Antihypertensive effect of a nanoemulsion of baccharis dracunculifolia leaves extract in sodium-dependent hypertensive rats.

Baccharis dracunculifolia (DC) is an important botanical source of Brazilian green propolis and have many compounds with potential antihypertensive activity. However, little is known about the specific antihypertensive properties of DC, or the mechanisms involved. Here we aimed to chemically characterise an ethanolic DC extract (eDC), test its antihypertensive properties and the involvement of neurogenic mechanisms using an animal model of salt-dependent hypertension. The chemical analysis of the eDC revealed the presence of many antihypertensive compounds. Administering the eDC in a nanoemulsion formulation (25 to 50 mg/kg) effectively normalised blood pressure in hypertensive rats. The result also suggested that neurogenic mechanisms are involved in the antihypertensive action of eDC. The treatment with p-coumaric acid (0.32 to 3 mg/kg), a polyphenol abundant in the eDC, produced no significant antihypertensive effect. The findings indicate that the eDC has antihypertensive properties, and that these effects may be mediated through neurogenic pressor mechanisms.

Reducing sugar intake through chronic swimming training: Exploring palatability changes and central vasopressin mechanisms.

Excessive sugar intake has been associated with the onset of several non-communicable chronic diseases seen in humans. Physical activity could affect sweet taste perception which may affect sugar intake. Therefore, it was investigated the chronic effects of swimming training on sucrose intake/preference, reactivity to sucrose taste, self-care in neurobehavioral stress, and the possible involvement of the vasopressin type V1 receptor in sucrose solution intake. Male Wistar rats, of from different cohorts were used, subjected to a sedentary lifestyle (SED) or swimming training (TR - 1 h/day, 5×/week, for 8 weeks, with no added load). Weekly intake was verified in SED and TR rats after access to a sucrose solution 1×/week, 2 h/day, for eight weeks. Chronic effects of swimming and/or a sedentary lifestyle were carried out three days after the end of the physical exercise protocol. Swimming training reduced the intake of sucrose solution from the third week onwards in the two-bottle test measured once a week for 8 weeks. After the ending of the swimming protocol, sucrose intake was also reduced as per its preference. This reduced intake is probably correlated with the carbohydrate aspect of sucrose since saccharin intake was not affected. In addition, chronic swimming training was shown to reduce ingestive responses, increase neutral responses, without interfering with aversive, in the sucrose solution taste reactivity test. In addition, these results are not related to a depressive-like behavior, nor to neurobehavioral stress. Furthermore, treatment with vasopressin V1 receptor antagonist abolished the reduced sucrose intake in trained rats. The results suggest that swimming performed chronically is capable of reducing intake and preference for sucrose by decreasing the palatability of sucrose without causing depressive-type behavior or stress. In addition, the results also suggest that central V1 vasopressin receptors are part of the mechanisms activated to reduce sucrose intake in trained rats.

Effects of Psidium guajava L. leaves extract on blood pressure control and IL-10 production in salt-dependent hypertensive rats.

Psidium guajava (guava) leaves extract displays anti-hypertensive properties by mechanisms not yet fully understood. Here, we investigated whether sympathetic drive and immune signaling mechanisms are involved with the antihypertensive effect of the guava extract in a model of salt-dependent hypertension. Raw guava extract (rPsE) was characterized by colorimetric and UPLC-MS techniques. Two doses of rPsE (100 and 200 mg/kg) were evaluated for anti-hypertensive effect using a suspension system (PsE). Weaned male Wistar rats were put on a high-salt diet (HSD, 0.90 % Na+) for 16 weeks and received gavages of PsE for the last 4 weeks. Blood pressure (BP) was measured at the end of treatment in conscious rats. The neurogenic pressor effect was assessed by ganglionic blockade with hexamethonium. Autonomic modulation of heart rate was evaluated by spectral analysis. The effects of orally administered PsE on lumbar sympathetic nerve activity (LSNA) were assessed in anesthetized rats. Blood IL-10, IL-17A, and TNF were measured. The increased neurogenic pressor effect of HSD rats was reduced by PsE 100 mg/kg, but not by 200 mg/kg. PsE (200 mg/kg) administration in anesthetized rats produced a greater fall in BP of HSD rats compared to standard salt diet (SSD) rats. PsE hypotensive response elicited an unproportionable increase in LSNA of HSD rats compared to SSD rats. PsE (200 mg/kg) increased plasma concentrations of IL-10 but had no effect on TNF or IL-17A. Our data indicate that the antihypertensive effects of PsE may involve autonomic mechanisms and immunomodulation by overexpression of IL-10 in salt-dependent hypertensive rats.

The gut-brain axis and sodium appetite: Can inflammation-related signaling influence the control of sodium intake?

Sodium is the main cation present in the extracellular fluid. Sodium and water content in the body are responsible for volume and osmotic homeostasis through mechanisms involving sodium and water excretion and intake. When body sodium content decreases below the homeostatic threshold, a condition termed sodium deficiency, highly motivated sodium seeking, and intake occurs. This is termed sodium appetite. Classically, sodium and water intakes are controlled by a number of neuroendocrine mechanisms that include signaling molecules from the renin-angiotensin-aldosterone system acting in the central nervous system (CNS). However, recent findings have shown that sodium and water intakes can also be influenced by inflammatory agents and mediators acting in the CNS. For instance, central infusion of IL-1ß or TNF-α can directly affect sodium and water consumption in animal models. Some dietary conditions, such as high salt intake, have been shown to change the intestinal microbiome composition, stimulating the immune branch of the gut-brain axis through the production of inflammatory cytokines, such as IL-17, which can stimulate the brain immune system. In this review, we address the latest findings supporting the hypothesis that immune signaling in the brain could produce a reduction in thirst and sodium appetite and, therefore, contribute to sodium intake control.

Swimming training improves cardiovascular autonomic dysfunctions and prevents renal damage in rats fed a high-sodium diet from weaning.

NEW FINDINGS: What is the central question of this study? How does swimming exercise training impact hydro-electrolytic balance, renal function, sympathetic contribution to resting blood pressure and cerebrospinal fluid (CSF) [Na+ ] in rats fed a high-sodium diet from weaning? What is the main finding and its importance? An exercise-dependent reduction in blood pressure was associated with decreased CSF [Na+ ], sympathetically driven vasomotor tonus and renal fibrosis indicating that the anti-hypertensive effects of swimming training in rats fed a high-sodium diet might involve neurogenic mechanisms regulated by sodium levels in the CSF rather than changes in blood volume. ABSTRACT: High sodium intake is an important factor associated with hypertension. High-sodium intake with exercise training can modify homeostatic hydro-electrolytic balance, but the effects of this association are mostly unknown. In this study, we sought to investigate the effects of swimming training (ST) on cerebrospinal fluid (CSF) Na+ concentration, sympathetic drive, blood pressure (BP) and renal function of rats fed a 0.9% Na+ (equivalent to 2% NaCl) diet with free access to water for 22 weeks after weaning. Male Wistar rats were assigned to two cohorts: (1) fed standard diet (SD) and (2) fed high-sodium (HS) diet. Each cohort was further divided into trained and sedentary groups. ST normalised BP levels of HS rats as well as the higher sympathetically related pressor activity assessed by pharmacological blockade of ganglionic transmission (hexamethonium). ST preserved the renal function and attenuated the glomerular shrinkage elicited by HS. No change in blood volume was found among the groups. CSF [Na+ ] levels were higher in sedentary HS rats but were reduced by ST. Our findings showed that ST effectively normalised BP of HS rats, independent of its effects on hydro-electrolytic balance, which might involve neurogenic mechanisms regulated by Na+ levels in the CSF as well as renal protection.

Salt-dependent hypertension and inflammation: targeting the gut-brain axis and the immune system with Brazilian green propolis.

Systemic arterial hypertension (SAH) is a major health problem around the world and its development has been associated with exceeding salt consumption by the modern society. The mechanisms by which salt consumption increase blood pressure (BP) involve several homeostatic systems but many details have not yet been fully elucidated. Evidences accumulated over the last 60 decades raised the involvement of the immune system in the hypertension development and opened a range of possibilities for new therapeutic targets. Green propolis is a promising natural product with potent anti-inflammatory properties acting on specific targets, most of them participating in the gut-brain axis of the sodium-dependent hypertension. New anti-hypertensive products reinforce the therapeutic arsenal improving the corollary of choices, especially in those cases where patients are resistant or refractory to conventional therapy. This review sought to bring the newest advances in the field articulating evidences that show a cross-talking between inflammation and the central mechanisms involved with the sodium-dependent hypertension as well as the stablished actions of green propolis and some of its biologically active compounds on the immune cells and cytokines that would be involved with its anti-hypertensive properties.

Fitness is improved by adjustments in muscle intracellular signaling in rats with renovascular hypertension 2K1C undergoing voluntary physical exercise.

AIM: To evaluate physical fitness and cardiovascular effects in rats with renovascular hypertension, two kidneys, one clip (2K1C) submitted to voluntary exercise (ExV). MAIN METHODS: 24 h after surgery (SHAM and 2K1C) rats were submitted to ExV for one week (adaptation). ExV adherent rats were separated into exercise (2K1C-EX and SHAM-EX) or sedentary (2K1C-SED and SHAM-SED) groups. After 4 weeks, exhaustion test, plasma lactate, cardiovascular parameters were evaluated and gastrocnemius muscle was removed for evaluation of gene expression of muscle metabolism markers (PGC1α; AMPK, SIRT-1, UCP-3; MCP-1; LDH) and of the redox process. KEY FINDINGS: ExV decreased blood lactate concentration and increased SOD and CAT activity and a SIRT-1 and UCP-3 gene expression in the gastrocnemius muscle of 2K1C-ExV rats compared to 2K1C-SED rats. Gene expressions of PGC1α, UCP-3, MCT-1, AMPK were higher in 2K1C-ExV rats compared to SHAM-SED rats. Blood pressure in 2K1C-ExV was lower compared to 2K1C-SED and higher in SHAM-SED rats. Reflex bradycardia in 2K1C-EX rats increased compared to 2K1C-SED and was similar to SHAM-SED. The variation in mean blood pressure induced by ganglion blocker hexamethonium and Ang II AT1 receptor antagonist, losartan in the 2K1C-ExV rats was smaller compared to the 2K1C-SED rats and it was similar to the SHAM-SED rats. SIGNIFICANCE: O ExV induced adaptive responses in 2K1C-ExV rats by decreasing sympathetic and Ang II activities and stimulating intracellular signaling that favors redox balance and reduced blood lactate concentration. These adaptive responses, then, contribute to reduced arterial pressure, improved baroreflex sensitivity and physical fitness of 2K1C rats.

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 cardiopulmonary 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 µPIms/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.

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.

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

NEW FINDINGS: What is the central question of this study? In this study, we sought to investigate whether cardiovascular responses to peripheral chemoreflex activation of rats recovered from protein restriction are related to activation of AT1 receptors. What is the main finding and its importance? This study highlights the fact that angiotensinergic mechanisms activated by AT1 receptors do not support increased responses to peripheral chemoreflex activation by KCN in rats recovered from protein restriction. Also, we found that protein restriction led to increased resting ventilation in adult rats, even after recovery. 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 (20 mg kg-1 i.v.). The peripheral chemoreflex was elicited by increasing doses of KCN (20-160 µg 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 beats min-1 and 856 ± 112 ml kg-1  min-1 ). Mean arterial pressure was not different between the groups. Pressor and bradycardic responses evoked by KCN (60 µg kg-1 ) were increased in R-PR (+45 ± 13 mmHg and -77 ± 47 beats min-1 ) compared with CG105 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.

Bezold-Jarisch reflex in sino-aortic denervated malnourished rats.

In this study we assessed the role of Bezold-Jarisch reflex (BJR) in the regulation of blood pressure (BP) of malnourished (MN) and control rats (CN) with sino-aortic denervation (SAD). Fischer rats were fed diets containing either 6% (MN) or 15% (CN) protein for 35 days after weaning. These rats underwent sham or SAD and catheterization of femoral artery and vein for BP measurements and drug injection. Phenylbiguanide (PBG 5 µg/kg, i.v.) for activation BJR, produced bradycardia (-317±22 bpm for CN vs. -372±16 bpm for MN) and hypotension (-57±4 mm Hg for CN vs. -54±6 mm Hg for MN. After SAD, MN rats had reduced hypotensive (-37±7 mm Hg for MN vs. -82±6 mm Hg for CN) and bradycardic (-124±17 for MN vs. -414±20 bpm CN) responses to BJR activation. To evaluate the contribution of the parasympathetic component due to BJR for the fall in BP, methyl atropine bromide, was given between two injections of PBG (5 µg/kg) separated by 10 min each other. Both bradycardic (-216±21 bpm before and -4±3 bpm after for CN -226±43 bpm before and -9±20 bpm after for MN) and hypotensive (-42±4 mm Hg before and -6±1 mm Hg after for CN -33±9 mm Hg before and -5±2 mm Hg after for MN) responses were abolished in CN and MN groups. These data indicate that dietary protein malnutrition changes the relation between baroreflex and BJR required for maintenance of the BP during malnourishment.

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 µg/kg, i.v.) and a depressor dose of sodium nitroprusside (SNP, 30 µg/kg, i.v.) before (control) and 5, 15, 30 and 60 min after AAC or NAC into the 4thV. Control PHE injection 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 baroreflex-mediated tachycardia evoked by SNP after AAC injection on 4thV (control: 151 ± 23bpm vs. 135 ± 18 bpm 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 ± 17 bpm 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.

Sympathoinhibition to Bezold-Jarisch reflex is attenuated in protein malnourished rats.

Malnutrition affects cardiovascular reflexes, including chemoreflex and baroreflex. In this study we assessed the hypothesis that malnourishment changes the responses in mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) evoked from Bezold-Jarisch reflex (BJR). Fischer rats were fed diets containing either (6% malnourished or 14% control) protein for 35 days after weaning. There were no differences in baseline MAP (102 ± 4 vs. 95 ± 3 mmHg) whereas higher baseline HR (478 ± 18 vs. 360 ± 11 bpm; P<0.05,) and reduced sympathoinhibition (ΔRSNA=-54 ± 9 vs. -84 ± 7%; P=0.0208) to BJR activation were found in malnourished rats. We conclude that malnutrition affects the sympathetic control of BJR.

Cardiovascular responses to hydrogen peroxide into the nucleus tractus solitarius.

The nucleus tractus solitarius (NTS), a major hindbrain area involved in cardiovascular regulation, receives primary afferent fibers from peripheral baroreceptors and chemoreceptors. Hydrogen peroxide (H(2)O(2)) is a relatively stable and diffusible reactive oxygen species (ROS), which acting centrally, may affect neural mechanisms. In the present study, we investigated effects of H(2)O(2) alone or combined with the glutamatergic antagonist kynurenate into the NTS on mean arterial pressure (MAP) and heart rate (HR). Conscious or anesthetized (urethane and alpha-chloralose) male Holtzman rats (280-320 g) were used. Injections of H(2)O(2) (125 to 1500 pmol/40 nl) into the intermediate NTS of anesthetized rats evoked dose-dependent and transient hypotension (-18 +/- 3 to -55 +/- 11 mmHg) and bradycardia (-16 +/- 5 to -116 +/- 40 bpm). Injection of the catalase inhibitor 3-amino-1,2,4-triazole (100 nmol/40 nl) into the NTS also produced hypotension and bradycardia. Previous injection of the ionotropic L-glutamate receptor antagonist kynurenate (7 nmol/40 nl) attenuated by 48% the bradycardic response, without changing the hypotension evoked by H(2)O(2) (500 pmol/40 nl) in anesthetized rats. The antioxidant L-ascorbate (600 pmol/80 nl) injected into the NTS attenuated the bradycardic (42%) and hypotensive (67%) responses to H(2)O(2) (500 pmol/40 nl) into the NTS. In conscious rats, injection of H(2)O(2) (50 nmol/100 nl) into the NTS also evoked intense bradycardia (-207 +/- 8 bpm) and hypotension (-54 +/- 6 mmHg) that were abolished by prior injection of kynurenate (7 nmol/100 nl). The results show that H(2)O(2) into the NTS induces hypotension and bradycardia probably due to activation of glutamatergic mechanisms.

Cardiopulmonary reflex is attenuated in iron overload conscious rats.

Increased iron intake can lead to iron accumulation in serum and tissues. Its has been described that serum and tissue iron overload increase reactive oxygen species (ROS) levels and reduce the effectiveness of the cardiovascular neural mechanisms involved in the maintenance of the arterial blood pressure whithin a narrow range of variation, therefore, iron overload may disrupt cardiovascular homeostasis contributing to physiopathological status development. In the present study we evaluated whether iron accumulated in serum or tissue of awake animals affect the cardiovascular homeostasis through changes in the cardiopulmonary reflex (CPR). We observed that the CPR is reduced in both serum and tissue iron overloaded groups, but no changes were found in the left ventricular pressure measurements, suggesting that iron-related effects are restrict to the CPR neural pathways. We also observed that the serum overloaded group presented lower basal heart rate levels, suggesting an increased parasympathetic efferent activity directed to the heart in this group. Taken together, our data suggest an important role for the iron-generated ROS to the cardiovascular homeostasis, especially regarding the CPR in awake animals.

Malnutrition enhances cardiovascular responses to chemoreflex activation in awake rats.

Several studies in the literature suggest that low-protein intake is associated with increases in sympathetic efferent activity and cardiovascular disease. Among the possible mechanisms, changes in the neurotransmission of cardiovascular reflexes have been implicated. Therefore, the present study comprised the evaluation of chemoreflex responsiveness in rats subjected to a low-protein diet during the 35 days after weaning. As a result, we observed that malnourished rats presented higher levels of baseline mean arterial pressure and heart rate and exhibited a mild increase in the pressor response to chemoreflex activation. They also exhibited a massive bradycardic response to chemoreflex activation. Interestingly, bilateral ligature of the carotid body arteries further increased baseline mean arterial pressure and heart rate in malnourished animals. The data suggest severe autonomic imbalance and/or change in the central interplay between neural and cardiovascular mechanisms.