Influence of Aerobic Training on the Reduced Vasoconstriction to Angiotensin II in Rats Exposed to Intrauterine Growth Restriction: Possible Role of Oxidative Stress and AT(2) Receptor of Angiotensin II

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 p47(phox) 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 p47(phox) protein expression and increased MnSOD and AT(2) 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 p47(phox). These effects are accompanied by increased expression of AT(2) receptor, which provide positive effects against Ang II-induced superoxide generation, resulting in attenuation of AngII-induced vasoconstriction.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Sch Med, Div Nephrol, São Paulo, BrazilUniv São Paulo, Dept Pharmacol, São Paulo, BrazilUniv São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Sci & Technol Inst, São Paulo, BrazilUniversidade Federal de São Paulo, Sch Med, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Sch Med, Div Nephrol, São Paulo, BrazilUniversidade Federal de São Paulo, Sci & Technol Inst, São Paulo, BrazilUniversidade Federal de São Paulo, Sch Med, Dept Physiol, São Paulo, BrazilFAPESP: 2007/58044-2FAPESP: 2010/51904-9Web of Scienc

Early Training-Induced Reduction of Angiotensinogen in Autonomic Areas-The Main Effect of Exercise on Brain Renin-Angiotensin System in Hypertensive Rats.

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

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

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

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

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

Baroreceptor-mediated activation of sympathetic nerve activity to salivary glands

Salivary gland function is regulated by both the sympathetic and parasympathetic nervous systems. Previously we showed that the basal sympathetic outflow to the salivary glands (SNA(SG)) was higher in hypertensive compared to normotensive rats and that diabetes reduced SNA(SG) discharge at both strains. In the present study we sought to investigate how SNA(SG) might be modulated by acute changes in the arterial pressure and whether baroreceptors play a functional role upon this modulation. To this end, we measured blood pressure and SNA(SG) discharge in Wistar-Kyoto rats (WRY-intact) and in WRY submitted to sinoaortic denervation (WRY-SAD). We made the following three major observations: (i) in WRY-intact rats, baroreceptor loading in response to intravenous infusion of the phenylephrine evoked an increase in SNA(SG) spike frequency (81%, p<0.01) accompanying the increase mean arterial pressure ((sic)MAP: +77 +/- 14 mmHg); (ii) baroreceptor unloading with sodium nitroprusside infusion elicited a decrease in SNA(SG) spike frequency (17%, p<0.01) in parallel with the fall in arterial blood pressure ((sic)MAP: 30 3 mmHg) in WRY-intact rats; iii) in the WRY-SAD rats, phenylephrine-evoked rises in the arterial pressure ((sic)MAP: +56 +/- 6 mmHg) failed to produce significant changes in the SNA(SG) spike frequency. Taken together, these data show that SNA(SG) increases in parallel with pharmacological-induced pressor response in a baroreceptor dependent way in anaesthetised rats. Considering the key role of SNA(SG) in salivary secretion, this mechanism, which differs from the classic cardiac baroreflex feedback loop, strongly suggests that baroreceptor signalling plays a decisive role in the regulation of salivary gland function. (C) 2012 Elsevier Inc. All rights reserved.Sao Paulo Foundation State for Research (FAPESP) [07/50554-1, 07/04085-0]FAPESP (Sao Paulo State Foundation for Research)FAPESP fellowship [09/16502-0]FAPESP fellowshi

Training-induced changes on Angiotensin II type 1 receptor (AT₁, <i>panels A</i>, <i>B and C</i>) and Mas receptor (<i>panels D</i>, <i>E and F</i>) mRNA expression in brain autonomic areas.

<p>Graphs show sequential changes within the PVN (panels <b>A</b> and <b>D</b>), NTS (panels <b>B</b> and <b>E</b>) and RVLM (panels <b>C</b> and <b>F</b>) of sedentary (S) and trained (T) WKY and SHR. (<i>n</i> = 5–8 rats/subgroup). Significances (P<0.05): * <i>vs</i> WKY, † <i>vs</i> S; ● <i>vs</i> week 0.</p

Photomicrographs illustrating the expression of angiotensinogen (Aogen, panel A), AT₁ (panel B) and Mas Receptor (panel C) within the PVN (upper panels), RVLM (center panels) and NTS (lower panels) in sedentary SHR at the beginning of protocols.

<p>Double staining for the RAS precursor and receptors (green) and neuN (red). In each pair of pictures, the right represents an amplification of dashed rectangle on the left. In all areas observe neuronal and extra-neuronal expression of precursor and receptors.</p

Values of pressure variability (SAP var), heart rate variability (PI var) and respective spectral components at the beginning (week 0) and the end (week 12) of protocols in sedentary (S) and trained (T) WKY and SHR.

<p>Values are means±SEM. Three-way factorial ANOVA. Significances (P<0.05): * <i>vs</i> WKY; † <i>vs</i> S; ● <i>vs</i> week 0.</p><p>Values of pressure variability (SAP var), heart rate variability (PI var) and respective spectral components at the beginning (week 0) and the end (week 12) of protocols in sedentary (S) and trained (T) WKY and SHR.</p

Training-induced changes on angiotensinogen (Aogen) expression in brain autonomic areas.

<p>Graphs show the sequential changes of Aogen mRNA expression within the PVN, NTS and RVLM of sedentary (S) and trained (T) WKY and SHR (<i>n</i> = 5–7 rats/subgroup). Significances (P<0.05): † <i>vs</i> S; ● <i>vs</i> week 0.</p