RESUMO
INTRODUCTION: Available studies have shown the involvement of nitric oxide (NO) in the processes that lead to neurodegeneration in Parkinson's disease (PD). Also, the use of inhibitors of the inducible isoform of NO-synthase (iNOS) promotes neuroprotection and attenuates dopamine (DA) loss in experimental models of Parkinsonism. In addition, NO also appears to be involved in cardiovascular changes in 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. The current study aimed to evaluate the effects of iNOS inhibition on cardiovascular and autonomic function in animals that were subjected to Parkinsonism by the administration of 6-OHDA. MATERIALS AND METHODS: The animals underwent stereotaxic surgery for bilateral microinfusion of the neurotoxin 6-OHDA (6 mg/mL in 0.2% ascorbic acid in sterile saline solution) or vehicle solution for the Sham group. From the day of stereotaxis until the day of femoral artery catheterization, the animals were treated with the iNOS inhibitor, S-methylisothiourea (SMT; 10 mg/kg; i. p.) or saline solution (0.9%; i. p.) for 7 days. The animals were divided into four groups: Sham-Saline, Sham-SMT, 6-OHDA-Saline, and 6-OHDA-SMT. Subsequent analyses were performed on these four groups. After 6 days, they underwent catheterization of the femoral artery, and 24 h later, mean arterial pressure (MAP) and heart rate (HR) were recorded. Another group of animals (the 6-OHDA and Sham groups) was assessed for aortic vascular reactivity after 7 days of bilateral infusion of 6-OHDA or vehicle, in which cumulative concentration-effect curves (CCEC) were made for phenylephrine (Phenyl), acetylcholine and sodium nitroprusside (NPS). Also, CCEC in the presence of Nw-nitro-arginine-methyl-ester (l-NAME) (10-5 M), SMT (10-6 M), and indomethacin (10-5 M) blockers were made. RESULTS: The effectiveness of the 6-OHDA lesion was confirmed with the reduction of DA in 6-OHDA animals. However, treatment with SMT could not reverse the loss of DA. Concerning the baseline parameters, SBP and MAP values were lower in 6-OHDA animals compared to their Sham control, with no effect of treatment with SMT. In the analysis of SBP variability, a decrease in variance, the VLFabs component, and the LFabs component were observed in the 6-OHDA groups when compared to their controls, regardless of treatment with SMT. It was also observed that intravenous injections of SMT resulted in an increase in BP and a decrease in HR. However, the response was not different between the Sham and 6-OHDA groups. In vascular function, there was a hyporeactivity to Phenyl in the 6-OHDA group, and when investigating the mechanisms of this hyporeactivity, it was seen that the Rmax to Phenyl increased with incubation with SMT, indicating that iNOS could be involved in the vascular hyporeactivity of animals with Parkinsonism. CONCLUSION: Thus, the set of results presented in this study suggests that part of the cardiovascular dysfunction in animals subjected to 6-OHDA Parkinsonism may be peripheral and involve the participation of endothelial iNOS.
Assuntos
Sistema Cardiovascular , Transtornos Parkinsonianos , Animais , Masculino , Ratos , Dopamina , Inibidores Enzimáticos/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Oxidopamina/farmacologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Fenilefrina , Ratos Wistar , Solução SalinaRESUMO
Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and heart failure in Latin American countries. The treatment of Chagas disease is directed at eliminating the parasite, decreasing the probability of cardiomyopathy and disrupting the disease transmission cycle. Benznidazole (BZ) and nifurtimox (Nfx) are recognized as effective drugs for the treatment of Chagas disease by the World Health Organization, but both have high toxicity and limited efficacy, especially in the chronic disease phase. At low doses, aspirin (ASA) has been reported to protect against T. cruzi infection. We evaluated the effectiveness of BZ in combination with ASA at low doses during the acute disease phase and evaluated cardiovascular aspects and cardiac lesions in the chronic phase. ASA treatment prevented the cardiovascular dysfunction (hypertension and tachycardia) and typical cardiac lesions. Moreover, BZ+ASA-treated mice had a smaller cardiac fibrotic area than BZ-treated mice. These results were associated with an increase in numbers of eosinophils and reticulocytes and levels of nitric oxide in the plasma and cardiac tissue of ASA-treated mice relative to respective controls. These effects of ASA and BZ+ASA in chronically infected mice were inhibited by pretreatment with the lipoxin A4 (LXA4) receptor antagonist Boc-2, indicating that the protective effects of ASA are mediated by ASA-triggered lipoxin. These results emphasize the importance of exploring new drug combinations for treatments of the acute phase of Chagas disease that are beneficial for patients with chronic disease.
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Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Aspirina/uso terapêutico , Doença de Chagas/tratamento farmacológico , Combinação de Medicamentos , Humanos , Camundongos , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêuticoRESUMO
Infection with the protozoan Trypanosoma cruzi causes Chagas disease and consequently leads to severe inflammatory heart condition; however, the mechanisms driving this inflammatory response have not been completely elucidated. Nitric oxide (NO) is a key mediator of parasite killing in T. cruzi-infected mice, and previous studies have suggested that leukotrienes (LTs) essentially regulate the NO activity in the heart. We used infected 5-lipoxygenase-deficient mice (5-LO-/-) to explore the participation of nitric oxide synthase isoforms, inducible (iNOS) and constitutive (cNOS), in heart injury, cytokine profile, and oxidative stress during the early stage of T. cruzi infection. Our evidence suggests that the cNOS of the host is involved in the resistance of 5-LO-/- mice during T. cruzi infection. iNOS inhibition generated a remarkable increase in T. cruzi infection in the blood and heart of mice, whereas cNOS inhibition reduced cardiac parasitism (amastigote nests). Furthermore, this inhibition associates with a higher IFN-γ production and lower lipid peroxidation status. These data provide a better understanding about the influence of NO-interfering therapies for the inflammatory response toward T. cruzi infection.
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Araquidonato 5-Lipoxigenase/sangue , Doença de Chagas/sangue , Doença de Chagas/enzimologia , Animais , Antioxidantes/metabolismo , Citocinas/sangue , Camundongos , Camundongos Knockout , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo II/sangue , Trypanosoma cruzi/patogenicidadeRESUMO
Nitric oxide (NO), an intercellular signaling molecule is relevant for circulatory autonomic control. Brain NO synthase (NOS) and NO levels were downregulated in pathological conditions, but rescued after exercise training. We hypothesized that exercise training was also able to improve NO modulation within the hypothalamic paraventricular nucleus (PVN) of healthy rats. Male Wistar rats were submitted to two 4-weeks protocols: i) swimming training (T) or kept sedentary (S), ii) l-arginine (62,5â¯mg/mL, 1â¯mL/day p. o.) or vehicle supplementation. Rats underwent stereotaxic surgery (PVN bilateral guide cannulas) and chronic catheterization of artery/vein. Arterial pressure (AP), heart rate (HR) and baroreflex sensitivity were recorded in conscious rats at rest and following a selective nNOS inhibitor (Nw-Propyl-l-Arginine, 4 nmol/100â¯nL) within the PVN. Rats were deeply anesthetized for brain perfusion/harvesting after respiratory arrest. In separate groups (T and S, l-arginine and Vehicle supplemented) not submitted to PVN cannulation, fresh and fixed brains were obtained for gene and protein nNOS expression (qPCR and immunohistochemistry) and nitrite levels (Griess reaction). T and l-arginine treatment were accompanied by resting bradycardia, augmented parasympathetic and reduced sympathetic activity to heart and vessels (power spectral analysis) and increased baroreflex sensitivity (Pâ¯<â¯0.05). In contrast, PVN nNOS inhibition blocked/attenuated these effects in addition to significantly increase in resting MAP and HR (with larger effects in T and l-arginine treated rats vs. respective controls, Pâ¯<â¯0.05). T increased nNOS gene and protein expression within the ventromedial and posterior PVN nuclei (Pâ¯<â¯0.05). PVN nitirite levels were also increased in T and l-arginine groups (Pâ¯<â¯0.05). Data strongly suggest that training by increasing NO availability within PVN preautonomic nuclei favors both the slow down of sympathetic and the augmentation of parasympathetic activity and facilitates baroreflex control, therefore improving autonomic regulation of the heart in healthy rats.
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Óxido Nítrico Sintase Tipo I/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Masculino , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Ratos , Ratos WistarRESUMO
It has been suggested that nitric oxide (NO) from iNOS source is involved in inflammation and oxidative stress, and hypertension in obese subjects involves an inflammatory process. However, no study evaluated the participation of iNOS inhibition on cardiovascular, autonomic, and inflammatory parameters in obese rats. Obesity was induced by the administration of 4 mg/g body weight of monosodium glutamate (MSG) or equimolar saline (CTR) in newborn rats. On the 60th day, treatment with aminoguanidine (Amino, 50 mg/kg), an iNOS inhibitor, or 0.9% saline, was started. On the 90th day, mean arterial pressure (MAP) and heart rate (HR) were recorded in conscious rats and autonomic modulation was conducted with the CardioSeries software. Plasma samples were collected to assess lipid peroxidation and prostaglandins (PGE2). In addition, iNOS immunohistochemistry in cardiac tissue was evaluated. MSG rats showed hypertension compared to CTR, and Amino treatment did not reverse it. Obese rats presented increased sympathetic and decreased parasympathetic modulation to the heart, reverted by Amino treatment. Plasma PGE2 was increased in obese rats, and Amino treatment decreased. Obese rats presented increased plasma lipoperoxidation, which was decreased after Amino treatment. Also, cardiac iNOS immunohistochemistry was decreased after Amino treatment. Our data suggest that iNOS activation is involved in the systemic and cardiac mechanisms of oxidative stress, inflammation, and autonomic dysfunction derived from obesity.
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Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Hipertensão/fisiopatologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Obesidade/fisiopatologia , Estresse Oxidativo , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Dinoprostona/sangue , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/induzido quimicamente , Inflamação/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Miocárdio/química , Óxido Nítrico Sintase Tipo II/análise , Obesidade/sangue , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Glutamato de SódioRESUMO
Exposure to microgravity induces autonomic and vestibular disorders such as alterations in cardiovascular function. The paraventricular nucleus of the hypothalamus (PVN) is known to be an important center for integrating autonomic and cardiovascular responses as blood volume reflexes. The acute effects promoted by microgravity and PVN involvement in cardiovascular and autonomic parameters have not yet been evaluated. Male Wistar rats were anesthetized to facilitate cannulae implantation in the PVN. After 3 days of surgical recovery, femoral artery and vein catheters were implanted for direct recording of blood pressure and heart rate (HR) in conscious animals to evaluate cardiovascular and autonomic changes in an acute protocol of head-down tilt (HDT) in nonanesthetized rats. During HDT, there was an increase in mean arterial pressure (11 ± 1 mmHg, P < 0.05) and a decrease in HR (-28 ± 5 bpm, P < 0.05). Spectral analysis of systolic arterial pressure showed an increase in the low-frequency (LF) component. In addition, HDT induced a reduction in the LF component and an increase in the high-frequency (HF) component of the pulse interval (PI). PVN inhibition with muscimol reversed bradycardia and blocked the reduction of the LF and HF increases in PI during HDT. These results suggest that the PVN participates in the cardiovascular compensation during HDT, especially modulating cardiac responses.
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Pressão Sanguínea/fisiologia , Decúbito Inclinado com Rebaixamento da Cabeça/fisiologia , Frequência Cardíaca/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Ausência de Peso , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Microinjeções/métodos , Muscimol/administração & dosagem , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
PURPOSE: This study aimed to analyze the hemodynamic and cardiac effects of direct renin inhibitor (DRI) treatment and swimming training in hypertensive rats. METHODS: Seventy-seven rats were divide into eight groups: sedentary normotensive (SN), trained normotensive (TN), sedentary normotensive treated with DRI (SN_DRI), trained normotensive treated with DRI (TN_DRI), sedentary hypertensive (SH), trained hypertensive (TH), sedentary hypertensive treated with DRI (SH_DRI), trained hypertensive treated with DRI (TH_DRI). Swimming training occurred for up to 60 min, five times a week for four weeks. The hypertensive animals were treated with 20 mg c kg(-1) c day(-1) L-NAME for four weeks. Groups treated with DRI received 10 mg c kg(-1) c day(-1) of aliskiren for four weeks. After the treatment period, all the animals underwent femoral artery catheterization surgery for direct measurement of cardiovascular variables. RESULTS: The SH group presented hypertension (136.4 ± 5.0 mmHg) compared to the SN (107.1 ± 1.7 mmHg). The TH group showed lower mean arterial pressure (MAP) than the SH (121.1 ± 1.3 mmHg), but the treatment with DRI did not attenuate hypertension (128.2 ± 4.9 mmHg). The analysis of collagen areas demonstrated that treatment with DRI may attenuate cardiac remodeling in situations of hypertension, in the condition of treatment alone or combined with physical training. CONCLUSION: Both interventions in combination may be more effective at reducing cardiovascular risk in hypertensive subjects.
Assuntos
Amidas/uso terapêutico , Pressão Sanguínea/fisiologia , Fumaratos/uso terapêutico , Hipertensão/tratamento farmacológico , NG-Nitroarginina Metil Éster/farmacologia , Condicionamento Físico Animal/métodos , Renina/antagonistas & inibidores , Natação/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Coração/fisiopatologia , Hipertensão/sangue , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Wistar , Renina/sangue , Fatores de RiscoRESUMO
The intracellular protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas disease, a serious disorder that affects millions of people in Latin America. Cell invasion by T. cruzi and its intracellular replication are essential to the parasite's life cycle and for the development of Chagas disease. Here, we present evidence suggesting the involvement of the host's cyclooxygenase (COX) enzymes during T. cruzi invasion. Pharmacological antagonists for COX-1 (aspirin) and COX-2 (celecoxib) caused marked inhibition of T. cruzi infection when rat cardiac cells were pretreated with these nonsteroidal anti-inflammatory drugs (NSAIDs) for 60 min at 37°C before inoculation. This inhibition was associated with an increase in the production of NO and interleukin-1ß and decreased production of transforming growth factor ß (TGF-ß) by cells. Taken together, these results indicate that COX-1 more than COX-2 is involved in the regulation of anti-T. cruzi activity in cardiac cells, and they provide a better understanding of the influence of TGF-ß-interfering therapies on the innate inflammatory response to T. cruzi infection and may represent a very pertinent target for new therapeutic treatments of Chagas disease.
Assuntos
Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Mioblastos Cardíacos/parasitologia , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/patogenicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Celecoxib , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Imunidade Inata/efeitos dos fármacos , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Óxido Nítrico/metabolismo , Pirazóis/farmacologia , Ratos , Sulfonamidas/farmacologia , Fator de Crescimento Transformador alfa/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Trypanosoma cruzi/efeitos dos fármacosRESUMO
We investigated the involvement of nitric oxide (NO) and reactive oxygen species (ROS) on autonomic cardiovascular parameters, vascular reactivity, and endothelial cells isolated from aorta of monosodium glutamate (MSG) obese rats. Obesity was induced by administration of 4 mg/g body wt of MSG or equimolar saline [control (CTR)] to newborn rats. At the 60th day, the treatment was started with N(G)-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg) or 0.9% saline. At the 90th day, after artery catheterization, mean arterial pressure (MAP) and heart rate were recorded. Plasma was collected to assess lipid peroxidation. Endothelial cells isolated from aorta were evaluated by flow cytometry and fluorescence intensity (FI) emitted by NO-sensitive dye [4,5-diaminofluoresceindiacetate (DAF-2DA)] and by ROS-sensitive dye [dihydroethidium (DHE)]. Vascular reactivity was made by concentration-response curves of acetylcholine. MSG showed hypertension compared with CTR. Treatment with L-NAME increased MAP only in CTR. The MSG induced an increase in the low-frequency (LF) band and a decrease in the high-frequency band of pulse interval. L-NAME treatment increased the LF band of systolic arterial pressure only in CTR without changes in MSG. Lipid peroxidation levels were higher in MSG and were attenuated after L-NAME. In endothelial cells, basal FI to DAF was higher in CTR than in MSG. In both groups, acetylcholine increased FI for DAF from basal. The FI baseline to DHE was higher in MSG than in CTR. Acetylcholine increased FI to DHE in the CTR group, but decreased in MSG animals. We suggest that reduced NO production and increased production of ROS may contribute to hypertension in obese MSG animals.
Assuntos
Endotélio Vascular/metabolismo , Hipertensão/fisiopatologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Obesidade/fisiopatologia , Estresse Oxidativo/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Endotélio Vascular/patologia , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/etiologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Obesidade/induzido quimicamente , Obesidade/complicações , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Glutamato de Sódio/efeitos adversos , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
The aim of this study was to determine whether exercise training combined with beta-blocker treatment promotes additional cardiovascular benefits compared with either intervention on its own. For this we used 76 Wistar rats distributed among different groups: normotensive sedentary (NS), normotensive trained (NT), normotensive sedentary treated with beta-blocker (NS_BB), normotensive trained treated with beta-blocker (NT_BB), hypertensive sedentary (HS), hypertensive trained (HT), hypertensive sedentary treated with a beta-blocker (HS_BB), and hypertensive trained rats treated with beta-blocker (HT_BB). Exercise training consisted of 4 weeks of swimming for 60 min a day, 5 days a week. Hypertension was induced with l-NAME (4 weeks), whereas the control rats received saline, and both the control and test rats received nebivolol. The animals underwent surgery to directly record their blood pressure. The HS group showed higher mean arterial pressure (MAP) (P = 0.000), systolic arterial pressure (P = 0.000), and diastolic arterial pressure (P = 0.000) compared with NS. MAP was higher in the HS compared with the HT (P = 0.002), HS_BB (P = 0.018), and HT_BB (P = 0.015) groups. Hearts from the HS group had a higher percentage of collagen compared with the NS and HS_BB groups. The HT_BB and HT groups only had a higher percentage of cardiac collagen by comparison with the HS_BB group. The HT_BB group showed higher levels of macrophages and neutrophils by comparison with the HT and HS_BB groups. Thus, treatment with a beta-blocker combined with physical training was associated with increased cardiovascular benefits over either intervention alone.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Benzopiranos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Etanolaminas/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/terapia , Condicionamento Físico Animal , Animais , Tamanho Celular , Colágeno/metabolismo , Edema/patologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Macrófagos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Nebivolol , Necrose , Neutrófilos/patologia , Ratos WistarRESUMO
The intracellular protozoan parasite Trypanosoma cruzi causes Chagas disease, a serious disorder that affects millions of people in Latin America. Cell invasion by T. cruzi and its intracellular replication are essential to the parasite's life cycle and for the development of Chagas disease. Here, we present evidence suggesting the involvement of the host's cyclooxygenase (COX) enzyme during T. cruzi invasion. Pharmacological antagonist for COX-1, aspirin (ASA), caused marked inhibition of T. cruzi infection when peritoneal macrophages were pretreated with ASA for 30 min at 37°C before inoculation. This inhibition was associated with increased production of IL-1ß and nitric oxide (NO(â)) by macrophages. The treatment of macrophages with either NOS inhibitors or prostaglandin E2 (PGE2) restored the invasive action of T. cruzi in macrophages previously treated with ASA. Lipoxin ALX-receptor antagonist Boc2 reversed the inhibitory effect of ASA on trypomastigote invasion. Our results indicate that PGE2, NO(â), and lipoxins are involved in the regulation of anti-T. cruzi activity by macrophages, providing a better understanding of the role of prostaglandins in innate inflammatory response to T. cruzi infection as well as adding a new perspective to specific immune interventions.
Assuntos
Aspirina/farmacologia , Macrófagos Peritoneais/parasitologia , Trypanosoma cruzi/patogenicidade , Animais , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II , Trypanosoma cruzi/efeitos dos fármacosRESUMO
BACKGROUND: Sepsis is a complex condition characterized by systemic host inflammation caused by an infection. Experimental and observational studies indicate that obesity, one of the components of metabolic syndrome (MetS), or aspirin (ASA) treatment could be associated with sepsis survival. However, the effects of ASA on septic mice with MetS-induced conditions have not been explored. METHODS: Swiss mice were administered monosodium glutamate (MSG) (4 mg/kg) during their first 5 days of life for MetS induction, while the control mice received an equimolar saline solution. MetS was validated in male mice on their 60th day of life. ASA treatment was administered for 15 days prior to sepsis (40 mg/kg). On the 75th day, sepsis was induced in MetS and control mice through cecal ligation and puncture (CLP). The effects of ASA on septic mice with MSG-induced MetS were assessed by determining survival rates, quantification of nitric oxide (NO), and cytokine levels in the plasma, while correlating these data with hematological, blood glucose and cardiovascular parameters. RESULTS: MetS was validated by Lee-Index (3 body weight/naso-anal length×1000), hypertension, and hyperglycemia in animals receiving MSG as neonates. In control animals, severe sepsis promoted hypoglycemia, which was associated with mortality, as well as increased plasma NO levels, hypotension, hematological alterations, and elevation of proinflammatory cytokines. In contrast, MetS and pre-treatment with ASA were able to prevent sepsis-related alterations. CONCLUSIONS: MetS and ASA pre-treatment provided protection against severe sepsis. However, ASA was ineffective in mice with MetS undergoing severe sepsis.
Assuntos
Aspirina , Citocinas , Síndrome Metabólica , Óxido Nítrico , Sepse , Animais , Sepse/tratamento farmacológico , Aspirina/uso terapêutico , Aspirina/administração & dosagem , Camundongos , Masculino , Síndrome Metabólica/tratamento farmacológico , Citocinas/sangue , Óxido Nítrico/metabolismo , Modelos Animais de Doenças , Glutamato de Sódio , Glicemia/análiseRESUMO
Chagas disease (CD), caused by Trypanosoma cruzi, is a neglected tropical disease prevalent in Latin America. Infected patients are treated to eliminate the parasite, reduce the cardiomyopathy risk, and interrupt the disease transmission cycle. The World Health Organization recognizes benznidazole (BZ) and nifurtimox as effective drugs for CD treatment. In the chronic phase, both drugs have low cure rates and serious side effects. T. cruzi infection causes intense tissue inflammation that controls parasite proliferation and CD evolution. Compounds that liberate nitric oxide (NO) (NO donors) have been used as anti-T. cruzi therapeutics. Currently, there is no evidence that nitroxyl (HNO) affects T. cruzi infection outcomes. This study investigated the effects of the HNO donor Angeli's salt (AS) on C57BL/6 mice infected with T. cruzi (Y strain, 5 × 103 trypomastigotes, intraperitoneally). AS reduced the number of parasites in the bloodstream and heart nests and increased the protective antioxidant capacity of erythrocytes in infected animals, reducing disease severity. Furthermore, in vitro experiments showed that AS treatment reduced parasite uptake and trypomastigote release by macrophages. Taken together, these findings from the murine model and in vitro testing suggest that AS could be a promising therapy for CD.
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Metabolic syndrome (MetS) is characterized by endocrine-metabolic and cardiac alterations that increase the risk of cardiovascular disease, dyslipidemia, and type-2 diabetes mellitus. Dietary supplementation with l-Arginine (L-Arg) is beneficial for fat loss, while chronic aerobic exercise has several benefits in reversing cardiovascular, autonomic, and metabolic dysfunctions caused by obesity. However, the association between these two approaches has not yet been described. This study aimed to evaluate the possible benefits of physical training, with or without l-Arg-supplementation, on cardiovascular, autonomic, and metabolic parameters in rats with MetS, which was induced by the subcutaneous administration of monosodium glutamate at 4 mg g-1day-1 in rats from the first to fifth day of life. Physical training on a treadmill and supplementation with l-Arg-in adulthood were carried out concomitantly for 8 weeks. After this, the animals underwent femoral artery catheterization to record their cardiovascular parameters and autonomic modulation. Organs and blood were removed to measure levels of nitrite, glucose, and hepatic steatosis. In adult rats with MetS, supplementation with l-Arg-in combination with physical training reduced hypertension, tachycardia, adipose tissue mass, free fatty acids, and hepatic steatosis. Supplementation with l-Arg-and physical training separately was beneficial in reducing several aspects of MetS, but a combination of both was especially effective in reducing adipose tissue and hepatic steatosis. Together, the two therapies can form a good strategy to combat MetS.
Assuntos
Síndrome Metabólica , Ratos , Animais , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/complicações , Síndrome Metabólica/terapia , Suplementos Nutricionais , Arginina/farmacologia , Arginina/uso terapêutico , Coração , Obesidade/metabolismoRESUMO
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra, causing motor changes. In addition to motor symptoms, non-motor dysfunctions such as psychological, sensory and autonomic disorders are recorded. Manifestations related to the autonomic nervous system include the cardiovascular system, as postural hypotension, postprandial hypotension, and low blood pressure. One of the mediators involved is the nitric oxide (NO). In addition to the known roles such as vasodilator, neuromodulator, NO acts as an important mediator of the immune response, increasing the inflammatory response provoked by PD in central nervous system. The use of non-specific NOS inhibitors attenuated the neurodegenerative response in animal models of PD. However, the mechanisms by which NO contributes to neurodegeneration are still not well understood. The literature suggest that the contribution of NO occurs through its interaction with superoxides, products of oxidative stress, and blocking of the mitochondrial respiratory chain, resulting in neuronal death. Most studies involving Parkinsonism models have evaluated brain NO concentrations, with little data available on its peripheral action. Considering that studies that evaluated the involvement of NO in the neurodegeneration in PD, through NOS inhibitors administration, showed neuroprotection in rats, it has prompted new studies to assess the participation of NOS isoforms in cardiovascular changes induced by parkinsonism, and thus to envision new targets for the treatment of cardiovascular disorders in PD. The aim of this study was to conduct a literature review to assess available information on the involvement of nitric oxide (NO) in cardiovascular aspects of PD.
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AIMS: The rostral ventrolateral medulla (RVLM) is the main sympathetic output of the central nervous system to control blood pressure. Reportedly, reactive oxygen species (ROS) can increase arterial pressure, leading to hypertension. As ROS increase the sympathetic tone in RVLM and obese animals present grater oxidative stress, it would be important to note this relationship. MAIN METHODS: Therefore, we evaluated the systemic and central effects (in the RVLM) of vitamin C (vit C, an antioxidant) on the redox balance and cardiovascular and autonomic profiles in hyperadipose male rats. We also evaluated the neurotransmission by L-glutamate (L-glu) and vit C in the RVLM of awake hyperadipose rats. KEY FINDINGS: Our study confirmed that hyperadipose rats were hypertensive and tachycardic, presented increased sympathetic and decreased parasympathetic modulation of the heart, and had increased plasma lipoperoxidation compared with the control rats (CTR). Oral vitamin C treatment reverted cardiovascular, autonomic, and plasma redox dysfunction. Hyperadipose rats presented a higher blood pressure increase after L-glu microinjection and a lower response to vit C in the RVLM compared with the CTR group. Biochemical analysis of redox balance in RVLM punches showed that hyperadipose rats have increased NBT and T-BARS, and after treatment with vit C, the oxidative profile decreased. The antioxidative activity of vit C reduced the amount of ROS in the RVLM area that might have resulted in lowered blood pressure and sympathetic modulation. SIGNIFICANCE: Our data suggest central and peripheral benefits of vit C treatment on cardiovascular, autonomic, and oxidative dysfunctions in hyperadipose animals.
Assuntos
Ácido Ascórbico/farmacologia , Hipertensão/tratamento farmacológico , Bulbo/metabolismo , Animais , Antioxidantes/farmacologia , Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Masculino , Bulbo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/farmacologia , Superóxido Dismutase/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismoRESUMO
We sought to investigate whether RVLM iNOS activity and oxidative profile may participate in the reduction of sympathetic responsiveness in swimming trained normotensive rats. Sedentary (S) and swimming trained (T) Wistar male rats chronically instrumented with an arterial catheter and guide cannula into the RVLM were submitted to continuous pressure and heart rate (HR) recordings and determination of autonomic control (power spectral analysis) before and after unilateral RVLM iNOS inhibition (aminoguanidine, 250 pmol/100 nL). Other S and T rats received local l-glutamate microinjection (5 nmol/100 nL). In separate S and T groups not submitted to brainstem cannulation, fresh bilateral RVLM punchs were collected for iNOS gene expression (qPCR); reduced glutathione and lipid peroxidation quantification (spectrophotometry); iron-reducing antioxidant (FRAP) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTSË+) scavenger assays. iNOS gene expression was confirmed in fixed RVLM slices (immunofluorescence). T rats exhibited resting bradycardia, lower sympathovagal balance, reduced RVLM iNOS gene/protein expression and higher antioxidant capacity. Decreased iNOS expression was positively correlated with reduced HR. Pressor and tachycardic response to l-Glutamate were smaller in T rats. Aminoguanidine microinjection reduced sympathetic activity in S rats but did not change it in T rats expressing reduced RVLM iNOS content. Our data indicate that iNOS, expressed in the RVLM of normotensive male rats, has tonic effects on sympathetic activity and that swimming training is an efficient tool to reduce iNOS expression and augment the antioxidant defense, thus reducing glutamatergic responsiveness and sympathetic drive to cardiovascular effectors.
Assuntos
Sistema Nervoso Autônomo/metabolismo , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Bulbo/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Ratos , NataçãoRESUMO
AIMS: Sepsis is a potentially fatal systemic inflammatory response and its underlying pathophysiology is still poorly understood. Studies suggest that obesity, a component of metabolic syndrome (MS), is associated with sepsis survival. Therefore, this study focused on investigating the influence of MS on mortality and cardiovascular dysfunction induced by sublethal cecal ligation and puncture (SL-CLP). MAIN METHODS: Newborn Swiss mice received monosodium glutamate (MSG) (4 mg kg-1 day-1, s.c.) during the first 5 d of life for MS induction, while the control pups received equimolar saline solution. On the 75th day, SL-CLP was used to induce mild sepsis (M-CLP) in the MS (MS-M-CLP) and control (SAL-M-CLP) mice. The effect of MS on sepsis in mice was assessed by determining the survival rate and quantification of nitric oxide (NO) in the plasma, and associating this data with hematological and cardiovascular parameters. KEY FINDINGS: MS improved the survival of septic mice, preventing impairment to hematological and cardiovascular parameters. In addition, MS attenuated plasmatic NO increase, which is a typical feature of sepsis. SIGNIFICANCE: These findings provide new insights into the relationship between obesity and mild sepsis in mice, thus revealing an approach in favor of the "obesity paradox."
Assuntos
Sistema Cardiovascular/fisiopatologia , Ceco/patologia , Síndrome Metabólica/fisiopatologia , Punções , Sepse/etiologia , Animais , Modelos Animais de Doenças , Ligadura , Camundongos , Óxido Nítrico/metabolismo , Análise de SobrevidaRESUMO
AIMS: Chagas disease is a neglected tropical disease. The ability of Trypanosoma cruzi to survive within phagocytes is likely a critical factor for T. cruzi dissemination in the host. For control of the parasite load and host survival, macrophage action is required. Concanavalin-A (Con-A) presents properties that modulate immune functions and protect hosts from several experimental infectious diseases. Here, we evaluated the effects of Con-A on peritoneal macrophages as well as on the course of experimental infection by T. cruzi. MAIN METHODS: BALB/c mice, a susceptible model for T. cruzi infection, were treated with Con-A via the intraperitoneal route and 3 days later infected with T. cruzi. We quantified parasitemia, cytokines and nitric oxide (NO). Peritoneal exudate and macrophages were collected for macrophage phenotyping and cell viability, NO and cytokine detection, as well as for T. cruzi internalization and release index determination. KEY FINDINGS: Con-A treatment induced IL-17a and NO production by cells from the peritoneal cavity, and M1 marker expression predominated on peritoneal macrophages. These cells are also more prone to producing TNF-α, IL-6 and NO when infected by T. cruzi and show high trypanocidal capacity. Due to a hostile peritoneal microenvironment caused by Con-A, which induces macrophage cNOS and iNOS expression, infected BALB/c mice showed reduced parasitemia and an increased survival rate. SIGNIFICANCE: We conclude that Con-A can induce peritoneal M1 macrophage polarization to increase trypanocidal activity, resulting in ameliorated systemic infection in a susceptible experimental model.
Assuntos
Polaridade Celular , Doença de Chagas/patologia , Concanavalina A/farmacologia , Interleucina-17/metabolismo , Macrófagos Peritoneais/patologia , Macrófagos Peritoneais/parasitologia , Óxido Nítrico/metabolismo , Trypanosoma cruzi/fisiologia , Animais , Polaridade Celular/efeitos dos fármacos , Doença de Chagas/metabolismo , Feminino , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Parasitemia/metabolismo , Parasitemia/patologia , Trypanosoma cruzi/efeitos dos fármacosRESUMO
AIMS: Parkinson's disease (PD) is a neurological disorder caused by environmental and genetic factors, characterized by the death of dopaminergic neurons of the substantia nigra pars compacta (SNpc), leading to a decrease of dopamine in the striatum. In addition to motor symptoms, PD has several abnormalities, among which are cardiovascular changes, such as orthostatic and postprandial hypotension, and blood pressure lability. Studies demonstrate gender differences in PD pathogenesis, indicating that female hormones have a protective role against disease development. However, no studies examining cardiovascular changes in a female rat model of parkinsonism exist. MAIN METHODS: Wistar female rats were subjected to ovariectomy (OVX) or sham surgery. After seven days, these animals were subjected to bilateral infusion of 6-hydroxydopamine (6-OHDA) or vehicle solution in their SNpc. On the 14th experimental day, a femoral artery catheterization was performed to record cardiovascular parameters after 24 h in conscious state. Analyses of cardiovascular variability and spontaneous baroreflex were performed. The nitrite (NO) concentration in the heart, thoracic aorta, abdominal aorta, and plasma was measured. KEY FINDINGS: The sham-6-OHDA group had no decrease in the mean arterial pressure compared to sham-saline group, whereas the OVX-6-OHDA group presented a baseline decrease in comparison to sham-6-OHDA. The OVX-6-OHDA group showed an NO increase in the heart and abdominal aorta, whereas the sham-6-OHDA group did not. The very low frequency variability component decreased in the sham-6-OHDA but not in the OVX-6-OHDA group. SIGNIFICANCE: We suggest a cardiovascular protection by ovarian hormones in PD with a possible NO involvement.