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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To investigate whether the manipulation of brain excitability by transcranial direct current stimulation (tDCS) modulates the heart rate variability (HRV), the effect of tDCS applied at rest on the left temporal lobe in athletes (AG) and non-athletes (NAG) was evaluated. The HRV parameters (natural logarithms of LF, HF, and LF/HF) was assessed in 20 healthy men before, and immediately after tDCS and sham stimulation. After anodal tDCS in AG the parasympathetic activity (HF(log)) increased (P<0.01) and the sympathetic activity (LF(log)) and sympatho-vagal balance (LF/HF(log)) decreased (P<0.01), whereas no significant effects were detected in NAG (P>0.05). No significant changes in HRV indexes were provoked by sham stimulation in both AG and NAG (P>0.05). In conclusion, tDCS applied on the left temporal lobe significantly increased the overall HRV in AG, enhancing the parasympathetic and decreasing the sympathetic modulation of heart rate. Consequently the sympatho-vagal balance decreased at rest in AG but not in NAG. Releasing a weak electric current to stimulate selected brain areas may induce favorable effects on the autonomic control to the heart in highly fit subjects.

In the present study we evaluated the effects of short-term pyridostigmine bromide (0.14 mg/mL) treatment started early after myocardial infarction (MI) on left ventricular (LV) and autonomic functions in rats. Male Wistar rats were divided into control, pyridostigmine, infarcted and infarcted + pyridostigmine-treated groups. Pyridostigmine was administered in the drinking water, starting immediately after MI or sham operation, for 11 days. Left ventricular function was evaluated indirectly by echocardiography and directly by LV catheterization. Cardiovascular autonomic control was evaluated by baroreflex sensitivity (BRS), heart rate variability (HRV) and pharmacological blockade. All evaluations started after 7 days pyridostigmine treatment and were finalized after 11 days treatment. Pyridostigmine prevented the impairment of +dP/dT and reduced the MI area in infarcted + pyridostigmine compared with infarcted rats (7 ± 3% vs 17 ± 4%, respectively). Mean blood pressure was restored in infarcted + pyridostigmine compared with infarcted rats (103 ± 3 vs 94 ± 3 mmHg, respectively). In addition, compared with the infarcted group, pyridostigmine improved BRS, as evaluated by tachycardic (1.6 ± 0.2 vs 2.5 ± 0.2 b.p.m./mmHg, respectively) and bradycardic (-0.42 ± 0.01 vs -1.9 ± 0.1 b.p.m./mmHg) responses, and reduced the low frequency/high frequency ratio of HRV (0.81 ± 0.11 vs 0.24 ± 0.14, respectively). These improvements are probably associated with increased vagal tone and reduced sympathetic tone in infarcted + pyridostigmine compared with infarcted rats. In conclusion, the data suggest that short-term pyridostigmine treatment started early after MI can improve BRS, HRV and parasympathetic and sympathetic tone in experimental rats. These data may have potential clinical implications because autonomic markers have prognostic significance after MI.

The study investigated the heart rate (HR) and heart rate variability (HRV) before, during, and after stretching exercises performed by subjects with low flexibility levels. Ten men (age: 23 ± 2 years; weight: 82 ± 13 kg; height: 177 ± 5 cm; sit-and-reach: 23 ± 4 cm) had the HR and HRV assessed during 30 minutes at rest, during 3 stretching exercises for the trunk and hamstrings (3 sets of 30 seconds at maximum range of motion), and after 30 minutes postexercise. The HRV was analyzed in the time ('SD of normal NN intervals' [SDNN], 'root mean of the squared sum of successive differences' [RMSSD], 'number of pairs of adjacent RR intervals differing by >50 milliseconds divided by the total of all RR intervals' [PNN50]) and frequency domains ('low-frequency component' [LF], 'high-frequency component' [HF], LF/HF ratio). The HR and SDNN increased during exercise (p < 0.03) and decreased in the postexercise period (p = 0.02). The RMSSD decreased during stretching (p = 0.03) and increased along recovery (p = 0.03). At the end of recovery, HR was lower (p = 0.01), SDNN was higher (p = 0.02), and PNN50 was similar (p = 0.42) to pre-exercise values. The LF increased (p = 0.02) and HF decreased (p = 0.01) while stretching, but after recovery, their values were similar to pre-exercise (p = 0.09 and p = 0.3, respectively). The LF/HF ratio increased during exercise (p = 0.02) and declined during recovery (p = 0.02), albeit remaining higher than at rest (p = 0.03). In conclusion, the parasympathetic activity rapidly increased after stretching, whereas the sympathetic activity increased during exercise and had a slower postexercise reduction. Stretching sessions including multiple exercises and sets acutely changed the sympathovagal balance in subjects with low flexibility, especially enhancing the postexercise vagal modulation.

Background & PurposeToll-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 approachOur 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 ResultsAcute 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 & ImplicationsTLR4 signaling promotes autonomic dysfunction, inflammation and microglia activation, through neuronal ER stress, in the PVN.

Masson GS, Nair AR, Silva Soares PP, Michelini LC, Francis J. Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR. Am J Physiol Heart Circ Physiol 309: H1115-H1122, 2015. First published August 7, 2015; doi:10.1152/ajpheart.00349.2015.-Exercise training (ExT) is recommended to treat hypertension along with pharmaceutical antihypertensive therapies. Effects of ExT in hypothalamic content of high mobility box 1 (HMGB1) and microglial activation remain unknown. We examined whether ExT would decrease autonomic and cardiovascular abnormalities in spontaneously hypertensive rats (SHR), and whether these effects were associated with decreased HMGB1 content, microglial activation, and inflammation in the hypothalamic paraventricular nucleus (PVN). Normotensive Wistar-Kyoto (WKY) rats and SHR underwent moderate-intensity ExT for 2 wk. After ExT, cardiovascular (heart rate and arterial pressure) and autonomic parameters (arterial pressure and heart rate variability, peripheral sympathetic activity, cardiac vagal activity, and baroreflex function) were measured in conscious and freely-moving rats through chronic arterial and venous catheterization. Cerebrospinal fluid, plasma, and brain were collected for molecular and immunohistochemistry analyses of the PVN. In addition to reduced heart rate variability, decreased vagal cardiac activity and increased mean arterial pressure, heart rate, arterial pressure variability, cardiac, and vasomotor sympathetic activity, SHR had higher HMGB1 protein expression, IB-␣ phosphorylation, TNF-␣ and IL-6 protein expression, and microglia activation in the PVN. These changes were accompanied by higher plasma and cerebrospinal fluid levels of HMGB1. The ExT ϩ SHR group had decreased expression of HMGB1, CXCR4, SDF-1, and phosphorylation of p42/44 and IB-␣. ExT reduced microglial activation and proinflammatory cytokines content in the PVN, and improved autonomic control as well. Data suggest that training-induced downregulation of activated HMGB1/CXCR4/microglia/proinflammatory cytokines axis in the PVN of SHR is a prompt neural adaptation to counterbalance the deleterious effects of inflammation on autonomic control. exercise training; baroreflex; brain inflammation; CXCR4; hypertension NEW & NOTEWORTHY Spontaneously hypertensive rats have increased HMGB1 content and CXCR4 signaling in the hypothalamic paraventricular nucleus, which contributes to microglial activation, proinflammatory cytokines production, and, finally, to autonomic dysfunction. Aerobic training decreases HMGB1 content, microglia activation and proinflammatory cytokines expression by inhibiting HMGB1-CXCR4 signaling pathway in the hypothalamic paraventricular nucleus. Aerobic training induces neuroinflammatory adaptations and autonomic benefits independent of the arterial pressure fall.AUTONOMIC DYSFUNCTION is defined as a misbalance between sympathetic and vagal activity associated with baroreflex dysfunction and increased a...

BACKGROUND:The respiratory pattern is often modified or even blocked during flexibility exercises, but little is known about the cardiovascular response to concomitant stretching and the Valsalva maneuver (VM) in healthy subjects.OBJECTIVES:This study evaluated the heart rate (HR), systolic blood pressure (SBP), and rate-pressure product (RPP) during and after large and small muscle group flexibility exercises performed simultaneously with the VM.METHODS:Asymptomatic volunteers (N  =  22) with the following characteristics were recruited: age, 22 ± 3 years; weight, 73 ± 6 kg; height, 175 ± 5 cm; HR at rest, 66 ± 9 BPM; and SBP at rest, 113 ± 10 mmHg. They performed two exercises: four sets of passive static stretching for 30 s of the dorsi-flexion (DF) of the gastrocnemius and the hip flexion (HF) of the ischio-tibialis. The exercises were performed with (V+) or without (V-) the VM in a counterbalanced order. The SBP and HR were measured, and the RPP was calculated before the exercise session, at the end of each set, and during a 30-min post-exercise recovery period.RESULTS:The within-group comparisons showed that only the SBP and RPP increased throughout the sets (p<0.05), but no post-exercise hypotension was detected. The between-group comparisons showed that greater SBP increases were related to the VM and to a larger stretched muscle mass. Differences for a given set were identified for the HR (the HFV+ and HFV- values were higher than the DFV+ and DFV- values by approximately 12 BPM), SBP (the HFV+ value was higher than the DFV+ and DFV- values by approximately 12 to 15 mmHg), and RPP (the HFV+ value was higher than the HFV- value by approximately 2000 mmHGxBPM, and the HFV+ value was higher than the DFV+ and DFV- values by approximately 4000 mmHGxBPM).CONCLUSION:Both the stretched muscle mass and the VM influence acute cardiovascular responses to multiple-set passive stretching exercise sessions.