Ivabradine restores tonic cardiovascular autonomic control and reduces tachycardia, hypertension and left ventricular inflammation in post-weaning protein malnourished rats.

Malnutrition results in autonomic imbalance and heart hypertrophy. Overexpression of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the left ventricles (LV) is linked to hypertrophied hearts and abnormal myocardium automaticity. Given that ivabradine (IVA) has emerging pleiotropic effects, in addition to the widely known bradycardic response, this study evaluated if IVA treatment could repair the autonomic control and cardiac damages in malnourished rats. AIM: Assess the impact of IVA on tonic cardiovascular autonomic control and its relationship with hemodynamics regulation, LV inflammation, and HCN gene expression in post-weaning protein malnutrition condition. MAIN METHODS: After weaning, male rats were divided into control (CG; 22 % protein) and malnourished (MG; 6 % protein) groups. At 35 days, groups were subdivided into CG-PBS, CG-IVA, MG-PBS and MG-IVA (PBS 1 ml/kg or IVA 1 mg/kg) received during 8 days. We performed jugular vein cannulation and electrode implant for drug delivery and ECG registration to assess tonic cardiovascular autonomic control; femoral cannulation for blood pressure (BP) and heart rate (HR) assessment; and LV collection to evaluate ventricular remodeling and HCN gene expression investigation. KEY FINDINGS: Malnutrition induced BP and HR increases, sympathetic system dominance, and LV remodeling without affecting HCN gene expression. IVA reversed the cardiovascular autonomic imbalance; prevented hypertension and tachycardia; and inhibited the LV inflammatory process and fiber thickening caused by malnutrition. SIGNIFICANCE: Our findings suggest that ivabradine protects against malnutrition-mediated cardiovascular damage. Moreover, our results propose these effects were not attributed to HCN expression changes, but rather to IVA pleiotropic effects on autonomic control and inflammation.

Are hemoglobin-derived peptides involved in the neuropsychiatric symptoms caused by SARS-CoV-2 infection?

Follow-up of patients affected by COVID-19 has unveiled remarkable findings. Among the several sequelae caused by SARS-CoV-2 viral infection, it is particularly noteworthy that patients are prone to developing depression, anxiety, cognitive disorders, and dementia as part of the post-COVID-19 syndrome. The multisystem aspects of this disease suggest that multiple mechanisms may converge towards post-infection clinical manifestations. The literature provides mechanistic hypotheses related to changes in classical neurotransmission evoked by SARS-CoV-2 infection; nonetheless, the interaction of peripherally originated classical and non-canonic peptidergic systems may play a putative role in this neuropathology. A wealth of robust findings shows that hemoglobin-derived peptides are able to control cognition, memory, anxiety, and depression through different mechanisms. Early erythrocytic death is found during COVID-19, which would cause excess production of hemoglobin-derived peptides. Following from this premise, the present review sheds light on a possible involvement of hemoglobin-derived molecules in the COVID-19 pathophysiology by fostering neuroscientific evidence that supports the contribution of this non-canonic peptidergic pathway. This rationale may broaden knowledge beyond the currently available data, motivating further studies in the field and paving ways for novel laboratory tests and clinical approaches.

Are hemoglobin-derived peptides involved in the neuropsychiatric symptoms caused by SARS-CoV-2 infection?

Follow-up of patients affected by COVID-19 has unveiled remarkable findings. Among the several sequelae caused by SARS-CoV-2 viral infection, it is particularly noteworthy that patients are prone to developing depression, anxiety, cognitive disorders, and dementia as part of the post-COVID-19 syndrome. The multisystem aspects of this disease suggest that multiple mechanisms may converge towards post-infection clinical manifestations. The literature provides mechanistic hypotheses related to changes in classical neurotransmission evoked by SARS-CoV-2 infection; nonetheless, the interaction of peripherally originated classical and non-canonic peptidergic systems may play a putative role in this neuropathology. A wealth of robust findings shows that hemoglobin-derived peptides are able to control cognition, memory, anxiety, and depression through different mechanisms. Early erythrocytic death is found during COVID-19, which would cause excess production of hemoglobin-derived peptides. Following from this premise, the present review sheds light on a possible involvement of hemoglobin-derived molecules in the COVID-19 pathophysiology by fostering neuroscientific evidence that supports the contribution of this non-canonic peptidergic pathway. This rationale may broaden knowledge beyond the currently available data, motivating further studies in the field and paving ways for novel laboratory tests and clinical approaches.

Lasting effects of ketamine and isoflurane administration on anxiety- and panic-like behavioral responses in Wistar rats.

In clinical and laboratory practice, the use of anesthetics is essential in order to perform surgeries. Anesthetics, besides causing sedation and muscle relaxation, promote several physiological outcomes, such as psychotomimetic alterations, increased heart rate, and blood pressure. However, studies depicting the behavioral effect induced by ketamine and isoflurane are conflicting. In the present study, we assessed the behavioral effects precipitated by ketamine and isoflurane administration. We have also evaluated the ketamine effect on cell cytotoxicity and viability in an amygdalar neuronal primary cell culture. Ketamine (80 mg/kg) caused an anxiogenic effect in rats exposed to the elevated T-maze test (ETM) 2 and 7 days after ketamine administration. Ketamine (40 and 80 mg/kg) administration also decreased panic-like behavior in the ETM. In the light/dark test, ketamine had an anxiogenic effect. Isoflurane did not change animal behavior on the ETM. Neither ketamine nor isoflurane changed the spontaneous locomotor activity in the open field test. However, isoflurane-treated animals explored less frequently the OF central area seven days after treatment. Neither anesthetic caused oxidative damage in the liver. Ketamine also reduced cellular metabolism and led to neuronal death in amygdalar primary cell cultures. Thus, our work provides evidence that ketamine and isoflurane induce pronounced long lasting anxiety-related behaviors in male rats.

Pre- and Post-Conditioning of the Heart: An Overview of Cardioprotective Signaling Pathways.

Since the discovery of ischemic pre- and post-conditioning, more than 30 years ago, the knowledge about the mechanisms and signaling pathways involved in these processes has significantly increased. In clinical practice, on the other hand, such advancement has yet to be seen. This article provides an overview of ischemic pre-, post-, remote, and pharmacological conditioning related to the heart. In addition, we reviewed the cardioprotective signaling pathways and therapeutic agents involved in the above-mentioned processes, aiming to provide a comprehensive evaluation of the advancements in the field. The advancements made over the last decades cannot be ignored and with the exponential growth in techniques and applications. The future of pre- and post-conditioning is promising.

Tobacco-Free Cigarette Smoke Exposure Induces Anxiety and Panic-Related Behaviours in Male Wistar Rats.

Smokers, who generally present with lung damage, are more anxious than non-smokers and have an associated augmented risk of panic. Considering that lung damage signals specific neural pathways that are related to affective responses, the aim of the present study was to evaluate the influence of pulmonary injury on anxiety and panic-like behaviours in animals exposed to cigarette smoke with and without tobacco. Male Wistar rats were divided into the following groups: a control group (CG); a regular cigarette group (RC); and a tobacco-free cigarette (TFC) group. Animals were exposed to twelve cigarettes per day for eight consecutive days. The animals were then exposed to an elevated T-maze and an open field. The RC and TFC groups presented increases in inflammatory cell inflow, antioxidant enzyme activity, and TBARS levels, and a decrease in the GSH/GSSG ratio was observed in the TFC group. Exposure to RC smoke reduced anxiety and panic-related behaviours. On the other hand, TFC induced anxiety and panic-related behaviours. Thus, our results contradict the concept that nicotine is solely accountable for shifted behavioural patterns caused by smoking, in that exposure to TFC smoke causes anxiety and panic-related behaviours.

New insights on amygdala: Basomedial amygdala regulates the physiological response to social novelty.

The amygdala has been associated with a variety of functions linked to physiological, behavioral and endocrine responses during emotional situations. This brain region is comprised of multiple sub-nuclei. These sub-nuclei belong to the same structure, but may be involved in different functions, thereby making the study of each sub-nuclei important. Yet, the involvement of the basomedial amygdala (BMA) in the regulation of emotional states has yet to be defined. Therefore, the aim of our study was to investigate the regulatory role of the BMA on the responses evoked during a social novelty model and whether the regulatory role depended on an interaction with the dorsomedial hypothalamus (DMH). Our results showed that the chemical inhibition of the BMA by the microinjection of muscimol (γ-aminobutyric acid (GABAA) agonist) promoted increases in mean arterial pressure (MAP) and heart rate (HR), whereas the chemical inhibition of regions near the BMA did not induce such cardiovascular changes. In contrast, the BMA chemical activation by the bilateral microinjection of bicuculline methiodide (BMI; GABAA antagonist), blocked the increases in MAP and HR observed when an intruder rat was suddenly introduced into the cage of a resident rat, and confined to the small cage for 15min. Additionally, the increase in HR and MAP induced by BMA inhibition were eliminated by DMH chemical inhibition. Thus, our data reveal that the BMA is under continuous GABAergic influence, and that its hyperactivation can reduce the physiological response induced by a social novelty condition, possibly by inhibiting DMH neurons.

Hepatic inflammatory biomarkers and its link with obesity and chronic diseases.

INTRODUCTION: The low-grade inflammation and insulin resistance are two events that could be present in varying degrees, on obesity and chronic diseases. The degree of subclinical inflammation can be gauged by measuring the concentrations of some inflammatory biomarkers, including the hepatic origin ones. Some of those biomarkers are sialic acid, α1-antitrypsin and the C-terminal fragment of alpha1-antitrypsin, ceruloplasmin, fibrinogen, haptoglobin, homocystein and plasminogen activator inhibitor-1. OBJECTIVES: To approach the relation between adiposity and hepatic inflammatory markers, and to assess the possible associations between hepatic inflammatory biomarkers and obesity, as well as their capacity of predicting chronic diseases such as type 2 diabetes and atherotrombotic cardiovascular diseases. METHODS: We used electronic scientific databases to select articles without restricting publication year. RESULTS: The sialic acid predicts the chance increase to become type 2 diabetic independently of BMI. Moreover, the α1-antitripsin, ceruloplasmin, fibrinogen and haptoglobulin biomarkers, seem predict the chance increase to become type 2 diabetic, dependently, of BMI. So, this process could be aggravated by obesity. The concentrations of fibrinogen, homocystein and PAI-1 increase proportionally to insulin resistance, showing its relation with metabolic syndrome (insulin resistance state) and with type 2 diabetes. In relation to cardiovascular diseases, every biomarkers reported in this review seem to increase the risk, becoming useful in add important prognostic. CONCLUSION: This review integrates the knowledge concerning the possible interactions of inflammatory mediators, in isolation or in conjunction, with obesity and chronic diseases, since these biomarkers play different functions and follow diverse biochemical routes in human body metabolism.

Introdución: El bajo grado de inflamación y la resistencia a la insulina son dos eventos que podrían estar presentes en mayor o menor grado, en la obesidad y las enfermedades crónicas. El grado de inflamación subclínica se puede evaluar por medición de las concentraciones de algunos biomarcadores inflamatorios, incluyendo los de origen hepático. Algunos de estos biomarcadores son el ácido siálico, 1-antitripsina y el fragmento C-terminal de la alfa 1-antitripsina, ceruloplasmina, fibrinógeno, haptoglobina, la homocisteína y el inhibidor-1 del activador del plasminógeno. Objetivos: Evaluar la relación entre la obesidad y los marcadores de inflamación hepática, y las posibles asociaciones entre los biomarcadores inflamatorios hepáticos y la obesidad, así como su capacidad de predicción de las enfermedades crónicas como la diabetes tipo 2 y enfermedades cardiovasculares aterotromboticas. Métodos: Se utilizaron bases científicas electrónicas para selección de artículos, sin límite de año de publicación. Resultados: El ácido siálico predice el aumento de convertirse en diabéticos tipo 2 independientemente del IMC. Por otra parte, los biomarcadores 1-antitripsina, ceruloplasmina, fibrinógeno y haptoglobulina, parecen predecir el aumento de convertirse en diabético tipo 2, dependiente, de IMC. Por lo tanto, este proceso podría verse agravada por la obesidad. Las concentraciones de fibrinógeno, homocisteína y PAI-1 incrementam proporcionalmente a la insulinoresisténcia, mostrando su relación con el síndrome metabólico (estado de resistencia insulínica) y con la diabetes tipo 2. En relación con las enfermedades cardiovasculares, cada biomarcador informado en esta revisión parece aumentar el riesgo, llegando a ser muy útil en el complemento pronóstico. CONCLUSION: Esta revisión se integra el conocimiento acerca de las posibles interacciones de los mediadores inflamatorios, en forma aislada o en combinación, con la obesidad y las enfermedades crónicas, ya que estos biomarcadores desempeñan funciones diferentes y siguen diversas rutas bioquímicas en el metabolismo del cuerpo humano.

Malnutrition alters the cardiovascular responses induced by central injection of tityustoxin in Fischer rats.

Scorpion envenoming and malnutrition are considered two important public health problems in Brazil, involving mainly children. Both these conditions are more common among the economically stratified lower income portion of the population, thus suggesting that these factors should be analyzed concomitantly. It is known that cardiorespiratory manifestations, as cardiac arrhythmias, arterial hypertension and hypotension, pulmonary edema and circulatory failure are the main "causa mortis" of scorpion envenomation. Additionally, there are evidences in the literature that deficiencies in dietary intake endanger the CNS and modify the cardiovascular homeostasis. Then, the objective of this work is to evaluate the protein malnourished effect on cardiovascular responses induced by tityustoxin (TsTX, an α-type toxin extracted from the Tityus serrulatus scorpion venom). Fischer rats (n = 20) were injected i.c.v. with TsTX and divided in control and malnorished groups, which were, respectively, submitted to a control and a low-protein diet. Arterial pressure recordings were done until death of the animals. Although both groups presented an increased mean arterial pressure after TsTX injection, this increase was smaller and delayed in malnourished rats, when compared to control rats. In addition, heart rate increased only in rats from the control group. Finally, malnourished rats had an increase in survival time (9:9/13.5 vs. 15.5:10.5/18 min; p = 0.0009). In summary, our results suggest that the protein restriction attenuates the cardiovascular manifestations resulting from TsTX action on CNS.

[Acceptance of handmade products containing nuts and fructooligosaccharides]. / Aceptación de productos artesanales formulados con nueces y fructooligosacáridos.

INTRODUCTION: Prebiotic and food with functional properties are beneficial for consumers through prevention of many diseases. AIM: Verify the acceptance of handmade product (chocolate bar, soy sweet and sweet bread) formulated based on oil seeds (flaxseed, peanut and Brazil nut) and or fructooligosaccharides (FOS). METHODS: Four samples of each handmade product were prepared adding different concentrations of oil seed and FOS. The sensory evaluation was performed by a sample of 373 consumers; 126, 121 and 126 tasters of chocolate bar, soy sweet and sweet bread, respectively, using a hedonic scale of nine points. The results were submitted to analysis of variance (ANOVA) and Tukey's test. RESULTS AND DISCUSSION: Observing the trials averages, we inferred that samples of sweet bread with Brazil nut and/or FOS had the greater acceptance. However, all the samples are good market alternatives because they had presented averages between 6 and 9 points, and conferred accretion of omega-3 and omega-6 fatty acids, protein, fiber, antioxidant vitamins and minerals, as well as, phytochemicals, which plays an important role in health promotion. CONCLUSION: The handmade products formulated based on oil seeds and FOS had good acceptance and can improve the consumer dietary patterns. But, in order to prove the functionality of these products, new studies should be performed.

Introducción: Los prebióticos y alimentos con propiedades funcionales proporcionan beneficios para la salud de los consumidores a través de la prevención de muchas enfermedades. Objetivo: Verificar la aceptación de productos artesanales (chocolate en barra, dulce de soja y pan dulce) formulados con nueces (linaza, maní y nueces de Brasil) y, o fructooligosacáridos (FOS). Métodos: Cuatro muestras de cada producto fueron preparados con adición de diferentes concentraciones de nueces y FOS. La evaluación sensorial se realizó mediante una muestra de 373 consumidores, con 126, 121 y 126 probadores para muestras de chocolate en barra, dulce de soja y pan dulce, respectivamente, utilizándose la escala hedónica de nueve puntos. Los resultados fueron sometidos a Análisis de Varianza (ANOVA) y el test de Tukey. Resultados y Discusión: Observándose las medias de los juzgamientos, se infiere que las muestras con mayor aceptación han sido de pan dulce con nueces de Brasil y, o FOS. Sin embargo, todas las muestras son buenas alternativas de mercado y se lo mostró un promedio de entre 6 y 9 puntos, más un aumento de ácidos grasos omega 3 y 6, proteínas, fibras, vitaminas, antioxidantes y minerales, así como fitoquímicos, los cuales desempeñan un papel importante en la promoción de la salud. Conclusión: Los productos artesanales formulados con oleaginosas y, o FOS tuvieron una buena aceptabilidad y pueden mejorar los hábitos alimentarios de los consumidores. Pero para probar la funcionalidad de estos productos, se necesitan nuevos estudios.

Protein malnutrition modifies medullary neuronal recruitment in response to intermittent stimulation of the baroreflex.

Protein malnutrition after weaning changes the neurotransmission in neural pathways that organize cardiovascular reflexes in rats. The present study evaluates whether protein malnutrition alters the expression of c-fos protein (immediate-early gene expression) in central areas involved in the control of cardiovascular reflexes after intermittent stimulation of the baroreflex. The main nuclei we focused were paraventricular hypothalamus (PVH); nucleus tract solitarii (NTS); rostral ventromedial medulla (RVMM); rostral (RVLM) and caudal ventrolateral medulla (CVLM). Male Fisher rats at 28 days were submitted to two different isocaloric diets during the subsequent 35 days: control (CT) (15% protein) and malnourished (MN) (6% protein). thirtymin of intermittent (every 3 min) baroreflex stimulation was performed by infusing phenylephrine (Phe-0.25 mM) or, as control, 0.9% NaCl (Sal). Following ninety minutes, animals were anesthetized and perfused. The removed brains were sectioned (35 µm) and used for c-fos immunohistochemistry. Images were analyzed using the software Leica Q Win. Despite not altering the baseline MAP, malnutrition increased baseline HR and expression of c-fos in RVMM. Increases in c-fos expression after intermittent stimulation of baroreflex were evident in the PVH, medial NTS and CVLM in both dietary protocols. Current data further revealed a differential neuronal recruitment to stimulation of baroreflex in the caudal commissural and rostral NTS and RVLM of MN. We conclude that protein malnutrition modifies the cardiovascular control and the pattern of central response to baroreflex stimulation.