Gisele Cristiane Vaz

Emotional stress and sympathetic activity: Contribution of dorsomedial hypothalamus to cardiac arrhythmias

Maintenance of homeostasis in normal or stressful situations depends upon mechanisms controlling autonomic activity. Central requirement for changes in sympathetic output resulting from emotional stress must be adjusted to the input signals from visceral sensory afferent (feedback response) for an optimum cardiovascular performance. There is a large body of evidence indicating that emotional stress can lead to cardiovascular disease. Reviewing the descending pathways from dorsomedial hypothalamus, a key region involved in the cardiovascular response to emotional stress, we discuss the interactions between mechanisms controlling the sympathetic output to the cardiovascular system and the possible implications in cardiovascular disease.

Association Between Exercise-Induced Hyperthermia and Intestinal Permeability: A Systematic Review

BackgroundProlonged and strenuous physical exercise increases intestinal permeability, allowing luminal endotoxins to translocate through the intestinal barrier and reach the bloodstream. When recognized by the immune system, these endotoxins trigger a systemic inflammatory response that may affect physical performance and, in severe cases, induce heat stroke. However, it remains to be elucidated whether there is a relationship between the magnitude of exercise-induced hyperthermia and changes in intestinal permeability.ObjectiveIn this systematic review, we evaluated whether an exercise-induced increase in core body temperature (TCore) is associated with an exercise-induced increase in intestinal permeability.MethodsThe present systematic review screened the MEDLINE/PubMed and Web of Science databases in September 2016, without any date restrictions. Sixteen studies that were performed in healthy participants, presented original data, and measured both the exercise-induced changes in TCore and intestinal permeability were selected. These studies assessed intestinal permeability through the measurement of sugar levels in the urine and measurement of intestinal fatty acid binding protein or lipopolysaccharide levels in the blood.ResultsExercise increased both TCore and intestinal permeability in most of the 16 studies. In addition, a positive and strong correlation was observed between the two parameters (r = 0.793; p < 0.001), and a TCore exceeding 39 °C was always associated with augmented permeability.ConclusionThe magnitude of exercise-induced hyperthermia is directly associated with the increase in intestinal permeability.

Functional topography of cardiovascular regulation along the rostrocaudal axis of the rat posterior insular cortex

Cardiovascular (CV) representation has been identified within the insular cortex (IC) and a lateralization of function previously suggested. In order to further understand the role of IC on cardiovascular control, the present study compared the CV responses evoked by stimulation of N‐metil‐D‐aspartate (NMDA) receptors in the right and left posterior IC at different rostrocaudal levels. Intracortical microinjections of NMDA were performed into the IC of male Wistar rats anaesthetized with urethane (1.4 g/kg) prepared for blood pressure, heart rate and renal sympathetic nerve activity. Gene expression of NMDA receptor subunits NR2A and NR2B in the IC was confirmed by RT‐PCR. Immunofluorescence for the NMDA receptor NR1 subunit was demonstrated in the IC (coordinates anteroposterior (AP) +1.5, 0.0 and −1.5 mm). A cardiac sympathoinhibitory site was identified, more rostrally located than identified in previous studies. A site of sympathoexcitatory cardiac control was identified more caudal to this region in agreement with earlier work. Under the experimental conditions, no lateralization of cardiovascular function was identified with chemical stimulation eliciting the same responses from either left or right insular cortices. No tonic role of the insula on cardiovascular control was identified with the use of the NMDA antagonist, AP‐5. Peri‐insular microinjection of NMDA was without cardiovascular effect indicating the specificity of the insula as a cardiovascular regulatory site. The current study reveals a functional topography for autonomic cardiovascular control along the rostrocaudal axis of the posterior IC.

Excitatory Amino Acid Receptors Mediate Asymmetry and Lateralization in the Descending Cardiovascular Pathways from the Dorsomedial Hypothalamus

The dorsomedial hypothalamus (DMH) and lateral/dorsolateral periaqueductal gray (PAG) are anatomically and functionally connected. Both the DMH and PAG depend on glutamatergic inputs for activation. We recently reported that removal of GABA-ergic tone in the unilateral DMH produces: asymmetry, that is, a right- (R-) sided predominance in cardiac chronotropism, and lateralization, that is, a greater increase in ipsilateral renal sympathetic activity (RSNA). In the current study, we investigated whether excitatory amino acid (EAA) receptors in the DMH–PAG pathway contribute to the functional interhemispheric difference. In urethane (1.2 to 1.4 g/kg, i.p.) anesthetized rats, we observed that: (i) nanoinjections of N-methyl D-aspartate (NMDA 100 pmol/100 nl) into the unilateral DMH produced the same right-sided predominance in the control of cardiac chronotropy, (ii) nanoinjections of NMDA into the ipsilateral DMH or PAG evoked lateralized RSNA responses, and (iii) blockade of EAA receptors in the unilateral DMH attenuated the cardiovascular responses evoked by injection of NMDA into either the R- or left- (L-) PAG. In awake rats, nanoinjection of kynurenic acid (1 nmol/100 nL) into the L-DMH or R- or L-PAG attenuated the tachycardia evoked by air stress. However, the magnitude of stress-evoked tachycardia was smallest when the EAA receptors of the R-DMH were blocked. We conclude that EAA receptors contribute to the right-sided predominance in cardiac chronotropism. This interhemispheric difference that involves EAA receptors was observed in the DMH but not in the PAG.

Increased Jejunal Absorption of Glucose in Rats Submitted to Blockade of GABAA Receptors in the Hypothalamic Paraventricular Nucleus

In this study we investigated the status of jejunal absorption and peripheral metabolism of glucose following disinhibition of paraventricular nucleus (PVN) induced by the GABAA antagonist bicuculline methiodide (BMI). Adult male Wistar rats (270-300g) were anesthetized to implant unilateral guide cannula targeted to PVN for later microinjec- tion of BMI (10 pmol/100 nl, n=6) or vehicle (NaCl 0.9 % /100 nl, n=5). The jejunal loop was isolated and perfused (0.5 mL/min) with Tyrode solution containing twice the normal concentrations of glucose, sodium, and potassium. After mi- croinjections into PVN, perfusate and blood samples were taken every 10 min over a 40 min period. In comparison with vehicle, BMI into PVN increased glucose absorption at 30 min (1.2 ± 0.1 vs. 1.8 ± 0.1 � mol/min; *P<0.05) and at 40 min (1.3 ± 0.2 vs. 2.4 ± 0.3 � mol/min; *P<0.05), whereas plasma insulin was significantly reduced (0.5 ± 0.04 vs. 0.3 ± 0.04 ng/ml, *P<0.01). At the end of the experiment, samples from the liver and gastrocnemius muscle were taken to measure levels of glycogen, intermediate metabolites of the glycolytic pathway and ATP. Compared to control, muscle glucose-6- phosphate (0.380 ± 0.063 vs. 0.253 ± 0.020 � mol/g; P<0.05) and ATP (0.166 ± 0.065 vs. 0.038 ± 0.013 � mol/g; *P<0.05) were reduced in the group microinjected with BMI into PVN. We conclude that PVN disinhibition changes the absorption and peripheral glucose metabolism.

Liposome-entrapped GABA modulates the expression of nNOS in NG108-15 cells

BACKGROUND Liposomes are concentric lipid vesicles that allow a sustained release of entrapped substances. GABA (γ-aminobutyric acid) is the most prevalent inhibitory neurotransmitter in the central nervous system. NEW METHOD Using GABA-containing liposomes (GL) prepared by the freeze-thawing method, we determined the effect of sustained release of GABA on expression of neuronal nitric oxide synthase (nNOS) and GABAA receptor (GABAAR) in an in vitro neuronal model. RESULTS Neuronal cell line NG108-15 treated with different doses of GL during 24h showed an increase in expression of GABAAR (54 and 50% with 10 and 20ng doses, respectively) and nNOS (138, 157 and 165% with 20, 50 and 100ng doses, respectively) compared with cells treated with empty liposomes (EL). Additionally, cells treated with 50ng of GL showed an increase in GABAAR (23%) after 1h followed by an increase in nNOS (55, 46 and 55%) at 8, 12 and 24h time points, respectively. Immunofluorescence experiments confirmed an increase in nNOS (134%) and basal intracellular levels of nitric oxide (84%) after GL treatment. Further, treatment of cells with GL showed a decrease in expression of a protein inhibitor of nNOS (PIN) (26, 66 and 57% with 20, 50 and 100ng doses respectively) compared with control. COMPARISON WITH EXISTING METHODS This is first demonstration for the development of GL that allows sustained slow release of this neurotransmitter. CONCLUSION These results suggest that a slow release of GABA can change the expression of nNOS possibly via alteration in PIN levels in neuronal cells.

GABA-containing liposomes: neuroscience applications and translational perspectives for targeting neurological diseases

There are multiple challenges for neuropharmacology in the future. Undoubtedly, one of the greatest challenges is the development of strategies for pharmacological targeting of specific brain regions for treatment of diseases. GABA is the main inhibitory neurotransmitter in the central nervous system, and dysfunction of GABAergic mechanisms is associated with different neurological conditions. Liposomes are lipid vesicles that are able to encapsulate chemical compounds and are used for chronic drug delivery. This short review reports our experience with the development of liposomes for encapsulation and chronic delivery of GABA to sites within the brain. Directions for future research regarding the efficacy and practical use of GABA-containing liposomes for extended periods of time as well as understanding and targeting neurological conditions are discussed.