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, IκB-α phosphorylation, TNF-α 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 + SHR group had decreased expression of HMGB1, CXCR4, SDF-1, and phosphorylation of p42/44 and IκB-α. 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.
Background:The effects of hypertension and exercise training (T) on the sequential interplay between renin-angiotensin system (RAS), autonomic control and heart remodeling during the development of ...hypertension in spontaneously hypertensive rats (SHR), was evaluated.Methods and Results:Time course changes of these parameters were recorded in 4-week-old SHR submitted to a T or sedentary (S) protocol. Wistar Kyoto rats served as controls. Hemodynamic recordings were obtained in conscious rats at experimental weeks 0, 1, 2, 4, and 8. The left ventricle (LV) was collected to evaluate RAS gene and protein expression, cardiomyocytes’ hypertrophy and collagen accumulation. Pre-hypertensive SHR exhibited augmented AT1R gene expression; at 5 weeks, they presented with elevated pressure, increased LV angiotensinogen and ACE mRNA expression, followed by sympathoexcitation (from the 8thweek onwards). Marked AT1R protein content, myocytes’s hypertrophy, collagen deposition and increased pressure variability were observed in 12-week-old sedentary SHR. In addition to attenuating all these effects, T activated Mas receptor expression augmented parasympathetic modulation of the heart, and delayed the onset and reduced the magnitude, but did not block the development of genetic hypertension.Conclusions:The close temporal relationship between changes in the LV ACE-Ang II-AT1R axis, autonomic control and cardiac remodeling at both the establishment of hypertension and during exercise training reveals the essential role played by the AT1R pathway in driving cardiac remodeling and autonomic modulation during the transition from the pre- to hypertensive phase.
Exercise training (T) blunts functional deficits and renin-angiotensin system (RAS) hyperactivity in hypertensive individuals. There is no information on T-induced temporal changes of brain RAS. We ...evaluate now the simultaneous effects of T on functional responses and time course changes in the expression/activity of brain RAS components in autonomic cardiovascular-controlling areas.
Spontaneously hypertensive rats (SHR) and age-matched normotensive controls (WKY) were trained for 0, 1, 2, 4, 8 and 12 weeks. Sedentary (S) groups served as time-controls. After arterial pressure (AP) and heart rate (HR) recordings at rest, fresh and fixed brains were harvested for qPCR and immunofluorescence assays. SHR-S vs. WKY-S exhibited higher mean AP (MAP) and HR, increased pressure variability and sympathetic activity, elevated AT1 receptor (AT1) expression in nucleus tractus solitarii (NTS) and higher Mas receptor expression in the rostroventrolateral medulla (RVLM). In SHR, T promptly (T2 on) reduced sympathetic variability to heart/vessels and largely decreased angiotensinogen expression in the paraventricular hypothalamic nucleus (PVN) and NTS, with a late RVLM reduction (T4). AT1 expression was only reduced at T12 (PVN and NTS) with transient, not maintained Mas receptor changes in PVN and RVLM. These responses were accompanied by baseline MAP and HR reduction in the SHR-T (from T4 on). In the SHR group, PVN angiotensinogen expression correlated positively with sympathetic activity, resting MAP and HR. In WKY-T, a precocious (T2-T12) RVLM AT1 decrease preceded the appearance of resting bradycardia (from T8 on).
Early and maintained reduction of angiotensinogen content in autonomic areas of the SHR is the most prominent effect of training on brain RAS. Down-regulation of PVN RAS expression is an essential factor to drive cardiovascular benefits in SHR-T, while resting bradycardia in WKY-T is correlated to RVLM AT1 reduction.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SUMMARY
1
The role of vasopressinergic and oxytocinergic (VPergic and OTergic, respectively) projections to the brain stem in the modulation of heart rate control is discussed on the basis of both ...changes in the peptide content of the dorsal brain stem (DBS) and functional effects following reflex‐ and exercise‐induced activation in the presence and/or absence of receptor blockade within the nucleus tractus solitarius (NTS) and/or peripheral autonomic block.
2
Experimental data showed a dual effect of NTS VPergic projections on reflex control: (i) to maintain tonically the reflex sensitivity; and (ii) to reset reflex bradycardia towards higher heart rate values when transiently activated. The VPergic drive causes less sympathetic inhibition during pressure increases, mainly by reducing peripheral information going to NTS second‐order neurons. Treadmill running increases the vasopressin content within the DBS. This activates NTS V1 receptors to cause a significant improvement of exercise tachycardia in both sedentary and trained rats.
3
The OTergic drive to DBS areas (NTS/dorsal motor nucleus of the vagus) is also tonic for baroreceptor reflex control: it improves reflex bradycardia by facilitating vagal outflow to the heart. An acute bout of exercise increases DBS oxytocin (OT) content in trained rats, causing a significant blunting of exercise tachycardia only in this group. In both sedentary and trained groups, basal heart rate varies inversely with DBS OT content, the resting bradycardia of trained rats being associated with higher OT content.
4
Specific coordinated activation of VPergic and OTergic suprabulbar pathways is essential to adjust heart rate and cardiac output to circulatory demand at rest and during exercise in both sedentary and trained individuals.
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BFBNIB, DOBA, FSPLJ, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The metabolic syndrome (MetS) is an obesity-associated disorder of pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered neural autonomic ...regulation, are important components and drivers of pathogenesis. Galantamine, an acetylcholinesterase inhibitor and a cholinergic drug that is clinically-approved (for Alzheimer's disease) has been implicated in neural cholinergic regulation of inflammation in several conditions characterized with immune and metabolic derangements. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS.
The effects of galantamine treatment, 8 mg daily for 4 weeks or placebo, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (
= 22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment.
Galantamine treatment significantly increased antioxidant enzyme activities, including SOD +1.65 USOD/mg protein, 95% CI 0.39-2.92,
= 0.004 and CAT +0.93 nmol/mg, 95% CI 0.34-1.51,
= 0.01, decreased lipid peroxidation thiobarbituric acid reactive substances log scale 0.72 pmol/mg, 95% CI 0.46-1.07,
= 0.05, and systemic nitrite levels log scale 0.83 μmol/mg protein, 95% CI 0.57-1.20,
= 0.04 compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment.
Low-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates neural autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with the cholinergic drug galantamine to ameliorate MetS.
Intrauterine growth restriction (IUGR) is associated with impaired vascular function, which contributes to the increased incidence of chronic disease. The aim of this study was to investigate whether ...aerobic training improves AngII-induced vasoconstriction in IUGR rats. Moreover, we assess the role of superoxide dismutase (SOD) isoforms and NADPH oxidase-derived superoxide anions in this improvement. Female Wistar rats were randomly divided into two groups on day 1 of pregnancy. A control group was fed standard chow ad libitum, and a restricted group was fed 50% of the ad libitum intake throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to 4 experimental groups: sedentary control (SC), trained control (TC), sedentary restricted (SRT), and trained restricted (TRT). The training protocol was performed on a treadmill and consisted of a continuous 60-min session 5 days/week for 10 weeks. Following aerobic training, concentration-response curves to AngII were obtained in endothelium-intact aortic rings. Protein expression of SOD isoforms, AngII receptors and the NADPH oxidase component p47phox was assessed by Western blot analysis. The dihydroethidium was used to evaluate the in situ superoxide levels under basal conditions or in the presence of apocynin, losartan or PD 123,319. Our results indicate that aerobic training can prevent IUGR-associated increases in AngII-dependent vasoconstriction and can restore basal superoxide levels in the aortic rings of TRT rats. Moreover, we observed that aerobic training normalized the increased p47phox protein expression and increased MnSOD and AT2 receptor protein expression in thoracic aortas of SRT rats. In summary, aerobic training can result in an upregulation of antioxidant defense by improved of MnSOD expression and attenuation of NADPH oxidase component p47phox. These effects are accompanied by increased expression of AT2 receptor, which provide positive effects against Ang II-induced superoxide generation, resulting in attenuation of AngII-induced vasoconstriction.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H+ buffering, regulation of Ca2+ transients ...and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1−/−) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1−/− resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1−/− resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca2+ peaks and slowed Ca2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca2+ handling and excitation-contraction coupling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Due to upward resetting of baroreceptors, tachycardia coexists with increased pressure during dynamic exercise. This review critically evaluates current knowledge of proposed mechanisms to explain ...the continuous resetting of baroreflex control of heart rate and sympathetic nerve activity during and after exercise and exercise training. Of interest is the exercise-induced upward resetting that occurs in hypertensive and normotensive individuals. Accumulated evidence indicates that not only somatosensory afferents, but also inputs from central command projecting to the nucleus tractus solitarius (NTS) in the dorsal brainstem may mediate inhibition of excitatory neurotransmission on barosensitive neurons. Specific coordinated activation of vasopressinergic and oxytocinergic projections to the NTS is essential to tonically maintain baroreflex sensitivity and to adjust heart rate and cardiac output to circulatory demand at rest and during exercise in both sedentary and trained individuals. These findings reinforce the paramount importance of the NTS in integration of cardiovascular control during exercise.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Knowing that exercise training reduces arterial pressure in hypertensive individuals and that pressure fall is accompanied by blockade of brain renin-angiotensin system, we sought to investigate ...whether training (T) affects central renin-angiotensin system. Spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto controls (WKY) were submitted to training or kept sedentary (S) for 3 months. After functional recordings, brain was removed and processed for autoradiography (brain stem sequential slices hybridized with S-oligodeoxynucleotide probes for angiotensinogen Aogen and angiotensin II type 1 AT1A receptors). Resting arterial pressure and heart rate were higher in SHRS (177±2 mm Hg, 357±12 bpm versus 121±1 mm Hg, 320±9 bpm in WKYS; P<0.05). Training was equally effective to enhance treadmill performance and to cause resting bradycardia (−10%) in both groups. Training-induced blood pressure fall (−6.3%) was observed only in SHRT. In SHRS (versus WKYS) AT1A and Aogen mRNA expression were significantly increased within the NTS and area postrema (average of +67% and +41% for AT1A and Aogen, respectively; P<0.05) but unchanged in the gracilis nucleus. Training did not change AT1A expression but reduced NTS and area postrema Aogen mRNA densities specifically in SHRT (P<0.05 versus SHRS, with values within the range of WKY groups). In SHRs, NTS Aogen mRNA expression was correlated with resting pressure (y=5.95x +41; r=0.55; P<0.05), with no significant correlation in the WKY group. Concurrent training-induced reductions of both Aogen mRNA expression in brain stem cardiovascular-controlling areas and mean arterial pressure only in SHRs suggest that training is as efficient as the renin-angiotensin blockers to reduce brain renin-angiotensin system overactivity and to decrease arterial pressure.
Aging is accompanied by considerable deterioration of homeostatic systems, such as autonomic imbalance characterized by heightened sympathetic activity, lower parasympathetic tone, and depressed ...heart rate (HR) variability, which are aggravated by hypertension. Here, we hypothesized that these age-related deficits in aged hypertensive rats can be ameliorated by exercise training, with benefits to the cardiovascular system. Therefore, male 22-mo-old spontaneously hypertensive rats (SHRs) and age-matched Wistar Kyoto (WKY) submitted to moderate-intensity exercise training (T) or kept sedentary (S) for 8 wk were evaluated for hemodynamic/autonomic parameters, baroreflex sensitivity, cardiac sympathetic/parasympathetic tone and analysis of dopamine β-hydroxylase (DBH+) and oxytocin (OT+) pathways of autonomic brain nuclei. Aged SHR-S versus WKY-S exhibited elevated mean arterial pressure (MAP: +51%) and HR (+20%), augmented pressure/HR variability, no cardiac vagal tone, and depressed reflex control of the heart (HR range, -28%; gain, -49%). SHR-T exhibited a lower resting HR, a partial reduction in the MAP (-14%), in the pressure/HR variabilities, and restored parasympathetic modulation, with improvement of baroreceptor reflex control when compared with SHR-S. Exercise training increased the ascending DBH+ projections conveying peripheral information to the paraventricular nucleus of hypothalamus (PVN), augmented the expression of OT+ neurons, and reduced the density of DBH+ neurons in the rostral ventrolateral medulla (RVLM) of SHR-T. Data indicate that exercise training induces beneficial neuroplasticity in brain autonomic circuitry, and it is highly effective to restore the parasympathetic tone, and attenuation of age-related autonomic imbalance and baroreflex dysfunction, thus conferring long-term benefits for cardiovascular control in aged hypertensive individuals.
Exercise training reduces high blood pressure and cardiovascular autonomic modulation in aged hypertensive rats. The dysfunction in the baroreflex sensitivity and impaired parasympathetic tone to the heart of aged hypertensive rats are restored by exercise training. Exercise induces beneficial neuroplasticity in the brain nuclei involved with autonomic control of cardiovascular function of aged hypertensive rats.
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