Endogenous hydrogen peroxide in the hypothalamic paraventricular nucleus regulates sympathetic nerve activity responses to L-glutamate.

Endogenous hydrogen peroxide in the hypothalamic paraventricular nucleus regulates sympathetic nerve activity responses to L-glutamate. J Appl Physiol 113: 1423?1431, 2012. First published September 13, 2012; doi:10.1152/japplphysiol.00912.2012.?The hypothalamic paraventricular nucleus (PVN) is important for maintenance of sympathetic nerve activity (SNA) and cardiovascular function. PVNmediated increases of SNA often involve the excitatory amino acid L-glutamate (L-glu), whose actions can be positively and negatively modulated by a variety of factors, including reactive oxygen species. Here, we determined modulatory effects of the highly diffusible reactive oxygen species hydrogen peroxide (H2O2) on responses to PVN L-glu. Renal SNA (RSNA), arterial blood pressure, and heart rate were recorded in anesthetized rats. L-Glu (0.2 nmol in 100 nl) microinjected unilaterally into PVN increased RSNA (P 0.05), without affecting mean arterial blood pressure or heart rate. Effects of endogenously generated H2O2 were determined by comparing responses to PVN L-glu before and after PVN injection of the catalase inhibitor 3-amino-1,2,4-triazole (ATZ; 100 nmol/200 nl, n 5). ATZ alone was without effect on recorded variables, but attenuated the increase of RSNA elicited by PVN L-glu (P 0.05). PVN injection of exogenous H2O2 (5 nmol in 100 nl, n 4) and vehicle (artificial cerebrospinal fluid) were without affect, but H2O2, like ATZ, attenuated the increase of RSNA to PVN L-glu (P 0.05). Tonic effects of endogenous H2O2 were determined by PVN injection of polyethylene glycol-catalase (1.0 IU in 200 nl, n 5). Whereas polyethylene glycol-catalase alone was without effect, increases of RSNA to subsequent PVN injection of L-glu were increased (P 0.05). From these data, we conclude that PVN H2O2 tonically, but submaximally, suppresses RSNA responses to L-glu, supporting the idea that a change of H2O2 availability within PVN could influence SNA regulation under physiological and/or disease conditions

Central antioxidant therapy inhibits parasympathetic baroreflex control in conscious rats.

Baroreceptor reflex is an important system for neural control of blood pressure. Recently, reactive oxygen species (ROS) have been shown to play an important role in neuronal activity of central areas related to blood pressure control. The aim of this study was to investigate the effects elicited by ascorbic acid (AAC) and N-acetylcysteine (NAC) injections into the 4thV on the parasympathetic component of the baroreflex. Male Wistar rats were implanted with a stainless steel guide cannula into the 4thV. One day prior to the experiments, the femoral artery and vein were cannulated for pulsatile arterial pressure, mean arterial pressure and heart rate measurements and drug administration, respectively. After baseline recordings, the baroreflex was tested with a pressor dose of phenylephrine (PHE, 3_g/kg, i.v.) and a depressor dose of sodium nitroprusside (SNP, 30_g/kg, i.v.) before (control) and 5, 15, 30 and 60 min after AACorNACinto the 4thV. ControlPHEinjection induced baroreflex-mediated bradycardia (?93?13 bpm, n = 7). Interestingly, after AAC injection into the 4thV, PHE injection produced a transient tachycardia at 5 (40?23 bpm), 15 (26?22 bpm) and 30 min (59?21 bpm). No changes were observed in baroreflexmediated tachycardia evoked by SNP after AAC injection on 4thV (control: 151?23bpm vs. 135?18bpm at 5 min after AAC, n = 7). In the NAC treated group, PHE induced a reduction in reflex bradycardia at 5 min when compared to control (?11?17bpm vs. ?83?15 bpm, n = 7). No changes were observed in baroreflex-mediated tachycardia evoked by SNP after NAC injection on 4thV. The antioxidants AAC and NAC may act in the central nervous system affecting the parasympathetic component of the cardiac baroreflex

Maternal high-fat diet triggers metabolic syndrome disorders that are transferred to first and second offspring generations.

A high-fat (H) diet increases metabolic disorders in offspring. However, there is great variability in the literature regarding the time of exposure, composition of the H diets offered to the genitors and/or offspring and parameters evaluated. Here, we investigated the effect of a H diet subjected to the genitors on different cardio-metabolic parameters on first (F1)- and second (F2)-generation offspring. Female Fischer rats, during mating, gestation and breast-feeding, were subjected to the H diet (G0HF) or control (G0CF) diets. Part of F1 offspring becomes G1 genitors for generating the F2 offspring. After weaning, F1 and F2 rats consumed only the C diet. Nutritional, biometric, biochemical and haemodynamic parameters were evaluated. G0HF genitors had a reduction in food intake but energy intake was similar to the control group. Compared with the control group, the F1H and F2H offspring presented increased plasma leptin, insulin and fasting glucose levels, dietary intake, energy intake, adiposity index, mean arterial pressure, sympathetic drive evidenced by the hexamethonium and insulin resistance. Our data showed that only during mating, gestation and breast-feeding, maternal H diet induced cardio-metabolic disorders characteristic of human metabolic syndrome that were transferred to both females and males of F1 and F2 offspring, even if they were fed control diet after weaning. This process probably occurs due to the disturbance in mechanisms related to leptin that increases energy intake in F1H and F2H offspring. The present data reinforce the importance of balanced diet during pregnancy and breast-feeding for the health of the F1 and F2 offspring

Cardiopulmonary reflex and blood pressure response after swimming and treadmill exercise in hypertensive rats.

Cardiopulmonary sensitivity was evaluated after exercise training through swimming and running in spontaneously hypertensive rats (SHR) that were divided into three groups: (a) run exercise; (b) swim exercise; and (c) sedentary. For 8 wks, the run exercise was performed on a treadmill while the swim exercise was performed by swimming. Cardiopulmonary reflex was evaluated by chemical and mechanical pathways through the injections of phenylbiguanide (PBG) (5.0 mg?kg-1) and volume expansion with isotonic saline (0.75% of body weight), respectively. Both types of exercise training decreased systolic blood pressure (SBP) compared to the sedentary group. The swim trained group reduced SBP faster than the run trained group. The sensitivity of the chemically activated endings of the cardiopulmonary reflex was increased in both exercise-trained groups for hypotensive response. The exercise training groups had higher levels of urine output after acute volume expansion. The production of urine showed that swimming and treadmill training were more efficient than the sedentary group. These results indicate that: (a) exercise improved cardiopulmonary reflex sensitivity; and (b) swim training led to a faster SBP reduction and a more sensitive reflex response to pressure stimuli

Baroreflex function in conscious rats submitted to iron overload.

Our hypothesis is that iron accumulated in tissue, rather than in serum, may compromise cardiovascular control. Male Fischer 344 rats weighing 180 to 220 g were divided into 2 groups. In the serum iron overload group (SIO, N = 12), 20 mg elemental iron was injected ip daily for 7 days. In the tissue iron overload group (TIO, N = 19), a smaller amount of elemental iron was injected (10 mg, daily) for 5 days followed by a resting period of 7 days. Reflex heart rate responses were elicited by iv injections of either phenylephrine (0.5 to 5.0 ?g/kg) or sodium nitroprusside (1.0 to 10.0 ?g/kg). Baroreflex curves were determined and fitted to sigmoidal equations and the baroreflex gain coefficient was evaluated. To evaluate the role of other than a direct effect of iron on tissue, acute treatment with the iron chelator deferoxamine (20 mg/kg, iv) was performed on the TIO group and the baroreflex was re-evaluated. At the end of the experiments, evaluation of iron levels in serum confirmed a pronounced overload for the SIO group (30-fold), in contrast to the TIO group (2-fold). Tissue levels of iron, however, were higher in the TIO group. The SIO protocol did not produce significant alterations in the baroreflex curve response, while the TIO protocol produced a nearly 2-fold increase in baroreflex gain (-4.34 ? 0.74 and -7.93 ? 1.08 bpm/mmHg, respectively). The TIO protocol animals treated with deferoxamine returned to sham levels of baroreflex gain (-3.7 ? 0.3 sham vs -3.6 ? 0.2 bpm/mmHg) 30 min after the injection. Our results indicate an effect of tissue iron overload on the enhancement of baroreflex sensitivity

Cardiovascular responses to L-glutamate microinjection into the NTS are abrogated by reduced glutathione.

Redox imbalance in regions of the CNS controlling blood pressure is increasingly recognized as a leading factor for hypertension. Nucleus tractus solitarius (NTS) of the dorsomedial medulla is the main region receiving excitatory visceral sensory inputs that modulate autonomic efferent drive to the cardiovascular system. This study sought to determine the capacity of reduced glutathione, a major bioactive antioxidant, to modulate NTS-mediated control of cardiovascular function in unanaesthetized rats. Male Fischer 344 rats were used for microinjection experiments. Cardiovascular responses to l-glutamate were first used to verify accurate placement of injections into the dorsomedial region comprising the NTS. Next, responses to GSH or vehicle were recorded followed by responses to l-glutamate again at the same site. GSH microinjection increased mean arterial pressure (MAP) compared to vehicle and abrogated responses to subsequent injection of l-glutamate. These data indicate that GSH microinjection into the NTS affects blood pressure regulation by dorsomedial neuronal circuits and blunts l-glutamate driven excitation in this region. These findings raise the possibility that increased antioxidant actions of GSH in NTS could contribute to autonomic control dysfunctions of the cardiovascular system

Changes in cardiovascular responses to chemoreflex activation of rats recovered from protein restriction are not related to AT1 receptors.

The effects of a low-protein diet followed by recovery on cardiorespiratory responses to peripheral chemoreflex activation were tested before and after systemic angiotensin II type 1 (AT1) receptor antagonism. Male Fischer rats were divided into control and recovered (R-PR) groups after weaning. The R-PR rats were fed a low-protein (8%) diet for 35 days and recovered with a normal protein (20%) diet for 70 days. Control rats received a normal protein diet for 105 days (CG105). After cannulation surgery, mean arterial pressure, heart rate, respiratory frequency, tidal volume and minute ventilation were acquired using a digital recording system in freely moving rats. The role of angintensin II was evaluated by systemic antagonism of AT1 receptors with losartan (20mg kg?1 i.v.). The peripheral chemoreflex was elicited by increasing doses of KCN (20?160 ?g kg min?1, i.v.). At baseline, R-PR rats presented increased heart rate and minute ventilation (372 ? 34 beats min?1 and 1.274 ? 377 ml kg?1 min?1) compared with CG105 animals (332?22 beatsmin?1 and 856?112 ml kg?1 min?1).Mean arterial pressure was not different between the groups.Pressor andbradycardic responses evokedbyKCN(60?gkg?1) were increased in R-PR (+45?13mmHgand?77?47 beatsmin?1) comparedwithCG105 rats (+25 ? 17 mmHg and ?27 ? 28 beats min?1), but no difference was found in the tachypnoeic response. These differences were preserved after losartan. The data suggest that angiotensin II acting on AT1 receptors may not be associated with the increased heart rate, increased minute ventilation and acute cardiovascular responses to peripheral chemoreflex activation in rats that underwent postweaning protein restriction followed by recovery

Acute volume expansion decreased baroreflex response after swimming but not after running exercise training in hypertensive rats.

Background: Physical training (ET) is important to restore the reflex sensitivity involved in controlling blood pressure in various diseases. Recent investigations have demonstrated an interaction between cardiopulmonar baroreceptors and arterial baroreflex during dynamic exercise.Objective: Considering that acute and chronic hemodynamic responses to swimming (SW) are different from the race (RUN), the objective of this study was to evaluate the effect of SW and RUN on baroreflex response before and after acute volume expansion in spontaneously hypertensive rats (SHR).Methods: SHR were divided into three groups: RUN, SW and sedentary (SED) groups. After training, the mean arterial pressure (MAP) and heart rate (HR) were recorded. Baroreflex response was assessed before and after acute volume expansion.Results: Both ET conditions reduced basal levels of HR and MAP. The first volume of injected isotonic saline solution (1.25% of body weight) produced a greater decrease in HR for the SW group (?105.8 ? 8.7 bpm) compared to RUN groups (?68 ? 5.2 bpm) and SED(?49.8 ? 7.2 bpm). Both training modalities increase the baroreflex response in relation to the SED group, but after the total volume expansion, the SW group presented attenuated response (0.7 ? 0.1 ?PIms/mmHg) compared to RUN (1.5 ? 0.17 PIms/mmHg) and was not different from SED group (0.8 ? 0.2 mPIms/mmHg). Conclusion: The results show that the swim-trained group has a different baroreflex response to that observed by the run-trained group after the activation of the load receptors by saline expansion

Increased activity of the renin-angiotensin and sympathetic nervous systems is required for regulation of the blood pressure in rats fed a low-protein diet.

Previous studies have shown that postweaning protein restriction induces changes in the sympathetic nervous system in rats, leading to alterations in cardiovascular parameters. In addition, the renin?angiotensin system is also affected in these animals. Here, we hypothesized that adjustments in the interaction between the RAS and SNS underlie the cardiovascular adaptations observed in rats fed a low-protein diet. Thus, we evaluated the alterations in the mean arterial pressure (MAP) and heart rate of Fisher rats fed a protein-deficient diet before and after systemic administration of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II (Ang II) type 1 (AT1) receptor antagonist losartan alone or in combination with the ?1-adrenergic receptor antagonist prazosin. Administration of enalapril or losartan decreased the MAP only of rats under protein restriction. Prazosin injection after the infusion of losartan caused a further decrease in the MAP of malnourished rats. In contrast, only the administrationof prazosin elicited a reductionin theMAPof control animals.Whenthe sequence of administrationof the antagonistswasinverted, infusion of prazosin inanimals fedthe standard or the low-protein diet induced a reduction in the MAP that was further decreased by the subsequent injection of losartan. Importantly, in both protocols the responses ofmalnourished animals to losartan were markedly greater when compared with the control group. Moreover, these animals presented lower levels of circulatingAng II and a reduced responsiveness to Ang II. In contrast, the expression of AT1 receptors in the aorta ofmalnourished animals was increased. Thus, our data suggest that the renin?angiotensin system is an important factor supporting blood pressure in rats fed a low-protein diet and that the sympathetic nervous system activity in these animals is under strong influence of Ang II acting via AT1 receptors

Swimming training induces liver adaptations to oxidative stress and insulin sensitivity in rats submitted to high-fat diet.

Oxidative stress, physical inactivity and high-fat (FAT) diets are associated with hepatic disorders such as metabolic syndrome (MS). The therapeutic effects of physical training (PT) were evaluated in rats with MS induced by FAT diet for 13 weeks, on oxidative stress and insulin signaling in the liver, during the last 6 weeks. FAT-sedentary (SED) rats increased body mass, retroperitoneal fat, mean arterial pressure (MAP) and heart rate (HR), and total cholesterol, serum alanine aminotransferase, glucose and insulin. Livers of FAT-SED rats increased superoxide dismutase activity, thiobarbituric acid-reactive substances, protein carbonyl and oxidized glutathione (GSSG); and decreased catalase activity, reduced glutathione/GSSG ratio, and the mRNA expression of insulin receptor substrate 1 (IRS-1) and serine/threonine kinase 2. FAT-PT rats improved in fitness and reduced their body mass, retroperitoneal fat, and glucose, insulin, total cholesterol, MAP and HR; and their livers increased superoxide dismutase and catalase activities, the reduced glutathione/GSSG ratio and the expression of peroxisome proliferator-activated receptor gamma and insulin receptor compared to FAT-SED rats. These findings indicated adaptive responses to PT by restoring the oxidative balance and insulin signaling in the liver and certain biometric and biochemical parameters as well as MAP in MS rats