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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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 -1 day -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., Competing Interests: Declaration of Competing Interest The authors declare that they have no potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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 × 10 3 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.

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., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Martins-Pinge, de Jager, de Campos, Bezerra, Turini and Pinge-Filho.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.", (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 (ABTS˙ + ) 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The aim was to evaluate if maternal treatment with metformin (MET) during pregnancy and lactation could be safe for metabolic and cardiovascular parameters of adult male and female offspring. Materials and methods: Wistar female rats were treated with MET (293 mg/kg/d) or tap water, by gavage during gestation (METG or CTRG) or gestation and lactation (METGL or CTRGL). Results: At 75 days of life, male and female MET offspring presented similar blood pressure when compared with their CTR. The heart rate of female METGL was higher than in the CTRGL. The insulin sensitivity, basal glycaemia, body weight, Lee index of obesity, plasmatic concentration of triglycerides, total cholesterol and fat acid of male and female MET were similar to CTR groups. Lower fat pad deposition was observed in female METG and METGL. Conclusion: MET exposure during gestational and lactation does not program cardiovascular and metabolic alterations in adult offspring life.

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 A 4 (LXA 4 ) 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., (Copyright © 2020 American Society for Microbiology.)

We evaluated the influence of metabolic syndrome (MS) on acute Trypanosoma cruzi infection. Obese Swiss mice, 70 days of age, were subjected to intraperitoneal infection with 5 × 10 2 trypomastigotes of the Y strain. Cardiovascular, oxidative, inflammatory, and metabolic parameters were evaluated in infected and non-infected mice. We observed higher parasitaemia in the infected obese group (IOG) than in the infected control group (ICG) 13 and 15 days post-infection. All IOG animals died by 19 days post-infection (dpi), whereas 87.5% of the ICG survived to 30 days. Increased plasma nitrite levels in adipose tissue and the aorta were observed in the IOG. Higher INF- γ and MCP-1 concentrations and lower IL-10 concentrations were observed in the IOG compared to those in the ICG. Decreased insulin sensitivity was observed in obese animals, which was accentuated after infection. Higher parasitic loads were found in adipose and hepatic tissue, and increases in oxidative stress in cardiac, hepatic, and adipose tissues were characteristics of the IOG group. Thus, MS exacerbates experimental Chagas disease, resulting in greater damage and decreased survival in infected animals, and might be a warning sign that MS can influence other pathologies.

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., Competing Interests: The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work., (Copyright © 2019 Carolina Panis et al.)

Aim: Parkinson's disease (PD) is a progressive neurodegenerative disease that manifests itself clinically after reaching an advanced pathological stage. Besides motor signals, PD patients present cardiovascular and autonomic alterations. Recent data showed that rats induced to Parkinsonism by 6-hydroxydopamine (6-OHDA) administration in the substantia nigra pars compacta (SNpc) showed lower mean arterial pressure (MAP) and heart rate (HR), as reduction in sympathetic modulation. The paraventricular nucleus of the hypothalamus (PVN) is an important site for autonomic and cardiovascular control, and amino acid neurotransmission has a central role. We evaluate PVN amino acid neurotransmission in cardiovascular and autonomic effects of 6-OHDA Parkinsonism., Methods: Male Wistar rats were submitted to guide cannulas implantation into the PVN. 6-OHDA or sterile saline (sham) was administered bilaterally in the SNpc. After 7 days, cardiovascular recordings in conscious state was performed., Results: Bicuculline promoted an increase in MAP and HR in sham group and exacerbated those effects in 6-OHDA group. NBQX (non-NMDA inhibitor) did not promote changes in sham as in 6-OHDA group. On the other hand, PVN microinjection of LY235959 (NMDA inhibitor) in sham group did not induced cardiovascular alterations, but decreased MAP and HR in 6-OHDA group. Compared to Sham group, 6-OHDA lesion increased the number of neuronal nitric oxide synthase (nNOS)-immunoreactive neurons in the PVN and, nNOS inhibition promoted higher increases in MAP and HR., Conclusion: Our data suggest that the decreased baseline blood pressure and heart rate in animals with Parkinsonism may be due to an increased GABAergic tone via nNOS in the PVN., (© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

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 (62,5 mg/mL, 1 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/100 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 ( † P < 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, † P < 0.05). T increased nNOS gene and protein expression within the ventromedial and posterior PVN nuclei ( † P < 0.05). PVN nitirite levels were also increased in T and l-arginine groups ( † P < 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., (Copyright © 2018. Published by Elsevier Inc.)

Aim: Autonomic modulation responds to ovarian hormones and estrogen increases nitric oxide bioavailability. Also, females have minor susceptibility to sepsis and a higher survival rate. However, few studies have evaluated the role of estrogen in cardiovascular, autonomic, and oxidative parameters during initial endotoxemia and under inducible nitric oxide synthase (iNOS) inhibition in female rats. Methods: Female wistar rats were subjected to ovariectomy and divided into three groups: OVX (ovariectomized), OVX+E (OVX plus daily estradiol) and SHAM (false surgery). After 8 weeks, mean arterial pressure (MAP) and heart rate (HR) were recorded in non-anesthetized catheterized rats, before and after intravenous LPS injection, preceded by S-methylisothiourea sulfate (SMT) injection, or sterile saline. Cardiovascular recordings underwent spectral analysis for evaluation of autonomic modulation. Two hours after LPS, plasma was collected to assess total radical-trapping antioxidant (TRAP), nitrite levels (NO2), lipoperoxidation (LOOH), and paraoxonase 1 (PON1) activity. Results: Two hours after LPS, females treated with SMT presented a decrease of MAP, when compared to saline-LPS groups. At this same time, all SMT+LPS groups presented an increase of sympathetic and a decrease of parasympathetic modulation of HR. Two hours after saline+LPS, OVX presented decreased total radical-trapping antioxidant (TRAP) compared to SHAM. When treated with SMT+LPS, OVX did not altered TRAP, while estradiol reduced LOOH levels. Conclusion: iNOS would be responsible for sympathetic inhibition and consumption of antioxidant reserves of females during endotoxemia, since iNOS is inhibited, treatment with estradiol could be protective in inflammatory challenges.

Studies showed that physical exercise decreases the risk of developing Parkinson's disease (PD) as slowing its progression. Nitric oxide (NO) increases in the substantia nigra pars compacta (SNpc) of individuals with PD. However, no study has evaluated the effects of exercise on peripheral NO levels and its modulatory effects on cardiovascular dysfunctions of subjects with PD. Trained (T) or sedentary (S) animals underwent stereotactic surgery for bilateral 6-hydroxydopamine (6-OHDA) or vehicle microinfusion (Sham group). After 6 days, the animals were catheterized for baseline parameters, followed by inhibition of NOS by Nw-nitro-arginine-methyl ester (L-NAME, 10 mg/kg - i.v.). Nitrite concentration was performed in the aorta, heart, kidney, adrenal and plasma. After exercise, the animals presented resting bradycardia (6-OHDA T and Sham T). NO was increased in the aorta of 6-OHDA S, and decreased in 6-OHDA T animals. In the heart, NO was increased in Sham T compared to sedentary and decreased in 6-OHDA T relative to 6-OHDA S and Sham T animals. At the kidney, NO decrease in 6-OHDA S and Sham T when compared to Sham S and, in adrenal gland, there was a decrease in 6-OHDA T in relation to 6-OHDA S. L-NAME promoted lower increases in MAP in 6-OHDA groups. The decreases of HR were enhanced due to physical training. 6-OHDA S group presented decreased systolic arterial pressure variability, not altered by exercise. Our data showed alterations in peripheral NO in the association of exercise with Parkinsonism in the cardiovascular function., (Copyright © 2018 Elsevier Inc. All rights reserved.)

It is known that autonomic modulation is responsive to ovarian hormone levels and that estrogen increases nitric oxide (NO) bioavailability. However, little is known about the interaction of nitric oxide synthase (NOS) isoforms with autonomic modulation, oxidative stress and cardiovascular risk in females. This study aimed to investigate cardiovascular, autonomic and oxidative parameters after selective NOS inhibition. A spectral analysis of systolic arterial pressure (SAP) and heart rate variability (HRV) was performed. NO levels, total antioxidant capacity (TRAP), lipid hydroperoxides (LOOH) and paraoxonase 1 (PON1) activity were measured in the plasma of rats treated with L-NG-nitroarginine methyl ester (L-NAME), S-methylisothiourea (SMT) or saline. Wistar rats, ovariectomized (OVX) with or without estradiol treatment (1mg/kg/day) or with a false ovariectomy (SHAM), were submitted to artery and vein catheterization. Cardiovascular parameters were evaluated before and after the administration of saline or NOS inhibitors. After 2h, plasma samples were collected for biochemical measurement. At baseline, cardiovascular and autonomic parameters were not different among the groups. L-NAME, the constitutive NOS isoform (cNOS) inhibitor, promoted an increase in mean arterial pressure (MAP) and a reduction in the low frequency band (LF) of SAP of SHAM rats, but this increase was smaller in OVX animals, which also showed a reduction in PON1 activity. The decreased activity of PON1 caused by L-NAME was prevented in the OVX+E group. SMT, an inducible NOS isoform (iNOS) inhibitor, promoted an increase in MAP and in the LF of SAP, in interbeat interval (IBI) parameters at LFnu and in LF/HF ratio of HRV in all groups, but the OVX+E had lower levels of NO when compared with the OVX group. Our data suggest that while cNOS contributes to maintaining the activity of PON1 in OVX rats, iNOS activity maintains the levels of NO in OVX+E rats., (Copyright © 2017 Elsevier Inc. All rights reserved.)

There is evidence suggesting that exercise training (ET) acts as a factor toward resistance to Trypanosoma cruzi infection. However, the effects of mean arterial pressure (MAP), heart rate (HR), and nitric oxide (NO) during the acute phase of infection has not been elucidated yet. Swiss mice were randomly assigned into four groups: sedentary control (SC, n = 30), trained control (TC, n = 30), sedentary infected (SI, n = 30), and trained infected (TI, n = 30). ET was performed on the treadmill for 9 weeks. After training, the mice were infected with 5 × 10 3 trypomastigotes of T. cruzi (Y strain) or PBS. We observed resting bradycardia and improved performance in trained animals compared with sedentary ones. On the 20th day post-infection (DPI), we found a decrease in HR in SI animals compared to TI animals (699.73 ± 42.37 vs. 742.11 ± 25.35 bpm, respectively, P < 0.05). We also observed increased production of NO in cardiac tissue on the 20th DPI in the SI group, normalized in TI group (20.73 ± 2.74 vs. 6.51 ± 1.19 μM, respectively). Plasma pro-inflammatory cytokines (IL-12, TNF-α, IFN-γ,) and MCP-1 were increased in SI animals, but decreased in TI animals. The increase in parasitemia on the 15th and 17th DPI in the SI group was attenuated in the TI group. Our results suggest that previous ET plays a preventive role in resistance to T. cruzi infection, modulating cardiovascular aspects, inflammatory reaction, and NO levels of infected mice.

Long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) are known to modulate a variety of immune cell functions. On occasion, this has led to diminished host resistance to certain viral and bacterial infections. Little is known about the impact of n-3 PUFA on host resistance to parasitic infection, however, based on results from a small study conducted more than two decades ago, we hypothesized that providing mice LC n-3 PUFA will diminish host resistance to Trypanosoma cruzi, the parasitic pathogen responsible for Chagas disease. To investigate this, C57BL/6 mice were supplemented by gavage (0.6% v/w) with phosphate-buffered saline, corn oil (CO), or menhaden fish oil (FO, a fat source rich in LC n-3 PUFA) for 15 days prior to T cruzi (Y strain) challenge and throughout the acute phase of infection. FO supplementation was associated with a transient 2-fold greater peak of blood parasitemia at 7 days postinfection (dpi), whereas subsequent cardiac parasitemia was ~60% lower at 12 dpi. FO treatment also ameliorated the leukopenia and thrombocytopenia observed in the early stages of a T cruzi infection. FO supplementation reduced circulating and cardiac nitric oxide at 7 and 12 dpi, respectively. FO supplementation altered ex vivo prostaglandin E 2 and cytokine and chemokine production by splenocytes isolated from uninfected and infected mice. Overall, our results suggest that oral administration of LC n-3 PUFA from FO can have beneficial effects on the host in the early course of a T cruzi infection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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 (PGE 2 ). 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 PGE 2 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.

We evaluated the effects of swimming training on nitric oxide (NO) modulation to glutamate microinjection within the rostral ventrolateral medulla (RVLM) in conscious freely moving rats. Male Wistar rats were submitted to exercise training (Tr) by swimming or kept sedentary (Sed) for 4 weeks. After the last training session, RVLM guide cannulas and arterial/venous catheters were chronically implanted. Arterial pressure (AP), heart rate (HR), and baroreflex control of HR (loading/unloading of baroreceptors) were recorded in conscious rats at rest. Pressor response to L-glutamate in the RVLM was compared before and after blockade of local nitric oxide (NO) production. In other Tr and Sed groups, brain was harvested for gene (qRT-PCR) and protein (immunohistochemistry) expression of NO synthase (NOS) isoforms and measurement of NO content (nitrite assay) within the RVLM. Trained rats exhibited resting bradycardia (average reduction of 9%), increased baroreflex gain (Tr: -4.41 ± 0.5 vs. Sed: -2.42 ± 0.31 b/min/mmHg), and unchanged resting MAP. The pressor response to glutamate was smaller in the Tr group (32 ± 4 vs. 53 ± 2 mmHg, p < 0.05); this difference disappeared after RVLM pretreatment with carboxy-PTIO (NO scavenger), Nw-Propyl-L-Arginine and L-NAME (NOS inhibitors). eNOS immunoreactivity observed mainly in RVLM capillaries was higher in Tr, but eNOS gene expression was reduced. nNOS gene and protein expression was slightly reduced (-29 and -9%, respectively, P > 0.05). Also, RVLM NO levels were significantly reduced in Tr (-63% vs. Sed). After microinjection of a NO-donor, the attenuated pressor response of L-glutamate in Tr group was restored. Data indicate that swimming training by decreasing RVLM NO availability and glutamatergic neurotransmission to locally administered glutamate may contribute to decreased sympathetic activity in trained subjects.

Epigenetics has recently been linked to molecular adaptive responses evoked by physical exercise and stress. Herein we evaluated the effects of physical exercise on global DNA methylation and expression of the Dnmt1 gene in the rat brain and also verified its potential to modulate responses evoked by repeated restraint stress (RRS). Wistar rats were classified into the following experimental groups: (1) physically active (EX): animals submitted to swimming during postnatal days 53-78 (PND); (2) stress (ST): animals submitted to RRS during 75-79PND; (3) exercise-stress (EX-ST): animals submitted to swimming during 53-78PND and to RRS during 75-79PND, and (4) control (CTL): animals that were not submitted to intervention. Samples from the hippocampus, cortex and hypothalamus were obtained at 79PND. The global DNA methylation profile was assessed using an ELISA-based method and the expression of Dnmt1 was evaluated by real-time PCR. Significantly increased methylation was observed in the hypothalamus of animals from the EX group in comparison to CTL. Comparative analysis involving the EX-ST and ST groups revealed increased global DNA methylation in the hippocampus, cortex, and hypothalamus of EX-ST, indicating the potential of physical exercise in modulating the responses evoked by RRS. Furthermore, decreased expression of the Dnmt1 gene was observed in the hippocampus and hypothalamus of animals from the EX-ST group. In summary, our data indicate that physical exercise affects DNA methylation of the hypothalamus and might modulate epigenetic responses evoked by RRS in the hippocampus, cortex, and hypothalamus., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is mainly characterized by motor signals. However, non-motor signals also affect and decrease the quality of life of PD patients. Among these non-motor signs are cardiovascular disorders as orthostatic hypotension, postprandial hypotension and cardiac arrhythmias, which may be due to the involvement of both central nervous system and peripheral autonomic nervous system. In the present study we investigated the cardiovascular function, evaluating cardiovascular reflexes (chemoreflex and baroreflex), in an animal model of Parkinsonism induced by bilateral infusion of the toxin 6-hydroxydopamine (6-OHDA), in the substantia nigra pars compacta (SNpc). The results showed that the animals induced to Parkinsonism had lower arterial pressure (AP) and heart rate HR) compared to control animals. We showed that after activation of the baroreceptors by phenylephrine (Phe) and sodium nitroprusside (SNP), the baroreflex sensitivity index was not changed between the groups. However, there was a greater increase in the AP when stimulated with Phe and greater tachycardia when stimulated with SNP in 6-OHDA animals. After activation of the peripheral chemoreceptors through KCN injection (cytotoxic hypoxia), there was a higher increase in pressor and bradycardic response in injured animals with bilateral 6-OHDA. These changes in the cardiovascular reflexes may be important adjustments mechanisms to maintain the cerebral blood flow in those animals, and may be a result of denervation supersensitivity to catecholamines in autonomic targets., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Obesity-induced abnormalities, such as insulin resistance, dyslipidemia and hypertension, are frequently correlated with low-grade inflammation, a process that may depend on normal spleen function. This study investigated the role of the spleen in the obesity induced by monosodium glutamate (MSG) treatment., Materials/methods: MSG-obese and lean control (CON) rats were subjected to splenectomy (SPL) or non-operated (NO)., Results: MSG-NO rats presented a high adipose tissue content, insulin resistance, dyslipidemia and islet hypersecretion, accompanied by hypertrophy of both pancreatic islets and adipocytes when compared with CON-NO rats. In addition, changes in nitric oxide response were found in islets from the MSG-NO group without associated alterations in inducible nitric oxide synthase (iNOS) or IL1β expression. MSG-NO also presented increased leukocyte counts and augmented LPS-induced nitric oxide production in macrophages. Splenectomy of MSG-obese animals decreased insulin hypersecretion, normalized the nitric oxide response in the pancreatic islets, improved insulin sensitivity and reduced hypertrophy of both adipocytes and islets, when compared with MSG-NO rats., Conclusion: Results show that splenectomy attenuates the progression of the obesity modulating pancreas functions in MSG-obese rats., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (© 2015 Wiley Periodicals, Inc.)

Objective: Evaluate the effects caused by L-DOPA on cardiovascular and autonomic parameters in an animal model of Parkinsonism induced by 6-hydroxydopamine (6-OHDA)., Methods: Adult male Wistar rats were subjected to bilateral microinfusion of 6-OHDA or saline (sham group) in the substantia nigra, and treated by gavage with L-DOPA or water for 7 days after surgery. On the 6th day the rats were subjected to femoral artery catheterization for cardiovascular recording. Mean arterial pressure (MAP) and heart rate (HR) were evaluated at baseline and during head up tilt (HUT) protocol. Spectral analysis of cardiovascular variability was performed using the V2.4 CardioSeries software v2.4. The lesion was quantified by dopamine levels in the striatum., Results: Dopamine levels in the striatum were decreased in 6-OHDA rats (sham: 4.79 ± 0.49 ng/mg; 6-OHDA: 1.99 ± 0.68 ng/mg) and were not recovered by Prolopa treatment. Baseline values of MAP and HR were not different between groups. HUT induced an increase in MAP and HR (ΔMAP: 17 ± 1 mm Hg, ΔHR: 39 ± 4 bpm) that were attenuated in 6-OHDA and in Prolopa treated animals. At baseline, the systolic arterial pressure (SAP) variance was lower in the 6-OHDA AND sham prolopa groups. Spontaneous baroreflex sensitivity was higher at baseline in the 6-OHDA group as compared to all studied groups., Conclusions: Our data suggest that treatment with Prolopa did not interfere with cardiovascular variables at baseline. However, during HUT, the 6-OHDA and Prolopa control animals presented a lower cardiovascular compensation, suggesting a possible autonomic impairment in Parkinsonism induced by 6-OHDA.

The vulnerability of epigenetic marks of brain cells to environmental stimuli and its implication for health have been recently debated. Thus, we used the rat model of acute restraint stress (ARS) to evaluate the impact of stress on the global DNA methylation and on the expression of the Dnmt1 and Bdnf genes of hippocampus, cortex, hypothalamus and periaqueductal gray (PAG). Furthermore, we verified the potential of physical exercise to modulate epigenetic responses evoked by ARS. Sedentary male Wistar rats were submitted to ARS at the 75th postnatal day (PND), whereas animals from a physically active group were previously submitted to swimming sessions (35-74th PND) and to ARS at the 75th PND. Global DNA methylation profile was quantified using an ELISA-based method and the quantitative expression of the Dnmt1 and Bdnf genes was evaluated by real-time PCR. ARS induced a decrease in global DNA methylation in hippocampus, cortex and PAG of sedentary animals and an increased expression of Bdnf in PAG. No change in DNA methylation was associated with ARS in the exercised animals, although it was associated with abnormal expression of Dnmt1 and Bdnf in cortex, hypothalamus and PAG. Our data reveal that ARS evokes adaptive changes in global DNA methylation of rat brain that are independent of the expression of the Dnmt1 gene but might be linked to abnormal expression of the Bdnf gene in the PAG. Furthermore, our evidence indicates that physical exercise has the potential to modulate changes in DNA methylation and gene expression consequent to ARS., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Trypanosoma cruzi is the causative agent of Chagas disease. Approximately 8 million people are thought to be affected with this disease worldwide. T. cruzi infection causes an intense inflammatory response, which is critical for the control of parasite proliferation and disease development. Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are an emergent class of pharmaceutical derivatives with promising utility as chemopreventive agents. In this study, we investigated the effect of NO-indomethacin on parasite burden, cell invasion, and oxidative stress in erythrocytes during the acute phase of infection. NO-indomethacin was dissolved in dimethyl formamide followed by i.p. administration of 50 ppm into mice 30 min after infection with 5×10(3) blood trypomastigote forms (Y strain). The drug was administered every day until the animals died. Control animals received 100 μL of drug vehicle via the same route. Within the NO-indomethacin-treatment group, parasitemia and mortality (100%) were higher and oxidative stress in erythrocytes, anemia, and entry of parasites into macrophages were significantly greater than that seen in controls. Increase in the entry and survival of intracellular T. cruzi was associated with inhibition of nitric oxide production by macrophages treated with NO-indomethacin (2.5 μM). The results of this study provide strong evidence that NO-NSAIDs potently inhibit nitric oxide production, suggesting that NO-NSAID-based therapies against infections would be difficult to design and would require caution., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

It is important to elucidate the mechanism of dysautonomias in patients with Parkinson's disease; therefore, this study aimed to investigate the cardiovascular and autonomic changes that occur in an animal model of Parkinsonism. Adult male Wistar rats were anesthetized before bilateral microinfusions of 6-hydroxydopamine (6-OHDA) into the substantia nigra. The sham group underwent the same surgical procedure but received vehicle. After 7 days, the mean arterial pressure (MAP) and heart rate (HR) were measured, and various drugs were injected into conscious rats through cannulas previously implanted in the femoral artery and vein. Spectral analyses of systolic arterial pressure (SAP) and pulse interval (PI) were conducted with the CardioSeries software as the spontaneous baroreflex gain and effectivity. The animals were subjected to α-, β-adrenergic, or muscarinic receptor antagonism. For confirmation of the lesion, the levels of dopamine in the striatum were quantified by high-performance liquid chromatography. Animals that underwent 6-OHDA microinfusion had lower MAP and HR compared with those in the sham group. Spectral analysis of SAP showed that 6-OHDA animals exhibited a decrease in the sympathetic component. The PI values did not differ between groups. After the administration of muscarinic and β-adrenergic antagonists, the cardiovascular measures did not differ between the groups. However, upon administration of the α-adrenergic antagonist, the 6-OHDA animals exhibited a lower decrease in the MAP. We report cardiovascular impairments in 6-OHDA animals, possibly due to decreased sympathetic activity. Determination of the origin of these changes (central or peripheral) requires further investigation., (Copyright © 2015 the American Physiological Society.)

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&#95;DRI), trained normotensive treated with DRI (TN&#95;DRI), sedentary hypertensive (SH), trained hypertensive (TH), sedentary hypertensive treated with DRI (SH&#95;DRI), trained hypertensive treated with DRI (TH&#95;DRI). Swimming training occurred for up to 60 min, five times a week for four weeks. The hypertensive animals were treated with 20 mg ċ kg(-1) ċ day(-1) L-NAME for four weeks. Groups treated with DRI received 10 mg ċ kg(-1) ċ 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.

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-1β and decreased production of transforming growth factor β (TGF-β) 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-β-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., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

The toxic effects of paclitaxel (PTX) and its solubilizing agent cremophor EL (CREL) have been well established in vitro; however, the in vivo mechanisms underlying this toxicity remain unclear. Thus, the aim of this study was to analyze the in vivo toxicity induced by infusion of PTX and CREL and to investigate the involvement of oxidative stress as a potential mechanism for this toxicity. We treated male Wistar rats with PTX and/or CREL for 1h using human-equivalent doses (PTX+CREL/ethanol+NaCl 175mg/m(2) or CREL+ethanol+NaCl) and sacrificed immediately or 24h after these drug infusions to systemic biochemical evaluations. Hidrosoluble vitamin E (vitE, Trolox) was added as a control in some groups. The oxidative profile was determined by measuring erythrocyte and plasma lipid peroxidation, superoxide dismutase and catalase activities, reduced glutathione (GSH) levels, red blood cell (RBC) counts, hemoglobin profile, plasma total radical-trapping antioxidant parameter (TRAP), plasma lipid peroxidation, nitric oxide levels and malondialdehyde levels. Our findings showed that CREL infusion triggered immediate high plasma lipid peroxidation and augmented TRAP, while PTX caused immediate TRAP consumption and metahemoglobin formation. Pronounced oxidative effects were detected 24h after infusion, when CREL treatment enhanced RBC counts and plasma lipid peroxidation, increased catalase activity, and decreased TRAP levels. On the other hand, after 24h, PTX-infused rats showed reduced catalase activity and reduced metahemoglobin levels. These data indicate the existence of a continuous oxidative stress generation during CREL-PTX treatment and highlight CREL as primarily responsible for the in vivo oxidative damage to RBCs., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2014 the American Physiological Society.)

The injection of cytokines such as TNF-α induces muscle pain. Herein, it was addressed the role of endogenous TNF-α/TNFR1 signaling in intense acute swimming-induced muscle mechanical hyperalgesia in mice. Mice were exposed to water during 30 s (sham) or to a single session of 30-120 min of swimming. Intense acute swimming induced a dose-dependent (time of exercise-dependent) muscle mechanical hyperalgesia, which peaked after 24 h presenting characteristics of delayed onset muscle soreness (DOMS). The intense acute swimming (120 min)-induced muscle mechanical hyperalgesia was reduced in etanercept (soluble TNF receptor) treated and TNFR1 deficient ((-/-)) mice. TNF-α levels increased 2 and 4 h after intense acute swimming in soleus muscle (but not in gastrocnemius), and spinal cord, respectively. Exercise induced an increase of myeloperoxidase activity and decrease in reduced glutathione levels in an etanercept-sensitive and TNFR1-dependent manners in the soleus muscle, but not in the gastrocnemius muscle. Concluding, TNF-α/TNFR1 signaling mediates intense acute swimming-induced DOMS by an initial role in the soleus muscle followed by spinal cord, inducing muscle inflammatory hyperalgesia and oxidative stress. The knowledge of these mechanisms might contribute to improve the training of athletes, individuals with physical impairment and intense training such as military settings., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The autonomic nervous system is importantly involved in the maintenance of arterial pressure during orthostatic challenges. However, little is known about the specific central areas involved in these cardiovascular compensations. It has been proposed that the paraventricular nucleus of the hypothalamus (PVN) is involved in cardiovascular reflex responses related to blood volume. Our hypothesis is that PVN is involved in autonomic modulation during an orthostatic challenge (head up tilt, HUT). Adult male Wistar rats, instrumented with guide cannulas to the PVN and femoral artery and vein catheters were submitted to mean arterial pressure (MAP) and heart rate (HR) recordings in conscious state. After baseline parameters the rats were submitted to HUT. The spectral analysis during HUT showed an increase in low-frequency oscillation of systolic arterial pressure (SAP) (LF: 14.21±2.73-32.44±8.43 mmHg(2)) and pulse interval (PI) (LF: 14.05±4.25-51.79±10.64 n.u.) and a decrease in high-frequency oscillation (HF; 84.52±4.82-47.49±10.30 n.u.). Previous bilaterally microinjection of cobalt chloride (1 mM/100 nl), a calcium channel blocking agent, into the PVN decreased LF oscillations of SAP (LF: 32.44±8.43-13.23±1.87 mmHg(2)) as well as in PI (LF: 12.38±3.76-5.03±1.20 ms(2)). Muscimol microinjection (40 mM), a GABAA agonist, decreased LF component of PI oscillations (LF: 51.79±10.64-25.76±5.34 n.u.). The baroreflex gain was not altered by HUT, but during tilt, with PVN previously inhibited by muscimol or cobalt chloride, the gain was reduced. Our data suggest that the PVN participates in the brain circuitry involved in autonomic adjustment during orthostatic challenges., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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-1β and nitric oxide (NO(∙)) 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(∙), 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.

Background: Aerobic physical capacity plays an important role in reducing morbidity and mortality rates in subjects with cardiovascular diseases. This action is often related to an improvement in the autonomic modulation of heart rate variability (HRV). However, controversies remain regarding the effects of physical training on cardiac autonomic control in healthy subjects. Therefore, our objective was to investigate whether aerobic capacity interferes with the autonomic modulation of HRV and whether gender differences exist., Methods: Healthy men and women (N=96) were divided into groups according to aerobic capacity: low (VO2: 22-38 ml/kg(-1) min(-1)), moderate (VO2: 38-48 ml/kg(-1) min(-1)) and high (VO2 >48 ml/kg(-1) min(-1).) We evaluated the hemodynamic parameters and body composition. The autonomic modulation of HRV was investigated using spectral analysis. This procedure decomposes the heart rate oscillatory signal into frequency bands: low frequency (LF=0.04-0.15Hz) is mainly related to sympathetic modulation, and high frequency (HF=0.15-0.5Hz) corresponds to vagal modulation., Results: Aerobic capacity, regardless of gender, determined lower values of body fat percentage, blood pressure and heart rate. In turn, the spectral analysis of HRV showed that this parameter did not differ when aerobic capacity was considered. However, when the genders were compared, women had lower LF values and higher HF values than the respective groups of men., Conclusion: The results suggest that aerobic physical capacity does not interfere with HRV modulation; however, the cardiac modulatory balance differs between genders and is characterized by a greater influence of the autonomic vagal component in women and by the sympathetic component in men.

The paraventricular nucleus (PVN) of the hypothalamus is an important site for autonomic and neuroendocrine regulation. Experiments in anesthetized animals and in vitro indicate an interaction among gamma-aminobutyric acid (GABA), nitric oxide (NO), and glutamate in the PVN. The cardiovascular role of the PVN and interactions of these neurotransmitters in conscious animals have not been evaluated fully. In chronically instrumented conscious rats, mean arterial pressure (MAP) and heart rate (HR) responses to microinjections (100 nl) in the region of the PVN were tested. Bilateral blockade of ionotropic excitatory amino acid (EAA) receptors (kynurenic acid, Kyn) in the PVN produced small but significant decreases in MAP and HR. GABA(A) receptor blockade (bicuculline, Bic), and inhibition of NO synthase [(NOS), N-(G)-monomethyl-L-arginine, L-NMMA] each increased MAP and HR. The NO donor sodium nitroprusside (SNP) produced depressor responses that were attenuated by Bic. NOS inhibition potentiated both pressor responses to the selective EAA agonist, N-methyl-D-aspartic acid (NMDA), and depressor responses to Kyn. Increases in MAP and HR due to Bic were blunted by prior blockade of EAA receptors. Thus, pressor responses to GABA blockade require EAA receptors and GABA neurotransmission contributes to NO inhibition. Tonic excitatory effects of glutamate in the PVN are tonically attenuated by NO. These data demonstrate that, in the PVN of conscious rats, GABA, glutamate, and NO interact in a complex fashion to regulate arterial pressure and HR under normal conditions.

We aimed to examine the cardiovascular function by tonic and baroreflex alterations in obese rats induced by monosodium glutamate (MSG). Neonatal male Wistar rats were injected with MSG (4 mg/g body weight) or equimolar saline (control, C). At 90 days, all rats were anesthetized for catheterization of the femoral artery for mean arterial pressure (MAP) and heart rate (HR) recordings in the conscious state. After baseline, we performed IV treatment with hexamethonium (25 mg/kg), or atropine (1 mg/kg) or propranolol (3 mg/kg). We also performed the spectral analysis of heart rate variability (HRV) and baroreflex sensitivity. Baseline comparison showed that obese rats are hypertensive compared with control (C=110±2 mmHg; MSG=: 123±3 mmHg, P<0.05). After ganglionic blockade with hexamethonium the differences in MAP between control and obese rats disappeared. Beta adrenergic blockade with propranolol induced a greater decrease in heart rate compared with control. The analysis of HRV showed that obese rats have increased modulation by both components of the autonomic nervous system compared with control rats. The baroreflex gain showed increased sensitivity for the parasympathetic component in the obese rats (C=-2.41±0.25; MSG=-3.34±0.23 bpm/mmHg) compared with control. Our data suggest that both components of autonomic cardiac tonus and the parasympathetic component of the baroreflex sensitivity are increased in the MSG obese rat. It is possible that the parasympathetic alterations observed in these MSG obese rats may have originated from central areas of cardiovascular control., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The paraventricular nucleus of hypothalamus (PVN) is a well known site of integration for autonomic and cardiovascular responses, and the glutamate neurotransmitter plays an important role. The aim of our study was to evaluate the cardiovascular parameters and autonomic modulation by means of spectral analysis after ionotropic glutamate receptor inhibition in the PVN in conscious sedentary (S) or swimming trained (ST) rats. After exercise training protocol, adult male Wistar rats, instrumented with guide cannulae to PVN and artery and vein catheters were submitted to mean arterial pressure (MAP) and heart rate (HR) recording. At baseline, physical training induced a resting bradycardia (S: 379 ± 3, ST: 349 ± 2 bpm, Pb<0.05) and promoted adaptations in HRV characterized by an increase of HF in normalized values and a decrease of LF in absolute and normalized units compared with the sedentary group. Microinjection of kynurenic acid (KYNA) in the PVN of sedentary and trained rats promoted decreases in MAP and HR, but the decrease in HR was smaller in the trained animals (ΔHRS: -48 ± 7, ST: -28 ± 4 bpm, Pb<0.05). Furthermore, the differences in baseline parameters of pulse interval, found between sedentary and trained animals, disappeared after KYNA microinjection in the PVN. Our data suggest that the cardiovascular and autonomic adaptations to the heart induced by exercise training may involve glutamatergic mechanisms in the PVN.

The literature suggests that both obesity and hypertension are associated with increased sympathetic nerve activity. In the present study we evaluated the renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) in hyperadipose rats induced by neonatal administration of monosodium glutamate (MSG). Neonatal Wistar male rats were injected with MSG (4 mg/g body weight ID) or equimolar saline (control) for 5 days. At 90th day, all rats were anesthetized (urethane 1.4 g/kg) and prepared for MAP, HR and renal sympathetic nerve activity recordings. The anesthetized MSG rats presented baseline hypertension and increased baseline RSNA compared with control. Our results suggest the involvement of the renal sympathetic nervous system in the physiopathology of the MSG obesity., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

We evaluated the involvement of paraventricular nucleus (PVN) in the changes in mean arterial pressure (MAP) and heart rate (HR) during an orthostatic challenge (head up tilt, HUT). Adult male Wistar rats, instrumented with guide cannulas to PVN and artery and vein catheters were submitted to MAP and HR recording in conscious state and induction of HUT. The HUT induced an increase in MAP and HR and the pretreatment with prazosin and atenolol blocked these effects. After inhibition of neurotransmission with cobalt chloride (1 mM/100 nl) into the PVN the HR parameters did not change, however we observed a decrease in MAP during HUT. Our data suggest the involvement of PVN in the brain circuitry involved in cardiovascular adjustment during orthostatic challenges., (Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

We evaluate the effects of chronic treatment with celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, on blood pressure (BP) and heart rate variability (HRV) in obese rats induced by neonatal monosodium glutamate (MSG). The animals were treated with celecoxib or saline for 30 days (from the 60th to the 90th day of age). On the 90th day, the MSG obesity induced an increase in the low-frequency (LF) component (CTR=5.69±18.30ms(2), MSG=38.49±6.27ms(2)) and a decrease in the high-frequency (HF) component of HRV (CTR=71.48±6.22ms(2), MSG=50.94±7.03ms(2)), which were unchanged by celecoxib treatment. We suggest that HRV in MSG obesity involves a greater sympathetic modulation not related with COX-2 products., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The autonomic nervous system plays a key role in maintaining homeostasis under normal and pathological conditions. The sympathetic tone, particularly for the cardiovascular system, is generated by sympathetic discharges originating in specific areas of the brainstem. Aerobic exercise training promotes several cardiovascular adjustments that are influenced by the central areas involved in the output of the autonomic nervous system. In this review, we emphasize the studies that investigate aerobic exercise training protocols to identify the cardiovascular adaptations that may be the result of central nervous system plasticity due to chronic exercise. The focus of our study is on some groups of neurons involved in sympathetic regulation. They include the nucleus tractus solitarii, caudal ventrolateral medulla and the rostral ventrolateral medulla that maintain and regulate the cardiac and vascular autonomic tonus. We also discuss studies that demonstrate the involvement of supramedullary areas in exercise training modulation, with emphasis on the paraventricular nucleus of the hypothalamus, an important area of integration for autonomic and neuroendocrine responses. The results of these studies suggest that the beneficial effects of physical activity may be due, at least in part, to reductions in sympathetic nervous system activity. Conversely, with the recent association of physical inactivity with chronic disease, these data may also suggest that increases in sympathetic nervous system activity contribute to the increased incidence of cardiovascular diseases associated with a sedentary lifestyle.

It is well known that regular physical exercise alter cardiac function and autonomic modulation of heart rate variability (HRV). The paraventricular nucleus of hypothalamus (PVN) is an important site of integration for autonomic and cardiovascular responses, where nitric oxide (NO) plays an important role. The aim of our study was to evaluate the cardiovascular parameters and autonomic modulation by means of spectral analysis after nitric oxide synthase (NOS) inhibition in the PVN in conscious sedentary (S) or swimming trained (ST) rats. After swimming training protocol, adult male Wistar rats, instrumented with guide cannulas to PVN and femoral artery and vein catheters were submitted to mean arterial pressure (MAP) and heart rate (HR) recording. At baseline, the physical training induced a resting bradycardia (S: 374±5, ST: 346±1bpm) and promoted adaptations in HRV characterized by an increase in high-frequency oscillations (HF; 26.43±6.91 to 88.96±2.44) and a decrease in low-frequency oscillations (LF; 73.57±6.91 to 11.04±2.44) in normalized units. The microinjection of N(ω)-nitro-l-arginine methyl ester (l-NAME) in the PVN of sedentary and trained rats promoted increase in MAP and HR. l-NAME in the PVN did not significantly alter the spectral parameters of HRV of sedentary animals, however in the trained rats increased LF oscillations (11.04±2.44 to 27.62±6.97) and decreased HF oscillations (88.96±2.44 to 72.38±6.97) in normalized units compared with baseline. Our results suggest that NO in the PVN may collaborate to cardiac autonomic modulation after exercise training., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Aims: the purpose of the present work was to investigate the effect of cyclooxygenase-2 (COX-2) inhibition on the cardiovascular and inflammatory aspects promoted by monosodium glutamate (MSG)-induced obesity in rats., Main Methods: Neonatal Wistar male rats were injected with MSG (4 mg/g body weight ID) or equimolar saline (control). Treatment with celecoxib (50 mg/kg ip) or saline (0.9% NaCl ip) began at 60 days of age. At 90 days, all rats were anesthetized for catheterization of the femoral artery, and the mean arterial pressure (MAP) and heart rate (HR) were recorded once consciousness was regained., Key Findings: MSG obese rats were hypertensive (MAP=138±4 mm Hg) compared with controls (MAP=118±2 mm Hg). After treatment with celecoxib, the hypertension was attenuated (MAP=126±2 mm Hg) in obese rats without changes in HR. The retroperitoneal and periepididymal fat weighed more in obese rats (Obese: Retro=7.08±0.51, Peri=6.36±0.81, CONTROL: Retro=3.60±0.46; Peri=3.24±0.42), but celecoxib did not alter these parameters. Plasma nitric oxide levels were not different between groups. However, the level of plasma prostaglandins, the immunohistochemical staining of COX-2 in cardiac tissue and plasma lipoperoxidation were higher in obese rats, and celecoxib attenuated these parameters. MSG produced liver steatosis that was also attenuated following celecoxib treatment., Significance: Our data demonstrate an association between increased blood pressure and products of COX-2 in obese rats, suggesting a role for prostaglandins in the hypertensive and inflammatory aspects of MSG-induced obesity., (2010 Elsevier Inc. All rights reserved.)