventional male mice were fed a western diet and the NOS inhibitor l-NAME in combination with sodium nitrate (NaNO3) or placebo (NaCl) in the drinking water. Cardiometabolic parameters including blood pressure, glucose tolerance and body composition were measured after six weeks treatment. Mice in both placebo groups showed increased body weight and fat mass, reduced lean mass, impaired glucose tolerance and elevated blood pressure. In conventional mice, nitrate treatment partly prevented the cardiometabolic disturbances induced by a western diet and l-NAME. In contrast, in germ-free mice nitrate had no such beneficial effects. In separate cardiovascular experiments, using conventional and germ-free animals, we assessed NO-like signalling downstream of nitrate by administration of sodium nitrite (NaNO2) via gavage. In this acute experimental setting, nitrite lowered blood pressure to a similar degree in both groups. Likewise, isolated vessels from germ-free mice robustly dilated in response to the NO donor sodium nitroprusside. In conclusion, our findings demonstrate the obligatory role of host-microbiota in bioactivation of dietary nitrate, thus contributing to its favourable cardiometabolic effects.
Assuntos
Doenças Cardiovasculares/genética , Sistema Cardiovascular/metabolismo , Interações entre Hospedeiro e Microrganismos/genética , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/patologia , Sistema Cardiovascular/microbiologia , Sistema Cardiovascular/patologia , Dieta Ocidental/efeitos adversos , Humanos , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Nitratos/farmacologia , Óxido Nítrico Sintase/genética , Nitritos/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
This study was designed to investigate the effects of a newly synthesized carboxymethyl-glucan (CM-G) on blood pressure (BP), baroreflex sensitivity (BRS) and sympathetic vascular modulation in renovascular hypertensive rats. Male Wistar rats were divided into four groups: Sham (n = 10); 2K1C (subjected to renal artery clipping to induce renovascular hypertension, n = 10); Sham + CM-G (treated with CM-G, n = 7) and 2K1C + CM-G (treated with CM-G, n = 7). The daily treatment with CM-G (40 mg/kg) was performed for 2 weeks. Blood pressure, heart rate (HR), systolic BP variability, baroreflex sensitivity (BRS) and sympathetic vascular tone were evaluated. After six weeks of renal artery clipping, 2K1C rats exhibited arterial hypertension (171 ± 11 vs. 118 ± 4 mmHg, p < 0.05), impaired BRS (-1.30 ± 0.10 vs. -2.59 ± 0.17 bpm.mmHg-1, p < 0.05) and enhanced sympathetic activity as shown by the hexamethonium test (-60 ± 5 vs. -33 ± 2 ΔmmHg, p < 0.05) when compared to sham rats. Oral administration of CM-G in renovascular hypertensive rats reduced hypertension (126 ± 4 vs. 171 ± 11 mmHg, p < 0.05) and improved the BRS (-2.03 ± 0.16 vs. -1.30 ± 0.10 bpm.mmHg-1, p < 0.05) in 2K1C rats when compared to placebo. Those effects seem to be caused by a reduction in sympathetic activity. The present study revealed for the first time that CM-G treatment reduces arterial hypertension and restores arterial baroreflex sensitivity via a reduction in the sympathetic tone in conscious renovascular hypertensive rats.
RESUMO
It is known that circulating angiotensin II (ANG-II) acts on the circumventricular organs (CVOs), which partially lack a normal blood-brain barrier, to stimulate pressor responses, vasopressin (AVP), and oxytocin (OT) secretion, as well as sodium and water intake. Although ANG-II type 1 receptors (AT1R) are expressed in neurons and astrocytes, the involvement of CVOs glial cells in the neuroendocrine, cardiovascular and behavioral responses induced by central ANG II remains to be further elucidated. To address this question, we performed a set of experiments combining in vitro studies in primary hypothalamic astrocyte cells (HACc) and in vivo intracerebroventricular (icv) microinjections into the lateral ventricle of awake rats. Our results showed that ANG-II decreased glutamate uptake in HACc. In addition, in vivo studies showed that fluorocitrate (FCt), a reversible glial inhibitor, increased OT secretion and mean arterial pressure (MAP) and decreased breathing at rest. Furthermore, previous FCt decreased AVP secretion and sodium intake induced by central ANG-II. Together, our findings support that CVOs glial cells are important in mediating neuroendocrine and cardiorespiratory functions, as well as central ANG-II-induced AVP release and salt-intake behavior in awake rats. In the light of our in vitro studies, we propose that these mechanisms are, at least in part, by ANG-II-induced astrocyte mediate reduction in glutamate extracellular clearance.
RESUMO
ADAM17 is a metalloprotease and disintegrin that lodges in the plasmatic membrane of several cell types and is able to cleave a wide variety of cell surface proteins. It is somatically expressed in mammalian organisms and its proteolytic action influences several physiological and pathological processes. This review focuses on the structure of ADAM17, its signaling in the cardiovascular system and its participation in certain disorders involving the heart, blood vessels, and neural regulation of autonomic and cardiovascular modulation.
RESUMO
The paraventricular nucleus of the hypothalamus (PVN) contains heterogeneous populations of neurons involved in autonomic and neuroendocrine regulation. The PVN plays an important role in the sympathoexcitatory response to increasing circulating levels of angiotensin II (Ang-II), which activates AT1 receptors in the circumventricular organs (OCVs), mainly in the subfornical organ (SFO). Circulating Ang-II induces a de novo synthesis of Ang-II in SFO neurons projecting to pre-autonomic PVN neurons. Activation of AT1 receptors induces intracellular increases in reactive oxygen species (ROS), leading to increases in sympathetic nerve activity (SNA). Chronic sympathetic nerve activation promotes a series of metabolic disorders that characterizes the metabolic syndrome (MetS): dyslipidemia, hyperinsulinemia, glucose intolerance, hyperleptinemia and elevated plasma hormone levels, such as noradrenaline, glucocorticoids, leptin, insulin, and Ang-II. This review will discuss the contribution of our laboratory and others regarding the sympathoexcitation caused by peripheral Ang-II-induced reactive oxygen species along the subfornical organ and paraventricular nucleus of the hypothalamus. We hypothesize that this mechanism could be involved in metabolic disorders underlying MetS.
RESUMO
In the present study we evaluated the role of purinergic mechanisms in the PVN on the tonic modulation of the autonomic function to the cardiovascular system as well on the cardiovascular responses to peripheral chemoreflex activation in awake rats. Guide-cannulae were bilaterally implanted in the direction of the PVN of male Wistar rats. Femoral artery and vein were catheterized one day before the experiments. Chemoreflex was activated with KCN (80 µg/0.05 ml, i.v.) before and after microinjections of P2 receptors antagonist into the PVN. Microinjection of PPADS, a non selective P2X antagonist, into the PVN (n=6) produced a significant increase in the baseline MAP (99±2 vs 112±3 mmHg) and HR (332±8 vs 375±8 bpm) but had no effect on the pressor and bradycardic responses to chemoreflex activation. Intravenous injection of vasopressin receptors antagonist after microinjection of PPADS into the PVN produced no effect on the increased baseline MAP. Simultaneous microinjection of PPADS and KYN into the PVN (n=6) had no effect in the baseline MAP, HR or in the pressor and bradycardic responses to chemoreflex activation. We conclude that P2 purinoceptors in the PVN are involved in the modulation of baseline autonomic function to the cardiovascular system but not in the cardiovascular responses to chemoreflex activation in awake rats.
Assuntos
Vias Autônomas/fisiologia , Pressão Sanguínea/fisiologia , Neurônios/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Receptores Purinérgicos P2/fisiologia , Animais , Vias Autônomas/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Masculino , Microinjeções/métodos , Neurônios/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/anatomia & histologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Cianeto de Potássio/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos , Ratos Wistar , Receptores Purinérgicos P2/efeitos dos fármacos , Vigília/fisiologiaRESUMO
GABAergic, nitrergic and glutamatergic mechanisms in the PVN on the baseline mean arterial pressure (MAP), heart rate (HR) and on the cardiovascular responses to chemoreflex activation in awake rat were evaluated. Chemoreflex was activated with KCN before and after microinjections into the PVN. Bicuculline into the PVN increased baseline MAP (94+/-3 vs 113+/-5 mmHg) and HR (350+/-9 vs 439+/-18 bpm) but had no effect on the pressor (49+/-5 vs 47+/-6 mmHg) or bradicardic (-213+/-23 vs -256+/-42 bpm) responses (n=7). Kynurenic acid into the PVN (n=6) produced no significant changes in the MAP (98+/-3 vs 100+/-3 mmHg), HR (330+/-5 vs 339+/-12 mmHg) or in the pressor (50+/-4 vs 42+/-4 mmHg) and bradicardic (-252+/-4 vs -285+/-16 bpm) responses to chemoreflex. L-NAME into the PVN (n=8) produced increase in the MAP (94+/-3 vs 113+/-5 mmHg) and HR (350+/-9 vs 439+/-18 bpm) but had no effect on the pressor (52+/-5 vs 47+/-6 mmHg) or bradicardic (-253+/-19 vs -320+/-25 bpm) responses to chemoreflex. We conclude that GABA(A) and nitric oxide in the PVN are involved in the maintenance of the baseline MAP but not in the modulation of the responses to chemoreflex. The results also show that Glutamate receptors in the PVN are not involved in maintenance of the baseline MAP, HR or in the cardiovascular responses to chemoreflex in awake rats.
Assuntos
Pressão Sanguínea/fisiologia , Óxido Nítrico/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Bicuculina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Células Quimiorreceptoras/efeitos dos fármacos , Células Quimiorreceptoras/fisiologia , Cianatos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Ácido Glutâmico/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Ácido Cinurênico/farmacologia , Masculino , Microinjeções , NG-Nitroarginina Metil Éster/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologiaRESUMO
RESUMO: Essa revisão tem como objetivo apresentar a experiência do nosso laboratório, acumulada ao longo dos últimos anos no estudo da neurotransmissão do componente simpatoexcitatório do quimiorreflexo no núcleo do trato solitário (NTS) de ratos. Essa abordagem experimental tem sido utilizada como um modelo para o melhor entendimento dos mecanismos neuroquímicos envolvidos na geração e modulação da atividade simpática, a qual tem importantes repercussões para o sistema cardiovascular tanto em condições fisiológicas quanto em condições fisiopatológicas como a hipertensão arterial. O foco específico dessa revisão está centrado na neurotransmissão do componente simpato-excitatório do quimiorreflexo no núcleo do trato solitário (NTS) e apresentamos vários métodos e abordagens experimentais que estão sendo utilizados com vistas ao melhor entendimento desse complexo sistema de neurotransmissão. Com essa combinação de métodos, que vão desde um neurônio do NTS até o rato acordado e com livre movimentação, queremos ilustrar as múltiplas possibilidades de abordagens experimentais contemporâneas, as quais estão nos proporcienando as condições materiais para estender os horizontes dessa importante área do conhecimento.