Publications by authors named "Ruy R Campos"

76 Publications

Renal sympathetic activation triggered by the rostral ventrolateral medulla is dependent of spinal cord AT1 receptors in Goldblatt hypertensive rats.

Peptides 2021 Dec 24;146:170660. Epub 2021 Sep 24.

Cardiovascular Division, Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil. Electronic address:

Spinal cord neurons contribute to elevated sympathetic vasomotor activity in renovascular hypertension (2K1C), particularly, increased actions of angiotensin II. However, the origin of these spinal angiotensinergic inputs remains unclear. The present study aimed to investigate the role of spinal angiotensin II type 1 receptor (AT1) receptors in the sympathoexcitatory responses evoked by the activation of the rostral ventrolateral medulla (RVLM) in control and 2K1C Goldblatt rats. Hypertension was induced by clipping of the left renal artery. After 6 weeks, a catheter (PE-10) filled with losartan was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anesthetized rats. The effects of glutamate microinjection into the RVLM on blood pressure (BP), heart rate (HR), and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated in the presence or absence of spinal AT1 blockade. Tachycardic, pressor, and renal sympathoexcitatory effects caused by RVLM activation were significantly blunted by losartan in 2K1C rats, but not in control rats. However, no differences were found in the gene expression of angiotensin-converting enzyme, angiotensinogen, and renin in the spinal cord segments between the groups. In conclusion, acute sympathoexcitation induced by RVLM activation is dependent on the spinal AT1 receptor in Goldblatt, but not in control, rats. The involvement of other central cardiovascular nuclei in spinal angiotensinergic actions, as well as the source of angiotensin II, remains to be determined in the Goldblatt model.
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http://dx.doi.org/10.1016/j.peptides.2021.170660DOI Listing
December 2021

Retroperitoneal adipose tissue denervation improves cardiometabolic and autonomic dysfunction in a high fat diet model.

Life Sci 2021 Oct 21;283:119841. Epub 2021 Jul 21.

Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil. Electronic address:

Sympathetic vasomotor overactivity is a major feature leading to the cardiovascular dysfunction related to obesity. Considering that the retroperitoneal white adipose tissue (rWAT) is an important fat visceral depot and receives intense sympathetic and afferent innervations, the present study aimed to evaluate the effects evoked by bilateral rWAT denervation in obese rats. Male Wistar rats were fed with HFD for 8 consecutive weeks and rWAT denervation was performed at the 6th week. Arterial pressure, splanchnic and renal sympathetic vasomotor nerve activities were assessed and inflammation and the components of the renin -angiotensin system were evaluated in different white adipose tissue depots. HFD animals presented higher serum levels of leptin and glucose, an increase in arterial pressure and splanchnic sympathetic nerve activity; rWAT denervation, normalized these parameters. Pro-inflammatory cytokines levels were significantly increased, as well as RAAS gene expression in WAT of HFD animals; rWAT denervation significantly attenuated these changes. In conclusion, HFD promotes vasomotor sympathetic overactivation and inflammation with repercussions on the cardiovascular system. In conclusion, the neural communication between WAT and the brain is fundamental to trigger sympathetic vasomotor activation and this pathway is a possible new therapeutic target to treat obesity-associated cardiovascular dysfunction.
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http://dx.doi.org/10.1016/j.lfs.2021.119841DOI Listing
October 2021

Effects of renal denervation on cardiovascular, metabolic and renal functions in streptozotocin-induced diabetic rats.

Life Sci 2021 Aug 29;278:119534. Epub 2021 Apr 29.

Cardiovascular Division, Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. Electronic address:

Diabetes promotes renal sympathetic hyperactivity, autonomic imbalance, and cardiovascular and renal dysfunction. Bilateral renal denervation (BRD) has emerged as a treatment for diabetes; however, the mechanisms that underlie the beneficial effects of BRD are unknown.

Aims: The present study evaluated the effects of BRD on autonomic, cardiovascular, metabolic, and renal function in streptozotocin-diabetic rats.

Main Methods: Wistar rats were separated into three experimental groups: control (CTR), diabetic (DM), and diabetic that underwent BRD (DM BRD). BRD was performed two weeks after STZ-diabetes induction, the experiments were performed four weeks after DM induction. This study evaluated sympathetic vasomotor nerve activity in different territories (renal, lumbar and splanchnic), arterial baroreceptor reflex, metabolic and renal function.

Key Findings: BRD significantly reduced glycemia, glycosuria, albuminuria, and SGLT2 gene expression in the kidney in DM rats. Renal sympathetic nerve activity (rSNA) was significantly increased and splanchnic sympathetic nerve activity (sSNA) was significantly decreased in DM rats, without changes in lumbar sympathetic nerve activity (lSNA). BRD was able to normalize sSNA and significantly increase lSNA in DM rats compared to control rats. Additionally, cardiac baroreceptor sensitivity was impaired in DM rats, and BRD significantly improved baroreflex sensitivity.

Significance: Our data suggest that renal nerves play an important role in autonomic, cardiovascular, and renal dysfunction in STZ-DM rats. Thus, sympathetic renal hyperactivity should be considered a possible therapeutic target in diabetic patients.
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http://dx.doi.org/10.1016/j.lfs.2021.119534DOI Listing
August 2021

Renal Sensory Activity Regulates the γ-Aminobutyric Acidergic Inputs to the Paraventricular Nucleus of the Hypothalamus in Goldblatt Hypertension.

Front Physiol 2020 15;11:601237. Epub 2020 Dec 15.

Department of Physiology, Cardiovascular Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

Renal sensory activity is centrally integrated within brain nuclei involved in the control of cardiovascular function, suggesting that renal afferents regulate basal and reflex sympathetic vasomotor activity. Evidence has shown that renal deafferentation (DAx) evokes a hypotensive and sympathoinhibitory effect in experimental models of cardiovascular diseases; however, the underlying mechanisms involved in this phenomenon need to be clarified, especially those related to central aspects. We aimed to investigate the role of renal afferents in the control of γ-aminobutyric acid (GABA)ergic inputs to the paraventricular nucleus (PVN) of the hypothalamus in renovascular hypertensive (2K1C) rats and their influence in the regulation of cardiovascular function. Hypertension was induced by clipping the left renal artery. After 4 weeks, renal DAx was performed by exposing the left renal nerve to a 33 mM capsaicin solution for 15 min. After 2 weeks of DAx, microinjection of muscimol into the PVN was performed in order to evaluate the influence of GABAergic activity in the PVN and its contribution to the control of renal sympathetic nerve activity (rSNA) and blood pressure (BP). Muscimol microinjected into the PVN triggered a higher drop in BP and rSNA in the 2K1C rats and renal DAx mitigated these responses. These results suggest that renal afferents are involved in the GABAergic changes found in the PVN of 2K1C rats. Although the functional significance of this phenomenon needs to be clarified, it is reasonable to speculate that GABAergic alterations occur to mitigate microglia activation-induced sympathoexcitation in the PVN of 2K1C rats.
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http://dx.doi.org/10.3389/fphys.2020.601237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769809PMC
December 2020

Effects of physical exercise on baroreflex sensitivity and renal sympathetic nerve activity in chronic nicotine-treated rats.

Can J Physiol Pharmacol 2021 Aug 8;99(8):786-794. Epub 2020 Dec 8.

Departamento de Fisiologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil.

Chronic nicotine exposure may increase cardiovascular risk by impairing the cardiac autonomic function. Besides, physical exercise (PE) has shown to improve cardiovascular health. Thus, we aimed to investigate the effects of PE on baroreflex sensitivity (BRS), heart rate variability (HRV), and sympathetic nerve activity (SNA) in chronically nicotine-exposed rats. Male Wistar rats were assigned to four independent groups: Control (treated with saline solution), Control+Ex (treated with saline and submitted to treadmill training), Nicotine (treated with Nicotine), and Nicotine+Ex (treated with nicotine and submitted to treadmill training). Nicotine (1 mg·kg) was administered daily for 28 consecutive days. PE consisted of running exercise (60%-70% of maximal aerobic capacity) for 45 min, 5 days per week, for 4 weeks. At the end of the protocol, cardiac BRS, HRV, renal SNA (rSNA), and renal BRS were assessed. Nicotine treatment decreased absolute values of HRV indexes, increased low frequency/high frequency ratio of HRV, reduced the bradycardic and sympatho-inhibitory baroreceptor reflex responses, and reduced the rSNA. PE effectively restored time-domain HRV indexes, the bradycardic and sympatho-inhibitory reflex responses, and the rSNA in chronic nicotine-treated rats. PE was effective in preventing the deterioration of time-domain parameters of HRV, arterial baroreceptor dysfunction, and the rSNA after nicotine treatment.
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http://dx.doi.org/10.1139/cjpp-2020-0381DOI Listing
August 2021

The involvement of renal afferents in the maintenance of cardiorenal diseases.

Am J Physiol Regul Integr Comp Physiol 2021 01 4;320(1):R88-R93. Epub 2020 Nov 4.

Department of Physiology, Cardiovascular Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, Sao Paulo, Brazil.

Elevated sympathetic vasomotor activity is a common feature of cardiorenal diseases. Therefore, the sympathetic nervous system is an important therapeutic target, particularly the fibers innervating the kidneys. In fact, renal denervation has been applied clinically and shown promising results in patients with hypertension and chronic kidney disease. However, the underlying mechanisms involved in the cardiorenal protection induced by renal denervation have not yet been fully clarified. This mini-review highlights historical and recent aspects related to the role of renal sensory fibers in the control of cardiorenal function under normal conditions and in experimental models of cardiovascular disease. Results have demonstrated that alterations in renal sensory function participate in the maintenance of elevated sympathetic vasomotor activity and cardiorenal changes; as such, renal sensory fibers may be a potential therapeutic target for the treatment of cardiorenal diseases. Although it has not yet been applied in clinical practice, selective afferent renal denervation may be promising, since such an approach maintains efferent activity and can provide more refined control of renal function compared with total renal denervation. However, more studies are needed to understand the mechanisms by which renal afferents partially contribute to such changes, in addition to the need to evaluate the safety and advantages of the approach for application in the clinical practice.
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http://dx.doi.org/10.1152/ajpregu.00225.2020DOI Listing
January 2021

Role of spinal neurons in the maintenance of elevated sympathetic activity: a novel therapeutic target?

Am J Physiol Regul Integr Comp Physiol 2020 09 24;319(3):R282-R287. Epub 2020 Jun 24.

Cardiovascular Physiology Division, Department of Physiology, Universidade Federal de São Paulo, Escola Paulista de Medicina, Sao Paulo, Brazil.

The control of sympathetic vasomotor activity involves a complex network within the brain and spinal circuits. An extensive range of studies has indicated that sympathoexcitation is a common feature in several cardiovascular diseases and that strategies to reduce sympathetic vasomotor overactivity in such conditions can be beneficial. In the present mini-review, we present evidence supporting the spinal cord as a potential therapeutic target to mitigate sympathetic vasomotor overactivity in cardiovascular diseases, focusing mainly on the actions of spinal angiotensin II on the control of sympathetic preganglionic neuronal activity.
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http://dx.doi.org/10.1152/ajpregu.00122.2020DOI Listing
September 2020

Interaction between angiotensin II and GABA in the spinal cord regulates sympathetic vasomotor activity in Goldblatt hypertension.

Neurosci Lett 2020 05 15;728:134976. Epub 2020 Apr 15.

Cardiovascular Division, Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil. Electronic address:

Previous studies have been described changes in brain regions contributing to the sympathetic vasomotor overactivity in Goldblatt hypertension (2K1C). Furthermore, changes in the spinal cord are also involved in the cardiovascular and autonomic dysfunction in renovascular hypertension, as intrathecal (i.t.) administration of Losartan (Los) causes a robust hypotensive/sympathoinhibitory response in 2K1C but not in control rats. The present study evaluated the role of spinal γ-aminobutyric acid (GABA)-ergic inputs in the control of sympathetic vasomotor activity in the 2K1C rats. Hypertension was induced by clipping the renal artery. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of i.t. injection of bicuculline (Bic) on blood pressure (BP), renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated over 40 consecutive minutes in the presence or absence of spinal AT1 antagonism. I.t. Bic triggered a more intense pressor and sympathoexcitatory response in 2K1C rats, however, these responses were attenuated by previous i.t. Los. No differences in the gene expression of GAD 65 and GABA-A receptors subunits in the spinal cord segments were found. Thus, the sympathoexcitation induced by spinal GABA-A blockade is dependent of local AT1 receptor in 2K1C but not in control rats. Excitatory angiotensinergic inputs to sympathetic preganglionic neurons are tonic controlled by spinal GABAergic actions in Goldblatt hypertension.
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http://dx.doi.org/10.1016/j.neulet.2020.134976DOI Listing
May 2020

Pattern of sympathetic vasomotor activity induced by GABAergic inhibition in the brain and spinal cord.

Pharmacol Rep 2020 Feb 8;72(1):67-79. Epub 2020 Jan 8.

Cardiovascular Division, Department of Physiology, Universidade Federal de São Paulo, Escola Paulista de Medicina, Rua Botucatu, 862, Ground Floor, CEP 04023-060, São Paulo, SP, Brazil.

Background: Knowledge of the central areas involved in the control of sympathetic vasomotor activity has advanced in the last few decades. γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammal nervous system, and a microinjection of bicuculline, an antagonist of GABA type A (GABA-A) receptors, into the paraventricular nucleus of the hypothalamus (PVN) alters the pattern of sympathetic activity to the renal, splanchnic and lumbar territories. However, studies are needed to clarify the role of GABAergic inputs in other central areas involved in the sympathetic vasomotor activity. The present work studied the cardiovascular effects evoked by GABAergic antagonism in the PVN, RVLM and spinal cord.

Methods And Results: Bicuculline microinjections (400 pMol in 100 nL) into the PVN and rostral ventrolateral medulla (RVLM) as well as intrathecal administration (1.6 nmol in 2 µL) evoked an increase in blood pressure, heart rate, and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively), inducing a higher coherence between rSNA and sSNA patterns. However, some of these responses were more intense when the GABA-A antagonism was performed in the RVLM than when the GABA-A antagonism was performed in other regions.

Conclusions: Administration of bicuculline into the RVLM, PVN and SC induced a similar pattern of renal and splanchnic sympathetic vasomotor burst discharge, characterized by a low-frequency (0.5 Hz) and high-amplitude pattern, despite different blood pressure responses. Thus, the differential control of sympathetic drive to different targets by each region is dependent, in part, on tonic GABAergic inputs.
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http://dx.doi.org/10.1007/s43440-019-00025-wDOI Listing
February 2020

Afferent innervation of the ischemic kidney contributes to renal dysfunction in renovascular hypertensive rats.

Pflugers Arch 2020 03 10;472(3):325-334. Epub 2020 Jan 10.

Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo - Escola Paulista de Medicina (UNIFESP-EPM), São Paulo, Brazil.

The ablation of renal nerves, by destroying both the sympathetic and afferent fibers, has been shown to be effective in lowering blood pressure in resistant hypertensive patients. However, experimental studies have reported that the removal of sympathetic fibers may lead to side effects, such as the impairment of compensatory cardiorenal responses during a hemodynamic challenge. In the present study, we evaluated the effects of the selective removal of renal afferent fibers on arterial hypertension, renal sympathetic nerve activity, and renal changes in a model of renovascular hypertension. After 4 weeks of clipping the left renal artery, afferent renal denervation (ARD) was performed by exposing the left renal nerve to a 33 mM capsaicin solution for 15 min. After 2 weeks of ARD, we found reduced MAP (~ 18%) and sympathoexcitation to both the ischemic and contralateral kidneys in the hypertensive group. Moreover, a reduction in reactive oxygen species was observed in the ischemic (76%) and contralateral (27%) kidneys in the 2K1C group. In addition, ARD normalized renal function markers and proteinuria and podocin in the contralateral kidney. Taken altogether, we show that the selective removal of afferent fibers is an effective method to reduce MAP and improve renal changes without compromising the function of renal sympathetic fibers in the 2K1C model. Renal afferent nerves may be a new target in neurogenic hypertension and renal dysfunction.
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http://dx.doi.org/10.1007/s00424-019-02346-4DOI Listing
March 2020

Impairment of natriuresis and diuresis induced by intrarenal adrenoceptor mechanisms in an experimental model of cirrhosis in rats.

Heliyon 2019 Dec 19;5(12):e03066. Epub 2019 Dec 19.

Department of Morphology, Health Sciences Center, Universidade Federal do Espírito Santo, Brazil.

The contribution of intrarenal alpha-2 adrenergic receptors in mediating the enhanced renal excretory responses evoked by the alpha-2-agonist xylazine was examined in a model of cirrhosis in rats. In sham-operated rats, xylazine (0.2 mg/kg, .) increased diuresis and natriuresis (urine flow, control: 78 ± 12.1, 10 min: 155 ± 17, 20 min: 194 ± 19, 30 min: 146 ± 16, 40 min: 114 ± 13, 50 min: 95 ± 10.5 μl/min/g; urinary sodium excretion, control: 6.75 ± 2.08, 10 min: 7.12 ± 2.1, 20 min: 13.4 ± 4.6, 30 min: 14.6 ± 4.02, 40 min: 12.05 ± 2.35, 50 min: 12.7 ± 2.45 μeq/min/g), which was accompanied by a significant reduction in renal sympathetic nerve activity (RSNA) (control: 100, 10 min: 39.5 ± 5.8, 20 min: 53 ± 8.8, 30 min: 72 ± 7.0, 40 min: 83 ± 5.0, 50 min: 94 ± 6.1 AU). Xylazine (0.2 mg/kg) in cirrhotic animals, despite resulting in a significant reduction in RSNA (control: 100, 10 min: 73 ± 4.3*, 20 min: 70 ± 5.0*, 30 min: 76 ± 7.0*, 40 min: 85 ± 5.5*, 50 min: 92 ± 4.8* AU), was unable to increase natriuresis. A higher dose (20 mg/kg) of xylazine was not capable of increasing natriuresis and diuresis, even in the presence of a robust reduction in RSNA. Renal denervation did not alter the onset and time course of cirrhosis. The results indicated that during the development of cirrhosis, there is an adaptive process that disables the intrarenal alpha-2 adrenoceptor mechanisms that selectively promote water and urinary sodium excretion via a sympathetic renal nerve-independent mechanism. Thus, in cirrhotic rats, the diuresis/natriuresis induced by xylazine is independent on RSNA. Intrarenal and/or hormonal changes are probably involved in the impairment of xylazine-induced diuresis/natriuresis in cirrhosis.
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http://dx.doi.org/10.1016/j.heliyon.2019.e03066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931082PMC
December 2019

Selective afferent renal denervation mitigates renal and splanchnic sympathetic nerve overactivity and renal function in chronic kidney disease-induced hypertension.

J Hypertens 2020 04;38(4):765-773

Department of Physiology, Escola Paulista de Medicina, Universidade Federal de Säo Paulo.

Background: Clinical and experimental evidence have shown that renal denervation, by removing both the sympathetic and afferent nerves, improves arterial hypertension and renal function in chronic kidney disease (CKD). Given the key role of renal sympathetic innervation in maintaining sodium and water homeostasis, studies have indicated that the total removal of renal nerves leads to impaired compensatory mechanisms during hemodynamic challenges.

Method: In the present study, we hypothesized that afferent (or sensory) fibers from the diseased kidney contribute to sympathetic overactivation to the kidney and other target organ, such as the splanchnic region, contributing to hypertension in CKD. We used a method to remove selectively the afferent renal fibers (periaxonal application of 33 mmol/l capsaicin) in a rat model of CKD, the 5/6 nephrectomy.

Results: Three weeks after afferent renal denervation (ARD), we found a decrease in mean arterial pressure (∼15%) and normalization in renal and splanchnic sympathetic nerve hyperactivity in the CKD group. Interestingly, intrarenal renin--angiotensin system, as well as renal fibrosis and function and proteinuria were improved after ARD in CKD rats.

Conclusion: The findings demonstrate that afferent fibers contribute to the maintenance of arterial hypertension and reduced renal function that are likely to be mediated by increased sympathetic nerve activity to the renal territory as well as to other target organs in CKD.
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http://dx.doi.org/10.1097/HJH.0000000000002304DOI Listing
April 2020

Differential sympathetic vasomotor control by spinal AT and V1a receptors in the acute phase of hemorrhagic shock.

Eur J Pharmacol 2020 Jan 20;866:172819. Epub 2019 Nov 20.

Cardiovascular Division, Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil. Electronic address:

The role of the renin-angiotensin-aldosterone system and arginine vasopressin (AVP) as humoral components in maintaining blood pressure (BP) during hemorrhagic shock (HS) is well established. However, little is known about the role of angiotensin II (Ang II) and AVP in the control of preganglionic sympathetic neuron activity. We studied the effects evoked by spinal Ang II type I (AT) and V1a receptors antagonism on cardiovascular and sympathetic responses during HS. A catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anesthetized rats. The effects of HS on BP, heart rate (HR), and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were analyzed in the presence or absence (HS rats) of intrathecally injected losartan (HS-Los rats) or V1a antagonist (HS-V1a rats). The right femoral artery was catheterized for bleeding. Using a 5 ml syringe, hemorrhage was maintained continuously until a BP reduction of ~50 mmHg was achieved. We found that bleeding caused a reflex increase in HR, rSNA and sSNA in the HS rats. However, such responses were attenuated in the HS-Los rats. HS-V1a rats showed a reflex increase in HR, rSNA and sSNA in terms of frequency (spikes/s) but not in amplitude. Nevertheless, the BP recovery of the groups was similar. Our data showed that spinal AT receptors are essential for sympathoexcitation during the acute phase of HS. Moreover, spinal AVP seems to be a neuromodulator that controls the recruitment of spinal sympathetic vasomotor neurons during the acute phase of HS.
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http://dx.doi.org/10.1016/j.ejphar.2019.172819DOI Listing
January 2020

Treatment with Mesenchymal Stem Cells Improves Renovascular Hypertension and Preserves the Ability of the Contralateral Kidney to Excrete Sodium.

Kidney Blood Press Res 2019 31;44(6):1404-1415. Epub 2019 Oct 31.

Department of Medicine, Renal Division, Federal University of São Paulo, São Paulo, Brazil,

Background: Mesenchymal stem cells (MSC) improve renal function and renovascular hypertension in the 2-kidney 1-clip model (2K-1C). While MSC play an immunomodulatory role, induce neoangiogenesis, and reduce fibrosis, they do not correct sodium loss by the contra-lateral kidney.

Objectives: We investigated the tubular function of both stenotic and contralateral kidneys and the effect of MSC treatment by evaluating diuresis, natriuresis, and the expression of the main water and sodium transporters.

Method: Adult Wistar rats were allocated into four groups: control (CT), CT+MSC, 2K-1C, and 2K-1C+MSC. MSC (2 × 105) were infused through the tail vein 3 and 5 weeks after clipping. Systolic blood pressure (SBP) was monitored weekly by plethysmography. Six weeks after clipping, 24-hour urine and blood samples were collected for biochemical analysis. Gene expression of the Na/H exchanger-3, epithelial sodium channel, Na/K-ATPase, Na/K/2Cl cotransporter, and aquaporins 1 and 2 (AQP1 and AQP2) were analyzed by RT-PCR. Intrarenal distribution of AQP1 and AQP2 was analyzed by immunohistochemistry.

Results: In hypertensive 2K-1C animals, MSC prevented additional increases in BP. AQP1, but not AQP2, was suppressed in the contralateral kidney, resulting in significant increase in urinary flow rate and sodium excretion. Gene expressions of sodium transporters were similar in both kidneys, suggesting that the high perfusing pressure in the contralateral kidney was responsible for increased natriuresis. Contralateral hypertensive kidney showed signs of renal deterioration with lower GFR in spite of normal RPF levels.

Conclusions: MSC treatment improved renal function and enhanced the ability of the contralateral kidney to excrete sodium through a tubular independent mechanism contributing to reduce SBP.
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http://dx.doi.org/10.1159/000503346DOI Listing
June 2020

Pattern of sympathetic vasomotor activity in a model of hypertension induced by nitric oxide synthase blockade.

Physiol Rep 2019 07;7(14):e14183

Department of Physiology, Cardiovascular Division, Escola Paulista de Medicina-Universidade Federal de São Paulo, São Paulo, Brazil.

We aimed to investigate the effects of nitric oxide (NO) synthesis inhibition by NO synthase inhibitor N-nitro-L-arginine-methyl ester (L-NAME) treatment on the sympathetic vasomotor nerve activity (SNA) on two sympathetic vasomotor nerves, the renal and splanchnic. NO plasma level and systemic oxidative stress were assessed. Hypertension was induced by L-NAME (20 mg/kg per day, by gavage, for seven consecutive days) in male Wistar rats. At the end of the treatment, blood pressure, heart rate, arterial baroreflex sensitivity, renal SNA (rSNA), and splanchnic SNA (sSNA) were assessed in urethane anesthetized rats. L-NAME-treated rats presented increased blood pressure (152 ± 2 mmHg, n = 17) compared to the control group (101 ± 2 mmHg, n = 15). Both rSNA (147 ± 10, n = 15 vs. 114 ± 5 Spikes/s, n = 9) and sSNA (137 ± 13, n = 14 vs. 74 ± 13 spikes/s, n = 9) were significantly increased in the L-NAME-treated compared to the control group. A differential response on baroreflex sensitivity was found, with a significant reduction for rSNA but not for sSNA arterial baroreceptor sensitivity in L-NAME-treated rats. The adjusted regression model revealed that the reduction of systemic NO levels partially explains the variation in sSNA and blood pressure, but not rSNA. Taken together, our data show that hypertension induced by NO synthase blockade is characterized by increased SNA to the rSNA and sSNA. In addition, we found that the rats that had the greatest reduction in NO levels in plasma by L-NAME were those that developed higher blood pressure levels. The reduction in the NO level partially explains the variations in sSNA but not in rSNA.
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http://dx.doi.org/10.14814/phy2.14183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642275PMC
July 2019

Melatonin attenuates renal sympathetic overactivity and reactive oxygen species in the brain in neurogenic hypertension.

Hypertens Res 2019 11 17;42(11):1683-1691. Epub 2019 Jul 17.

Department of Physiology, Campus São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

Sympathetic overactivation contributes to the pathogenesis of both experimental and human hypertension. We have previously reported that oxidative stress in sympathetic premotor neurons leads to arterial baroreflex dysfunction and increased sympathetic drive to the kidneys in an experimental model of neurogenic hypertension. In this study, we hypothesized that melatonin, a potent antioxidant, may be protective in the brainstem regions involved in the tonic and reflex control of blood pressure (BP) in renovascular hypertensive rats. Neurogenic hypertension was induced by placing a silver clip (gap of 0.2 mm) around the left renal artery, and after 5 weeks of renal clip placement, the rats were treated orally with melatonin (30 mg/kg/day) by gavage for 15 days. At the end of melatonin treatment, we evaluated baseline mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), and the baroreflex control of heart rate (HR) and rSNA. Reactive oxygen species (ROS) were detected within the brainstem regions by dihydroethidium staining. Melatonin treatment effectively reduced baseline MAP and sympathoexcitation to the ischemic kidney in renovascular hypertensive rats. The baroreflex control of HR and rSNA were improved after melatonin treatment in the hypertensive group. Moreover, there was a preferential decrease in ROS within the rostral ventrolateral medulla (RVLM) and the nucleus of the solitary tract (NTS). Therefore, our study indicates that melatonin is effective in reducing renal sympathetic overactivity associated with decreased ROS in brainstem regions that regulate BP in an experimental model of neurogenic hypertension.
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http://dx.doi.org/10.1038/s41440-019-0301-zDOI Listing
November 2019

Renal denervation reduces sympathetic overactivation, brain oxidative stress, and renal injury in rats with renovascular hypertension independent of its effects on reducing blood pressure.

Hypertens Res 2019 05 20;42(5):628-640. Epub 2018 Dec 20.

Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

The underlying mechanisms by which renal denervation (RD) decreases blood pressure (BP) remain incompletely understood. In this study, we investigated the effects of ischemic kidney denervation on different sympathetic outflows, brain and renal expression of angiotensin-II receptors, oxidative stress and renal function markers in the 2-kidney, 1-clip (2K-1C) rat model. Surgical RD was performed in Wistar male rats 4-5 weeks after clip implantation. After 10 days of RD, BP, and the activity of sympathetic nerves projecting to the contralateral kidney (rSNA) and splanchnic region were partially reduced in 2K-1C rats, with no change in systemic renin-angiotensin system (RAS). To distinguish the effects of RD from the reduction in BP, 2K-1C rats were treated with hydralazine by oral gavage (25 mg/kg/day for 1 week). RD, but not hydralazine, normalized oxidative stress in the sympathetic premotor brain regions and improved intrarenal RAS, renal injury, and proteinuria. Furthermore, different mechanisms led to renal injury and oxidative stress in the ischemic and contralateral kidneys of 2K-1C rats. Injury and oxidative stress in the ischemic kidney were driven by the renal nerves. Although RD attenuated rSNA, injury and oxidative stress persisted in the contralateral kidney, probably due to increased BP. Therefore, nerves from the ischemic kidney at least partially contribute to the increase in BP, sympathetic outflows, brain oxidative stress, and renal alterations in rats with renovascular hypertension. Based on these findings, the reduction in oxidative stress in the brain is a central mechanism that contributes to the effects of RD on Goldblatt hypertension.
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http://dx.doi.org/10.1038/s41440-018-0171-9DOI Listing
May 2019

Targeting the polarization of tumor-associated macrophages and modulating mir-155 expression might be a new approach to treat diffuse large B-cell lymphoma of the elderly.

Cancer Immunol Immunother 2019 Feb 14;68(2):269-282. Epub 2018 Nov 14.

Department of Clinical and Experimental Oncology, Universidade Federal de São Paulo, Rua Diogo de Faria, 824, 5° andar, Hemocentro, CEP 04037-002, Sao Paulo, Brazil.

Aging immune deterioration and Epstein-Barr (EBV) intrinsic mechanisms play an essential role in EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV + DLBCLe) pathogenesis, through the expression of viral proteins, interaction with host molecules and epigenetic regulation, such as miR-155, required for induction of M1 phenotype of macrophages. This study aims to evaluate the relationship between macrophage polarization pattern in the tumor microenvironment and relative expression of miR-155 in EBV + DLBCLe and EBV-negative DLBCL patients. We studied 28 EBV + DLBCLe and 65 EBV-negative DLBCL patients. Tumor-associated macrophages (TAM) were evaluated by expression of CD68, CD163 and CD163/CD68 ratio (degree of M2 polarization), using tissue microarray. RNA was extracted from paraffin-embedded tumor samples for miR-155 relative expression study. We found a significantly higher CD163/CD68 ratio in EBV + DLBCLe compared to EBV-negative DLBCL. In EBV-negative DLBCL, CD163/CD68 ratio was higher among advanced-staged/high-tumor burden disease and overexpression of miR-155 was associated with decreased polarization to the M2 phenotype of macrophages. The opposite was observed in EBV + DLBCLe patients: we found a positive association between miR-155 relative expression and CD163/CD68 ratio, which was not significant after outlier exclusion. We believe that the higher CD163/CD68 ratio in this group is probably due to the presence of the EBV since it directly affects macrophage polarization towards M2 phenotype through cytokine secretion in the tumor microenvironment. Therapeutic strategies modulating miR-155 expression or preventing immuno-regulatory and pro-tumor macrophage polarization could be adjuvants in EBV + DLBCLe therapy since this entity has a rich infiltration of M2 macrophages in its tumor microenvironment.
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http://dx.doi.org/10.1007/s00262-018-2273-2DOI Listing
February 2019

Control of renal sympathetic nerve activity by neurotransmitters in the spinal cord in Goldblatt hypertension.

Brain Res 2018 11 20;1698:43-53. Epub 2018 Jun 20.

Cardiovascular Division, Department of Physiology, Universidade Federal de São Paulo, Escola Paulista de Medicina, Brazil. Electronic address:

The role of spinal cord neurons in renal sympathoexcitation remains unclear in renovascular hypertension, represented by the 2-kidney, 1-clip (2K1C) model. Thus, we aimed to assess the influence of spinal glutamatergic and AT1 angiotensin II receptors on renal sympathetic nerve activity (rSNA) in 2K1C Wistar rats. Hypertension was induced by clipping the renal artery with a silver clip. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of intrathecally (i.t.) injected kynurenic acid (KYN) or losartan (Los) on blood pressure (BP) and rSNA were analysed over 2 consecutive hours. KYN induced a significantly larger drop in rSNA among 2K1C rats than among control (CTL) rats (CTL vs. 2K1C: -8 ± 3 vs. -52 ± 9 spikes/s after 120'). Los also evoked a significantly larger drop in rSNA among 2K1C rats than among CTL rats starting at 80' after administration (CTL vs. 2K1C - 80 min: -10 ± 2 vs. -32 ± 6; 100 min: -15 ± 4 vs. -37 ± 9; 120 min: -12 ± 5 vs. -37 ± 8 spikes/s). KYN decreased BP similarly in the CTL and 2K1C groups; however, Los significantly decreased BP in the 2K1C group only. We found upregulation of AT1 gene expression in the T11-12 spinal segments in the 2K1C group but no change in gene expression for AT2 or ionotropic glutamate (NMDA, kainate and AMPA) receptors. Thus, our data show that spinal ionotropic glutamatergic and AT1 receptors contribute to increased rSNA in the 2K1C model, leading to the maintenance of hypertension; however, the participation of spinal AT1 receptors seems to be especially important in the establishment of sympathoexcitation in this model. The origins of those projections, i.e., the brain areas involved in establishing the activity of spinal glutamatergic and angiotensinergic pathways, remain unclear.
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http://dx.doi.org/10.1016/j.brainres.2018.06.025DOI Listing
November 2018

Variable role of carotid bodies in cardiovascular responses to exercise, hypoxia and hypercapnia in spontaneously hypertensive rats.

J Physiol 2018 08 12;596(15):3201-3216. Epub 2018 Feb 12.

Bristol CardioNomics Group, School of Physiology, Pharmacology and Neuroscience, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, UK.

Key Points: Carotid bodies play a critical role in maintaining arterial pressure during hypoxia and this has important implications when considering resection therapy of the carotid body in disease states such as hypertension. Curbing hypertension in patients whether resting or under stress remains a major global health challenge. We demonstrated previously the benefits of removing carotid body afferent input into the brain for both alleviating sympathetic overdrive and reducing blood pressure in neurogenic hypertension. We describe a new approach in rats for selective ablation of the carotid bodies that spares the functional integrity of the carotid sinus baroreceptors, and demonstrate the importance of the carotid bodies in the haemodynamic response to forced exercise, hypoxia and hypercapnia in conditions of hypertension. Selective ablation reduced blood pressure in hypertensive rats and re-set baroreceptor reflex function accordingly; the increases in blood pressure seen during exercise, hypoxia and hypercapnia were unaffected, abolished and augmented, respectively, after selective carotid body removal. The data suggest that carotid body ablation may trigger potential cardiovascular risks particularly during hypoxia and hypercapnia and that suppression rather than obliteration of their activity may be a more effective and safer route to pursue.

Abstract: The carotid body has recently emerged as a promising therapeutic target for treating cardiovascular disease, but the potential impact of carotid body removal on the dynamic cardiovascular responses to acute stressors such as exercise, hypoxia and hypercapnia in hypertension is an important safety consideration that has not been studied. We first validated a novel surgical approach to selectively resect the carotid bodies bilaterally (CBR) sparing the carotid sinus baroreflex. Second, we evaluated the impact of CBR on the cardiovascular responses to exercise, hypoxia and hypercapnia in conscious, chronically instrumented spontaneously hypertensive (SH) rats. The results confirm that our CBR technique successfully and selectively abolished the chemoreflex, whilst preserving carotid baroreflex function. CBR produced a sustained fall in arterial pressure in the SH rat of ∼20 mmHg that persisted across both dark and light phases (P < 0.001), with baroreflex function curves resetting around lower arterial pressure levels. The cardiovascular and respiratory responses to moderate forced exercise were similar between CBR and Sham rats. In contrast, CBR abolished the pressor response to hypoxia seen in Sham animals, although the increases in heart rate and respiration were similar between Sham and CBR groups. Both the pressor and the respiratory responses to 7% hypercapnia were augmented after CBR (P < 0.05) compared to sham. Our finding that the carotid bodies play a critical role in maintaining arterial pressure during hypoxia has important implications when considering resection therapy of the carotid body in disease states such as hypertension as well as heart failure with sleep apnoea.
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http://dx.doi.org/10.1113/JP275487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068247PMC
August 2018

Differential effects of renal denervation on arterial baroreceptor function in Goldblatt hypertension model.

Auton Neurosci 2017 12 21;208:43-50. Epub 2017 Jun 21.

Cardiovascular Division, Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil. Electronic address:

Sympathetic vasomotor activity is significantly increased in renovascular hypertension. Renal denervation (DnX) has emerged as a novel therapy for resistant hypertension to drug therapy. However, the underlying mechanisms regarding the reduction in blood pressure (BP) after DnX remain unclear. Thus, the aim of this study was to evaluate the effects of DnX of a clipped kidney on the baseline and baroreceptor reflex control of post-ganglionic sympathetic activity to the contralateral kidney (rSNA) and lumbar (lSNA) nerves in Goldblatt hypertensive rats (2K1C). Renal denervation of an ischaemic kidney (DxX - all visible bundles of nerves were dissected - 10% phenol) was performed 5weeks after clipping (gap width: 0.2mm). Ten days after DnX, BP was significantly reduced (16%) in the 2K1C compared with the undenervated 2K1C (p<0.05). DnX significantly reduced basal rSNA (control group (CT): 110±8, n=14; 2K1C: 150±8, n=12; 2K1C DnX: 89±7, spikes per second (spikes/s); p<0.05, n=8) and lSNA (CT: 137±8, n=8; 2K1C: 202±7, n=11; 2K1C DnX: 131±7, spikes/s; p<0.05, n=8) only in 2K1C rats. DnX significantly improved the arterial baroreceptor sensitivity of rSNA (CT: -2.3±0.2, n=11; 2K1C: -0.7±0.1, n=8; 2K1C DnX: -1.5±0.2, spikes/s/mmHg; p<0.05, n=5) and heart rate for tachycardic response (CT: -3.9±0.5, n=7; 2K1C: -1.9±0.1, n=8; 2K1C DnX: -3.3±0.4, bpm/mmHg; p<0.05, n=8), but not for lSNA in 2K1C rats. The results show that DnX normalized baseline sympathetic vasomotor activity to the lumbar and renal nerves, followed by a differential improvement in the arterial baroreceptor sensitivity. Whether the baroreceptor function sensitivity improvement induced by DnX is a cause or a consequence of BP reduction remains to be determined.
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http://dx.doi.org/10.1016/j.autneu.2017.06.002DOI Listing
December 2017

Reply.

J Hypertens 2017 08;35(8):1719-1720

Department of Physiology, School of Medicine, Federal University of São Paulo, São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.1097/HJH.0000000000001389DOI Listing
August 2017

Role of renal nerves in normal and pathophysiological conditions.

Auton Neurosci 2017 May 13;204:1-3. Epub 2016 Dec 13.

Department of Physiology, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.autneu.2016.12.003DOI Listing
May 2017

Stimulation of renal afferent fibers leads to activation of catecholaminergic and non-catecholaminergic neurons in the medulla oblongata.

Auton Neurosci 2017 05 19;204:48-56. Epub 2017 Jan 19.

Department of Physiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. Electronic address:

Presympathetic neurons in the rostral ventrolateral medulla (RVLM) including the adrenergic cell groups play a major role in the modulation of several reflexes required for the control of sympathetic vasomotor tone and blood pressure (BP). Moreover, sympathetic vasomotor drive to the kidneys influence natriuresis and diuresis by inhibiting the cAMP/PKA pathway and redistributing the Na/H exchanger isoform 3 (NHE3) to the body of the microvilli in the proximal tubules. In this study we aimed to evaluate the effects of renal afferents stimulation on (1) the neurochemical phenotype of Fos expressing neurons in the medulla oblongata and (2) the level of abundance and phosphorylation of NHE3 in the renal cortex. We found that electrical stimulation of renal afferents increased heart rate and BP transiently and caused activation of tyrosine hydroxylase (TH)-containing neurons in the RVLM and non-TH neurons in the NTS. Additionally, activation of the inhibitory renorenal reflex over a 30-min period resulted in increased natriuresis and diuresis associated with increased phosphorylation of NHE3 at serine 552, a surrogate for reduced activity of this exchanger, in the contralateral kidney. This effect was not dependent of BP changes considering that no effects on natriuresis or diuresis were found in the ipsilateral-stimulated kidney. Therefore, our data show that renal afferents leads to activation of catecholaminergic and non-catecholaminergic neurons in the medulla oblongata. When renorenal reflex is induced, NHE3 exchanger activity appears to be decreased, resulting in decreased sodium and water reabsorption in the contralateral kidney.
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http://dx.doi.org/10.1016/j.autneu.2017.01.003DOI Listing
May 2017

The antioxidant effects of green tea reduces blood pressure and sympathoexcitation in an experimental model of hypertension.

J Hypertens 2017 02;35(2):348-354

aDepartment of Physiology, Escola Paulista de Medicina, Universidade Federal de São PaulobDepartment of Biomaterials and Oral Biology, Faculdade de Odontologia, Universidade de São PaulocDepartment of Medicine, Universidade Federal de São Paulo, São PaulodDepartment of Plant Biology, Universidade Estadual de Campinas, CampinaeLaboratory of Multidisciplinary Research, Universidade São Francisco, São Paulo, Brazil.

Background: Oxidative stress is a key mediator in the maintenance of sympathoexcitation and hypertension in human and experimental models. Green tea is widely known to be potent antioxidant.

Objective: We aimed to evaluate the effects of green tea in a model of hypertension.

Methods: Hypertension was induced by the nitric oxide synthase inhibitor [N-nitro-L-arginine-methyl-ester (L-NAME); 20 mg/kg per day, orally, for 2 weeks] in male Wistar rats. After the first week of L-NAME treatment, animals received green tea ad libitum for 1 week. At the end of the treatment period, blood pressure, heart rate, baroreflex sensitivity, renal sympathetic nerve activity, and vascular and systemic oxidative stress were assessed.

Results: L-NAME-treated animals exhibited an increase in blood pressure (165 ± 2 mmHg) compared with control rats (103 ± 1 mmHg) and green tea treatment reduced hypertension (119 ± 1 mmHg). Hypertensive animals showed a higher renal sympathetic nerve activity (161 ± 12 spikes/s) than the control group (97 ± 2 spikes/s), and green tea also decreased this parameter in the hypertensive treated group (125 ± 5 spikes/s). Arterial baroreceptor function and vascular and systemic oxidative stress were improved in hypertensive rats after green tea treatment.

Conclusions: Taken together, short-term green tea treatment improved cardiovascular function in a hypertension model characterized by sympathoexcitation, which may be because of its antioxidant properties.
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http://dx.doi.org/10.1097/HJH.0000000000001149DOI Listing
February 2017

Total renal denervation reduces sympathoexcitation to different target organs in a model of chronic kidney disease.

Auton Neurosci 2017 05 1;204:81-87. Epub 2016 Dec 1.

Cardiovascular Division, Department of Physiology, Universidade Federal de São Paulo, Brazil. Electronic address:

It is known that increased sympathetic nerve activity in chronic kidney disease (CKD) progressively worsens kidney function and hypertension. We tested the hypothesis that total renal denervation contributes to reduce sympathetic activation to different beds and improves renal function in 5/6 nephrectomy model of CKD in male Wistar rats. After eight weeks of 5/6 nephrectomy surgery there was an increase in mean arterial pressure (CKD 179±22mmHg, n=6 vs. control animals 108±9; p<0.05, n=6) with no changes in heart rate (HR). Sympathetic nerve activity was increased at different levels to the remaining kidney, splanchnic and lumbar beds compared to control (CTL) group (CKD rSNA: 150±50, n=9 vs. CTL 96±15, n=9; CKD sSNA: 129±51, n=5 vs. CTL 34±14, n=6; CKD lSNA: 203±35, n=8 vs. CTL 146±21, spikes/s, n=7, p<0.05). Three weeks after total renal denervation (DNX) MAP was normalized in the CKD rats (124±19mmHg, n=5, p<0.05), with no change in HR. The lSNA was normalized (151±40, n=5, vs. CKD 203±35 spikes/s, n=8) and sSNA was decreased in 49% (64±34, n=5 vs. CKD 129±51 spikes/s, n=5, p<0.05). Renal function, assessed by creatinine plasma levels was improved after renal denervation (CKD 1.50±0.64, n=8; vs. CKD+DNX 0.82±0.22mg/mL, n=8, p<0.05). These findings demonstrate that renal nerves contribute to the maintenance of hypertension in CKD by increasing sympathoexcitation to other beds.
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http://dx.doi.org/10.1016/j.autneu.2016.11.006DOI Listing
May 2017

Increased Dietary Salt Changes Baroreceptor Sensitivity and Intrarenal Renin-Angiotensin System in Goldblatt Hypertension.

Am J Hypertens 2017 Jan 14;30(1):28-36. Epub 2016 Sep 14.

Cardiovascular Division-Department of Physiology, Universidade Federal de São Paulo, São Paulo, Brazil;

Background: Renovascular hypertension (2-kidney 1-clip model (2K1C)) is characterized by renin-angiotensin system (RAS) activation. Increased Angiotensin II (AngII) leads to sympathoexcitation, oxidative stress, and alterations in sodium and water balance.

Aim: The aim of this study was to evaluate whether a discrete increase in sodium chloride intake in 2K1C rats leads to changes in cardiovascular and autonomic function, oxidative stress, and renin angiotensin aldosterone system.

Methods: After 4 weeks of induction of hypertension, rats were fed a normal sodium diet (0.4% NaCl) or a high-sodium diet (2% NaCl) for 2 consecutive weeks. Experiments were carried out for 6 weeks after clipping. Mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), arterial baroreflex control of rSNA, and heart rate (HR) were assessed. Thiobarbituric acid reactive substances and glutathione were measured as indicators of systemic oxidative stress. Angiostensin-converting enzyme (ACE), ACE2, and angiotensinogen were evaluated in clipped and unclipped kidneys as also urinary angiotensinogen and plasma renin activity. Angiotensinogen, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) and ACE2 in clipped and unclipped kidneys were evaluated.

Results: High-sodium diet did not change systemic oxidative stress, and basal values of MAP, HR, or rSNA; however, increased renal (-0.7±0.2 vs. -1.5±0.1 spikes/s/mm Hg) and cardiac (-0.9±0.14 vs. -1.5±0.14 bpm/mm Hg) baroreceptor reflex sensitivity in 2K1C rats. Although there was no alteration in PRA, a high-salt diet significantly decreased urinary angiotensinogen, ACE, and ACE2 expressions in the clipped and unclipped kidneys.

Conclusions: Increased arterial baroreceptor control associated with a suppression of the intrarenal RAS in the 2K1C rats on high-salt diet provide a salt-resistant effect on hypertension and sympathoexcitation in renovascular hypertensive rats.
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http://dx.doi.org/10.1093/ajh/hpw107DOI Listing
January 2017

Autonomic and Renal Alterations in the Offspring of Sleep-Restricted Mothers During Late Pregnancy.

Clinics (Sao Paulo) 2016 Sep;71(9):521-7

Escola Paulista de Medicina - UNIFESP, Departamento de Fisiologia, São Paulo/SP, Brazil.

Objectives: Considering that changes in the maternal environment may result in changes in progeny, the aim of this study was to investigate the influence of sleep restriction during the last week of pregnancy on renal function and autonomic responses in male descendants at an adult age.

Methods: After confirmation of pregnancy, female Wistar rats were randomly assigned to either a control or a sleep restriction group. The sleep-restricted rats were subjected to sleep restriction using the multiple platforms method for over 20 hours per day between the 14th and 20th day of pregnancy. After delivery, the litters were limited to 6 offspring that were designated as offspring from control and offspring from sleep-restricted mothers. Indirect measurements of systolic blood pressure (BPi), renal plasma flow, glomerular filtration rate, glomerular area and number of glomeruli per field were evaluated at three months of age. Direct measurements of cardiovascular function (heart rate and mean arterial pressure), cardiac sympathetic tone, cardiac parasympathetic tone, and baroreflex sensitivity were evaluated at four months of age.

Results: The sleep-restricted offspring presented increases in BPi, glomerular filtration rate and glomerular area compared with the control offspring. The sleep-restricted offspring also showed higher basal heart rate, increased mean arterial pressure, increased sympathetic cardiac tone, decreased parasympathetic cardiac tone and reduced baroreflex sensitivity.

Conclusions: Our data suggest that reductions in sleep during the last week of pregnancy lead to alterations in cardiovascular autonomic regulation and renal morpho-functional changes in offspring, triggering increases in blood pressure.
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http://dx.doi.org/10.6061/clinics/2016(09)07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004573PMC
September 2016

Digitoxin improves cardiovascular autonomic control in rats with heart failure.

Can J Physiol Pharmacol 2016 Jun 17;94(6):643-50. Epub 2016 Jan 17.

a Cardiovascular Division, Department of Physiology, Universidade Federal de São Paulo, Escola Paulista de Medicina, Rua Botucatu, 862, CEP 04023-060, São Paulo, SP, Brazil.

The effects of chronic treatment with digitoxin on arterial baroreceptor sensitivity for heart rate (HR) and renal sympathetic nerve activity (rSNA) control, cardiopulmonary reflex, and autonomic HR control in an animal model of heart failure (HF) were evaluated. Wistar rats were treated with digitoxin, which was administered in their daily feed (1 mg/kg per day) for 60 days. The following 3 experimental groups were evaluated: sham, HF, and HF treated with digitoxin (HF + DIG). We observed an increase in rSNA in the HF group (190 ± 29 pps, n = 5) compared with the sham group (98 ± 14 pps, n = 5). Digitoxin treatment prevented an increase in rSNA (98 ± 14 pps, n = 7). Therefore, arterial baroreceptor sensitivity was decreased in the HF group (-1.24 ± 0.07 bpm/mm Hg, n = 8) compared with the sham group (-2.27 ± 0.23 bpm/mm Hg, n = 6). Digitoxin did not alter arterial baroreceptor sensitivity in the HF + DIG group. Finally, the HF group showed an increased low frequency band (LFb: 23 ± 5 ms(2), n = 8) and a decreased high frequency band (HFb: 77 ± 5 ms(2), n = 8) compared with the sham group (LFb: 14 ± 3 ms(2); HFb: 86 ± 3 ms(2), n = 9); the HF+DIG group exhibited normalized parameters (LFb: 15 ± 3 ms(2); HFb: 85 ± 3 ms(2), n = 9). In conclusion, the benefits of decreasing rSNA are not directly related to improvements in peripheral cardiovascular reflexes; such occurrences are due in part to changes in the central nuclei of the brain responsible for autonomic cardiovascular control.
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http://dx.doi.org/10.1139/cjpp-2015-0354DOI Listing
June 2016

Differential Sympathetic Vasomotor Activation Induced by Liver Cirrhosis in Rats.

PLoS One 2016 7;11(4):e0152512. Epub 2016 Apr 7.

Department of Physiology, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil.

We tested the hypothesis that there is a topographical sympathetic activation in rats submitted to experimental cirrhosis. Baseline renal (rSNA) and splanchnic (sSNA) sympathetic nerve activities were evaluated in anesthetized rats. In addition, we evaluated main arterial pressure (MAP), heart rate (HR), and baroreceptor reflex sensitivity (BRS). Cirrhotic Wistar rats were obtained by bile duct ligation (BDL). MAP and HR were measured in conscious rats, and cardiac BRS was assessed by changes in blood pressure induced by increasing doses of phenylephrine or sodium nitroprusside. The BRS and baseline for the control of sSNA and rSNA were also evaluated in urethane-anesthetized rats. Cirrhotic rats had increased baseline sSNA (BDL, 102 vs control, 58 spikes/s; p<0.05), but no baseline changes in the rSNA compared to controls. These data were accompanied by increased splanchnic BRS (p<0.05) and decreased cardiac (p<0.05) and renal BRS (p<0.05). Furthermore, BDL rats had reduced basal MAP (BDL, 93 vs control, 101 mmHg; p<0.05) accompanied by increased HR (BDL, 378 vs control, 356; p<0.05). Our data have shown topographical sympathetic activation in rats submitted to experimental cirrhosis. The BDL group had increased baseline sSNA, independent of dysfunction in the BRS and no changes in baseline rSNA. However, an impairment of rSNA and HR control by arterial baroreceptor was noted. We suggest that arterial baroreceptor impairment of rSNA and HR is an early marker of cardiovascular dysfunction related to liver cirrhosis and probably a major mechanism leading to sympathoexcitation in decompensated phase.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152512PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824371PMC
August 2016
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