Publications by authors named "Lisete C Michelini"

43 Publications

Swimming training reduces iNOS expression, augments the antioxidant defense and reduces sympathetic responsiveness in the rostral ventrolateral medulla of normotensive male rats.

Brain Res Bull 2021 May 23;170:225-233. Epub 2021 Feb 23.

Departament of Physiological Sciences, Center of Biological Sciences, State University of Londrina, Londrina, PR, Brazil. Electronic address:

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.
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http://dx.doi.org/10.1016/j.brainresbull.2021.02.023DOI Listing
May 2021

Activation of Oxytocin Neurons Improves Cardiac Function in a Pressure-Overload Model of Heart Failure.

JACC Basic Transl Sci 2020 May 25;5(5):484-497. Epub 2020 May 25.

Department of Pharmacology and Physiology, George Washington University, Washington, DC.

This work shows long-term restoration of the hypothalamic oxytocin (OXT) network preserves OXT release, reduces mortality, cardiac inflammation, fibrosis, and improves autonomic tone and cardiac function in a model of heart failure. Intranasal administration of OXT in patients mimics the short-term changes seen in animals by increasing parasympathetic-and decreasing sympathetic-cardiac activity. This work provides the essential translational foundation to determine if approaches that mimic paraventricular nucleus (PVN) OXT neuron activation, such as safe, noninvasive, and well-tolerated intranasal administration of OXT, can be beneficial in patients with heart failure.
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http://dx.doi.org/10.1016/j.jacbts.2020.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251188PMC
May 2020

Standardization of a new non-invasive device for assessment of arterial stiffness in rats: Correlation with age-related arteries' structure.

MethodsX 2020 27;7:100901. Epub 2020 Apr 27.

Joint Graduate Program in Physiological Sciences, PIPGCF, UFSCar/UNESP, São Carlos, SP, Brazil.

Pulse wave velocity (PWV) has become a gold standard index to quantify the stiffness of the aorta and is a predictor of cardiovascular events. A recent paper compared the pOpmètre, a device for measuring the finger-toe PWV, with other techniques and demonstrated its accuracy and validity. However, human devices do not allow the advancement of our knowledge on conditioning mechanisms. Based on its human validation, a new device, pOpet 1.0 system was designed for estimation of PWV in small animals and this present study aimed to standardize the pOpet 1.0 for estimation of arterial stiffness in rats, and to confirm its liability and stability as well as the reproducibility of assessments. Therefore several precautions were taken into consideration like as the correct position of the animal and photodiodes according to manufacturers' suggestions. Results indicated that estimation of PWV through the new pOpet 1.0 device exhibits good internal consistency, stability and objectivity in all tests performed between days and evaluators. Importantly, data suggest for the first time that this new device is able to detect changes in arterial stiffness that are conditioned by age and pressure-related arterial remodeling. • This new pOpet device is able to detect changes in vessel structure. • This new pOpet device exhibits good internal consistency, stability and objectivity in all tests performed • Correct position of the animal and photodiodes are crucial to obtain a very stable signal.
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http://dx.doi.org/10.1016/j.mex.2020.100901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225392PMC
April 2020

Activity-Dependent Neuroplastic Changes in Autonomic Circuitry Modulating Cardiovascular Control: The Essential Role of Baroreceptors and Chemoreceptors Signaling.

Front Physiol 2020 9;11:309. Epub 2020 Apr 9.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Aerobic exercise training improves the autonomic control of the circulation. Emerging evidence has shown that exercise induces neuroplastic adaptive changes in preautonomic circuitry controlling sympathetic/parasympathetic outflow to heart and vessels. The mechanisms underlying neuronal plasticity are, however, incompletely understood. Knowing that sinoaortic denervation blocks training-induced cardiovascular benefits, we investigate whether baroreceptors' and chemoreceptors' signaling are able to drive neuronal plasticity within medullary and supramedullary pathways controlling autonomic outflow. Male Wistar rats submitted to sinoaortic denervation (SAD) or dopamine β-hydroxylase-saporin lesion (DBHx) and respective controls (SHAM) were allocated to training (T) or sedentary (S) protocols for 8 weeks. After hemodynamic measurements at rest, rats were deeply anesthetized for brain harvesting. The density of DBH and oxytocin (OT) cell bodies and terminals were analyzed in brainstem and hypothalamic brain areas (double immunofluorescence reactions, optic and confocal microscopy). In SHAM rats training augmented the density of DBH+ neurons in the nucleus of solitary tract, increased the density of ascending NORergic projections and the number of DBH+ boutons contacting preautonomic OT+ neurons into paraventricular hypothalamic preautonomic nuclei, augmented the density of local OTergic neurons and enhanced the density of OT+ terminals targeting brainstem autonomic areas. These plastic changes occurred simultaneously with reduced sympathetic/increased parasympathetic activity, augmented baroreflex sensitivity and reduced resting heart rate. SAD reduced the density of both DBH+ fibers ascending from brainstem to paraventricular nucleus of hypothalamus and preautonomic OT+ neurons projecting to the brainstem, abrogated training-induced plastic changes and autonomic adaptive responses without changing the treadmill performance. Minor neuroplastic changes with preserved baroreflex sensitivity were observed in trained rats after partial selective disruption of ascending NORergic projections. Our data indicated that afferent inputs conveyed by arterial baroreceptors and chemoreceptors are the main stimuli to drive both inactivity-induced and activity-dependent neuroplasticity within the autonomic circuitry.
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http://dx.doi.org/10.3389/fphys.2020.00309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160511PMC
April 2020

Molecular Pathways Involved in Aerobic Exercise Training Enhance Vascular Relaxation.

Med Sci Sports Exerc 2020 10;52(10):2117-2126

Department of Physiology and Biophysics, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, BRAZIL.

Purpose: The beneficial effects of exercise training on the cardiovascular system are well known. Because our knowledge of exercise-induced vascular function is still limited, we aimed to uncover the molecular mechanisms conditioning the improved vascular relaxation in muscular arteries.

Methods: Male Wistar-Kyoto rats with the same ability to run on a treadmill after maximal exercise tests were allocated to the following two groups: trained (Tr) (treadmill, 50%-60% of maximal capacity, 5 d·wk) and untrained (UnTr). After 13 wk, the femoral arteries were harvested and used for functional, structural, and molecular analyses.

Results: Acetylcholine (ACh)-induced relaxation and nitric oxide (NO) production were enhanced in arteries from Tr rats compared with UnTr rats. Tr arteries exhibited reduced microRNA (miRNA)-124a expression (whose target is caveolin-1), increased the density of caveolae aligned along the sarcolemma and reduced ACh-induced relaxation in the presence of methyl-β-cyclodextrin, which disrupts caveolae. Higher endothelial NO synthase (eNOS) expression with lower miRNA-155 expression and the posttranslational modification of eNOS (phosphorylation of stimulatory Ser1177 and dephosphorylation of inhibitory Thr495) by the PI3-kinase/Akt1/2/3 pathway also contributed to the higher NO production induced by exercise training. Furthermore, increased Cu/Zn- and extracellular-superoxide dismutase expression and enhanced effects of their pharmacological scavenger activity on the ACh-induced response were observed in Tr arteries.

Conclusions: The results of the present study provide a molecular basis for exercise-induced NO bioavailability in healthy femoral arteries. Increased caveolae domain and eNOS expression/activity in Tr arteries are associated with downregulation of miRNA-124a and -155, as well as are involved with higher antioxidant defense, subsequently inducing a favorable endothelium-dependent milieu in Tr arteries.
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http://dx.doi.org/10.1249/MSS.0000000000002355DOI Listing
October 2020

Exercise training increases GAD65 expression, restores the depressed GABA receptor function within the PVN and reduces sympathetic modulation in hypertension.

Physiol Rep 2019 08;7(13):e14107

Department of Physiology & Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.

GABAergic inhibitory input within the paraventricular hypothalamic nucleus (PVN) plays a key role in restraining sympathetic outflow. Although experimental evidence has shown depressed GABA receptor function plus sympathoexcitation in hypertension and augmented GABA levels with reduced sympathetic activity after exercise training (T), the mechanisms underlying T-induced effects remain unclear. Here we investigated in T and sedentary (S) SHR and WKY: (1) time-course changes of hemodynamic parameters and PVN glutamic acid decarboxylase (GAD) isoforms' expression; (2) arterial pressure (AP) and heart rate (HR) responses, sympathetic/parasympathetic modulation of heart and vessels and baroreflex sensitivity to GABA receptor blockade within the PVN. SHR-S versus WKY-S exhibited higher AP and HR, increased sympathetic reduced parasympathetic modulation, smaller baroreflex sensitivity, and reduced PVN GAD65 immunoreactivity. SHR-T and WKY-T showed prompt maintained increase (2-8 weeks) in GAD65 expression (responsible for GABA vesicular pool synthesis), which occurred simultaneously with HR reduction in SHR-T and preceded MAP fall in SHR-T and resting bradycardia in WKY-T. There was no change in GAD67 expression (mainly involved with GABA metabolic pool). Resting HR in both groups and basal MAP in SHR were negatively correlated with PVN GAD65 expression. Normalized baroreflex sensitivity and autonomic control observed only in SHR-T were due to recovery of GABA receptor function into the PVN since bicuculline administration abolished these effects. Data indicated that training augments in both groups the expression/activity of GABAergic neurotransmission within presympathetic PVN neurons and restores GABA receptors' function specifically in the SHR, therefore strengthening GABAergic modulation of sympathetic outflow in hypertension.
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http://dx.doi.org/10.14814/phy2.14107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603325PMC
August 2019

Regulation of sympathetic vasomotor activity by the hypothalamic paraventricular nucleus in normotensive and hypertensive states.

Am J Physiol Heart Circ Physiol 2018 11 10;315(5):H1200-H1214. Epub 2018 Aug 10.

Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center , Houston, Texas.

The hypothalamic paraventricular nucleus (PVN) is a unique and important brain region involved in the control of cardiovascular, neuroendocrine, and other physiological functions pertinent to homeostasis. The PVN is a major source of excitatory drive to the spinal sympathetic outflow via both direct and indirect projections. In this review, we discuss the role of the PVN in the regulation of sympathetic output in normal physiological conditions and in hypertension. In normal healthy animals, the PVN presympathetic neurons do not appear to have a major role in sustaining resting sympathetic vasomotor activity or in regulating sympathetic responses to short-term homeostatic challenges such as acute hypotension or hypoxia. Their role is, however, much more significant during longer-term challenges, such as sustained water deprivation, chronic intermittent hypoxia, and pregnancy. The PVN also appears to have a major role in generating the increased sympathetic vasomotor activity that is characteristic of multiple forms of hypertension. Recent studies in the spontaneously hypertensive rat model have shown that impaired inhibitory and enhanced excitatory synaptic inputs to PVN presympathetic neurons are the basis for the heightened sympathetic outflow in hypertension. We discuss the molecular mechanisms underlying the presynaptic and postsynaptic alterations in GABAergic and glutamatergic inputs to PVN presympathetic neurons in hypertension. In addition, we discuss the ability of exercise training to correct sympathetic hyperactivity by restoring blood-brain barrier integrity, reducing angiotensin II availability, and decreasing oxidative stress and inflammation in the PVN.
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http://dx.doi.org/10.1152/ajpheart.00216.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297824PMC
November 2018

Exercise training abrogates age-dependent loss of hypothalamic oxytocinergic circuitry and maintains high parasympathetic activity.

J Neuroendocrinol 2018 Apr 14:e12601. Epub 2018 Apr 14.

Department of Physiology, Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo/SP, Brazil.

Neuroanatomical studies associating neuronal tract tracing and immunohistochemistry identified reciprocal (ascending noradrenergic/descending oxytocinergic, OTergic) connections between brainstem cardiovascular nuclei and the paraventricular hypothalamic nucleus (PVN). Previous functional studies indicated that exercise training (T) augmented the expression/activity of OTergic pathway and improve the autonomic control of the heart. Knowing that ageing is associated with autonomic dysfunction and sinoaortic denervation blocked T-induced beneficial effects, we hypothesized that T was able to reduce age-dependent impairment by improving the afferent signaling to PVN and augmenting OTergic modulation of cardiovascular control. We evaluated the combined effects of T and age on plastic remodeling of ascending dopamine β-hydroxylase (DBH+) and descending OT+ pathways and correlated them with cardiovascular parameters. Male Wistar rats were submitted to T or kept sedentary for 8 weeks. After evaluating arterial pressure, heart rate (HR), their variabilities and spectral components in conscious rats at rest, brains were harvested to analyze the plastic remodeling of brain autonomic nuclei (immunofluorescence + confocal microscopy). The density of DBH+ neurons within the nucleus of solitary tract (NTS) and caudal ventrolateral medulla, the number of DBH+ terminals overlapping OT+ neurons in PVN preautonomic nuclei, as well as the density of OT+ neurons and their projections to NTS and dorsal motor nucleus of the vagus were markedly reduced in S rats during 8-weeks of inactivity In contrast, these effects were completely blocked by T and reversed to a large augmentation of DBH+ and OT+ densities in both cell bodies and terminals within autonomic nuclei and target areas. All plastic changes observed correlated positively with parasympathetic activity to the heart (HF-PI, but not with LF-PI) and negatively with resting HR. Data indicate that T, by increasing beneficial neuroplastic adaptive changes within brainstem-PVN reciprocal network, abrogates age-dependent deleterious remodeling and augments parasympathetic modulation of the heart, therefore improving autonomic function. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/jne.12601DOI Listing
April 2018

Maintenance of Blood-Brain Barrier Integrity in Hypertension: A Novel Benefit of Exercise Training for Autonomic Control.

Front Physiol 2017 12;8:1048. Epub 2017 Dec 12.

Department Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

The blood-brain barrier (BBB) is a complex multicellular structure acting as selective barrier controlling the transport of substances between these compartments. Accumulating evidence has shown that chronic hypertension is accompanied by BBB dysfunction, deficient local perfusion and plasma angiotensin II (Ang II) access into the parenchyma of brain areas related to autonomic circulatory control. Knowing that spontaneously hypertensive rats (SHR) exhibit deficient autonomic control and brain Ang II hyperactivity and that exercise training is highly effective in correcting both, we hypothesized that training, by reducing Ang II content, could improve BBB function within autonomic brain areas of the SHR. After confirming the absence of BBB lesion in the pre-hypertensive SHR, but marked fluorescein isothiocyanate dextran (FITC, 10 kD) leakage into the brain parenchyma of the hypothalamic paraventricular nucleus (PVN), nucleus of the solitary tract, and rostral ventrolateral medulla during the established phase of hypertension, adult SHR, and age-matched WKY were submitted to a treadmill training (T) or kept sedentary (S) for 8 weeks. The robust FITC leakage within autonomic areas of the SHR-S was largely reduced and almost normalized since the 2nd week of training (T). BBB leakage reduction occurred simultaneously and showed strong correlations with both decreased LF/HF ratio to the heart and reduced vasomotor sympathetic activity (power spectral analysis), these effects preceding the appearance of resting bradycardia (T) and partial pressure fall (T). In other groups of SHR-T simultaneously infused with Ang II or saline (osmotic mini-pumps connected to a lateral ventricle cannula) we proved that decreased local availability of this peptide and reduced microglia activation (IBA1 staining) are crucial mechanisms conditioning the restoration of BBB integrity. Our data also revealed that Ang II-induced BBB lesion was faster within the PVN (T), suggesting the prominent role of this nucleus in driven hypertension-induced deficits. These original set of data suggest that reduced local Ang II content (and decreased activation of its downstream pathways) is an essential and early-activated mechanism to maintain BBB integrity in trained SHR and uncovers a novel beneficial effect of exercise training to improve autonomic control even in the presence of hypertension.
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http://dx.doi.org/10.3389/fphys.2017.01048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733101PMC
December 2017

Temporal changes in cardiac oxidative stress, inflammation and remodeling induced by exercise in hypertension: Role for local angiotensin II reduction.

PLoS One 2017 12;12(12):e0189535. Epub 2017 Dec 12.

Department of Physiology & Biophysics, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo, SP, Brazil.

Exercise training reduces renin-angiotensin system (RAS) activation, decreases plasma and tissue oxidative stress and inflammation in hypertension. However, the temporal nature of these phenomena in response to exercise is unknown. We sought to determine in spontaneously hypertensive rats (SHR) and age-matched WKY controls the weekly effects of training on blood pressure (BP), plasma and left ventricle (LV) Ang II and Ang-(1-7) content (HPLC), LV oxidative stress (DHE staining), gene and protein expression (qPCR and WB) of pro-inflammatory cytokines, antioxidant enzymes and their consequence on hypertension-induced cardiac remodeling. SHR and WKY were submitted to aerobic training (T) or maintained sedentary (S) for 8 weeks; measurements were made at weeks 0, 1, 2, 4 and 8. Hypertension-induced cardiac hypertrophy was accompanied by acute plasma Ang II increase with amplified responses during the late phase of LV hypertrophy. Similar pattern was observed for oxidative stress markers, TNF alpha and interleukin-1β, associated with cardiomyocytes' diameter enlargement and collagen deposition. SHR-T exhibited prompt and marked decrease in LV Ang II content (T1 vs T4 in WKY-T), normalized oxidative stress (T2), augmented antioxidant defense (T4) and reduced both collagen deposition and inflammatory profile (T8), without changing cardiomyocytes' diameter and LV hypertrophy. These changes were accompanied by decreased plasma Ang II content (T2-T4) and reduced BP (T8). SHR-T and WKY-T showed parallel increases in LV and plasma Ang-(1-7) content. Our data indicate that early training-induced downregulation of LV ACE-AngII-AT1 receptor axis is a crucial mechanism to reduce oxidative/pro-inflammatory profile and improve antioxidant defense in SHR-T, showing in addition this effect precedes plasma RAS deactivation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189535PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726656PMC
January 2018

Experimental Evidences Supporting Training-Induced Benefits in Spontaneously Hypertensive Rats.

Adv Exp Med Biol 2017 ;999:287-306

Department of Physiology & Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

It is well known that chronic hypertension is accompanied by several functional deficits in the central nervous system and peripheral tissues, most of which are corrected by exercise training. However, the biological mechanisms underlying these effects are not yet well understood. In the present chapter we summarize recent experimental evidence on cellular/molecular mechanisms supporting not only the deleterious effects of hypertension on autonomic control and peripheral circulatory deficits, but also their reversion by low to moderate aerobic exercise training. Interestingly, both hypertension and aerobic training exert their effects by acting exactly on the same pathways/mechanisms but in opposed directions.
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http://dx.doi.org/10.1007/978-981-10-4307-9_16DOI Listing
May 2018

Experimental Evidences Supporting the Benefits of Exercise Training in Heart Failure.

Adv Exp Med Biol 2017 ;999:181-206

Department of Physiology & Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

Heart Failure (HF), a common end point for many cardiovascular diseases, is a syndrome with a very poor prognosis. Although clinical trials in HF have achieved important outcomes in reducing mortality, little is known about functional mechanisms conditioning health improvement in HF patients. In parallel with clinical studies, basic science has been providing important discoveries to understand the mechanisms underlying the pathophysiology of HF, as well as to identify potential targets for the treatment of this syndrome. In spite of being the end-point of cardiovascular derangements caused by different etiologies, autonomic dysfunction, sympathetic hyperactivity, oxidative stress, inflammation and hormonal activation are common factors involved in the progression of this syndrome. Together these causal factors create a closed link between three important organs: brain, heart and the skeletal muscle. In the past few years, we and other groups have studied the beneficial effects of aerobic exercise training as a safe therapy to avoid the progression of HF. As summarized in this chapter, exercise training, a non-pharmacological tool without side effects, corrects most of the HF-induced neurohormonal and local dysfunctions within the brain, heart and skeletal muscles. These adaptive responses reverse oxidative stress, reduce inflammation, ameliorate neurohormonal control and improve both cardiovascular and skeletal muscle function, thus increasing the quality of life and reducing patients' morbimortality.
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http://dx.doi.org/10.1007/978-981-10-4307-9_11DOI Listing
May 2018

Moderate Treadmill Exercise Training Improves Cardiovascular and Nitrergic Response and Resistance to Infection in Mice.

Front Physiol 2017 18;8:315. Epub 2017 May 18.

Department of Physiological Sciences, Center of Biological Sciences, State University of LondrinaLondrina, Brazil.

There is evidence suggesting that exercise training (ET) acts as a factor toward resistance to 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, = 30), trained control (TC, = 30), sedentary infected (SI, = 30), and trained infected (TI, = 30). ET was performed on the treadmill for 9 weeks. After training, the mice were infected with 5 × 10 trypomastigotes of (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, < 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 infection, modulating cardiovascular aspects, inflammatory reaction, and NO levels of infected mice.
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http://dx.doi.org/10.3389/fphys.2017.00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435761PMC
May 2017

Exercise training preserves vagal preganglionic neurones and restores parasympathetic tonus in heart failure.

J Physiol 2016 11 29;594(21):6241-6254. Epub 2016 Aug 29.

Department of Physiology and Biophysics, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo, SP, Brazil.

Key Points: Heart Failure (HF) is accompanied by reduced ventricular function, activation of compensatory neurohormonal mechanisms and marked autonomic dysfunction characterized by exaggerated sympathoexcitation and reduced parasympathetic activity. With 6 weeks of exercise training, HF-related loss of choline acetyltransferase (ChAT)-positive vagal preganglionic neurones is avoided, restoring the parasympathetic tonus to the heart, and the immunoreactivity of dopamine β-hydroxylase-positive premotor neurones that drive sympathetic outflow to the heart is reduced. Training-induced correction of autonomic dysfunction occurs even with the persistence of abnormal ventricular function. Strong positive correlation between improved parasympathetic tonus to the heart and increased ChAT immunoreactivity in vagal preganglionic neurones after training indicates this is a crucial mechanism to restore autonomic function in heart failure.

Abstract: Exercise training is an efficient tool to attenuate sympathoexcitation, a hallmark of heart failure (HF). Although sympathetic modulation in HF is widely studied, information regarding parasympathetic control is lacking. We examined the combined effects of sympathetic and vagal tonus to the heart in sedentary (Sed) and exercise trained (ET) HF rats and the contribution of respective premotor and preganglionic neurones. Wistar rats submitted to coronary artery ligation or sham surgery were assigned to training or sedentary protocols for 6 weeks. After haemodynamic, autonomic tonus (atropine and atenolol i.v.) and ventricular function determinations, brains were collected for immunoreactivity assays (choline acetyltransferase, ChATir; dopamine β-hydroxylase, DBHir) and neuronal counting in the dorsal motor nucleus of vagus (DMV), nucleus ambiguus (NA) and rostroventrolateral medulla (RVLM). HF-Sed vs. SHAM-Sed exhibited decreased exercise capacity, reduced ejection fraction, increased left ventricle end diastolic pressure, smaller positive and negative dP/dt, decreased intrinsic heart rate (IHR), lower parasympathetic and higher sympathetic tonus, reduced preganglionic vagal neurones and ChATir in the DMV/NA, and increased RVLM DBHir. Training increased treadmill performance, normalized autonomic tonus and IHR, restored the number of DMV and NA neurones and corrected ChATir without affecting ventricular function. There were strong positive correlations between parasympathetic tonus and ChATir in NA and DMV. RVLM DBHir was also normalized by training, but there was no change in neurone number and no correlation with sympathetic tonus. Training-induced preservation of preganglionic vagal neurones is crucial to normalize parasympathetic activity and restore autonomic balance to the heart even in the persistence of cardiac dysfunction.
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http://dx.doi.org/10.1113/JP272730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088253PMC
November 2016

Ovarian Hormone Deprivation Reduces Oxytocin Expression in Paraventricular Nucleus Preautonomic Neurons and Correlates with Baroreflex Impairment in Rats.

Front Physiol 2016 13;7:461. Epub 2016 Oct 13.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo São Paulo, Brazil.

The prevalence of cardiovascular diseases including hypertension increases dramatically in women after menopause, however the mechanisms involved remain incompletely understood. Oxytocinergic (OTergic) neurons are largely present within the paraventricular nucleus of the hypothalamus (PVN). Several studies have shown that OTergic drive from PVN to brainstem increases baroreflex sensitivity and improves autonomic control of the circulation. Since preautonomic PVN neurons express different types of estrogen receptors, we hypothesize that ovarian hormone deprivation causes baroreflex impairment, autonomic imbalance and hypertension by negatively impacting OTergic drive and oxytocin levels in pre-autonomic neurons. Here, we assessed oxytocin gene and protein expression (qPCR and immunohistochemistry) within PVN subnuclei in sham-operated and ovariectomized Wistar rats. Conscious hemodynamic recordings were used to assess resting blood pressure and heart rate and the autonomic modulation of heart and vessels was estimated by power spectral analysis. We observed that the ovarian hormone deprivation in ovariectomized rats decreased baroreflex sensitivity, increased sympathetic and reduced vagal outflows to the heart and augmented the resting blood pressure. Of note, ovariectomized rats had reduced PVN oxytocin mRNA and protein expression in all pre-autonomic PVN subnuclei. Furthermore, reduced PVN oxytocin protein levels were positively correlated with decreased baroreflex sensitivity and negatively correlated with increased LF/HF ratio. These findings suggest that reduced oxytocin expression in OTergic neurons of the PVN contributes to the baroreflex dysfunction and autonomic dysregulation observed with ovarian hormone deprivation.
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http://dx.doi.org/10.3389/fphys.2016.00461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063006PMC
October 2016

Swimming Training Modulates Nitric Oxide-Glutamate Interaction in the Rostral Ventrolateral Medulla in Normotensive Conscious Rats.

Front Physiol 2016 13;7:221. Epub 2016 Jun 13.

Department of Physiological Sciences, Center of Biological Sciences, State University of Londrina Londrina, Brazil.

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.
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http://dx.doi.org/10.3389/fphys.2016.00221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904284PMC
July 2016

Endocrine-Autonomic Linkages.

Compr Physiol 2015 Jul;5(3):1281-323

Department of Physiology and Biophysics, Rosalind Franklin University of Medicine & Science, North Chicago, IL, USA.

Interaction between the autonomic nervous system and the neuroendocrine system is critical for maintenance of homeostasis in a wide variety of physiological parameters such as body temperature, fluid and electrolyte balance, and blood pressure and volume. The anatomical and physiological mechanisms underlying integration of the neuroendocrine and autonomic mechanisms responsible for eliciting integrated autonomic and neuroendocrine actions are the focus of this article. This includes a focus on the hypothalamic paraventricular nucleus, because it includes both neuroendocrine neurons and preganglionic autonomic neurons that regulate sympathetic and parasympathetic outflow. The "wired" and "nonwired" mechanisms within PVN that facilitate communication between these neuronal populations are described. The impact of peripheral hormones, specifically the adrenal and gonadal steroids, on the neuroendocrine and autonomic systems is discussed, and exercise is used as a specific example of a physiological challenge/stress that requires precise integration of neuroendocrine and autonomic responses to maintain cardiovascular, fluid, and energy homeostasis.
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http://dx.doi.org/10.1002/cphy.c140028DOI Listing
July 2015

Neural control of circulation and exercise: a translational approach disclosing interactions between central command, arterial baroreflex, and muscle metaboreflex.

Am J Physiol Heart Circ Physiol 2015 Aug 29;309(3):H381-92. Epub 2015 May 29.

Department of Physiology and Pharmacology, Fluminense Federal University, Niteroi, Brazil

The last 100 years witnessed a rapid and progressive development of the body of knowledge concerning the neural control of the cardiovascular system in health and disease. The understanding of the complexity and the relevance of the neuroregulatory system continues to evolve and as a result raises new questions. The purpose of this review is to articulate results from studies involving experimental models in animals as well as in humans concerning the interaction between the neural mechanisms mediating the hemodynamic responses during exercise. The review describes the arterial baroreflex, the pivotal mechanism controlling mean arterial blood pressure and its fluctuations along with the two main activation mechanisms to exercise: central command (parallel activation of central somatomotor and autonomic descending pathways) and the muscle metaboreflex, the metabolic component of exercise pressor reflex (feedback from ergoreceptors within contracting skeletal muscles). In addition, the role of the cardiopulmonary baroreceptors in modulating the resetting of arterial baroreflex is identified, and the mechanisms in the central nervous system involved with the resetting of baroreflex function during dynamic exercise are also described. Approaching a very relevant clinical condition, the review also presents the concept that the impaired arterial baroreflex function is an integral component of the metaboreflex-mediated exaggerated sympathetic tone in subjects with heart failure. This increased sympathetic activity has a major role in causing the depressed ventricular function observed during submaximal dynamic exercise in these patients. The potential contribution of a metaboreflex arising from respiratory muscles is also considered.
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http://dx.doi.org/10.1152/ajpheart.00077.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631530PMC
August 2015

Toll-like receptor 4 promotes autonomic dysfunction, inflammation and microglia activation in the hypothalamic paraventricular nucleus: role of endoplasmic reticulum stress.

PLoS One 2015 26;10(3):e0122850. Epub 2015 Mar 26.

Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America.

Background & Purpose: Toll-like receptor 4 (TLR4) signaling induces tissue pro-inflammatory cytokine release and endoplasmic reticulum (ER) stress. We examined the role of TLR4 in autonomic dysfunction and the contribution of ER stress.

Experimental Approach: Our study included animals divided in 6 experimental groups: rats treated with saline (i.v., 0.9%), LPS (i.v., 10mg/kg), VIPER (i.v., 0.1 mg/kg), or 4-PBA (i.p., 10 mg/kg). Two other groups were pretreated either with VIPER (TLR4 viral inhibitory peptide) LPS + VIPER (i.v., 0.1 mg/kg) or 4-Phenyl butyric acid (4-PBA) LPS + PBA (i.p., 10 mg/kg). Arterial pressure (AP) and heart rate (HR) were measured in conscious Sprague-Dawley rats. AP, HR variability, as well as baroreflex sensitivity (BrS), was determined after LPS or saline treatment for 2 hours. Immunofluorescence staining for NeuN, Ib1a, TLR4 and GRP78 in the hypothalamic paraventricular nucleus (PVN) was performed. TNF-α, TLR4 and GRP78 protein expression in the PVN were evaluated by western blot. Plasma norepinephrine levels were determined by ELISA.

Key Results: Acute LPS treatment increased HR and plasma norepinephrine concentration. It also decreased HR variability and high frequency (HF) components of HR variability, as well BrS. Acute LPS treatment increased TLR4 and TNF-α protein expression in the PVN. These hemodynamic and molecular effects were partially abrogated with TLR4 blocker or ER stress inhibitor pretreatment. In addition, immunofluorescence study showed that TLR4 is co-localized with GRP78in the neurons. Further inhibition of TLR4 or ER stress was able to attenuate the LPS-induced microglia activation.

Conclusions & Implications: TLR4 signaling promotes autonomic dysfunction, inflammation and microglia activation, through neuronal ER stress, in the PVN.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122850PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374971PMC
March 2016

Downregulation of the vascular renin-angiotensin system by aerobic training - focus on the balance between vasoconstrictor and vasodilator axes - .

Circ J 2015 25;79(6):1372-80. Epub 2015 Mar 25.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo.

Background: Hyperactivity of the renin-angiotensin system (RAS) and functional deficits in hypertension are reduced after exercise training. We evaluate in arteries, kidney and plasma of hypertensive rats the sequential effects of training on vascular angiotensinogen, Ang II and Ang (1-7) content.

Methods And Results: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were trained or kept sedentary (S) for 3 months. After hemodynamic measurements (weeks 0, 1, 2, 4, 8 and 12), blood, arteries and kidneys were obtained to quantify the angiotensin content (HPLC) and angiotensinogen expression (Western Blotting). SHR-S vs. WKY-S exhibited elevated pressure, increased angiotensinogen and angiotensins' content in the renal artery with a high Ang II/Ang (1-7) ratio (~5-fold higher than in the femoral artery, kidney and plasma, and 14-fold higher than in the aorta). Training promptly reduced angiotensinogen expression and downregulated the RAS in the renal SHR artery (1st-12th week), with a specific reduction of the vasoconstrictor axis; significant reduction of the AngII/Ang (1-7) ratio (36%, T4-T8) occurred simultaneously with significant pressure fall (5%). In other SHR arteries, plasma and kidneys and in all WKY tissues, T-induced AngII and Ang (1-7) reductions were proportional, maintaining the AngII/Ang (1-7) ratio.

Conclusions: Vascular RAS is not equally expressed in vessels, having crucial importance in the renal artery. In the renal SHR artery, training downregulates the vasoconstrictor and preserves the vasodilator axis while in other tissues and plasma training reduces both RAS axes, thus maintaining the vasoconstriction/vasodilatation balance in a lower level.
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http://dx.doi.org/10.1253/circj.CJ-14-1179DOI Listing
March 2016

Time-dependent effects of training on cardiovascular control in spontaneously hypertensive rats: role for brain oxidative stress and inflammation and baroreflex sensitivity.

PLoS One 2014 1;9(5):e94927. Epub 2014 May 1.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

Baroreflex dysfunction, oxidative stress and inflammation, important hallmarks of hypertension, are attenuated by exercise training. In this study, we investigated the relationships and time-course changes of cardiovascular parameters, pro-inflammatory cytokines and pro-oxidant profiles within the hypothalamic paraventricular nucleus of the spontaneously hypertensive rats (SHR). Basal values and variability of arterial pressure and heart rate and baroreflex sensitivity were measured in trained (T, low-intensity treadmill training) and sedentary (S) SHR at weeks 0, 1, 2, 4 and 8. Paraventricular nucleus was used to determine reactive oxygen species (dihydroethidium oxidation products, HPLC), NADPH oxidase subunits and pro-inflammatory cytokines expression (Real time PCR), p38 MAPK and ERK1/2 expression (Western blotting), NF-κB content (electrophoretic mobility shift assay) and cytokines immunofluorescence. SHR-S vs. WKY-S (Wistar Kyoto rats as time control) showed increased mean arterial pressure (172±3 mmHg), pressure variability and heart rate (358±7 b/min), decreased baroreflex sensitivity and heart rate variability, increased p47phox and reactive oxygen species production, elevated NF-κB activity and increased TNF-α and IL-6 expression within the paraventricular nucleus of hypothalamus. Two weeks of training reversed all hypothalamic changes, reduced ERK1/2 phosphorylation and normalized baroreflex sensitivity (4.04±0.31 vs. 2.31±0.19 b/min/mmHg in SHR-S). These responses were followed by increased vagal component of heart rate variability (1.9-fold) and resting bradycardia (-13%) at the 4th week, and, by reduced vasomotor component of pressure variability (-28%) and decreased mean arterial pressure (-7%) only at the 8th week of training. Our findings indicate that independent of the high pressure levels in SHR, training promptly restores baroreflex function by disrupting the positive feedback between high oxidative stress and increased pro-inflammatory cytokines secretion within the hypothalamic paraventricular nucleus. These early adaptive responses precede the occurrence of training-induced resting bradycardia and blood pressure fall.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094927PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006803PMC
December 2014

Melatonin modulates baroreflex control via area postrema.

Brain Behav 2013 Mar 17;3(2):171-7. Epub 2013 Feb 17.

São José dos Campos Technology Park, University Camilo Castelo Branco (UNICASTELO) São Paulo, Brazil ; Department of Physiology Institute of Biomedical Sciences, University of Sao Paulo Sao Paulo, Brazil.

Pineal gland and its hormone melatonin have been implicated in modulation of cardiovascular system. We aimed at studying the effects of melatonin on baroreflex sensitivity and the role of area postrema, as a component modulator of baroreflex arch. Mean arterial pressure (MAP) and heart rate (HR) were recorded in conscious freely moving rats. Baroreceptor reflex sensitivity was assessed by determining the HR responses to ramped infusions of phenylephrine (PE) and sodium nitroprusside (SNP)-induced MAP changes. Melatonin bolus (0.11 mg/kg) immediately followed by its continuous infusion (0.43 × 10(-9) mol/L at a rate of 0.65 mL/h for 30 min) in healthy normotensive rats produced a downward shift of baroreceptor reflex control with a substantial inhibition of reflex tachycardia (-32%) and potentiation of reflex bradycardia (+20%). Ablation of area postrema (APX group) induced a sustained decrease of MAP (101 ± 3 vs. 116 ± 3 mmHg, P < 0.05 in comparison with sham rats, respectively). The melatonin-induced alterations of baroreflex function observed in the sham group were abolished in the APX group. We conclude that circulating melatonin can modulate baroreceptor reflex control of HR, thus resetting it toward lower HR values. The modulatory effects of melatonin may be mediated via melatonin receptors in the area postrema, located outside the blood-brain barrier.
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http://dx.doi.org/10.1002/brb3.123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607157PMC
March 2013

The Angiotensin-melatonin axis.

Int J Hypertens 2013 8;2013:521783. Epub 2013 Jan 8.

Center of Innovation, Technology and Education-(CITE), Camilo Castelo Branco University (UNICASTELO), São José dos Campos Technology Park, Presidente Dutra Road Km 138, 12247-004 São José dos Campos, SP, Brazil.

Accumulating evidence indicates that various biological and neuroendocrine circadian rhythms may be disrupted in cardiovascular and metabolic disorders. These circadian alterations may contribute to the progression of disease. Our studies direct to an important role of angiotensin II and melatonin in the modulation of circadian rhythms. The brain renin-angiotensin system (RAS) may modulate melatonin synthesis, a hormone with well-established roles in regulating circadian rhythms. Angiotensin production in the central nervous system may not only influence hypertension but also appears to affect the circadian rhythm of blood pressure. Drugs acting on RAS have been proven effective in the treatment of cardiovascular and metabolic disorders including hypertension and diabetes mellitus (DM). On the other hand, since melatonin is capable of ameliorating metabolic abnormalities in DM and insulin resistance, the beneficial effects of RAS blockade could be improved through combined RAS blocker and melatonin therapy. Contemporary research is evidencing the existence of specific clock genes forming central and peripheral clocks governing circadian rhythms. Further research on the interaction between these two neurohormones and the clock genes governing circadian clocks may progress our understanding on the pathophysiology of disease with possible impact on chronotherapeutic strategies.
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http://dx.doi.org/10.1155/2013/521783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556444PMC
February 2013

Baroreceptor-mediated activation of sympathetic nerve activity to salivary glands.

Physiol Behav 2012 Oct 28;107(3):390-6. Epub 2012 Sep 28.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

Salivary gland function is regulated by both the sympathetic and parasympathetic nervous systems. Previously we showed that the basal sympathetic outflow to the salivary glands (SNA(SG)) was higher in hypertensive compared to normotensive rats and that diabetes reduced SNA(SG) discharge at both strains. In the present study we sought to investigate how SNA(SG) might be modulated by acute changes in the arterial pressure and whether baroreceptors play a functional role upon this modulation. To this end, we measured blood pressure and SNA(SG) discharge in Wistar-Kyoto rats (WKY-intact) and in WKY submitted to sinoaortic denervation (WKY-SAD). We made the following three major observations: (i) in WKY-intact rats, baroreceptor loading in response to intravenous infusion of the phenylephrine evoked an increase in SNA(SG) spike frequency (81%, p<0.01) accompanying the increase mean arterial pressure (ΔMAP: +77 ± 14 mmHg); (ii) baroreceptor unloading with sodium nitroprusside infusion elicited a decrease in SNA(SG) spike frequency (17%, p<0.01) in parallel with the fall in arterial blood pressure (ΔMAP: -30 ± 3 mmHg) in WKY-intact rats; iii) in the WKY-SAD rats, phenylephrine-evoked rises in the arterial pressure (ΔMAP: +56 ± 6 mmHg) failed to produce significant changes in the SNA(SG) spike frequency. Taken together, these data show that SNA(SG) increases in parallel with pharmacological-induced pressor response in a baroreceptor dependent way in anaesthetised rats. Considering the key role of SNA(SG) in salivary secretion, this mechanism, which differs from the classic cardiac baroreflex feedback loop, strongly suggests that baroreceptor signalling plays a decisive role in the regulation of salivary gland function.
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http://dx.doi.org/10.1016/j.physbeh.2012.09.012DOI Listing
October 2012

Peripheral chemoreceptors mediate training-induced plasticity in paraventricular nucleus pre-autonomic oxytocinergic neurons.

Exp Physiol 2013 Feb 7;98(2):386-96. Epub 2012 Aug 7.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of S˜ao Paulo, 05508-000 São Paulo, Brazil.

We showed previously that sino-aortic denervation prevented training-induced plasticity in pre-autonomic oxytocinergic neurons and blocked the beneficial effects of training. In this study, we investigate the combined effect of training and removal of specific chemoreceptor afferents on both cardiovascular parameters and oxytocin (OT) gene and protein expression within the hypothalamic paraventricular nucleus (PVN). Wistar rats and spontaneously hypertensive rats (SHRs) underwent carotid body denervation or sham surgery and were trained or kept sedentary for 3 months. After haemodynamic measurements at rest, rats were anaesthetized for brain perfusion. Fresh (perfused with PBS) and fixed brains (perfused with 4% paraformaldehyde) were processed for PVN OT mRNA (real-time PCR) and OT immunoreactivity within PVN subnuclei. In sham-operated rats, training improved treadmill performance and reduced resting heart rate (Wistar, -8%; SHRs, -10%), with a reduction in blood pressure only in SHRs (-8%). Training was accompanied by increased PVN OT mRNA expression (twofold increase in sham-operated SHRs) and peptide density in the posterior, ventromedial and dorsal cap PVN subnuclei (on average 70% increase in both strains), with significant correlations between OT content and training-induced resting bradycardia in sham-operated groups. Carotid body denervation did not interfere with the performance gain, abolished chemoreflex activation (without changing baroreflex control) and blocked training-induced cardiovascular adaptations and training-induced changes in PVN OT content in both strains. After carotid body denervation, there was no correlation between OT mRNA or OT immunoractivity and resting heart rate. The chronic absence of chemoreceptor inputs uncovers an unknown role of chemoreceptor signalling in driving the plasticity/activity of PVN oxytocinergic pre-autonomic neurons, thus mediating training-induced cardiovascular adaptive responses.
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http://dx.doi.org/10.1113/expphysiol.2012.065888DOI Listing
February 2013

Exercise training normalizes an increased neuronal excitability of NTS-projecting neurons of the hypothalamic paraventricular nucleus in hypertensive rats.

J Neurophysiol 2012 May 22;107(10):2912-21. Epub 2012 Feb 22.

Dept. of Physiology, Georgia Health Sciences Univ., Augusta, GA 30912, USA.

Elevated sympathetic outflow and altered autonomic reflexes, including impaired baroreflex function, are common findings observed in hypertensive disorders. Although a growing body of evidence supports a contribution of preautonomic neurons in the hypothalamic paraventricular nucleus (PVN) to altered autonomic control during hypertension, the precise underlying mechanisms remain unknown. Here, we aimed to determine whether the intrinsic excitability and repetitive firing properties of preautonomic PVN neurons that innervate the nucleus tractus solitarii (PVN-NTS neurons) were altered in spontaneously hypertensive rats (SHR). Moreover, given that exercise training is known to improve and/or correct autonomic deficits in hypertensive conditions, we evaluated whether exercise is an efficient behavioral approach to correct altered neuronal excitability in hypertensive rats. Patch-clamp recordings were obtained from retrogradely labeled PVN-NTS neurons in hypothalamic slices obtained from sedentary (S) and trained (T) Wistar-Kyoto (WKY) and SHR rats. Our results indicate an increased excitability of PVN-NTS neurons in SHR-S rats, reflected by an enhanced input-output function in response to depolarizing stimuli, a hyperpolarizing shift in Na(+) spike threshold, and smaller hyperpolarizing afterpotentials. Importantly, we found exercise training in SHR rats to restore all these parameters back to those levels observed in WKY-S rats. In several cases, exercise evoked opposing effects in WKY-S rats compared with SHR-S rats, suggesting that exercise effects on PVN-NTS neurons are state dependent. Taken together, our results suggest that elevated preautonomic PVN-NTS neuronal excitability may contribute to altered autonomic control in SHR rats and that exercise training efficiently corrects these abnormalities.
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http://dx.doi.org/10.1152/jn.00884.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362275PMC
May 2012

Cardiac benefits of exercise training in aging spontaneously hypertensive rats.

J Hypertens 2011 Dec;29(12):2349-58

Department of Physiology and Biophysics, Institute of Biomedical Science, University of Sao Paulo, São Paulo, Brazil.

Objective: To evaluate the effect of low-intensity chronic exercise training (ExT) on blood pressure (BP), as well as the cardiac alterations associated with hypertension in aging hypertensive rats.

Methods: Male spontaneously hypertensive rats (SHR; 21 months old) and their normotensive control Wistar-Kyoto (WKY) rats were submitted to low-intensity training protocol for 13 weeks. BP, cardiac morphological and morphometric analysis, as well as gene expression of fibrotic and inflammatory factors were analyzed at the end of the training period.

Results: ExT reduced BP and heart rate in aged SHR. Left ventricle hypertrophy, collagen volume fraction and wall-to-lumen ratio of myocardium arterioles were also decreased in trained SHR. However, ExT was unable to reverse the either reduced capillary density or the cardiac myocyte hypertrophy observed in SHR as compared with WKY rats. Trained SHR showed higher metalloproteinase-2/tissue inhibitor metalloproteinase-2 (MMP-2/TIMP-2) ratio and lower levels of α-smooth muscle actin, but similar levels of connective tissue growth factor, transforming growth factor beta or IL-1 beta to that of nontrained SHR.

Conclusion: Low to moderate-intensity chronic ExT reverses the cardiac alterations associated with hypertension: myocardial arteriole, left ventricle hypertrophy, collagen content and tachycardia. These changes could be consequence or cause of the reduction in BP observed in trained SHR. In addition, ExT does not worsen the underlying inflammatory burden associated with hypertension. Therefore, the data support a beneficial effect of ExT in aging SHR similar to that reported in young or middle-aged individuals, confirming that exercise is a healthy habit that induces cardiac improvements independently of age.
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http://dx.doi.org/10.1097/HJH.0b013e32834d2532DOI Listing
December 2011

Exercise training restores hypertension-induced changes in the elastic tissue of the thoracic aorta.

J Vasc Res 2011 10;48(6):513-24. Epub 2011 Aug 10.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Background/aims: Pharmacological antihypertensive therapies decrease both wall hypertrophy and collagen, but are unable to diminish the elastic content in the thoracic aorta. We investigated the effects of exercise training on aortic structure and function.

Methods: Spontaneously hypertensive rats (SHR) and normotensive rats (WKY), submitted to low-intensity training (T) or kept sedentary (S), were subjected to haemodynamic analyses. The thoracic aorta was processed for real-time PCR, light (morphometric/stereological evaluations) and electron microscopy.

Results: SHR(S) versus WKY(S) exhibited a higher heart rate, pressure and pulse pressure, increased α-actin, elastin and collagen mRNA expression, augmented wall volume and cross-sectional area (marked elastin/collagen content). In the SHR, training reduced pressure and heart rate, with slight reduction in pulse pressure. SHR(T) aortas exhibited small morphometric changes, reduced α-actin, elastin and collagen mRNA expression, normalization of increased elastic content, reduction in collagen/connective tissue and a decrease in smooth muscle cell volume (p < 0.05 for all comparisons). SHR(T) aortas showed improved circumferential orientation of smooth muscle cells and prevention of rupture/duplication of internal elastic lamina. No effects were observed in trained WKY aortas.

Conclusions: Training effectively corrects elastic, collagen and smooth muscle content in SHR aortas. These changes, by reducing aortic pulsatility, facilitate a buffering function and reduce the cardiovascular risk.
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http://dx.doi.org/10.1159/000329590DOI Listing
December 2011

Afferent signaling drives oxytocinergic preautonomic neurons and mediates training-induced plasticity.

Am J Physiol Regul Integr Comp Physiol 2011 Oct 27;301(4):R958-66. Epub 2011 Jul 27.

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

We showed previously that oxytocinergic (OTergic) projections from the hypothalamic paraventricular nucleus (PVN) to the dorsal brain stem mediate training-induced heart rate (HR) adjustments and that beneficial effects of training are blocked by sinoaortic denervation (SAD; Exp Physiol 94: 630-640; 1103-1113, 2009). We sought now to determine the combined effect of training and SAD on PVN OTergic neurons in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Rats underwent SAD or sham surgery and were trained (55% of maximal capacity) or kept sedentary for 3 mo. After hemodynamic measurements were taken at rest, rats were deeply anesthetized. Fresh brains were frozen and sliced to isolate the PVN; samples were processed for OT expression (real-time PCR) and fixed brains were processed for OT immunofluorescence. In sham rats, training improved treadmill performance and increased the gain of baroreflex control of HR. Training reduced resting HR (-8%) in both groups, with a fall in blood pressure (-10%) only in SHR rats. These changes were accompanied by marked increases in PVN OT mRNA expression (3.9- and 2.2-fold in WKY and SHR rats, respectively) and peptide density in PVN OTergic neurons (2.6-fold in both groups), with significant correlations between OT content and training-induced resting bradycardia. SAD abolished PVN OT mRNA expression and markedly reduced PVN OT density in WKY and SHR. Training had no effect on HR, PVN OT mRNA, or OT content following SAD. The chronic absence of inputs from baroreceptors and chemoreceptors uncovers the pivotal role of afferent signaling in driving both the plasticity and activity of PVN OTergic neurons, as well as the beneficial effects of training on cardiovascular control.
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http://dx.doi.org/10.1152/ajpregu.00104.2011DOI Listing
October 2011

Tyrosine hydroxylase immunoreactivity as indicator of sympathetic activity: simultaneous evaluation in different tissues of hypertensive rats.

Am J Physiol Regul Integr Comp Physiol 2011 Feb 9;300(2):R264-71. Epub 2010 Dec 9.

Dept. of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1524, 05508-900 São Paulo, SP, Brazil.

Vasomotor control by the sympathetic nervous system presents substantial heterogeneity within different tissues, providing appropriate homeostatic responses to maintain basal/stimulated cardiovascular function both at normal and pathological conditions. The availability of a reproducible technique for simultaneous measurement of sympathetic drive to different tissues is of great interest to uncover regional patterns of sympathetic nerve activity (SNA). We propose the association of tyrosine hydroxylase immunoreactivity (THir) with image analysis to quantify norepinephrine (NE) content within nerve terminals in arteries/arterioles as a good index for regional sympathetic outflow. THir was measured in fixed arterioles of kidney, heart, and skeletal muscle of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) (123 ± 2 and 181 ± 4 mmHg, 300 ± 8 and 352 ± 8 beats/min, respectively). There was a differential THir distribution in both groups: higher THir was observed in the kidney and skeletal muscle (∼3-4-fold vs. heart arterioles) of WKY; in SHR, THir was increased in the kidney and heart (2.4- and 5.3-fold vs. WKY, respectively) with no change in the skeletal muscle arterioles. Observed THir changes were confirmed by either: 1) determination of NE content (high-performance liquid chromatography) in fresh tissues (SHR vs. WKY): +34% and +17% in kidney and heart, respectively, with no change in the skeletal muscle; 2) direct recording of renal (RSNA) and lumbar SNA (LSNA) in anesthetized rats, showing increased RSNA but unchanged LSNA in SHR vs. WKY. THir in skeletal muscle arterioles, NE content in femoral artery, and LSNA were simultaneously reduced by exercise training in the WKY group. Results indicate that THir is a valuable technique to simultaneously evaluate regional patterns of sympathetic activity.
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http://dx.doi.org/10.1152/ajpregu.00687.2009DOI Listing
February 2011