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- Essential role of RVL medullary neuronal activity in the lng term maintenance of hypertension in conscious SHRPublication . Geraldes, Vera; Gonçalves-Rosa, Nataniel; Liu, Beihui; Paton, Julian F.R.; Rocha, IsabelBackground: It is well established that sympathetic nervous system is responsible for the onset, development and maintenance of neurogenic hypertension. The rostroventrolateral medulla (RVLM) and medullo-cervical pressor area (MCPA) are important central sympathoexcitatory regions whose role on neurogenic hypertension remains unknown. Objective: To establish RVLM and MCPA roles in the long-term regulation of blood pressure by depressing their neuron activity through the over-expression of hKir2.1-potassium channel in conscious spontaneously hypertensive rats (SHR). Methods: In SHR, a lentiviral vector LVV-hKir2.1 was microinjected into RVLM or MCPA areas. A sham group was injected with LVV-eGFP. Blood pressure (BP) and heart rate (HR) were continuously monitored for 75 days. Baroreflex and chemoreflex functions were evaluated. Baroreflex gain, chemoreflex sensitivity, BP and HR variability were calculated. Results: LVV-hKir2.1 expression in RVLM, but not in MCPA, produced a significant time-dependent decrease in systolic, diastolic, mean-BP and LF of systolic BP at 60-days post-injection. No significant changes were seen in LVV-eGFP RVLM injected SHR. Conclusion: Data show that chronic expression of Kir2.1 in the RVLM of conscious SHR caused a marked and sustained decrease in BP without changes in the baro- and peripheral chemoreceptor reflex evoked responses. This decrease was mostly due to a reduction in sympathetic output revealed indirectly by a decrease in the power density of the SBP-LF band. Our data are amongst the firsts to demonstrate the role of the RVLM in maintaining BP levels in hypertension in conscious SHR. We suggest that a decrease in RVLM neuronal activity is an effective anti-hypertensive treatment strategy.
- Orthostatic stress and baroreflex sensitivity: a window into autonomic dysfunction in lone paroxysmal atrial fibrillationPublication . Ferreira, Mónica; Laranjo, Sergio; Cunha, Pedro; Geraldes, Vera; Oliveira, Mario; Rocha, IsabelThe abnormal neural control of atria has been considered one of the mechanisms of paroxysmal atrial fibrillation (PAF) pathogenesis. The baroreceptor reflex has an important role in cardiovascular regulation and may serve as an index of autonomic function. This study aimed to analyze the baroreceptor reflex's role in heart rate regulation during upright tilt (HUT) in patients with lone PAF. The study included 68 patients with lone PAF and 34 healthy individuals who underwent baroreflex assessment. Parameters such as baroreflex sensitivity (BRS), number of systolic blood pressure (BP) ramps, and the baroreflex effectiveness index (BEI) were evaluated. The study found that PAF patients had comparable resting BPs and heart rates (HRs) to healthy individuals. However, unlike healthy individuals, PAF patients showed a sustained increase in BP with an upright posture followed by the delayed activation of the baroreceptor function with a blunted HR response and lower BEI values. This indicates a pronounced baroreflex impairment in PAF patients, even at rest. Our data suggest that together with BRS, BEI could be used as a marker of autonomic dysfunction in PAF patients, making it important to further investigate its relationship with AF recurrence after ablation and its involvement in cardiovascular autonomic remodeling.
- Insights into the background of autonomic medicinePublication . Laranjo, Sergio; Geraldes, Vera; Oliveira, Mário; Rocha, IsabelKnowledge of the physiology underlying the autonomic nervous system is pivotal for understanding autonomic dysfunction in clinical practice. Autonomic dysfunction may result from primary modifications of the autonomic nervous system or be secondary to a wide range of diseases that cause severe morbidity and mortality. Together with a detailed history and physical examination, laboratory assessment of autonomic function is essential for the analysis of various clinical conditions and the establishment of effective, personalized and precise therapeutic schemes. This review summarizes the main aspects of autonomic medicine that constitute the background of cardiovascular autonomic dysfunction.
- Therapeutic effects of IkB kinase inhibitor during systemic inflammationPublication . Amaro-Leal, Ângela; Shvachiy, Liana; Pinto, Rui; Geraldes, Vera; Rocha, Isabel; Mota-Filipe, HelderAnimal models of inflammatory diseases support the idea that nuclear factor κB (NF-κB) activation plays a pathophysiological role and is widely implicated in multiple organ dysfunction (MOD). Indeed, the inhibition of the IκB kinase (IKK) complex, involved in the NF-κB pathway, can represent a promising approach to prevent MOD. The present work employed a rat model of systemic inflammation to investigate the preventive effects of Inhibitor of IKK complex (IKK16). In male Wistar rats, systemic inflammation was induced by a tail vein injection of lipopolysaccharides (LPS challenge; 12 mg/kg). Treatment with IKK16 (1 mg/kg body weight) was administered, by tail vein, 15 min post-LPS. Age- and sex-matched healthy rats and LPS rats without treatment were used as controls. At 24 h post-IKK16 treatment, serum enzyme levels indicative of liver, kidney, pancreas and muscle function were evaluated by biochemical analysis, and RT-PCR technique was used to analyze gene expression of pro-inflammatory cytokines. Hemodynamic parameters were also considered to assess the LPS-induced inflammation. IKK16 treatment yielded a strong therapeutic effect in preventing LPS-induced elevation of serological enzyme levels, attenuating hepatic, renal, pancreatic and muscular dysfunction after LPS challenge. Moreover, as expected, LPS promoted a significantly overexpression of TNF-α, IL-6 and IL-1β in the heart, kidney, and liver; which was diminished by IKK16 treatment. The present study provides convincing evidence that selective inhibition of the IκB kinase complex through the action of IKK16, plays a protective role against LPS-induced multiple organ dysfunction by reducing the acute inflammatory response induced by endotoxin exposure.
- Study of lead accumulation in bones of Wistar rats by X-ray fluorescence analysis: aging effectPublication . Guimarães, Diana; Carvalho, Maria Luisa; Geraldes, Vera; Rocha, Isabel; Santos, José PauloThe accumulation of lead in several bones of Wistar rats with time was determined and compared for the different types of bones. Two groups were studied: a control group (n = 20), not exposed to lead and a contaminated group (n = 30), exposed to lead from birth, first indirectly through mother's milk, and then directly through a diet containing lead acetate in drinking water (0.2%). Rats age ranged from 1 to 11 months, with approximately 1 month intervals and each of the collections had 3 contaminated rats and 2 control rats. Iliac, femur, tibia-fibula and skull have been analysed by Energy Dispersive X-ray Fluorescence Technique (EDXRF). Samples of formaldehyde used to preserve the bone tissues were also analysed by Electrothermal Atomic Absorption (ETAAS), showing that there was no significant loss of lead from the tissue to the preservative. The bones mean lead concentration of exposed rats range from 100 to 300 μg g(-1) while control rats never exceeded 10 μg g(-1). Mean bone lead concentrations were compared and the concentrations were higher in iliac, femur and tibia-fibula and after that skull. However, of all the concentrations in the different collections, only those in the skull were statistically significantly different (p < 0.05) from the other types of bones. Analysis of a radar chart also allowed us to say that these differences tend to diminish with age. The Spearman correlation test applied to mean lead concentrations showed strong and very strong positive correlations between all different types of bones. This test also showed that mean lead concentrations in bones are negatively correlated with the age of the animals. This correlation is strong in iliac and femur and very strong in tibia-fibula and skull. It was also shown that the decrease of lead accumulation with age is made by three plateaus of accumulation, which coincide, in all analysed bones, between 2nd-3rd and 9th-10th months.
- Intermittent low-level lead exposure causes anxiety and cardiorespiratory impairmentPublication . Shvachiy, Liana; Geraldes, Vera; Amaro-Leal, Ângela; Rocha, IsabelAim: To characterize behavioural and cardiorespiratory changes in a new, intermittent low-level lead exposure animal model. Introduction: Lead (Pb) is a cumulative toxic metal affecting all body systems that are particularly vulnerable during developmental phase. Permanent lead exposure has been defined as a cause of behavioural changes, cognitive impairment, sympathoexcitation, tachycardia, hypertension and autonomic dysfunction. However, no studies have been performed to describe a new, intermittent low-level lead exposure profile, that has been increased in the past years. Methods: Foetuses were intermittently (PbI) exposed to water containing lead acetate (0.2%, w/v) throughout life until adulthood (28 weeks of age). A control group (without exposure, CTL), matching in age and sex was used. At 26 weeks, behavioural tests were performed for anxiety (Elevated Plus Maze Test) and locomotor activity (Open Field Test) assessment. Blood pressure (BP), electrocardiogram (ECG), heart rate (HR) and respiratory frequency (RF) rates were recorded at 28 weeks of age. Baroreflex gain (BRG) and chemoreflex sensitivity (ChS) were calculated. Student’s T-test was used (significance p < 0.05) for statistical analysis. Results: An intermittent lead exposure causes hypertension (increased diastolic and mean BP), increased RF, decreased baroreflex function and increased ChS, without significant changes in HR, when compared to CTL group. Regarding behavioral changes, the intermittent lead exposure model showed an anxiety-like behaviour without changes in locomotor activity. Conclusion: Intermittent low-level lead exposure induces changes on the cardiorespiratory profile characterized by hypertension, carotid chemosensitivity and baroreflex impairment. According to behavioural tests results, this study also shows that the exposure to lead during developmental phases causes anxiety in adult animals without locomotor activity impairment. In summary, this study brings new insights on the environmental factors that influence nervous and cardiovascular systems during development, which can help creating public policy strategies to prevent and control the adverse effects of Pb toxicity.
- From molecular to functional effects of different environmental lead exposure paradigmsPublication . Shvachiy, Liana; Amaro-Leal, Ângela; Outeiro, Tiago; Rocha, Isabel; Geraldes, VeraLead is a heavy metal whose widespread use has resulted in environmental contamination and significant health problems, particularly if the exposure occurs during developmental stages. It is a cumulative toxicant that affects multiple systems of the body, including the cardiovascular and nervous systems. Chronic lead exposure has been defined as a cause of behavioral changes, inflammation, hypertension, and autonomic dysfunction. However, different environmental lead exposure paradigms can occur, and the different effects of these have not been described in a broad comparative study. In the present study, rats of both sexes were exposed to water containing lead acetate (0.2% w/v), from the fetal period until adulthood. Developmental Pb-exposed (DevPb) pups were exposed to lead until 12 weeks of age (n = 13); intermittent Pb exposure (IntPb) pups drank leaded water until 12 weeks of age, tap water until 20 weeks, and leaded water for a second time from 20 to 28 weeks of age (n = 14); and the permanent (PerPb) exposure group were exposed to lead until 28 weeks of age (n = 14). A control group (without exposure, Ctrl), matched in age and sex was used. After exposure protocols, at 28 weeks of age, behavioral tests were performed for assessment of anxiety (elevated plus maze test), locomotor activity (open-field test), and memory (novel object recognition test). Metabolic parameters were evaluated for 24 h, and the acute experiment was carried out. Blood pressure (BP), electrocardiogram, and heart (HR) and respiratory (RF) rates were recorded. Baroreflex gain, chemoreflex sensitivity, and sympathovagal balance were calculated. Immunohistochemistry protocol for NeuN, Syn, Iba-1, and GFAP staining was performed. All Pb-exposed groups showed hypertension, concomitant with a decrease in baroreflex gain and chemoreceptor hypersensitivity, without significant changes in HR and RF. Long-term memory impairment associated with reactive astrogliosis and microgliosis in the dentate gyrus of the hippocampus, indicating the presence of neuroinflammation, was also observed. However, these alterations seemed to reverse after lead abstinence for a certain period (DevPb) and were enhanced when a second exposure occurred (IntPb), along with a synaptic loss. These results suggest that the duration of Pb exposure is more relevant than the timing of exposure, since the PerPb group presented more pronounced effects and a significant increase in the LF and HF bands and anxiety levels. In summary, this is the first study with the characterization and comparison of physiological, autonomic, behavioral, and molecular changes caused by different low-level environmental lead exposures, from the fetal period to adulthood, where the duration of exposure was the main factor for stronger adverse effects. These kinds of studies are of immense importance, showing the importance of the surrounding environment in health from childhood until adulthood, leading to the creation of new policies for toxicant usage control.
- Lead as an environmental toxicant in models of synucleinopathiesPublication . Shvachiy, Liana; Amaro-Leal, Ângela; Machado, Filipa; Rocha, Isabel; Geraldes, Vera; Outeiro, TiagoLead, a toxic heavy metal, is prevalent in various industrial applications, contributing to environmental contamination and significant health concerns. Lead affects various body systems, especially the brain, causing long-lasting cognitive and behavioral changes. While most studies have focused on continuous lead exposure, intermittent exposure, such as that caused by migration or relocations, has received less attention. Importantly, lead exposure intensifies the severity of Parkinson's disease (PD) and dementia with Lewy bodies, diseases involving the accumulation of alpha-synuclein (aSyn) in the brain and in the gut. Although the precise mechanisms underlying these observations remain unclear, oxidative stress and mitochondrial dysfunction likely play a role. Here, we investigated how two different profiles of lead exposure - continuous and intermittent - affect models of synucleinopathies. We found that lead exposure enhances the formation of aSyn inclusions, resulting in an increase in both their number and size in cell models. In addition, we found that animals injected with aSyn pre-formed fibrils display serine 129-phosphorylated aSyn inclusions and a reduction in astrocytes in the substantia nigra. These animals also display neuronal damage and alterations in locomotor activity, exploration behavior, anxiety, memory impairments and hypertension. Our results suggest a mechanistic link between environmental lead exposure and the onset and progression of diseases associated with aSyn pathology. Understanding the molecular and cellular interactions between lead and aSyn is crucial for shaping public health policies and may provide novel insight into strategies for mitigating the impact of environmental toxins on neurodegenerative processes involved in Parkinson's disease and related synucleinopathies.
- Lead in liver and kidney of exposed rats: aging accumulation studyPublication . Guimarães, Diana; Carvalho, Maria Luisa; Geraldes, Vera; Rocha, Isabel; Alves, Luís Cerqueira; Santos, José PauloThe concentration of lead in liver and kidneys of Wistar rats, fed with lead since fetal period in relation to their age and to a control group, was determined. A group of rats was exposed to lead acetate (n=30) in drinking water and the other group was exposed to normal water (n=20). Samples were collected from rats aging between 1 and 11 months and were analyzed by Energy Dispersive X-ray Fluorescence (EDXRF) without any chemical preparation. The EDXRF results were assessed by the PIXE (Proton Induced X-ray Emission) technique. The formaldehyde used to preserve the samples was also analyzed by ETAAS (Electro-Thermal Atomic Absorption Spectrometry) in order to verify if there was any loss of lead from the samples to the formaldehyde. We found that the loss was not significant (<2%). Concerning the mean values of the lead concentration measured in the contaminated soft tissues, in liver they range from 6 to 22μgg(-1), and in kidneys from 44 to 79μgg(-1). The control rats show, in general, values below the EDXRF detection limit (2μgg(-1)). The ratio kidney/liver ranges from 2 to 10 and is strongly positively correlated with the age of the animals. A Spearman correlation matrix to investigate the correlation between elemental concentrations and the dependence of these concentrations with age showed that there is a strong positive correlation with age for lead in the liver but not in the kidney. The correlation matrix showed also that the concentration of lead in these two soft tissues is not correlated. The lead accumulation in liver is made by different plateaus that strongly decrease with age. It was verified the existence of two levels of accumulation in kidney, not very highlighted, which might be indicative of a maximum accumulation level for lead in kidney.
- Acute vagal modulation of electrophysiology of the atrial and pulmonary veins increases vulnerability to atrial fibrillationPublication . Oliveira, Mario; da Silva, M. Nogueira; Geraldes, Vera; Xavier, Rita; Laranjo, Sergio; Silva, Vitor; Postolache, Gabriela; Ferreira, Rui; Rocha, IsabelVagal activity is thought to influence atrial electrophysiological properties and play a role in the initiation and maintenance of atrial fibrillation (AF). We evaluated the effects of acute vagal stimulation on atrial conduction, refractoriness of atrial and pulmonary veins (PVs) and inducibility of AF. An open-chest epicardial approach was performed in New Zealand White rabbits with preserved autonomic innervation. Atrial electrograms were obtained with four unipolar electrodes placed epicardially along the atria (n = 22) and an electrode adapted to the proximal left PV (n = 10). The cervical vagus nerve was stimulated with bipolar platinum electrodes (20 Hz). Epicardial activation was recorded in sinus rhythm, and effective refractory periods (ERPs), dispersion of refractoriness and conduction times from high-lateral right atrium (RA) to high-lateral left atrium (LA) and PVs assessed at baseline and during vagal stimulation. Burst pacing (50 Hz, 10 s), alone or combined with vagal stimulation, was applied to the right (RAA) and left atrial appendage (LAA) and PVs to induce AF. At baseline, ERPs were lower in PVs than in LA and LAA, but did not differ significantly from RA and RAA, and there was a significant delay in the conduction time from RA to PVs compared with the activation time from RA to LA (P < 0.01). During vagal stimulation, ERP decreased significantly at all sites, without significant differences in the dispersion of refractoriness, and the atrial conduction times changed from 39 ± 19 to 49 ± 9 ms (RA to PVs; n.s.) and from 14 ± 7 to 28 ± 12 ms (RA to LA; P = 0.01). Induction of AF was reproducible in 50% of cases with 50 Hz and in 82% with 50 Hz combined with vagal stimulation (P < 0.05). During vagal stimulation, AF cycle length decreased at all sites, and AF duration changed from 1.0 ± 0.9 to 14.0 ± 10.0 s (P < 0.01), with documentation of PV tachycardia in three cases. In 70% of the animals, AF ceased immediately after interruption of vagal stimulation. We conclude that in the intact rabbit heart, vagal activity prolongs interatrial conduction and shortens atrial and PV ERP, contributing to the vulnerability to the induction and maintenance of AF. This model may be useful in the assessment of the autonomic influence in the mechanisms underlying AF.
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