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.

Biomarkers in Hypertension and Hypertension-related Disorders.

Systemic arterial hypertension (SAH) is a major risk factor for several secondary diseases, especially cardiovascular and renal conditions. SAH has a high prevalence worldwide, and its precise and early recognition is important to prevent the development of secondary outcomes. In this field, the study of biomarkers represents an important approach to diagnosing and predicting the disease and its associated conditions. The use of biomarkers in hypertension and hypertension-related disorders, such as ischemic stroke, intracerebral hemorrhage, transient ischemic attack, acute myocardial infarction, angina pectoris and chronic kidney disease, are discussed in this review. Establishing a potential pool of biomarkers may contribute to a non-invasive and improved approach for their diagnosis, prognosis, risk assessment, therapy management and pharmacological responses to a therapeutic intervention to improve patients' quality of life and prevent unfavorable outcomes.

Linear and non-linear analysis of heart rate variability in HIV-positive patients on two different antiretroviral therapy regimens.

BACKGROUND: Cardiac autonomic dysfunction in HIV+ patients on different antiretroviral therapy (ART) regimens has been described. We aimed to characterize parameters of heart rate variability (HRV) and correlate with different classes of ART in HIV+ patients in three experimental conditions: rest, cold face, and tilt tests. METHODS: Cross-sectional study with three groups of age- and gender-matched individuals: group 1, 44 HIV+ patients undergoing combination therapy, with two nucleoside reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI); group 2, 42 HIV+ patients using two NRTI and protease inhibitors (PI's); and group 3, 35 healthy volunteers with negative HIV serology (control group). Autonomic function at rest and during cold face- and tilt-tests was assessed through computerized analysis of HRV, via quantification of time- and frequency domains by linear and non-linear parameters in the three groups. RESULTS: Anthropometric and clinical parameters were similar between both HIV groups, except CD4+ T lymphocytes, which were significantly lower in group 2 (p = 0.039). At baseline, time-domain linear HRV parameters, RMSSD and pNN50, and the correlation dimension, a non-linear HRV parameter (p < 0.001; p = 0.018; p = 0.019, respectively), as well as response of RMSSD to cold face test were also lower in the HIV+ group than in the control individuals (p < 0.001), while no differences among groups were detected in HRV parameters during the tilt test. CONCLUSIONS: Despite ART regimens, HIV+ patients presented lower cardiac vagal modulation than controls, whereas no difference was observed among the HIV groups, suggesting that higher cardiovascular risk linked to PIs may be associated with factors other than autonomic dysfunction.

Comparison of pulse wave analysis parameters by oscillometry in hypertensive diabetic and nondiabetic patients in a Brazilian outpatient care.

INTRODUCTION: Pulse wave analysis is an emerging approach that analyzes parameters comprising strong predictors of cardiovascular (CV) events and all-cause mortality, especially in patients with high CV risk based on established risk factors. This study used the oscillometric method, provided by the Mobil-o-Graph (PWA-EMI GmbH, Stolberg, Germany) device, to compare data regarding the pulse wave analysis parameters in hypertensive nondiabetic and diabetic patients. MATERIAL AND METHODS: In this cross-sectional study, 276 individuals were examined in the academic hypertension outpatient care unit of the Federal University of the Triângulo, in Mineiro, Brazil, from January to December 2016. The pulse wave analysis was performed by oscillometry, and its parameters were acquired from all patients. RESULTS: Of the 276 patients, 99 were diabetic and 177 nondiabetic. The mean systolic and pulse central blood pressure were significantly higher in diabetic patients than in nondiabetic patients (P = .008 and.0003, respectively). The mean peripheral systolic blood pressure and pulse pressure were also significantly higher in the diabetic group (P = .001 and P < .0001, respectively). The average pulse wave velocity (PWV, m/s) was 9.4 ±â€Š1.6 and 8.8 ±â€Š1.6 in the diabetic and nondiabetic groups, respectively (P = .003). CONCLUSION: The group of hypertensive diabetic patients had significantly higher central blood pressure, peripheral blood pressure, and PWV than the hypertensive nondiabetic patients. The patients with overlapping established CV risk factors presented values of the pulse wave analysis parameters consistent with higher central pressure and greater arterial stiffness.

T-Cell Immunophenotyping and Cytokine Production Analysis in Patients with Chagas Disease 4 Years after Benznidazole Treatment.

The major problem with Chagas disease is evolution of the chronic indeterminate form to a progressive cardiac disease. Treatment diminishes parasitemia but not clinical progression, and the immunological features involved are unclear. Here, we studied the clinical course and the immune response in patients with chronic-phase Chagas disease at 48 months after benznidazole treatment. Progression to the cardiac form of Chagas disease or its aggravation was associated with higher in vitro antigen-specific production of interferon gamma (IFN-γ) in patients with cardiac Chagas disease than in patients with the indeterminate form. Predominance of IFN-γ production over interleukin-10 (IL-10) production in antigen-specific cultures was associated with cardiac involvement. Significantly higher numbers of antigen-specific T helper 1 cells (T-Bet+ IFN-γ+) and a significantly higher IFN-γ+/IL-10+ ratio were observed in patients with cardiac Chagas disease than in patients with the indeterminate form. Cardiac damage was associated with higher numbers of T helper cells than cytotoxic T lymphocytes producing IFN-γ. Patients with cardiac Chagas disease had predominant CD25- and CD25low T regulatory (Treg) subpopulations, whereas patients with the indeterminate form manifested a higher relative mean percentage of CD25high Treg subpopulations. These findings suggest that at 48 months after benznidazole treatment, the disease can worsen or progress to the cardiac form. The progression may be related to increased IFN-γ production (mostly from CD4+ T cells) relative to IL-10 production and increased Treg percentages. Patients with the indeterminate form of Chagas disease show a more balanced ratio of proinflammatory and anti-inflammatory cytokines.

Effects of diabetes mellitus on myenteric neuronal density and sodium channel expression in the rat ileum.

Diabetes mellitus (DM) may lead to gastrointestinal motility disorders. Rodent models of DM indicate the presence of morpho-functional abnormalities of the enteric nervous system. Here, we evaluated whether experimental DM can cause changes in the excitatory cholinergic fibers, neuronal density, and voltage-gated sodium channel (Nav) expression in the myenteric plexus of the ileum. After streptozotocin-induced hyperglycemia in female rats progressed for eight weeks, triple immunofluorescence labeling experiments revealed that the neuronal density in DM rats was significantly lower than that in control. On average, the density of total neurons reduced by 52.2% (p = 0.0001), cholinergic neurons by 50.0% (p = 0.0068), and nitrergic neurons by 54.8% (p = 0.0042). The number of neurons per ganglionic area was also significantly reduced (to 28.2% of total neurons, p = 0.0002; 27.7% of cholinergic neurons, p = 0.0002, and 32.1% of nitrergic neurons, p = 0.0016). Furthermore, the density of the cholinergic fibers at the surface of the longitudinal muscle was significantly reduced (DM: 24 ±â€¯3%; p = 0.003, control: 41 ±â€¯2%); however, western-blot analysis did not indicate a reduction in the expression of choline acetyltransferase (ChAT) in the DM group. The Nav1.6 isoform was detected in different myenteric neurons of the ileum. RT-qPCR data did not suggest an alteration of transcripts for ChAT, neuronal nitric oxide synthase, Nav1.3, Nav1.6, or Nav1.7. Our data support the view that chronic DM leads to a reduction of excitatory cholinergic fibers and neuronal density. However, changes in sodium channel expression pattern, which could cause neuronal dysfunction, were not detected.

Reference values for short-term resting-state heart rate variability in healthy adults: Results from the Brazilian Longitudinal Study of Adult Health-ELSA-Brasil study.

Heart rate variability (HRV) is a psychophysiological phenomenon with broad implications, providing an accessible index of vagal function, underpinning psychological constructs, including the capacity for social engagement and emotion regulation, and may predict future morbidity and mortality. However, the lack of reference values for short-term HRV indices for participants of both sexes across the age spectrum is a limiting factor. This was the objective of the present study. Resting electrocardiographic records were obtained from 13,214 participants (both sexes, 35-74 years), and HRV indices in time and frequency domains (mean ± SD) were determined from 5-min records. Results were based on a subsample of 2,874 nonmedicated, healthy participants stratified by sex across 10-year age groupings. Men showed lower heart rate (HR, 64 ± 8 bpm vs. 68 ± 8 bpm, p < .05) and normalized high frequency (HF; 39.4 ± 18.0 normalized units [n.u.] vs. 50.4 ± 18.5 n.u., p < .05) than women, and higher N-N variance (2,214 ± 1,890 ms2 vs. 1,883 ± 1,635 ms2 , p < .05), standard deviation of all N-N intervals (SDNN; 43.7 ± 17.3 ms vs. 40.3 ± 15.8 ms, p < .05) and LF/HF (2.30 ± 2.68 vs. 1.33 ± 1.82, p < .05). HR and HF (n.u.) were also higher in younger than older women. LF/HF was lower in women than men. Percentile curves showed almost all HRV indices decreasing with aging. The availability of short-term, resting-state HRV reference values in a large sample of healthy and nonmedicated participants from 35-74 years will provide a valuable tool for researchers, clinicians, and those in the quantified-self community.

Exercise training improves hypertension-induced autonomic dysfunction without influencing properties of peripheral cardiac vagus nerve.

We examined the vagal transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained Spontaneously Hypertensive Rats (SHR). To this end, male SHR and Wystar-Kyoto (WKY) rats with 48-50weeks of age-old were divided into 4 groups: sedentary (SHRS, n=12) and trained (SHRT, n=14) hypertensive rats, sedentary (WKYS, n=13) and trained (WKYT, n=13) normotensive rats. The trained groups were submitted to swimming protocol for 9weeks. Blood pressure (BP), HR, HR variability (HRV), BP variability (BPV), baroreflex sensitivity and cardiac tonus were recorded in baseline conditions. Following, electric stimulation of peripheral vagus nerve was performed in anesthetized conditions. Resting bradycardia was observed in SHRT and WKYT when compared to their respective sedentary groups (p<0.001). The BP was lower in SHRT than in SHRS (p<0.001). The SHRT and WKYT rats showed higher baroreflex-mediated tachycardia values when compared to their respective sedentary counterparts (p<0.001). Baroreflex bradycardic response in SHRT was higher than in SHRS (p<0.005). The SHRT and WKYT rats showed a decreased sympathetic activity in comparison to their respective sedentary groups (p<0.05). The cardiac vagal tonus was higher in SHRT than in SHRS (p<0.05). Regarding the dynamic transducer properties of peripheral vagus nerve to the heart no difference was observed among the groups. In conclusion, our results demonstrate that exercise training decreased BP in SHR and improved cardiovascular autonomic balance to the heart without changes in transduction properties of peripheral cardiac vagus nerve.

Biological properties of cardiac mesenchymal stem cells in rats with diabetic cardiomyopathy.

Cardiomyopathy is a major outcome in patients with diabetes mellitus (DM) and contributes to the high morbidity/mortality observed in this disease. AIMS: To evaluate several biological properties of cardiac mesenchymal stem cells (cMSCs) in a rat model of streptozotocin-induced DM with concomitant diabetic cardiomyopathy. MAIN METHODS: After 10weeks of DM induction, diabetic and control rats were assessed using ECG and ventricular hemodynamics monitoring. Then, the hearts were excised and processed for histology and for extracting non-cardiomyocytic cells. A pool of these cells was plated for a colony forming units-fibroblasts (CFU-F) assay in order to estimate the number of cMSCs. The remaining cells were expanded to assess their proliferation rate as well as their osteogenic and adipogenic differentiation ability. KEY FINDINGS: DM rats presented intense hyperglycemia and changes in ECG, LV hemodynamic, cardiac mass index and fibrosis, indicating presence of DCM. The CFU-F assay revealed a higher number of cardiac CFU-Fs in DM rats (10.4±1.1CFU-F/105 total cells versus 7.6±0.7CFU-F/105 total cells in control rats, p<0.05), which was associated with a significantly higher proliferative rate of cMSCs in DM rats. In contrast, cMSCs from DM rats presented a lower capacity to differentiate into both osteogenic (20.8±4.2% versus 10.1±1.0% in control rats, p<0.05) and adipogenic lineages (4.6±1.0% versus 1.3±0.5% in control rats, p<0.05). SIGNIFICANCE: The findings suggest, for the first time, that in chronic DM rats with overt DCM, cMSCs increase in number and exhibit changes in several functional properties, which could be implicated in the pathogenesis of diabetic cardiomyopathy.

Comparison between symbolic and spectral analyses of short-term heart rate variability in a subsample of the ELSA-Brasil study.

Linear and nonlinear analyses of heart rate variability (HRV) have been largely used to evaluate the autonomic balance directed to the cardiovascular system. However, comparative studies evaluating the agreement between methods are scarce. Therefore, our aim was to examine the relationship between spectral (SPA; linear) and symbolic analyses (SYA; nonlinear) indexes. A subsample of 683 participants of the Brazilian Longitudinal Study of Adult Health was investigated. Linear and nonlinear analyses were obtained from 10 min ECG recording at rest. Reliability and agreement between methods were evaluated by kappa-statistic and proportion of agreement. According to SYA, the most frequent pattern was P1V (sympathovagal balance, without sympathetic or vagal predominance) comprising 62.7% of the sample, followed by P2V (vagal predominance) with 33.2%, and finally P0V pattern (sympathetic predominance) with 4.1%. Overall proportion of agreement between SYA and SPA was 39.68% (95% CI 0.360-0.433), with expected agreement by chance of 30.8%. Kappa value was 0.128 indicating a slight agreement between methods. Proportion of agreement was 7.93% (95% CI 0.032-0.126) for predominant sympathetic modulation, 10.39% (95% CI 0.075-0.132) for sympathovagal modulation, and 40.29% (95% CI 0.361-0.444) for parasympathetic modulation. Our data provide evidence for important differences between SPA and SYA on HRV analysis. More studies are needed to clarify the causes of disagreement between two methods designed to evaluate the autonomic modulation of heart beats.

Effects of cholinergic stimulation with pyridostigmine bromide on chronic chagasic cardiomyopathic mice.

The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido), on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con) or chronically infected (5 months) with Trypanosoma cruzi (chagasic:Chg) were treated or not (NT) with Pyrido for one month. At the end of this period, electrocardiogram (ECG); cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγ with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice.

Opposite effects of bone marrow-derived cells transplantation in MPTP-rat model of Parkinson's disease: a comparison study of mononuclear and mesenchymal stem cells.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model is a useful tool to study Parkinson's disease (PD) and was used in the present study to investigate the potential beneficial as well as deleterious effects of systemic bone-marrow mononuclear cell (BMMC) or mesenchymal stem cell (BM-MSC) transplantation. MPTP administration resulted in a breakdown of the blood-brain barrier and motor impairment in the open field test 24 h after surgery. Three and 7 days after receiving the lesion, the injured animals showed remaining motor impairment compared to the sham groups along with a significant loss of tyrosine hydroxylase-immunoreactive (TH-ir) cells in the substantia nigra pars compacta (SNpc). The MPTP-lesioned rats treated with BMMCs immediately after lesioning exhibited motor impairment similar to the MPTP-saline group, though they presented a significantly higher loss of TH-ir cells in the SNpc compared to the MPTP-saline group. This increased loss of TH-ir cells in the SNpc was not observed when BMMC transplantation was performed 24 h after MPTP administration. In contrast, in the MPTP animals treated early with systemic BM-MSCs, no loss of TH-ir cells was observed. BMMCs and BM-MSCs previously labeled with CM-DiI cell tracker were found in brain sections of all transplanted animals. In addition, cells expressing CD45, an inflammatory white blood cell marker, were found in all brain sections analyzed and were more abundant in the MPTP-BMMC animals. In these animals, Iba1+ microglial cells showed also marked morphological changes indicating increased microglial activation. These results show that systemic BMMC transplantation did not ameliorate or prevent the lesion induced by MPTP. Instead, BMMC transplantation in MPTP-lesioned rats accelerated dopaminergic neuronal damage and induced motor impairment and immobility behavior. These findings suggest that caution should be taken when considering cell therapy using BMMCs to treat PD. However, systemic BM-MSC transplantation that reaches the injury site and prevents neuronal damage after an MPTP infusion could be considered as a potential treatment for PD during the early stage of disease development.

Symptoms of anxiety and mood disturbance alter cardiac and peripheral autonomic control in patients with metabolic syndrome.

Previous investigations show that metabolic syndrome (MetSyn) causes sympathetic hyperactivation. Symptoms of anxiety and mood disturbance (AMd) provoke sympatho-vagal imbalance. We hypothesized that AMd would alter even further the autonomic function in patients with MetSyn. Twenty-six never-treated patients with MetSyn (ATP-III) were allocated to two groups, according to the levels of anxiety and mood disturbance: (1) with AMd (MetSyn + AMd, n = 15), and (2) without AMd (MetSyn, n = 11). Ten healthy control subjects were also studied (C, n = 10). AMd was determined using quantitative questionnaires. Muscle sympathetic nerve activity (MSNA, microneurography), blood pressure (oscillometric beat-to-beat basis), and heart rate (ECG) were measured during a baseline 10-min period. Spectral analysis of RR interval and systolic arterial pressure were analyzed, and the power of low (LF) and high (HF) frequency bands were determined. Sympatho-vagal balance was obtained by LF/HF ratio. Spontaneous baroreflex sensitivity (BRS) was evaluated by calculation of α-index. MSNA was greater in patients with MetSyn + AMd compared with MetSyn and C. Patients with MetSyn + AMd showed higher LF and lower HF power compared with MetSyn and C. In addition, LF/HF balance was higher in MetSyn + AMd than in MetSyn and C groups. BRS was decreased in MetSyn + AMd compared with MetSyn and C groups. Anxiety and mood disturbance alter autonomic function in patients with MetSyn. This autonomic dysfunction may contribute to the increased cardiovascular risk observed in patients with mood alterations.

Exercise-training reduced blood pressure and improve placental vascularization in pregnant spontaneously hypertensive rats--pilot study.

Assess the effects of exercise-training on resting arterial pressure and heart rate, placental fetuses morphologic alterations in pregnant spontaneously hypertensive rats (SHRs).Twenty SHRs and their respective control normotensive rats (WKY) were submitted or not to a swimming protocol during 9 weeks, resulting in four pregnant experimental groups: sedentary hypertensive (PSH), trained hypertensive (PTH), sedentary normotensive (PSN), and trained normotensive (PTN). Exercise-training by swimming attenuates arterial pressure in pregnant SHRs, and can contribute to an increase in the length of fetuses and the percentage of the vessels in the placenta.

Acute adenosine increases cardiac vagal and reduces sympathetic efferent nerve activities in rats.

Adenosine is the first drug of choice in the treatment of supraventricular arrhythmias. While the effects of adenosine on sympathetic nerve activity (SNA) have been investigated, no information is available on the effects on cardiac vagal nerve activity (VNA). We assessed in rats the responses of cardiac VNA, SNA and cardiovascular variables to intravenous bolus administration of adenosine. In 34 urethane-anaesthetized rats, cardiac VNA or cervical preganglionic sympathetic fibres were recorded together with ECG, arterial pressure and ventilation, before and after administration of three doses of adenosine (100, 500 and 1000 µg kg(-1)). The effects of adenosine were also assessed in isolated perfused hearts (n = 5). Adenosine induced marked bradycardia and hypotension, associated with a significant dose-dependent increase in VNA (+204 ± 56%, P < 0.01; +275 ± 120%, P < 0.01; and +372 ± 78%, P < 0.01, for the three doses, respectively; n = 7). Muscarinic blockade by atropine (5 mg kg(-1), i.v.) significantly blunted the adenosine-induced bradycardia (-56.0 ± 4.5%, P < 0.05; -86.2 ± 10.5%, P < 0.01; and -34.3 ± 9.7%, P < 0.01, respectively). Likewise, adenosine-induced bradycardia was markedly less in isolated heart preparations. Previous barodenervation did not modify the effects of adenosine on VNA. On the SNA side, adenosine administration was associated with a dose-dependent biphasic response, including overactivation in the first few seconds followed by a later profound SNA reduction. Earliest sympathetic activation was abolished by barodenervation, while subsequent sympathetic withdrawal was affected neither by baro- nor by chemodenervation. This is the first demonstration that acute adenosine is able to activate cardiac VNA, possibly through a central action. This increase in vagal outflow could make an important contribution to the antiarrhythmic action of this substance.

The relationship between heart rate variability and serum cytokines in chronic chagasic patients with persistent parasitemia.

BACKGROUND: Persistent parasitemia, immunological, and autonomic nervous system impairments may play an important role in the evolution and clinical outcome of the chronic phase of Chagas' disease by triggering functional cardiovascular changes. METHODS: Three groups were evaluated: 17 chronic chagasic patients with the indeterminate form (IChD), 12 chronic chagasic patients with cardiac forms (ChHD), and 29 individuals as a healthy control group. Parasitemia was assessed by polymerase chain reaction; hemoculture, heart rate variability by linear and nonlinear methods, and interleukin (IL)-1ß, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, and tumor necrosis factor-α, and interferon (IFN)-γ serum cytokines were assessed by enzyme-linked immune assay. RESULTS: Twenty-nine chronic chagasic patients were positive for parasitemia (17 IChD and 12 ChHD). Heart rate variability parameters in baseline condition and after cold face test were significantly decreased in chagasic patients compared to controls. Tilt tests showed no alteration. However, using nonlinear indices, ChHD patients presented lower values compared to IChD and controls. Differences in the expression of serum cytokines were observed between chagasic patients and controls. However, among the groups, ChHD presented higher median values of IL-10 and lower of IFN-γ compared to IChD. CONCLUSION: Both chagasic groups present an autonomic impairment using linear methods. The nonlinear methods revealed that the ChHD group had a higher cardiovascular risk. Serum cytokine concentrations between chagasic patients were similar. However, ChHD showed higher concentrations of IL-10 and lower of IFN-γ, suggesting some established process of immune regulation.

Genotoxic studies in hypertensive and normotensive rats treated with amiodarone.

Amiodarone, a benzofuran derivative, is a very effective antiarrhythmic medication, but has potential to cause side effects. Although its cytotoxicity potential is very well-known, there are few reports about its genotoxicity effects. Since amiodarone has not been investigated in genotoxicity studies, and the spontaneously hypertensive rat (SHR) is a well-characterized model for hypertension, the aim of the present study was to perform cytogenetic analysis on chromosome aberrations in bone marrow cells of SHRs and normotensive Wistar-Kyoto rats (WKYs) that received oral amiodarone treatment for 4 weeks. Amiodarone activity was also monitored using electrocardiograms. The presence of bradycardia in amiodarone-treated rats confirmed that this drug was really active. Metaphase analysis on bone marrow cells showed that there were significant differences in total chromosomal damage and percentage abnormal metaphase between WKY and SHR negative controls. In the SHR negative control, the frequencies of basal chromosomal aberrations and abnormal metaphases were significantly higher (p<0.05). There were high numbers of chromosomal aberrations in all amiodarone-treated groups, compared with negative controls. In amiodarone-treated groups, the most frequent chromosomal aberration was chromatid breaks. More chromosomal aberrations were found in WKYs that received amiodarone, with a statistically significant difference in comparison with negative controls (p<0.05). However, in SHR rats there was no significant difference between the amiodarone and negative groups regarding chromosomal damage induction. These results showed that treatment with amiodarone was genotoxic in WKYs, but not in SHRs. Further studies are needed to confirm whether amiodarone is genotoxic or efficient and harmless, among humans undergoing therapy.

Nitric oxide synthesis blockade increases hypertrophy and cardiac fibrosis in rats submitted to aerobic training.

OBJECTIVE: The objective of the present study was to evaluate cardiac tissue adaptations in rats submitted to aerobic training after nitric oxide (NO) synthesis blockade. METHODS: The animals (n=48) were divided into four groups: sedentary (CONTROL group); hypertensive after administration of NG-nitro-L-arginine methyl ester for 7 days (L-NAME Group); trained for 8 weeks through swimming exercises (TRAINED Group);trained and treated with L-NAME during the last week (L-NAME TRAINED Group). All the animals were submitted to the experiment procedures for blood pressure (BP) readings and cardiac morphometric evaluation. RESULTS: In comparison to the other groups, the L-NAME and L-NAME TRAINED groups were hypertensive (p<0.05); however, BP elevation in the L-NAME TRAINED group was significantly lower than the L-NAME group (p<0.05). The heart weight indexes for the TRAINED and L-NAME TRAINED groups were higher than the CONTROL and L-NAME groups (p<0.05). Also they had presented higher rates of macroscopic cardiac area and cardiac fibrosis in relation to the rest (p<0.05); comparisons revealed that the values for the L-NAME TRAINED group were significantly higher (p<0.05) than the others. CONCLUSION: Short term NO synthesis blockade in sedentary animals induced hypertension but did not cause cardiac hypertrophy. In the trained animals, the inhibition of NO synthesis attenuated hypertension, induced cardiac hypertrophy and significantly increased myocardial fibrosis, indicating that NO plays an important role in cardiac tissue adaptations caused by aerobic exercise.

O bloqueio da síntese do óxido nítrico promove aumento da hipertrofia e da fibrose cardíaca em ratos submetidos a treinamento aeróbio / Nitric oxide synthesis blockade increases hypertrophy and cardiac fibrosis in rats submitted to aerobic training

OBJETIVO: O presente estudo avaliou as adaptações teciduais cardíacas em ratos submetidos a treinamento aeróbio, após o bloqueio da síntese de óxido nítrico (NO). MÉTODOS: Os animais (n = 48) foram divididos em quatro grupos: sedentários (grupo CONTROLE), hipertensos após administração de Ng-nitro-L-arginina metil éster durante sete dias (grupo L-NAME), treinados por meio de natação durante oito semanas (grupo TREINADO) e treinados e tratados com L-NAME na última semana (grupo TREINADO L-NAME). Em todos os animais foi registrada a pressão arterial (PA) e realizada a avaliação morfométrica cardíaca. RESULTADOS: Os grupos L-NAME e TREINADO L-NAME apresentaram-se hipertensos em relação aos demais (p < 0,05), porém a elevação da PA no grupo TREINADO L-NAME foi significativamente menor em relação ao L-NAME (p < 0,05). Os grupos TREINADO e TREINADO L-NAME apresentaram índice de peso cardíaco maior que os grupos CONTROLE e L-NAME (p < 0,05). Também apresentaram maiores índices de área cardíaca macroscópica e de fibrose cardíaca em relação aos demais (p < 0,05) e, quando comparados, o grupo TREINADO L-NAME mostrou-se significativamente superior (p < 0,05). CONCLUSÃO: O bloqueio a curto prazo da síntese de NO, em animais sedentários, induziu hipertensão, sem no entanto causar hipertrofia cardíaca. Nos animais treinados, a inibição da síntese de NO atenuou a hipertensão e promoveu hipertrofia cardíaca com aumento expressivo da fibrose miocárdica, sugerindo importante papel do NO nas adaptações teciduais cardíacas induzidas pelo treinamento físico aeróbio.

OBJECTIVE: The objective of the present study was to evaluate cardiac tissue adaptations in rats submitted to aerobic training after nitric oxide (NO) synthesis blockade. METHODS: The animals (n=48) were divided into four groups: sedentary (CONTROL group); hypertensive after administration of NG-nitro-L-arginine methyl ester for 7 days (L-NAME Group); trained for 8 weeks through swimming exercises (TRAINED Group);trained and treated with L-NAME during the last week (L-NAME TRAINED Group). All the animals were submitted to the experiment procedures for blood pressure (BP) readings and cardiac morphometric evaluation. RESULTS: In comparison to the other groups, the L-NAME and L-NAME TRAINED groups were hypertensive (p<0.05); however, BP elevation in the L-NAME TRAINED group was significantly lower than the L-NAME group (p<0.05). The heart weight indexes for the TRAINED and L-NAME TRAINED groups were higher than the CONTROL and L-NAME groups (p<0.05). Also they had presented higher rates of macroscopic cardiac area and cardiac fibrosis in relation to the rest (p<0.05); comparisons revealed that the values for the L-NAME TRAINED group were significantly higher (p<0.05) than the others. CONCLUSION: Short term NO synthesis blockade in sedentary animals induced hypertension but did not cause cardiac hypertrophy. In the trained animals, the inhibition of NO synthesis attenuated hypertension, induced cardiac hypertrophy and significantly increased myocardial fibrosis, indicating that NO plays an important role in cardiac tissue adaptations caused by aerobic exercise.