Sympathetic Nerve Overactivity Research Articles

Nerve growth factor (Ngf) gene-driven semaphorin 3a (Sema3a) expression exacerbates thoracic aortic aneurysm dissection in mice.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease and currently there is no pharmacological therapy. Sympathetic nerve overactivity plays an important role in the development of TAAD. Sympathetic innervation is mainly controlled by nerve growth factor (NGF, a key neural chemoattractant) and semaphoring 3A (Sema3A, a key neural chemorepellent), while the roles of these two factors in aortic sympathetic innervation and especially TAAD are unknown. We hypothesized that genetically manipulating the NGF/Sema3A ratio by the Ngf -driven Sema3a expression approach may reduce aortic sympathetic nerve innervation and mitigate TAAD progression. A mouse strain of Ngf gene-driven Sema3a expression (namely NgfSema3a/Sema3a mouse) was established by inserting the 2A-Sema3A expression frame to the Ngf terminating codon using CRISPR/Cas9 technology. TAAD was induced by β-aminopropionitrile monofumarate (BAPN) both in NgfSema3a/Sema3a mice and wild type (WT) littermates. Contrary to our expectation, the BAPN-induced TAAD was severer in NgfSema3a/Sema3a mice than in wild-type (WT) mice. In addition, NgfSema3a/Sema3a mice showed higher aortic sympathetic innervation, inflammation and extracellular matrix degradation than the WT mice after BAPN treatment. The aortic vascular smooth muscle cells isolated from NgfSema3a/Sema3a mice and pretreated with BAPN in vivo for two weeks showed stronger capabilities of proliferation and migration than that from the WT mice. We conclude that the strategy of Ngf -driven Sema3a expression cannot suppress but worsens the BAPN-induced TAAD. By investigating the aortic phenotype of NgfSema3a/Sema3a mouse strain, we unexpectedly find a path to exacerbate BAPN-induced TAAD which might be useful in future TAAD studies.

Transcriptomic profiling reveals connection to lung autonomic nervous system dysfunction and inflammation in pulmonary artery hypertension rats

Abstract Background Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by elevated pulmonary artery pressure, right ventricular failure, and premature death. Previous studies showed autonomic nervous system (ANS) such as sympathetic nerve overactivity or impaired parasympathetic activity was implicated in the pathogenesis of PAH. However, PA remodeling and molecular mechanisms involved in ANS in PAH remain unclear. Purpose To unravel transcriptional regulation, underlying genes and signaling pathways linking to ANS in PAH. Methods Publicly available two RNA sequencing (RNAseq) datasets and one single-cell RNA sequencing (scRNAseq) data of lung from rats with PAH induced by high-dose monocrotaline (MCT) were downloaded and reprocessed. For RNA-seq data, STAR and RSEM were used for read alignment and gene expression qualification. Differential expression genes (DEGs) were identified using DSEseq2, after which enrichment analyses were implemented by clusterProfiler. scRNAseq data were analyzed using Seurat. Results Two RNAseq datasets identified a total of 6,046 and 2,172 DEGs respectively, including 2,945 and 1,228 up-regulated and 3,101 and 944 down-regulated. Overlapped DEGs genes among datasets were 1,123 genes. Functional enrichment analysis of downregulated DEGs in one data pointed out many dysregulated pathways related to nerve system, such as nervous system process, neuron projection, integral component of synaptic membrane in MCT-induced PAH rat (Fig. 1a). Both RNAseq datasets supported upregulated DEGs were also involved in pathways related to ANS including humoral immune response and synapse pruning (P<0.001) (Fig. 1a). Intriguingly, all four genes (Trem2, C1qa, C1qb and C1qc) in synapse pruning were progressively upregulated with severe PAH condition (P<0.05) (Fig. 1b, c). And RT-PCR results confirmed the expression level of these four genes were remarkably increased in PAH rats (P<0.0001) (Fig. 1d). These four genes are known marker genes for macrophages from lung and microglial cell from brain. scRNAseq data of lungs demonstrated these four genes were significantly upregulated in alveolar macrophages from MCT-PAH rats (P<0.001) (Fig. 1e). However, the pathogenic mechanisms of these four genes in nerve fibers from lungs underlying PAH have never been studied and would be further explored using histological analysis in this study. Conclusions Integrated bioinformatic analysis indicated the association of lung nervous system with PAH. Further, we identified four genes implicated in nervous system, previously reported to link to immune system and provide novel insights into the mechanisms underlying relationship between lung ANS and inflammation in the pathogenesis of PAH. The pathogenetic mechanism of these four genes is being further investigated. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The National Natural Science Foundation of Chinathe Nature Science Foundation of Hubei Province

Refractory arterial hypertension: hyperactivity of the sympathetic nervous system, kidney and approaches to antihypertensive drug therapy

Improving blood pressure (BP) control and reducing the risk of developing unfavorable cardiovascular and renal outcomes in patients with refractory hypertension (HTN) is an urgent problem of cardiology. According to clinical studies, patients with refractory HTN receiving intensive diuretic therapy with chlorthalidone and a mineralcorticoid receptor antagonist differ from patients with refractory HTN by a higher sympathetic nervous system (SNS) activity. Overactivity of sympathetic nerves may be one of the key pathogenetic factors that is involved in the kidney in the formation of refractory HTN, exerting a direct stimulating effect on the type 3 Na+ / H+ exchanger (NHE3) and type 2 sodium glucose cotransporter (SGLT2), which are involved in BP control by mechanism of pressure natriuresis. The review presents data on the peculiarities of sympathetic regulation of sodium tubular transport and the results of studies devoted the elucidating in the patients with resistant and refractory HTN the clinical efficacy of SGLT2 inhibitors glyflozins, sympatholytic reserpine and brain aminopeptidase A inhibitor firibastat, which suppresses the activity of central structures of SNS.

Uncovering Anti‐Arrhythmic Potential of Stellate Ganglion Purinergic Receptors

Cardiovascular disease affects over 30% of people worldwide and is one of the leading causes of death each year. Elevated sympathetic nerve activity is a common feature of cardiovascular disease, contributing to end‐organ damage, morbidity and mortality. Recent findings indicate that short‐circuiting sympathetic nerve overactivity by removal of the stellate ganglion can eradicate arrhythmias, emphasising the need for novel therapeutic targets to correct signalling non‐invasively.We have revealed upregulation of the P2X3 purinergic receptor in stellate ganglia of Spontaneously Hypertensive (SHR) compared to Wistar rats (16 week‐old), via RNASeq transcriptional profiling. We hypothesise that these purinergic receptors within cardiac stellate ganglia play a role in the excessive sympathetic drive to the heart in cardiovascular disease and can initiate cardiac arrhythmias. Thus, we have investigated the functional role of purinergic receptors in the stellate ganglion.Administration of ATP to acutely isolated post‐ganglionic sympathetic neurones from the stellate ganglia of Wistar rats (4‐6 week‐old) evokes a significant increase (Median; 0.21) in [Ca2+]i as measured by Fura‐2AM imaging (n=15, Wilcoxon matched‐pairs test; p<0.0001). This ATP‐induced calcium transient was inhibited by specific P2X3 receptor antagonism with either NF‐10 or AF‐130.Cardiac effects of stellate ganglion purinergic stimulation were investigated in the working heart‐brainstem preparation of Wistar rats (4‐6 week‐old). Increasing doses of ATP (50‐250 µg) delivered via microinjection (50‐250 µL) directly to the right stellate ganglion produced either a tachycardia (18 ± 6 bpm, n=6) or bradycardia (‐24 ± 12 bpm, n=5); these responses were typically found at distinct sites within the ganglion. Preliminary data from SHR suggest that higher doses of ATP (≥250µg) may be arrhythmogenic (n=3).P2X3 purinergic receptors are present in the sympathetic stellate ganglion and contribute to calcium ion flux and cardiac chronotropic regulation. Overexpression of P2X3 receptors is likely to contribute to excessive cardiac sympathetic activity and the development of hypertension and cardiac arrhythmias, making them a promising novel therapeutic target.

Perivascular adipose tissue modulates the effects of flavonoids on rat aorta rings: Role of superoxide anion and β3 receptors

Several studies demonstrate the beneficial effects of dietary flavonoids on the cardiovascular system. Since perivascular adipose tissue (PVAT) plays an active role in the regulation of vascular tone in both health and diseases, the present study aimed to assess the functional interaction between PVAT and flavonoids in vitro on rat aorta rings. Several flavonoids proved to display both antispasmodic and spasmolytic activities towards noradrenaline-induced contraction of rings deprived of PVAT (-PVAT). However, on PVAT-intact (+PVAT) rings, both actions of some flavonoids were lost and/or much decreased. In rings-PVAT, the superoxide donor pyrogallol mimicked the effect of PVAT, while in rings+PVAT the antioxidant mito-tempol restored both activities of the two most representative flavonoids, namely apigenin and chrysin. The Rho-kinase inhibitor fasudil, or apigenin and chrysin concentration-dependently relaxed the vessel active tone induced by the Rho-kinase activator NaF; the presence of PVAT counteracted apigenin spasmolytic activity, though only in the absence of mito-tempol. Similar results were obtained in rings pre-contracted by phenylephrine. Finally, when β3 receptors were blocked by SR59230A, vasorelaxation caused by both flavonoids was unaffected by PVAT. These data are consistent with the hypothesis that both noradrenaline and apigenin activated adipocyte β3 receptors with the ensuing release of mitochondrial superoxide anion, which once diffused toward myocytes, counteracted flavonoid vasorelaxant activity. This phenomenon might limit the beneficial health effects of dietary flavonoids in patients affected by either obesity and/or other pathological conditions characterized by sympathetic nerve overactivity.

The effect of dapsone in testosterone enanthate-induced polycystic ovary syndrome in rat

BackgroundOne of the most common reasons for infertility is polycystic ovary syndrome (PCOS). PCOS is related to metabolic syndrome, weight gain, type 2 diabetes mellitus, and cardiovascular diseases. Some of the causes of PCOS are dysfunction in the hypothalamus-pituitary-ovarian axis, insulin activity as well as over-activity of sympathetic nerves and elevation in serum levels of pro-inflammatory cytokines. Dapsone, a sulfonamide antibacterial agent, has anti-inflammatory effects such as decreasing inflammatory cytokine levels like TNF-α and IL-1β. MethodsPCOS was induced by subcutaneous injection of testosterone enanthate (1 mg/100 g) in 21 days old female rats for 35 days. Then, the MET control received metformin (300 mg/kg/day, orally) for 28 days, and to evaluate the efficacy of dapsone (DAP), the DAP group received (12.5 mg/kg, orally) for 28 days. Then, on the last day of the study, the rats were euthanized and the blood was collected to measure the serum levels of hormones, glucose, LDL, LDL/HDL and the left ovaries were dissected for histopathological assay. ResultsIn the PCOS group, the serum levels of glucose, LDL and LDL/HDL were significantly higher than in the control group (P < 0.001). In addition, the levels of LH, FSH and testosterone changed in the PCOS group compared to the control (P < 0.001). The histopathological morphology changes of the ovary of the PCOS group were significant. Treatment with dapsone and metformin reversed the effects of testosterone in the DAP and MET groups. ConclusionsBased on the data, dapsone displayed a good antiandrogenic role via decreasing the testosterone levels in PCOS-induced rats.

Relationship between truck driver fatigue and rear-end collision risk.

The fatigue of truck, bus, and taxi drivers has been a causal trigger for road accidents. However, the relationship between collision risk and the extent of objective fatigue has yet to be confirmed. In this study, we aimed to identify the relationship between autonomic nerve function as an objective parameter of fatigue and the extent of rear-end collision risk, which includes not only objectively risky events but also situations in which truck drivers require safety guidance from safety transport managers. Data of 33 truck driver participants (2 females, 31 males, 46.0 ± 9.1 years old, min–max: 24–65 years old) were analyzed. Drive recorder and automotive sensor data were collected over an eight-month period, and the autonomic nerve function during resting state in drivers was evaluated daily, pre- and post-shift, using pulse waves and electrocardiographic waveform measurement. The rear-end collision risk Index was developed using decision tree analysis of the audiovisual drive recorder data and distance data from the front automotive sensors. The rear-end collision risk index of shift-day was positively correlated with the sympathetic nerve activity index of post-shift condition on the previous day. This suggests that fatigue-related sympathetic nerve overactivity of post-shift condition increases the rear-end collision risk in the following day. Measures, such as actively seeking rest and undertaking fatigue recovery according to the degree of sympathetic nerve activity of post-shift condition, are necessary in order to prevent truck drivers’ rear-end collisions.

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

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. 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. 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. 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.

Obesity‐Induced Sympathoexcitation is Associated with Glial Senescence in the Brainstem

Previous studies from our laboratory showed that high fat diet‐induced obesity causes cellular senescence in the key brainstem region, the rostral ventrolateral medulla which is critical for the tonic and reflex control of sympathetic nervous system. Cellular senescence is characterized by a state of irreversible growth arrest and senescence‐associated secretory phenotype (SASP) in proliferating cells. In the current study, we wanted to investigate which cell type undergoes senescence in the brainstem in obesity. Neurons are post‐mitotic and do not undergo senescence, whereas glial cells can undergo senescence. Hence we hypothesized that obesity induces glial senescence in the brainstem. To address this hypothesis, 2‐month old C57BL/6J mice were fed with high fat diet (60% fat; n=5) and chow diet (10% fat; n=5) for 16 weeks. The animals were sacrificed at the end of the experiment, and their brains were collected for further processing. The freshly isolated brainstem was enzymatically digested (45 minutes, 37°C) and filtered through a 30μm mesh to form a cell suspension. Neuron isolation kit from Miltenyi Biotec was used to isolate glial and neuronal enriched cell population from the brainstem. RNA was extracted from these sorted cells and used for RT‐PCR analysis. Senescence was assessed using gene expression of cell cycle inhibitors and SASP factors. Data was analyzed by unpaired student’s t‐test and a p‐value less than 0.05 was considered statistically significant. We observed an increase in the gene expression of cell cycle inhibitors, p21 and p53 in the glial cell fraction isolated from the brainstem of obese mice compared to its lean counterparts. In addition, there was an increase in the mRNA levels of SASP factors such as the IL‐6 and MCP1 suggesting that obesity induces glial senescence in the brainstem. We were not able to obtain viable neurons for senescence analysis. Glial cells are known to play a supporting role in neuronal function through regulation of neurotransmission. Future studies will address glial cell specific mechanisms and understand how glia‐neuron crosstalk contributes to sympathetic nerve overactivity in obesity.Support or Funding InformationNIH‐HL148844 and RED account funds

TCT-30 Renal Denervation Improves Cardiac Function in a Swine Model of Heart Failure

Introduction: Sympathetic nerve overactivity plays a critical role in the pathogenesis of heart failure (HF). Renal denervation (RDN) is currently under evaluation for the treatment of resistant hypertension and reduces blood pressure by disruption of sympathetic pathways that modulate cardiovascular function. We have demonstrated cardioprotective actions of RDN in rodent models of acute myocardial infarction and HF. We sought to determine if RDN treatment could improve cardiac function in a clinically relevant large animal model of HF. Methods: Yucatan miniswine (n=14) underwent 75 min of proximal left anterior descending coronary artery balloon-occlusion followed by 18 wks of reperfusion to generate large transmural infarcts and heart failure. Cardiac function was measured every 3 wks by 2-D echocardiography. HF was defined as left ventricular ejection fraction (LVEF) TM Multi-Electrode System (St. Jude Medical, St. Paul, MN). RDN was performed from distal to proximal in each renal artery, with at total of 24 ablation points separated both longitudinally and rotationally under fluoroscopic guidance. Results: At 3 wks of reperfusion following myocardial ischemia, LVEF was reduced in all pigs (SHAM RDN, 29.92.7%; RDN, 31.41.9%) with no further decline at the 6 wk treatment timepoint. At 6 wks of reperfusion, SHAM RDN and RDN treatments were performed without complication. Three wks after RDN treatment, LVEF was increased compared to SHAM (33.52.5 and 48.04.6%, respectively). LVEF was further increased 6 wks after RDN treatment compared to SHAM (31.51.5 vs. 62.00.6%, respectively). Interestingly, LVEF was higher 6 wks post-RDN compared to 3 wks post-RDN ( p =0.047). Conclusions: Preliminary results demonstrate that RDN significantly improves cardiac function in a clinically relevant swine model of HF.

Renal Sympathetic Denervation: An Effective Non-Pharmacological Treatment Strategy for Sympathetic Over-Activation Related Diseases

The renal sympathetic nerve is a main target in cardiovascular diseases, because of the special relationship between the heart and kidney. Therefore, many drugs that inhibit the neuroendocrine system, such as angiotensin converting enzyme inhibitors/angiotensin receptor blocker (ACEI/ARB), beta blockers, and aldosterone inhibitors, have emerged to treat cardiovascular diseases. Renal sympathetic denervation (RDN) is the most influential non-pharmacological treatment method and was first reported by the Lancet in 2009. Although the negative conclusions of the Symplicity HTN-3 trial have hindered the application of RDN in resistant hypertension, there is increasing interest in RDN for the treatment of diseases other than hypertension because of its ability to inhibit sympathetic nerve overactivity. Therefore, we reviewed current studies about RDN with a focus on sympathetic nerve over-activation related diseases, such as, ventricular tachycardia, atrial fibrillation, myocardial remodeling, endothelium dysfunction, insulin resistance, obstructive sleep apnea, and so on.

The interplay between sympathetic overactivity, hypertension and heart rate variability (review, invited).

The control of arterial pressure is a complex interaction of the long- and short-term influences of hormones, local vascular factors, and neural mechanisms. The autonomic nervous system and its sympathetic arm play important roles in the regulation of blood pressure, and overactivity of sympathetic nerves may have an important role in the development of hypertension and related cardiovascular disorders. The baroreceptor system opposes either increases or decreases in arterial pressure, and the primary purpose of the arterial baroreflex is to keep blood pressure close to a particular set point over a relatively short period of time. The ability of the baroreflex to powerfully buffer acute changes in arterial pressure is well established, but the role of the arterial baroreceptor reflex in long-term control of arterial pressure has been a topic of many debate and controversy for decades. The sympathetic nervous system and arterial baroreceptor reflex control of renal sympathetic nerve activity has been proposed to play a role in long-term control of arterial pressure. The aim of this paper has been to review the postulated role of sympathetic activation.

Renal denervation

Severe hypertension, resistant to conventional antihypertensive medications, is associated with major adverse cardiovascular and cerebrovascular events and renal insufficiency. Renal sympathetic nerve over-activity frequently accompanies essential hypertension. Catheter-based renal sympathetic denervation leads to a reduction in renal and overall sympathetic nerve activity and improvement in blood pressure in the setting of severe resistant hypertension. In the following, we review the role of the renal sympathetic nervous system in blood pressure control and recent clinical experience with renal denervation. Furthermore, potential beneficial effects on diabetes control, obstructive sleep apnea, atrial and ventricular arrhythmias are discussed.

Effect of Reduced Sympathetic Hyperactivity on Cardiovascular Risk Factors in Kidney Transplantation Patients

BackgroundHyperactivity of the sympathetic nervous system caused by chronic kidney disease has detrimental effects on hypertension and cardiovascular morbidity. Kidney transplantation does not ameliorate sympathetic nerve overactivity; however, bilateral nephrectomy eliminates it. The aim of the study was to evaluate the effect of bilateral nephrectomy on risk factors for cardiovascular morbidity and mortality in long-term follow-up. Material and MethodsWe studied 24 kidney recipients aged 44 ± 13 years who had undergone native bilateral nephrectomy. The control group included 17 recipients with preserved native kidneys who were matched for age, gender, cause of end-stage renal disease, immunosuppressive treatment, and time after transplantation. The mean follow-up after transplantation was 103 months. We evaluated arterial blood pressure, pulse pressure, metabolic markers, allograft function, echocardiography, and cardiac morbidity in all patients throughout follow-up. ResultsSystolic and diastolic blood pressures, number of antihypertensive drugs, and pulse pressure (a marker of arterial stiffness), were significantly lower among the study versus the control group (P < .05). The left ventricular mass, left ventricular mass index, left ventricular posterior wall thickness, and interventricular septum thickness were also lower in the study than in the control group (P < .05). Cardiac morbidity, including ischemic heart disease, atrial fibrillation, heart failure and stroke, occurred in 4 (16%) study group and 6 (35%) control subjects. Metabolic disorders, namely, new onset diabetes after transplantation, hyperuricemia, and dyslipidemia, occurred with similar frequencies in both groups. Serum levels of creatinine and estimated glomerular filtration rates were comparable in both groups, remaining stable throughout the observation time. ConclusionsReduction of sympathetic hyperactivity by nephrectomy improved blood pressure control as well as decreased arterial stiffness and left ventricular hypertrophy over long-term follow-up. These results support native renal denervation to prevent the harmful effects of sympathetic hyperactivity on the cardiovascular system of renal transplant recipients.

Effect of Reduced Sympathetic Hyperactivity on Cardiovascular Risk Factors in Kidney Transplant Patients

Background: The hyperactivity of sympathetic nervous system caused by chronic kidney disease severely impacts on hypertension, impairment of renal function and cardiovascular morbidity. A kidney transplantation does not ameliorate sympathetic nerve over-activity. This could be achieved by bilateral nephrectomy. The aim of the study was to evaluate the effect of bilateral nephrectomy on renal transplant outcome, particularly, on the risk factors for cardiovascular morbidity and mortality in long term follow-up. Material and methods: A total of 24 patients at age of 44±13 years who had undergone native bilateral nephrectomy were studied. Nephrectomy was performed in 21 patients before and in 3 after transplantation due to polycystic kidney disease (13 patients), refractory hypertension (1), vesico-urinary reflux (2) and other causes. The control group entailed 17 kidney recipients with preserved native kidneys matched for age, gender, cause of ESRD, immunosuppressive treatment and time after transplantation. The mean follow-up after transplantation was 103 months. In all patients arterial blood pressure, pulse pressure, metabolic markers, allograft function, and cardiac morbidity were evaluated throughout the follow-up. In 11 patients from the study group and 11 from the control group echocardiography was performed to evaluate left ventricular hypertrophy at the end of the follow-up. Results: Systolic blood pressure was lower in the study group than in the control at 24 months after transplantation (132±12 vs 146±11 mmHg; P< 0.05). Diastolic blood pressure was also lower at 96-th month (77±5 vs 86±7 mmHg; P< 0.01). The number of antihypertensive drugs was significantly lower in the study group (1.3±1.2 vs 2.3±0.9; P=0.003) during follow-up. Pulse pressure, a marker of arterial stiffness, was significantly lower in the study group (51 vs 59 P< 0.05). Corresponding differences were observed for left ventricular mass (309±122 vs 370±112 g; P=0.065), left ventricular mass index (162±57 vs 199±50; P=0.09), and interventricular septum thickness (13.6±2.5 vs 15.7±3.2 mm; P< 0.05). Cardiac morbidity including ischemic heart disease, atrial fibrillation, heart failure and stroke occurred in 4 patients (16%) from the study group and 6 (35%) from the control group. Metabolic disorders namely NODAT, hyperuricemia and hyperlipidemia occurred with similar frequency in both groups. Hemoglobin level was significantly lower in nephrectomized patients (12.5 vs 14.5 g/dL; P=0.05) within 2 year follow-up period. Serum level of creatinine and eGFR were comparable in both groups and remained stable for the time of observation. Conclusions: Reduction of sympathetic hyperactivity by nephrectomy, improved control over blood pressure, decreased arterial stiffness, prevents left ventricular hyperthrophy and may protect patients from cardiovascular morbidity. These results might support performing renal denervation to prevent the harmful effects of sympathetic nervous system.

Early‐stage changes to neurovascular morphology and telemetric measurement of sympathetic nerve activity in streptozotocin‐induced diabetic rats

Chronic sympathetic nerve overactivity is an established consequent of Type 1 Diabetes Mellitus (T1DM) and is known to induce both micro and macroangiopathy. Telemetry is used to monitor real‐time sympathetic nerve activity (SNA) to measure neuropathic progression in T1DM. This study aimed to examine changes in the neurovascular morphology of early‐stage streptozotocin (STZ)‐induced T1DM rats and determine if telemetry is sensitive to neuropathic changes in SNA. Animals were separated into control (C, n=9) and T1DM (D, n=9) groups. Diabetes was induced using multiple doses of STZ consisting of 20mg/Kg per day for 5 days. In three animals from each group, electrodes were placed around isolated renal nerves and telemeters were implanted abdominally. Measurements of SNA were recorded weekly over 12 hour periods. All animals were euthanized 6 weeks post STZ treatment. Compared to C, D showed a decrease in blood vessel number (t (10) = 4.44, p &lt; 0.001) and size (t (10) = 3.60, p &lt; 0.05), an increase in sympathetic fiber size (t (9) = –2.34, p &lt; 0.05) but no difference in fiber number in sciatic nerves. Despite these morphological changes, SNA in C and D was not statistically different in frequency or amplitude at any time‐point during the 6 week period. Though morphological changes are observed early in STZ diabetes, neurophysiological changes recorded by telemetry may be too slight or variable to be clearly distinguished.

Sympathetic Neural Mechanisms in Human Blood Pressure Regulation

Sympathetic neural function is essential to human blood pressure regulation, and overactivity of sympathetic nerves may have an important role in the development of hypertension and related cardiovascular disorders. Importantly, there is extensive interindividual variability in sympathetic vasoconstrictor nerve activity, even among healthy, young, normotensive people. Therefore, the relevance of each person's level of sympathetic nerve activity for his or her blood pressure must be evaluated in the context of other factors contributing to the overall level of blood pressure, including cardiac output and vascular adrenergic responsiveness. We include evidence showing that the balance of factors contributing to normal blood pressure in young people is influenced by sex. Hypertension itself can be multifactorial, but it is often associated with elevated sympathetic nerve activity, which can be reversed by some pharmacologic antihypertensive treatments. Although much work remains to be done in this area, an appropriate recognition of the complexity of integrated physiological regulation and of the importance of interindividual variability will be key factors in moving forward to even better understanding and treatment.

Resting muscle sympathetic nerve activity, cardiac metaiodobenzylguanidine uptake, and exercise tolerance in patients with left ventricular dysfunction

BackgroundSympathetic nerve overactivity and reduced exercise tolerance are characteristic features of patients with heart failure. However, to what extent sympathetic nerve overactivity contributes to limiting exercise tolerance has not been clearly defined. MethodsMyocardial iodine 123-metaiodobenzylguanidine (MIBG) scintigraphy, muscle sympathetic nerve activity (MSNA), and cardiopulmonary exercise testing were performed within 3 days in 30 patients with left ventricular dysfunction (LVD). Cardiac sympathetic nerve activity was estimated using H/M ratio and washout rate (WR) of 123I-MIBG imaging. MSNA was recorded by microneurography. ResultsThe patients with peak VO2 < 20 mL/minute/kg (group II, n = 15) had significantly higher MSNA and WR, and lower H/M ratio than those with peak VO2≧ 20 mL/minute/kg (group I, n = 15) (P < .05). Peak VO2 had negative correlations with MSNA and WR (r = 0.58, 0.56), and positive correlations with early H/M ratio and delayed H/M ratio (r = 0.71, 0.75) in group II. Moreover, MSNA had negative correlations with early H/M ratio and delayed H/M ratio (r = 0.78, 0.66), and a positive correlation with WR (r = 0.79) in group II. However, similar relations were not found in group I. ConclusionsA link between cardiac and peripheral sympathetic nerve activities contributed to limiting exercise tolerance in patients with LVD patients and reduced exercise tolerance.

Analysis of Factors that Affect Short-Term Blood Pressure Variability in Patients with Chronic Renal Failure

Recent reports suggest the relationship of short-term blood pressure (BP) variability to cardiovascular target organ damage. In this study, short-term BP variability was assessed as the standard deviation of daytime and nighttime BP in 36 hospitalized patients with chronic renal failure (CRF) who underwent ambulatory BP monitoring. Positive correlations were observed between body mass index (BMI) and daytime systolic and diastolic BP variability, BMI and nighttime diastolic BP variability, cholesterol and daytime systolic BP variability, cholesterol and nighttime systolic and diastolic BP variability, nocturnal decline in BP and nighttime diastolic BP variability, and plasma concentration of norepinephrine (p-NE) and nighttime systolic BP variability. In multivariate linear regression analyses, BMI showed the strongest association with daytime and nighttime diastolic BP variability (p < .005 and p < .05). On the other hand, cholesterol and p-NE were the primary determinants of daytime and nighttime systolic BP variability, respectively (p < .01 and p < .0005). Interestingly, CRF patients with ischemic heart disease (IHD) had significantly increased daytime systolic and diastolic BP variability and nighttime systolic BP variability (p < .05 or less). Furthermore, logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor of IHD in patients with CRF (odds ratio 1.50 [95% confidence interval 1.01 to 2.25]; p < .05). Taken together, short-term BP variability is suggested to be affected by BMI, cholesterol, and p-NE in CRF patients. Furthermore, sympathetic nerve overactivity may be involved in cardiovascular complications in CRF patients through the increase in nighttime systolic BP variability.

Early altered renal sodium handling determined by lithium clearance in spontaneously hypertensive rats (SHR): Role of renal nerves

The mechanism by which blood pressure rises in the SHR strain remains to be elucidated. Since the long-term changes in renal sodium tubule handling associated with genetic hypertension have not been examined in detail, we hypothesized that SHR hypertension development may result from sustained renal sympathetic nerve overactivity and consequently decreased urinary sodium excretion. To test this hypothesis, we assessed renal sodium handling and cumulative sodium balance for 10 consecutive weeks in unanesthetized renal-denervated SHR, performed prior to the start of the entire 10-week metabolic studies, and their age-matched normotensive and hypertensive controls. The present investigation shows that SHR excreted less sodium than Wistar-Kyoto (WKy) rats during the initial 3-week observation period (p < 0.05). This tendency was reversed when SHR were 10-wk old. Fractional urinary sodium excretion (FENa +) was significantly lower in 3 and 6-wk-old SHR when compared with the WKy age-matched group, as follows: SHR 3-wk-old: 0.33 ± 0.09% and WKy 3-wk-old: 0.75 ± 0.1% (P < 0.05); SHR 6-wk-old: 0.52 ± 0.12% and WKy 6-wk-old: 0.83 ± 0.11%. The decreased FENa + in young SHR was accompanied by a significant increase in proximal sodium reabsorption (FEPNa +) compared with the normotensive age-matched control group (P < 0.01). This increase occurred despite unchanged creatinine clearance (CCr) and fractional post-proximal sodium excretion (FEPPNa +)in all groups studied. The decreased urinary sodium excretion response in SHR up to the age of 6 weeks was significantly eradicated by bilateral renal denervation of SHR 3-wk-old: 0.33 ± 0.09% and SHR 6-wk-old: 0.52 ± 0.12% to Dx SHR 3-wk-old: 1.02 ± 0.2% and Dx SHR 6-wk-old: 0.94 ± 0.2% (P < 0.01), in renal denervated rats. The current data suggest that neural pathways may play an instrumental role on renal sodium reabsorption as result of sustained sympathetic nervous system overexcitability.