Renal Nerve Activity Research Articles

Peripheral Chemoreceptor Ablation Modulates Renal MiR‐155/KLF4 Expression in Chronic Heart Failure

Background and SignificanceRecent evidence suggests aberrant carotid body chemoreceptor (CBC) function contributes to tonic elevation of renal nerve activity and reductions in renal blood flow in chronic heart failure (CHF). These changes combined with anemia and capillary rarefaction likely contribute to tissue hypoxia, and may drive renal fibrosis and attendant dysfunction. Previous work indicates that stable expression of hypoxia‐inducible factor 1‐α (HIF1α) and down regulation of MiR‐155 drive gene programs that mediate epithelial‐mesenchymal transition (EMT) in renal tubular epithelial cells, including increases in Krüppel‐like factor 4 (KLF4) and matrix metalloproteinase 9 (MMP9). To date, no studies have examined this signaling pathway in CHF, thus our objective was to determine the influence of CBC on renal cortical expression of HIF1α, KLF4, MiR‐155, MMP9, and α‐smooth muscle actin (SMA) in CHF.HypothesisWe hypothesize that CBC‐mediated reductions in renal blood flow activate EMT pathways in CHF by exacerbating tissue hypoxia, leading to sustained accumulation of HIF1α, downregulation of MiR‐155, and KLF4/MMP9/SMA induction.MethodsTo address this hypothesis, we measured expression of HIF1α, MiR‐155, KLF4, MMP9, and SMA in renal cortical tissue from sham, and CHF animals (n=4–8 per group) with and without ablation of the CBC (CBA). CHF was induced in rats by coronary artery ligation (CAL) and CBA was performed (4 weeks post‐CAL) by cryogenic ablation. CHF was confirmed via echocardiography under isoflurane anesthesia (1–1.5%). At 8‐weeks post‐CAL, rats were humanely euthanized and renal cortical tissue was collected and analyzed for HIF1α, KLF4, MMP9, and SMA expression via western blot and MiR‐155 expression by RT‐qPCR.ResultsEjection fraction was 72±2% in sham animals, 34±2% in CHF animals, and 32±2% in CHF‐CBA animals (p<0.05 sham vs. CHF and CHF‐CBA). Expression of HIF1α was 1.37±0.33 in CHF rats relative to sham, and 1.25±0.15 in CHF‐CBA relative to sham. KLF4 was 1.64±0.25 in CHF rats relative to sham, and this effect was attenuated in CHF‐CBA (1.06±0.16 relative to sham, p<0.05 vs. CHF). MMP9 expression in CHF rats was 1.79±0.43 relative to sham and 1.092±0.23 in CHF‐CBA relative to sham. SMA expression in CHF rats was 0.58±0.17 relative to sham and 0.83±0.15 relative to sham in CHF‐CBA. MiR‐155 expression in CHF rats was 0.48±0.11 relative to sham, and this effect was attenuated by CBA (0.73±0.12 relative to sham, p<0.05 vs. CHF).ConclusionThese results suggest a novel relationship between CBC function and expression of renal cortical MiR‐155 and KLF4 in CHF, and that CBA has the potential to influence EMT pathways in the kidney in this pathophysiological setting.Support or Funding InformationThis work was supported by a grant from NHLBI (1 R15 HL138600‐01)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract 20949: Impact of Renal Denervation on Autonomic Nerve Activity

Introduction: Recent studies reported potential antiarrhythmic effect of catheter-based renal denervation (RDN). We sought to evaluate impacts of RDN on cardiac autonomic nerve activity in ambulatory canine model. Methods: Telemetry devices (D70-EEE, DSI) were implanted in 17 mongrel dogs to record ambulatory nerve activity simultaneously from left stellate ganglion (SG), superior left ganglionated plexus (SLGP), and left renal nerve. After 1 week of baseline nerve activity recording, RDN was performed at both renal arteries using a specialized catheter (Symplicity TM , Medtronic) (n=10). A control animals underwent autonomic nerve recording operation but with sham procedure (n=3). Bilateral surgical stripping of the renal nerve adventitia was performed in 4 dogs (n=4, surgical RDN). One-minute integrated nerve activities were quantified and compared among groups up to 2 weeks. Results: Renal nerve acvitivity (RNA) decreased after catheter RDN (-6.7±13.4% from baseline), while RNA increased after sham operation by 7.4±9.5% (p=0.103). After surgical RDN, no RNA was observed. In contrast to the increased SG nerve activity (SGNA) after sham operation (+2.2±11.4%), SGNA decreased after catheter RDN (-2.1±10.8%, p=0.073) and surgical RDN (-10.6±13.1%, p=0.061 vs. control). SLGP nerve activity (SLGPNA) also increased by 7.1±3.1% after sham operation, while SLGPNA decreased after catheter-based (-8.1±13.9%, p=0.008), and surgical RDN (-6.3±10.2%, p=0.073 vs. control). Immunohistochemistry showed increment of TH (tyrosine hydroxylase)-negative cells in SG after RDN (% of TH-negative cells: control=1.8%, catheter RDN=5.5% [p=0.058 vs. control], surgical RDN=7.35% [p=0.039, vs. control]). Conclusions: The response of renal nerve and cardiac autonomic nerve activity to catheter based RDN was diverse. Renal denervation decreased SGNA and SLGPNA, with neural remodeling at SG. These results may support anti-arrhythmic effects of RDN.

Abstract P445: Sympathetic and Renal Mechanisms of Age-related Hypertension

Hypothesis: Sympathoexcitation and sodium retention contribute to age-related hypertension (HTN). Methods: Three, 8, and 16 month old male SD rats underwent an IV volume expansion (VE; 5% BW) and MAP, HR, urine output and paraventricular nucleus (PVN) neuronal activation (c-Fos expression) were assessed. In separate groups of rats fed a 21 day normal (NS; 0.6% NaCl) or high salt (HS; 4% NaCl) diet, measures of 1) ex vivo afferent renal nerve (ARN) activity (norepinephrine (NE)-evoked substance P release) or 2) MAP, HR, NCC activity (ΔUNaV to IV HCTZ, 2mg/kg) and sympathetic tone (plasma and renal NE content, ΔMAP to IV hexamethonium) were assessed. Separate groups of rats underwent bilateral renal denervation (RDNX) or chronic NCC antagonism (SC HCTZ, 4mg/kg/d, 14d) and MAP was assessed (N=4/gp). Results: Acute VE-evoked natriuresis, diuresis, and PVN parvocellular neuronal activation were impaired in aged rats. Aged rats exhibited reduced ARN activity on a NS diet and failed to increase ARN activity during a HS diet. In aged rats, basal MAP, NCC activity and sympathetic tone were increased and HS-evoked suppression of NCC activity and sympathetic tone was impaired. Chronic NCC antagonism and RDNX attenuated age-related HTN (MAP [mmHg] 16mo 149±3 vs RDNX 139±1 vs SC HCTZ 136±5, P<0.05). Conclusion: Our data suggest that the ARN, which have been implicated in the regulation of sympathetic outflow and renal sodium excretion, are impaired in age-related HTN. We speculate that an age-related decrease in ARN activity promotes sympathoexcitation, perhaps in part via reduced activation of PVN sympathoinhibitory parvocellular neurons, resulting in NCC-mediated sodium retention and HTN.

Abstract P213: Metabolic and Cardiovascular Effects of Melanocortin-4 Receptors in Leptin Receptor-expressing Neurons

Studies in both humans and rodents have clearly established a role for melanocortin-4 receptor (MC4R) in energy homeostasis, sympathetic and cardiovascular function. Both MC4R-deficient humans and rodents develop severe obesity while keeping the sympathetic tone and blood pressure below or within the normal range, indicating that MC4R is required for obesity-associated sympathetic overdrive and hypertension. Indeed, sympathetic overdrive and cardiovascular side effect have been a major problem in developing anti-obesity drugs that target MC4R. Thus, better understanding the neural substrates that mediate distinct metabolic and sympathetic actions of MC4R is needed to provide a more specific target to treat obesity and associated hypertension. We have recently mapped the pattern of co-expression of MC4R and leptin receptor (LepR) and found that, throughout entire mouse brain, these two metabolically important receptors are uniquely co-expressed only in neurons of two brain regions, including the lateral hypothalamic area (LHA) and the periaqueductal gray (PAG). To specifically test the role of MC4R in LepR-expressing neurons, we generated mice with MC4R expression only in LepR-positive neurons by breeding Cre-dependently “reactivatable” MC4R-null mice (MC4R-TB) to LepR-Cre mice. We found that specific re-expression of MC4Rs only in LepR-positive neurons partially suppresses body weight gain especially in female mice (MC4R-TB 31.73 ± 2.2g vs. MC4R-TB::LepR-Cre 27.97 ± 1.8 g, p=0.0013). Direct multi-fiber recording of renal nerve activity (RSNA), however, revealed that neither baseline activity nor MC4R agonist-induced RSNA is significantly altered by restoration of MC4R signaling in LepR-positive neurons (change of RSNA in MC4R-TB 8.844 ± 3.05 vs. MC4R-TB::LepR-Cre 11.95 ± 2.7, p>0.05). Our results suggest that MC4R signaling in leptin-responsive neurons is sufficient to suppress body weight in female mice, but seemingly has no effect on sympathetic traffic to the kidney. Further investigation of the effect of MC4Rs in LepR-positive neurons on blood pressure regulation is underway.

Extravascular renal denervation ameliorates juvenile hypertension and renal damage resulting from experimental hyperleptinemia in rats.

Material obesity in rodents is associated with neonatal hyperleptinemia and hypertension of sympathetic origin in adult offspring. Previously, we reported that experimentally induced hyperleptinemia in rat pups results in adulthood hypertension. Here, we addressed the hypothesis that experimental neonatal hyperleptinemia, through renal nerve activation, adversely affects adult renal function. Sprague-Dawley male and female pups were treated with neonatal leptin (3 mg/kg, intraperitoneal) or neonatal saline, twice daily from postnatal day 9-14. Juvenile (1 month) neonatal leptin and neonatal saline rats were subjected to either bilateral renal denervation, unilateral renal denervation or Sham surgery. Arterial pressure was telemetrically monitored. Juvenile neonatal leptin rats with intact renal nerves demonstrated increased mean arterial pressure (MAP) accompanied by local renin-angiotensin system overactivity and reduced glomerular filtration rate. Bilateral renal denervation in rats protected against neonatal leptin-induced MAP, renal renin-angiotensin system and impaired glomerular filtration rate. A two-fold increase in sympathetically mediated tubulointerstitial damage in young adult (2 months) neonatal leptin females, was suppressed by unilateral renal denervation, independent of MAP. Neonatal leptin rats also demonstrated increases in urinary protein, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Raised blood pressure was associated with increased salt sensitivity and with sustained renal dysfunction in adulthood. We propose that neonatal hyperleptinemia programmes long-term renal structural and functional damage, through renal sympathetic nerve activation.

High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation.

Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter-driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.

Renal Nerves and Long-Term Control of Arterial Pressure.

The objective of this review is to provide an in-depth evaluation of how renal nerves regulate renal and cardiovascular function with a focus on long-term control of arterial pressure. We begin by reviewing the anatomy of renal nerves and then briefly discuss how the activity of renal nerves affects renal function. Current methods for measurement and quantification of efferent renal-nerve activity (ERNA) in animals and humans are discussed. Acute regulation of ERNA by classical neural reflexes as well and hormonal inputs to the brain is reviewed. The role of renal nerves in long-term control of arterial pressure in normotensive and hypertensive animals (and humans) is then reviewed with a focus on studies utilizing continuous long-term monitoring of arterial pressure. This includes a review of the effect of renal-nerve ablation on long-term control of arterial pressure in experimental animals as well as humans with drug-resistant hypertension. The extent to which changes in arterial pressure are due to ablation of renal afferent or efferent nerves are reviewed. We conclude by discussing the importance of renal nerves, relative to sympathetic activity to other vascular beds, in long-term control of arterial pressure and hypertension and propose directions for future research in this field. © 2017 American Physiological Society. Compr Physiol 7:263-320, 2017.

The innervation of the kidney in renal injury and inflammation: a cause and consequence of deranged cardiovascular control.

Extensive investigations have revealed that renal sympathetic nerves regulate renin secretion, tubular fluid reabsorption and renal haemodynamics which can impact on cardiovascular homoeostasis normally and in pathophysiological states. The significance of the renal afferent innervation and its role in determining the autonomic control of the cardiovascular system is uncertain. The transduction pathways at the renal afferent nerves have been shown to require pro-inflammatory mediators and TRPV1 channels. Reno-renal reflexes have been described, both inhibitory and excitatory, demonstrating that a neural link exists between kidneys and may determine the distribution of excretory and haemodynamic function between the two kidneys. The impact of renal afferent nerve activity on basal and reflex regulation of global sympathetic drive remains opaque. There is clinical and experimental evidence that in states of chronic kidney disease and renal injury, there is infiltration of T-helper cells with a sympatho-excitation and blunting of the high- and low-pressure baroreceptor reflexes regulating renal sympathetic nerve activity. The baroreceptor deficits are renal nerve-dependent as the dysregulation can be relieved by renal denervation. There is also experimental evidence that in obese states, there is a sympatho-excitation and disrupted baroreflex regulation of renal sympathetic nerve activity which is mediated by the renal innervation. This body of information provides an important basis for directing greater attention to the role of renal injury/inflammation causing an inappropriate activation of the renal afferent nerves as an important initiator of aberrant autonomic cardiovascular control.

Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function.

Heart failure is characterized by the loss of sympathetic innervation to the ventricles, contributing to impaired cardiac function and arrhythmogenesis. We hypothesized that renal denervation (RDx) would reverse this loss. Male Wistar rats underwent myocardial infarction (MI) or sham surgery and progressed into heart failure for 4 wk before receiving bilateral RDx or sham RDx. After additional 3 wk, left ventricular (LV) function was assessed, and ventricular sympathetic nerve fiber density was determined via histology. Post-MI heart failure rats displayed significant reductions in ventricular sympathetic innervation and tissue norepinephrine content (nerve fiber density in the LV of MI+sham RDx hearts was 0.31 ± 0.05% vs. 1.00 ± 0.10% in sham MI+sham RDx group, P < 0.05), and RDx significantly increased ventricular sympathetic innervation (0.76 ± 0.14%, P < 0.05) and tissue norepinephrine content. MI was associated with an increase in fibrosis of the noninfarcted ventricular myocardium, which was attenuated by RDx. RDx improved LV ejection fraction and end-systolic and -diastolic areas when compared with pre-RDx levels. This is the first study to show an interaction between renal nerve activity and cardiac sympathetic nerve innervation in heart failure. Our findings show denervating the renal nerves improves cardiac sympathetic innervation and function in the post-MI failing heart.

Taurine Supplementation Reduces Renal Nerve Activity in Male Rats in which Renal Nerve Activity was Increased by a High Sugar Diet.

This study tests the hypothesis that taurine supplementation reduces sugar-induced increases in renal sympathetic nerve activity related to renin release in adult male rats. After weaning, male rats were fed normal rat chow and drank water containing 5% glucose (CG) or water alone (CW) throughout the experiment. At 6-7 weeks of age, each group was supplemented with or without 3% taurine in drinking water until the end of experiment. At 7-8 weeks of age, blood chemistry and renal nerve activity were measured in anesthetized rats. Body weights slightly and significantly increased in CG compared to CW groups but were not significantly affected by taurine supplementation. Plasma electrolytes except bicarbonate, plasma creatinine, and blood urea nitrogen were not significantly different among the four groups. Mean arterial pressure significantly increased in both taurine treated groups compared to CW, while heart rates were not significantly different among the four groups. Further, all groups displayed similar renal nerve firing frequencies at rest and renal nerve responses to sodium nitroprusside and phenylephrine infusion. However, compared to CW group, CG significantly increased the power density of renin release-related frequency component, decreased that of sodium excretion-related frequency component, and decreased that of renal blood flow-related frequency component. Taurine supplementation completely abolished the effect of high sugar intake on renal sympathetic activity patterns. These data indicate that in adult male rats, high sugar intake alters the pattern but not firing frequency of sympathetic nerve activity to control renal function, and this effect can be improved by taurine supplementation.

OS 29-03 INCREASED NEUROKININ RELEASE FROM AFFERENT RENAL NERVES IS ACCOMPANIED BY DECREASED AFFERENT ELECTRIC ACTIVITY

Objective: Afferent renal nerves exhibit a dual function. They influence intrarenal immunological processes by release of neurokinins like CGRP and control central sympathetic outflow via afferent electrical activity. The former seems to be important in renal inflammation whereas the sympathetic modulation by afferent electrical activity is not fully understood in cardiovascular disease and hypertension. Hence, we hypothesized that augmented effects of CGRP in renal inflammation occur with increased afferent renal nerve activity. Design and Method: As inflammatory model, normotensive renal inflammation (RI) was induced by i.v. injection of 1.75 mg/kg BW OX-7 antibody to rats to avoid confounding blood pressure effects by choosing a hypertensive model in the first place. Animals were investigated neurophysiologically and pathomorphologically using standard techniques 6 days after RI induction. Results: Blood pressure (BP) was normal, hence confounding BP effects were unlikely. RI rats exhibited albuminuria (61 ± 6 μg/24 h), infiltration of macrophages in the interstitium (26 ± 4 cells/hp field) and glomeruli (3.7 ± 0.6 cells/glomerular X-section). Pretreatment with the CGRP antagonist rCGRP 8-37 (15 nmol/kg) significantly reduced proteinuria and macrophage infiltration suggesting increased activity of CGRP. In an in-vitro assay, renal RI tissue exhibited increased CGRP release (14 ± 3 pg/ml vs. controls 6.8 ± 2.8 pg/ml; p < 0.05, n = 8). RI tissue from renally denervated rats showed no CGRP. Afferent renal nerve activity (ARNA; spikes/sec) was unexpectedly lower in RI compared to controls (8.0 ± 1.8 vs. 27.4 ± 4.1 Hz, n = 6, p < 0.05). On the other hand, the burst-frequency renal sympathetic nerve activity (RSNA) in RI was significantly higher than in controls (14.7 ± 0.9 vs. 11.5 ± 0.9 bursts/sec; n = 6, p < 0.05). Conclusions: In contrast to our hypothesis increased release of neurogenic CGRP aggravating RI occurred with decreased ARNA. Increased RSNA pointed to a reduced tonic inhibition by ARNA. The latter mechanism might worsen sympathetic dysregulation and renal damage as in hypertension.

Abstract 121: Afferent Renal Nerve Chemo- and Mechanosensitive Responses and the Modulation of Sodium Homeostasis and Blood Pressure

Aim: We hypothesize that challenges to sodium homeostasis differentially activate chemo- vs. mechanosensitive afferent renal nerves to evoke sympathoinhibition, sodium homeostasis and normotension in the Sprague-Dawley (SD) rat. Methods: Conscious SD rats, post sham (S) or afferent renal nerve ablation (Renal-CAP; capsaicin 33 mM) underwent IV volume expansion (VE; 5% BW) or IV sodium loading (1M NaCl Infusion – constant infusion volume) and HR, MAP, natriuresis and PVN neuronal activation (c-Fos expression) were assessed (N=4/gp). Naïve SD rats were fed a 0.6% (NS) or 4% NaCl (HS) diet for 21 days and afferent renal nerve activity was assessed as norepinephrine (NE) (1250 pmol) and NaCl-evoked (450mM) substance P (SP) release in a renal pelvic assay (N=4/gp). Radiotelemetered SD rats post S or Renal-CAP immediately prior a 0.6% (NS) or 4% NaCl (HS) diet underwent continuous MAP monitoring. On day-21 plasma and renal NE content was assessed (N=5/group). Results: Renal-CAP attenuated the natriuretic and PVN parvocellular responses to IV VE (peak UNaV [μeq/min]; S 43±4 vs Renal-CAP 26±6, P&lt;0.05, PVN Medial Parvocellular neuronal activation [c-fos positive cells]; S 49±6 vs Renal-CAP 22±5 P&lt;0.05) and evoked increased MAP (MAP 90min post-VE [mmHg] S 118±3 vs Renal-CAP 132±4, P&lt;0.05). In contrast Renal-CAP did not alter the natriuresis to IV 1M NaCl (UNaV [μeq/min]; S 21±4 vs Renal-CAP 21±3) or increase MAP. In naïve SD rats HS-intake did not alter MAP and suppressed plasma and renal NE (P&lt;0.05). HS intake increased NE, but not NaCl, mediated afferent renal nerve activity (NE-evoked peak ΔSP [ng/ml); NS 14±2, HS 22±3, P&lt;0.05, NaCl-evoked peak ΔSP [ng/ml]; NS 17±3, HS 16±2). Renal-CAP immediately prior to a HS-intake persistently increased MAP (Day 21 MAP [mmHg] S HS 106±4, Renal-CAP HS 123±5, P&lt;0.05) and attenuated HS-evoked global and renal sympathoinhibition (P&lt;0.05). Conclusion: The mechanosensitive afferent renal nerves mediate acute natriuresis and blood pressure regulation via activation of PVN sympathoinhibitory neurons. During HS intake the afferent renal nerves counter the development of salt-sensitive hypertension via a mechanism involving increased mechano but not chemosensitive afferent nerve responsiveness to potentiate sympathoinhibition.

OS 11-03 Role of renal nervous activity in the development of renovascular hypertension in rats

OS 11-03 Role of renal nervous activity in the development of renovascular hypertension in rats

Normotension, hypertension and body fluid regulation: brain and kidney

The fraction of hypertensive patients with essential hypertension (EH) is decreasing as the knowledge of mechanisms of secondary hypertension increases, but in most new cases of hypertension the pathophysiology remains unknown. Separate neurocentric and renocentric concepts of aetiology have prevailed without much interaction. In this regard, several questions regarding the relationships between body fluid and blood pressure regulation are pertinent. Are all forms of EH associated with sympathetic overdrive or a shift in the pressure-natriuresis curve? Is body fluid homoeostasis normally driven by the influence of arterial blood pressure directly on the kidney? Does plasma renin activity, driven by renal nerve activity and renal arterial pressure, provide a key to stratification of EH? Our review indicates that (i) a narrow definition of EH is useful; (ii) in EH, indices of cardiovascular sympathetic activity are elevated in about 50% of cases; (iii) in EH as in normal conditions, mediators other than arterial blood pressure are the major determinants of renal sodium excretion; (iv) chronic hypertension is always associated with a shift in the pressure-natriuresis curve, but this may be an epiphenomenon; (v) plasma renin levels are useful in the analysis of EH only after metabolic standardization and then determination of the renin function line (plasma renin as a function of sodium intake); and (vi) angiotensin II-mediated hypertension is not a model of EH. Recent studies of baroreceptors and renal nerves as well as sodium intake and renin secretion help bridge the gap between the neurocentric and renocentric concepts.

Electrical stimulation–based evaluation for functional modification of renal autonomic nerve activities induced by catheter ablation

Catheter ablation of the renal artery can be performed without apparent angiographic stenosis. This suggests that renal nerve function can be attenuated with minor structural damage to the renal artery. To clarify this hypothesis, we examined the relationship between electrical nerve stimulation (ENS)-induced blood pressure (BP) response and severity of histological injury of the renal artery using an acute canine model of renal artery ablation. An irrigation catheter was inserted into the renal arteries of 8 dogs, and radiofrequency current was delivered at 15, 20, or 25 W. ENS was applied to each artery before and after ablation. Before ablation, ENS increased the BP and heart rate from 145 ± 15/86 ± 13 to 189 ± 21/111 ± 19 mm Hg and from 116 ± 9 to 130 ± 6 beats/min, respectively. Heart rate variability indices and serum catecholamine levels were elevated concomitantly. After ablation, the ENS-induced increase in BP and heart rate were markedly attenuated after 15 W ablation and those were nearly completely inhibited after 20 or 25 W ablation. An increase in heart rate variability indices and serum catecholamine levels became insignificant regardless of the applied energy. Renal artery angiograms revealed stenotic lesions only after 25 W ablation procedures. Histological studies showed mild to moderate injury of the arterial wall and autonomic nerves caused by 20 and 25 W ablation procedures, whereas only minor changes caused by 15 W ablation. Functional renal autonomic nerve ablation is potentially performable with the guidance of ENS.

Renal denervation for the treatment of resistant hypertension: definition, patient selection and description of the procedure. 2012 Position paper of the Italian Society of Hypertension

Hypertension is responsible for a relevant burden of cardiovascular morbidity and mortality worldwide. Although several appropriate and integrated pharmacological strategies are available, blood pressure control still remains largely unsatisfactory. Failure to achieve effective blood pressure control in treated hypertensive patients may have a substantial impact on overall cardiovascular risk, since it significantly increases the risk of both macrovascular and microvascular complications. Hypertension is arbitrarily defined as "resistant" or "refractory" when recommended blood pressure goals (clinic blood pressure <140/90 mmHg, or <130/80 mmHg in patients with type 2 diabetes mellitus) are not achieved, despite changes in lifestyle and treatment with adequate doses of at least three antihypertensive drugs from different classes, including a diuretic. A new non-pharmacological option for the treatment of patients with resistant hypertension has recently become available. Renal sympathetic denervation is a minimally invasive procedure performed via femoral access that uses radiofrequency catheter ablation to disable renal sympathetic afferent and efferent nerves. It results in isolation of renal parenchymal and juxtaglomerular cells from the abnormal enhancement of renal adrenergic nerve activity. The present position paper of the Italian Society of Hypertension provides a diagnostic and therapeutic approach to the early identification and effective clinical management of patients with resistant hypertension, who may be candidates for renal denervation. These indications may have important implications not only from a clinical viewpoint but also from an economic perspective. The accurate identification of patients with resistant hypertension and the appropriate selection of patients eligible for this procedure may help improve blood pressure control and reduce the risk of cardiovascular and cerebrovascular complications in these patients.

The Potential Role of Catheter-Based Renal Sympathetic Denervation in Chronic and End-Stage Kidney Disease.

Sympathetic activation is a hallmark of chronic and end-stage renal disease and adversely affects cardiovascular prognosis. Hypertension is present in the vast majority of these patients and plays a key role in the progressive deterioration of renal function and the high rate of cardiovascular events in this patient cohort. Augmentation of renin release, tubular sodium reabsorption, and renal vascular resistance are direct consequences of efferent renal sympathetic nerve stimulation and the major components of neural regulation of renal function. Renal afferent nerve activity directly influences sympathetic outflow to the kidneys and other highly innervated organs involved in blood pressure control via hypothalamic integration. Renal denervation of the kidney has been shown to reduce blood pressure in many experimental models of hypertension. Targeting the renal nerves directly may therefore be specifically useful in patients with chronic and end-stage renal disease. In this review, we will discuss the potential role of catheter-based renal denervation in patients with impaired kidney function and also reflect on the potential impact on other cardiovascular conditions commonly associated with chronic kidney disease such as heart failure and arrhythmias.

Unilateral renal ischaemia in rats induces a rapid secretion of inflammatory markers to renal lymph and increased capillary permeability.

A better understanding of the inflammatory process associated with renal ischaemia-reperfusion (IR) injury may be clinically important. In this study we examined the role of the kidney in production of inflammatory mediators by analysing renal lymph after 30 min unilateral occlusion of renal artery followed by 120 min reperfusion, as well as the effect of IR on size selectivity for proteins in both glomerular and peritubular capillaries. All measured mediators increased dramatically in renal hilar lymph, plasma and renal cortical tissue samples and returned to control levels after 120 min reperfusion. The responses were differentiated; interleukin-1β, monocyte chemoattractant protein-1 and leptin were markedly increased in plasma before reperfusion, reflecting an extrarenal response possibly induced by afferent renal nerve activity from the ischaemic kidney. Tumour necrosis factor-α was the only mediator showing elevated lymph-to-plasma ratio following 30 min reperfusion, indicating that most cytokines were released directly into the bloodstream. The IR-induced rise in cytokine levels was paralleled by a significant increase in high molecular weight plasma proteins in both lymph and urine. The latter was shown as a 14- to 166-fold increase in glomerular sieving coefficient of plasma proteins assessed by a novel proteomic approach, and indicated a temporarily reduced size selectivity of both glomerular and peritubular capillaries. Collectively, our data suggest that cytokines from the ischaemic kidney explain most of the rise in plasma concentration, and that the locally produced substances enter the systemic circulation through transport directly to plasma and not via the interstitium to lymph.

Characteristics of renal sympathetic nerve single units in rabbits with angiotensin‐induced hypertension

We examined the effect of chronic angiotensin (Ang II)-induced hypertension on activity of postganglionic renal sympathetic units to determine whether altered whole renal nerve activity is due to recruitment or changes in firing frequency. Rabbits were treated with a low (20 ng kg(-1) min(-1), 8 weeks) or high dose (50 ng kg(-1) min(-1), 4 weeks) of Ang II before the experiment under chloralose-urethane anaesthesia. Spontaneously active units were detected from multiunit recordings using an algorithm that separated units by action potential shape using templates that matched spikes within a prescribed standard deviation. Multiunit sympathetic nerve activity was 40% higher in rabbits treated with low-dose Ang II than in sham (P = 0.012) but not different in high-dose Ang II. Resting firing frequency was similar in sham rabbits (1.00 ± 0.09 spikes s(-1), n = 144) and in those treated with high-dose Ang II (1.10 ± 0.08 spikes s(-1), n = 112) but was lower with low-dose Ang II (0.65 ± 0.08 spikes s(-1), n = 149, P < 0.05). Unit firing rhythmicity was linked to the cardiac cycle and was similar in sham and low-dose Ang II groups but 29-32% lower in rabbits treated with high-dose Ang II (P < 0.001). Cardiac linkage followed a similar pattern during hypoxia. All units showed baroreceptor dependency. Baroreflex gain and range were reduced and curves shifted to the right in Ang II groups. Firing frequency during hypoxia increased by +39% in low-dose Ang II and +82% in shams, but the greatest increase was in the high-dose Ang II group (+103%, P(dose) = 0.001). Responses to hypercapnia were similar in all groups. Increases in sympathetic outflow in hypertension caused by low-dose chronic Ang II administration are due to recruitment of neurons, but high-dose Ang II increases firing frequency in response to chemoreceptor stimuli independently of the arterial baroreceptors.

Abstract 139: Renal Afferent Nerve Sensitivity and the Pathophysiology of Salt-sensitive Hypertension

Aim: Altered renal afferent nerve responsiveness contributes to hypertension in the Spontaneously Hypertensive rat. We hypothesized that increased salt-intake differentially impacts the renal afferent nerve sensitivity in salt-resistant vs salt-sensitive rats. Methods: Groups of naïve Sprague-Dawley (SD), Dahl Salt-Resistant (DSR), Dahl Salt-Sensitive (DSS) or SD rats receiving a s.c. norepinephrine (NE:600ng/min) infusion were fed a 0.4% (NS) or 8% NaCl (HS) diet for 14 (SD) or 21 days (DSR &amp; DSS). Following HS intake MAP and plasma NE content were determined. Via a renal pelvis preparation afferent nerve activity was assessed as NE-evoked (6250 pmol) substance P (SP) release (N=5/gp). Results: Salt-resistant phenotypes (SD &amp; DSR) remain normotensive and exhibit HS-evoked suppression of plasma NE and increased renal afferent nerve release of substance P. In contrast in salt-sensitive phenotypes (DSS and NE infused SD) a high salt diet evoked hypertension, increased plasma NE and abolished sodium evoked increased responsiveness of the renal afferent release of substance P. Significance symbols: *p&lt;0.05 vs. resp. NS gp; τ p&lt;0.05 vs. resp. SD Naïve gp. value. Conclusion: These data support a role of the afferent renal nerves in blood pressure regulation during high salt-intake. Increased responsiveness of the renal afferent nerves contributes to the maintenance of normotension in a salt-resistant rat phenotype. Conversely, our data suggest that in salt-sensitive phenotypes excess release of NE triggers impaired activation of the renal afferent nerves, a factor we postulate contributes to the development of salt-sensitive hypertension.