Assessing the efficacy of renal denervation in patients with resistant arterial hypertension: a systematic review and meta-analysis

BACKGROUND/INTRODUCTION: Renal denervation (RDN) is an innovative procedure designed to regulate the renal sympathetic nervous system for the control of arterial hypertension (HTN). RDN emerges as an alternative for patients with resistant arterial hypertension. Despite this, the clinical efficacy of RDN is still not fully understood. PURPOSE: Therefore, we aimed to compare the use of renal denervation versus sham procedure or pharmacological treatment in patients with resistant HTN. METHODS: We performed a systematic search of PubMed, Embase, Cochrane databases for randomized controlled trials (RCTs) comparing the use of renal denervation procedures and sham procedure or pharmacological treatment in patients with resistant HTN. Statistical analyses were performed using R Studio 4.3.2. Heterogeneity was examined with the Cochran Q test I² statistics. Mean difference (MD) with 95% CI were pooled across trials. P values of < 0.05 were considered statistically significant. The primary continuous outcomes of interest were change from baseline in systolic blood pressure (SBP), diastolic blood pressure (DBP) and serum creatinine. RESULTS: Twenty-one RCTs reporting data on 3345 patients were included in this meta-analysis. Among them, 2004 (59,91%) received renal denervation and 1341 (40,09%) received pharmacological treament or sham procedure. Follow-up ranged from 2 to 48 months. The mean age of patients between studies ranged from 50.7 to 65 years. Compared to control group, RDN significantly reduced Systolic Blood Pressure (SBP) (MD -3.53 mmHg; 95% CI -5.94 to -1.12; I2 = 74%) and Diastolic Blood Pressure (DBP) (MD -1.48 mmHg; 95% CI -2.56 to -0.40; I2 = 51%). Regarding serum creatinine (MD -2.51; 95% CI -7.90 to 2.87; I2 = 40%) there was no significant difference between RDN and control groups. CONCLUSION: In this meta-analysis of RCTs of patients with resistant HTN, RDN was associated with a reduction in SBP and DBP compared to sham procedure or pharmacological treatment.

Role of the sympathetic nervous system in cancer-associated cachexia and tumor progression in tumor-bearing BALB/c mice.

BACKGROUND: Adipose and muscle tissue wasting outlines the cachectic process during tumor progression. The sympathetic nervous system (SNS) is known to promote tumor progression and research suggests that it might also contribute to cancer-associated cachexia (CAC) energetic expenditure through fat wasting. METHODS: We sympathectomized L5178Y-R tumor-bearing male BALB/c mice by intraperitoneally administering 6-hydroxydopamine to evaluate morphometric, inflammatory, and molecular indicators of CAC and tumor progression. RESULTS: Tumor burden was associated with cachexia indicators, including a 10.5% body mass index (BMI) decrease, 40.19% interscapular, 54% inguinal, and 37.17% visceral adipose tissue loss, a 12% food intake decrease, and significant (p = 0.038 and p = 0.0037) increases in the plasmatic inflammatory cytokines IL-6 and IFN-γ respectively. Sympathectomy of tumor-bearing mice was associated with attenuated BMI and visceral adipose tissue loss, decreased interscapular Ucp-1 gene expression to basal levels, and 2.6-fold reduction in Mmp-9 relative gene expression, as compared with the unsympathectomized mice control group. CONCLUSION: The SNS contributes to CAC-associated morphometric and adipose tissue alterations and promotes tumor progression in a murine model.

Abnormal neurovascular control during central and peripheral chemoreceptors stimulation in heart failure patients with preserved ejection fraction.

PURPOSE: Central and peripheral chemoreceptors are hypersensitized in patients with heart failure with reduced ejection fraction. Whether this autonomic alteration occurs in patients with heart failure with preserved ejection fraction (HFpEF) remains little known. We test the hypothesis that the central and peripheral chemoreflex control of muscle sympathetic nerve activity (MSNA) is altered in HFpEF. METHODS: Patients aged 55-80 years with symptoms of heart failure, body mass index ≤ 35 kg/m2, left ventricular ejection fraction > 50%, left atrial volume index > 34 mL/m2, left ventricular early diastolic filling velocity and early diastolic tissue velocity of mitral annulus ratio (E/e' index) ≥ 13, and BNP levels > 35 pg/mL were included in the study (HFpEF, n = 9). Patients without heart failure with preserved ejection fraction (non-HFpEF, n = 9), aged-paired, were also included in the study. Peripheral chemoreceptors stimulation (10% O2 and 90% N2, with CO2 titrated) and central chemoreceptors stimulation (7% CO2 and 93% O2) were conducted for 3 min. MSNA was evaluated by microneurography technique, and forearm blood flow (FBF) by venous occlusion plethysmography. RESULTS: During hypoxia, MSNA responses were greater (p < 0.001) and FBF responses were lower in patients with HFpEF (p = 0.006). Likewise, MSNA responses during hypercapnia were higher (p < 0.001) and forearm vascular conductance (FVC) levels were lower (p = 0.030) in patients with HFpEF. CONCLUSIONS: Peripheral and central chemoreflex controls of MSNA are hypersensitized in patients with HFpEF, which seems to contribute to the increase in MSNA in these patients. In addition, peripheral and central chemoreceptors stimulation in patients with HFpEF causes muscle vasoconstriction.

Reduced sympathetic activity is associated with the development of pain and muscle atrophy in a female rat model of fibromyalgia.

Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain accompanied by fatigue and muscle atrophy. Although its etiology is not known, studies have shown that FM patients exhibit altered function of the sympathetic nervous system (SNS), which regulates nociception and muscle plasticity. Nevertheless, the precise SNS-mediated mechanisms governing hyperalgesia and skeletal muscle atrophy in FM remain unclear. Thus, we employed two distinct FM-like pain models, involving intramuscular injections of acidic saline (pH 4.0) or carrageenan in prepubertal female rats, and evaluated the catecholamine content, adrenergic signaling and overall muscle proteolysis. Subsequently, we assessed the contribution of the SNS to the development of hyperalgesia and muscle atrophy in acidic saline-injected rats treated with clenbuterol (a selective ß2-adrenergic receptor agonist) and in animals maintained under baseline conditions and subjected to epinephrine depletion through adrenodemedullation (ADM). Seven days after inducing an FM-like model with acidic saline or carrageenan, we observed widespread mechanical hyperalgesia along with loss of strength and/or muscle mass. These changes were associated with reduced catecholamine content, suggesting a common underlying mechanism. Notably, treatment with a ß2-agonist alleviated hyperalgesia and prevented muscle atrophy in acidic saline-induced FM-like pain, while epinephrine depletion induced mechanical hyperalgesia and increased muscle proteolysis in animals under baseline conditions. Together, the results suggest that reduced sympathetic activity is involved in the development of pain and muscle atrophy in the murine model of FM analyzed.

Chagas Cardiomyopathy and Myocardial Sympathetic Denervation.

PURPOSE OF REVIEW: More than a century since its discovery, the pathogenesis of Chagas heart disease (CHD) remains incompletely understood. The role of derangements in the autonomic control of the heart in triggering malignant arrhythmia before the appearance of contractile ventricular impairment was reviewed. RECENT FINDINGS: Although previous investigations had demonstrated the anatomical and functional consequences of parasympathetic dysautonomia upon the heart rate control, only recently, coronary microvascular disturbances and sympathetic denervation at the ventricular level have been reported in patients and experimental models of CHD, exploring with nuclear medicine methods their impact on the progression of myocardial dysfunction and cardiac arrhythmias. More important than parasympathetic impaired sinus node regulation, recent evidence indicates that myocardial sympathetic denervation associated with coronary microvascular derangements is causally related to myocardial injury and arrhythmia in CHD. Additionally, 123I-MIBG imaging is a promising tool for risk stratification of progression of ventricular dysfunction and sudden death.

Anatomical study with clinical significance of communicating and visceral branching of the cervical and upper thoracic sympathetic trunk.

Current advances in the management of the autonomic nervous system in various cardiovascular diseases, and in treatments for pain or sympathetic disturbances in the head, neck, or upper limbs, necessitate a thorough understanding of the anatomy of the cervicothoracic sympathetic trunk. Our objective was to enhance our understanding of the origin and distribution of communicating branches and visceral cervicothoracic sympathetic nerves in human fetuses. This was achieved through a comprehensive topographic systematization of the branching patterns observed in the cervical and upper thoracic ganglia, along with the distribution of communicating branches to each cervical spinal nerve. We conducted detailed sub-macroscopic dissections of the cervical and thoracic regions in 20 human fetuses (40 sides). The superior and cervicothoracic ganglia were identified as the cervical sympathetic ganglia that provided the most communicating branches on both sides. The middle and accessory cervical ganglia contributed the fewest branches, with no significant differences between the right and left sides. The cervicothoracic ganglion supplied sympathetic branches to the greatest number of spinal nerves, spanning from C5 to T2. The distribution of communicating branches to spinal nerves was non-uniform. Notably, C3, C4, and C5 received the fewest branches, and more than half of the specimens showed no sympathetic connections. C1 and C2 received sympathetic connections exclusively from the superior ganglion. Spinal nerves that received more branches often did so from multiple ganglia. The vertebral nerve provided deep communicating branches primarily to C6, with lesser contributions to C7, C5, and C8. The vagus nerve stood out as the cranial nerve with the most direct sympathetic connections. The autonomic branching pattern and connections of the cervicothoracic sympathetic trunk are significantly variable in the fetus. A comprehensive understanding of the anatomy of the cervical and upper thoracic sympathetic trunk and its branches is valuable during autonomic interventions and neuromodulation. This knowledge is particularly relevant for addressing various autonomic cardiac diseases and for treating pain and vascular dysfunction in the head, neck, and upper limbs.

Evening but not morning aerobic training improves sympathetic activity and baroreflex sensitivity in elderly patients with treated hypertension.

The blood pressure-lowering effect of aerobic training is preceded by improving cardiovascular autonomic control. We previously demonstrated that aerobic training conducted in the evening (ET) induces a greater decrease in blood pressure than morning training (MT). To study whether the greater blood pressure decrease after ET occurs through better cardiovascular autonomic regulation, this study aimed to compare MT versus ET on muscle sympathetic nerve activity (MSNA) and baroreflex sensitivity (BRS) in treated patients with hypertension. Elderly patients treated for hypertension were randomly allocated into MT (n = 12, 07.00-10.00 h) or ET (n = 11, 17.00-20.00 h) groups. Both groups trained for 10 weeks, 3 times/week, cycling for 45 min at moderate intensity. Beat-to-beat blood pressure (finger photoplethysmography), heart rate (electrocardiography) and MSNA (microneurography) were assessed at the initial and final phases of the study at baseline and during sequential bolus infusions of sodium nitroprusside and phenylephrine (modified-Oxford technique) to evaluate cardiac and sympathetic BRS. Mean blood pressure decreased significantly after ET but not after MT (-9 ± 11 vs. -1 ± 8 mmHg, P = 0.042). MSNA decreased significantly only after ET with no change after MT (-12 ± 5 vs. -3 ± 7 bursts/100 heart beats, P = 0.013). Sympathetic BRS improved after ET but not after MT (-0.8 ± 0.7 vs. 0.0 ± 0.8 bursts/100 heart beats/mmHg, P = 0.052). Cardiac BRS improved similarly in both groups (ET: +1.7 ± 1.8 vs. MT: +1.4 ± 1.9 ms/mmHg, Pphase  ≤ 0.001). In elderly patients treated for hypertension, only ET decreased mean blood pressure and MSNA and improved sympathetic BRS. These findings revealed that the sympathetic nervous system has a key role in ET's superiority to MT in blood pressure-lowering effect. KEY POINTS: Reducing muscle nerve sympathetic activity and increasing sympathetic baroreflex sensitivity plays a key role in promoting the greater blood pressure reduction observed with evening training. These findings indicated that simply changing the timing of exercise training may offer additional benefits beyond antihypertensive medications, such as protection against sympathetic overdrive and loss of baroreflex sensitivity, independent markers of mortality. Our new findings also suggest new avenues of investigation, such as the possibility that evening aerobic training may be beneficial in other clinical conditions with sympathetic overdrive, such as congestive heart failure and hypertrophic cardiomyopathy.

Intra- and interday reliability of sympathetic transduction to blood pressure in young, healthy adults.

Microneurographic recordings of muscle sympathetic nerve activity (MSNA) and the succeeding changes in beat-to-beat blood pressure (i.e., sympathetic transduction) provide important insights into the neural control of the circulation in humans. Despite its widespread use, the reliability of this technique remains unknown. Herein, we assessed the intra- and interday test-retest reliability of signal-averaging sympathetic transduction to blood pressure. Data were analyzed from 15 (9 M/6 F) young, healthy participants who completed two baseline recordings of fibular nerve MSNA separated by 60 min (intraday). The interday reliability was obtained in a subset of participants (n = 13, 9 M/4 F) who completed a follow-up MSNA study. Signal-averaging sympathetic transduction was quantified as peak change in diastolic (DBP) and mean arterial pressure (MAP) following a burst of MSNA. Analyses were also computed considering different MSNA burst sizes (quartiles of normalized MSNA) and burst patterns (singlets, couplets, triplets, and quadruplets+), as well as nonburst responses. Intraclass-correlation coefficients (ICCs) were used as the main reliability measure. Peak changes in MAP [intraday: ICC = 0.76 (0.30-0.92), P = 0.006; interday: ICC = 0.91 (0.63-0.97), P < 0.001] demonstrated very good to excellent reliability. Sympathetic transduction of MSNA burst size displayed moderate to very good reliability, though the reliability of MSNA burst pattern was poor to very good. Nonburst responses revealed poor intraday [ICC = 0.37 (-1.05 to 0.80), P = 0.21], but very good interday [ICC = 0.76 (0.18-0.93), P = 0.01] reliability. Intraday reliability measures were consistently lower than interday reliability. Similar results were obtained using DBP. Collectively, these findings provide evidence that the burst-triggering signal-averaging technique is a reliable measure of sympathetic transduction to blood pressure in young, healthy adults.NEW & NOTEWORTHY We found that signal-averaging sympathetic transduction to blood pressure displayed very good to excellent intra- and interday test-retest reliability in healthy, young adults. Reliability analyses according to muscle sympathetic burst size, burst pattern, and nonburst response were less consistent. Results were similar when using diastolic or mean arterial pressure in the transduction calculation. These findings suggest that the signal-averaging technique can be used with confidence to investigate sympathetic transduction to blood pressure in humans across time.

Multi-Organ Increase in Norepinephrine Levels after Central Leptin Administration and Diet-Induced Obesity.

Autonomic innervation is important to regulate homeostasis in every organ of the body. The sympathetic nervous system controls several organs associated with metabolism and reproduction, including adipose tissue, the liver, and the ovaries. The sympathetic nervous system is controlled within the central nervous system by neurons located in the hypothalamus, which in turn are regulated by hormones like leptin. Leptin action in the hypothalamus leads to increased sympathetic activity in the adipose tissue. In this short report, we propose that leptin action in the brain also controls the sympathetic innervation of other organs like the liver and the ovary. We performed two experiments: We performed an intracerebroventricular (ICV) injection of leptin and measured norepinephrine levels in several organs, and we used a validated model of overnutrition and obesity to evaluate whether an increase in leptin levels coexists with high levels of norepinephrine in the liver and ovaries. Norepinephrine was measured by ELISA in adipose tissue and by HPLC-EC in other tissues. Leptin was measured by ELISA. We found that the ICV injection of leptin increases norepinephrine levels in several organs, including the liver and ovaries. Also, we found that diet-induced obesity leads to an increase in leptin levels while inducing an increase in norepinephrine levels in the liver and ovaries. Finally, since hyperactivity of the sympathetic nervous system is observed both in non-alcoholic fatty liver disease and polycystic ovary syndrome, we think that an increase in norepinephrine levels induced by hyperleptinemia could be involved in the pathogenesis of both diseases.

Neurovascular and hemodynamic responses to mental stress and exercise in severe COVID-19 survivors.

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m2) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m2) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (P < 0.001), and FBF and FVC responses were attenuated (P < 0.05). MAP was similar between the groups (P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (P > 0.05). MAP was lower in COVID-19 survivors (P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

Deletion of the Transient Receptor Potential Vanilloid 1 Channel Attenuates Sympathoexcitation and Hypertension and Improves Glomerular Filtration Rate in 2-Kidney-1-Clip Rats.

BACKGROUND: Renal denervation lowers arterial blood pressure in both clinical populations and multiple experimental models of hypertension. This therapeutic effect is partly attributed to the removal of overactive renal sensory nerves. The TRPV1 (transient receptor potential vanilloid 1) channel is highly expressed in renal sensory nerves and detects changes in noxious and mechanosensitive stimuli, pH, and chemokines. However, the extent to which TRPV1 channels contribute to 2-kidney-1-clip (2K1C) renovascular hypertension has not been tested. METHODS: We generated a novel Trpv1-/- (TRPV1 knockout) rat using CRISPR/Cas9 and 26-bp deletion in exon 3 and induced 2K1C hypertension. RESULTS: The majority (85%) of rat renal sensory neurons retrogradely labeled from the kidney were TRPV1-positive. Trpv1-/- rats lacked TRPV1 immunofluorescence in the dorsal root ganglia, had a delayed tail-flick response to hot but not cold water, and lacked an afferent renal nerve activity response to intrarenal infusion of the TRPV1 agonist capsaicin. Interestingly, 2K1C hypertension was significantly attenuated in male Trpv1-/- versus wild-type rats. 2K1C hypertension significantly increased the depressor response to ganglionic blockade, total renal nerve activity (efferent and afferent), and afferent renal nerve activity in wild-type rats, but these responses were attenuated in male Trpv1-/- rats. 2K1C hypertension was attenuated in female rats with no differences between female strains. Finally, glomerular filtration rate was reduced by 2K1C in wild-type rats but improved in Trpv1-/- rats. CONCLUSIONS: These findings suggest that renovascular hypertension requires activation of the TRPV1 channel to elevate renal afferent and sympathetic nerve activity, reduce glomerular filtration rate, and increase arterial blood pressure.

Evidences That Sympathetic Overactivity and Neurogenic Hypertension Correlate with Changes in the Respiratory Pattern in Rodent Models of Experimental Hypoxia.

The main question of this chapter is as follows: What is the contribution of changes in the sympathetic-respiratory coupling to the hypertension observed in some experimental models of hypoxia? Although there is evidence supporting the concept that sympathetic-respiratory coupling is increased in different models of experimental hypoxia [chronic intermittent hypoxia (CIH) and sustained hypoxia (SH)], it was also observed that in some strains of rats and in mice, these experimental models of hypoxia do not affect the sympathetic-respiratory coupling and the baseline arterial pressure. The data from studies performed in rats (different strains, male and female, and in the natural sleep cycle) and mice submitted to chronic CIH or SH are critically discussed. The main message from these studies performed in freely moving rodents and in the in situ working heart-brainstem preparation is that experimental hypoxia changes the respiratory pattern, which correlates with increased sympathetic activity and may explain the hypertension observed in male and female rats previously submitted to CIH or SH.

Sympathetic control of the coronary circulation during trigeminal nerve stimulation in humans.

PURPOSE: We sought to investigate the sympathetic mechanism controlling coronary circulation during trigeminal nerve stimulation in healthy women. METHODS: The protocol consisted of 3 min of trigeminal nerve stimulation (TGS) with cold stimuli to the face, in two conditions: (1) control and ß-blockade (oral propranolol), and (2) control and α-blockade (oral prazosin). RESULTS: Thirty-one healthy young subjects (women: n = 13; men: n = 18) participated in the study. By design, TGS decreased heart rate (HR), and increased blood pressure (BP) and cardiac output (CO). Before the ß-blockade coronary blood velocity (CBV-Δ1.4 ± 1.3 cm s-1) increased along with the decrease of coronary vascular conductance index (CVCi-Δ-0.04 ± 0.04 cm s-1 mmHg-1) during TGS and the ß-blockade abolished the CBV increase and a further decrease of CVCi was observed with TGS (Δ-0.06 ± 0.07 cm s-1 mmHg-1). During the α-blockade condition before the blockade, the CBV increased (Δ0.93 ± 1.48 cm s-1) along with the decrease of CVCi (Δ-0.05 ± 1.12 cm s-1 mmHg-1) during TGS, after the α-blockade CBV (Δ0.98 ± cm s-1) and CVCi (Δ-0.03 ± 0.06 cm s-1 mmHg-1) response to TGS did not change. CONCLUSION: Coronary circulation increases during sympathetic stimulation even with a decrease in heart rate.

Autonomic Regulation of Inflammation in Conscious Animals.

Bioelectronic medicine is a novel field in modern medicine based on the specific neuronal stimulation to control organ function, cardiovascular, and immune homeostasis. However, most studies addressing neuromodulation of the immune system have been conducted on anesthetized animals, which can affect the nervous system and neuromodulation. Here, we review recent studies involving conscious experimental rodents (rats and mice) to better understand the functional organization of neural control of immune homeostasis. We highlight typical experimental models of cardiovascular regulation, such as electrical activation of the aortic depressor nerve or the carotid sinus nerve, bilateral carotid occlusion, the Bezold-Jarisch reflex, and intravenous administration of the bacterial endotoxin lipopolysaccharide. These models have been used to investigate the relationship between neuromodulation of the cardiovascular and immune systems in conscious rodents (rats and mice). These studies provide critical information about the neuromodulation of the immune system, particularly the role of the autonomic nervous system, i.e., the sympathetic and parasympathetic branches acting both centrally (hypothalamus, nucleus ambiguus, nucleus tractus solitarius, caudal ventrolateral medulla, and rostral ventrolateral medulla), and peripherally (particularly spleen and adrenal medulla). Overall, the studies in conscious experimental models have certainly highlighted to the reader how the methodological approaches used to investigate cardiovascular reflexes in conscious rodents (rats and mice) can also be valuable for investigating the neural mechanisms involved in inflammatory responses. The reviewed studies have clinical implications for future therapeutic approaches of bioelectronic modulation of the nervous system to control organ function and physiological homeostasis in conscious physiology.

Neurogenic Background for Emotional Stress-Associated Hypertension.

PURPOSE OF REVIEW: The response to natural stressors involves both cardiac stimulation and vascular changes, primarily triggered by increases in sympathetic activity. These effects lead to immediate flow redistribution that provides metabolic support to priority target organs combined with other key physiological responses and cognitive strategies, against stressor challenges. This extremely well-orchestrated response that was developed over millions of years of evolution is presently being challenged, over a short period of time. In this short review, we discuss the neurogenic background for the origin of emotional stress-induced hypertension, focusing on sympathetic pathways from related findings in humans and animals. RECENT FINDINGS: The urban environment offers a variety of psychological stressors. Real or anticipatory, emotional stressors may increase baseline sympathetic activity. From routine day-to-day traffic stress to job-related anxiety, chronic or abnormal increases in sympathetic activity caused by emotional stressors can lead to cardiovascular events, including cardiac arrhythmias, increases in blood pressure and even sudden death. Among the various alterations proposed, chronic stress could modify neuroglial circuits or compromise antioxidant systems that may alter the responsiveness of neurons to stressful stimuli. These phenomena lead to increases in sympathetic activity, hypertension and consequent cardiovascular diseases. The link between anxiety, emotional stress, and hypertension may result from an altered neuronal firing rate in central pathways controlling sympathetic activity. The participation of neuroglial and oxidative mechanisms in altered neuronal function is primarily involved in enhanced sympathetic outflow. The significance of the insular cortex-dorsomedial hypothalamic pathway in the evolution of enhanced overall sympathetic outflow is discussed.

Central angiotensin 1-7 triggers brown fat thermogenesis.

We tested the hypothesis that third ventricular (3V) injections of angiotensin 1-7 (Ang 1-7) increases thermogenesis in brown adipose tissue (BAT), and whether the Mas receptor mediates this response. First, in male Siberian hamsters (n = 18), we evaluated the effect of Ang 1-7 in the interscapular BAT (IBAT) temperature and, using selective Mas receptor antagonist A-779, the role of Mas receptor in this response. Each animal received 3V injections (200 nL), with 48 h intervals: saline; Ang 1-7 (0.03, 0.3, 3, and 30 nmol); A-779 (3 nmol); and Ang 1-7 (0.3 nmol) + A-779 (3 nmol). IBAT temperature increased after 0.3 nmol Ang 1-7 compared with Ang 1-7 + A-779 at 20, 30, and 60 min. Also, 0.3 nmol Ang 1-7 increased IBAT temperature at 10 and 20 min, and decreased at 60 min compared with pretreatment. IBAT temperature decreased after A-779 at 60 min and after Ang 1-7 + A-779 at 30 and 60 min compared with the respective pretreatment. A-779 and Ang 1-7 + A-779 decreased core temperature at 60 min compared with 10 min. Then, we evaluated blood and tissue Ang 1-7 levels, and the expression of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) in IBAT. Male Siberian hamsters (n = 36) were killed 10 min after one of the injections. No changes were observed in blood glucose, serum and IBAT Ang 1-7 levels, and ATGL. Ang 1-7 (0.3 nmol) increased p-HSL expression compared with A-779 and increased p-HSL/HSL ration compared with other injections. Ang 1-7 and Mas receptor immunoreactive cells were found in brain regions that coincide with the sympathetic nerves outflow to BAT. In conclusion, 3V injection of Ang 1-7 induced thermogenesis in IBAT in a Mas receptor-dependent manner.

Sympathetic dysregulation induced by postnatal intermittent hypoxia.

STUDY OBJECTIVES: Exposure to postnatal chronic intermittent hypoxia (pCIH), as experienced in sleep-disordered breathing, is a risk factor for developing cardiorespiratory diseases in adulthood. pCIH causes respiratory instability and motor dysfunction that persist until adult life. In this study, we investigated the impact of pCIH on the sympathetic control of arterial pressure in rats. METHODS AND RESULTS: Neonate male Holtzman rats (P0-1) were exposed to pCIH (6% O2 for 30 seconds, every 10 minutes, 8 h/day) during their first 10-15 days of life, while control animals were maintained under normoxia. In early adult life (P25-40), freely behaving pCIH animals (n = 13) showed higher baseline arterial pressure levels linked to augmented sympathetic-mediated variability than control animals (n = 12, p < 0.05). Using decerebrated in situ preparations, we found that juvenile pCIH rats exhibited a twofold increase in thoracic sympathetic nerve activity (n = 14) and elevated firing frequency of ventromedullary presympathetic neurons (n = 7) compared to control rats (n = 6-7, p < 0.05). This pCIH-induced sympathetic dysregulation was associated with increased HIF-1α (hypoxia-inducible factor 1 alpha) mRNA expression in catecholaminergic presympathetic neurons (n = 5, p < 0.05). At older age (P90-99), pCIH rats displayed higher arterial pressure levels and larger depressor responses to ganglionic blockade (n = 6-8, p < 0.05), confirming the sympathetic overactivity state. CONCLUSIONS: pCIH facilitates the vasoconstrictor sympathetic drive by mechanisms associated with enhanced firing activity and HIF-1α expression in ventromedullary presympathetic neurons. This excessive sympathetic activity persists until adulthood resulting in high blood pressure levels and variability, which contribute to developing cardiovascular diseases.