Efferent Renal Sympathetic Activity Research Articles

GLP-1 mediated diuresis and natriuresis are blunted in heart failure and restored by selective afferent renal denervation

BackgroundGlucagon-like peptide-1 (GLP-1) induces diuresis and natriuresis. Previously we have shown that GLP-1 activates afferent renal nerve to increase efferent renal sympathetic nerve activity that negates the diuresis and natriuresis as a negative feedback mechanism in normal rats. However, renal effects of GLP-1 in heart failure (HF) has not been elucidated. The present study was designed to assess GLP-1-induced diuresis and natriuresis in rats with HF and its interactions with renal nerve activity.MethodsHF was induced in rats by coronary artery ligation. The direct recording of afferent renal nerve activity (ARNA) with intrapelvic injection of GLP-1 and total renal sympathetic nerve activity (RSNA) with intravenous infusion of GLP-1 were performed. GLP-1 receptor expression in renal pelvis, densely innervated by afferent renal nerve, was assessed by real-time PCR and western blot analysis. In separate group of rats after coronary artery ligation selective afferent renal denervation (A-RDN) was performed by periaxonal application of capsaicin, then intravenous infusion of GLP-1-induced diuresis and natriuresis were evaluated.ResultsIn HF, compared to sham-operated control; (1) response of increase in ARNA to intrapelvic injection of GLP-1 was enhanced (3.7 ± 0.4 vs. 2.0 ± 0.4 µV s), (2) GLP-1 receptor expression was increased in renal pelvis, (3) response of increase in RSNA to intravenous infusion of GLP-1 was enhanced (132 ± 30% vs. 70 ± 16% of the baseline level), and (4) diuretic and natriuretic responses to intravenous infusion of GLP-1 were blunted (urine flow 53.4 ± 4.3 vs. 78.6 ± 4.4 µl/min/gkw, sodium excretion 7.4 ± 0.8 vs. 10.9 ± 1.0 µEq/min/gkw). A-RDN induced significant increases in diuretic and natriuretic responses to GLP-1 in HF (urine flow 96.0 ± 1.9 vs. 53.4 ± 4.3 µl/min/gkw, sodium excretion 13.6 ± 1.4 vs. 7.4 ± 0.8 µEq/min/gkw).ConclusionsThe excessive activation of neural circuitry involving afferent and efferent renal nerves suppresses diuretic and natriuretic responses to GLP-1 in HF. These pathophysiological responses to GLP-1 might be involved in the interaction between incretin-based medicines and established HF condition. RDN restores diuretic and natriuretic effects of GLP-1 and thus has potential beneficial therapeutic implication for diabetic HF patients.

Glucagon‐like peptide‐1 mediated renal sympathetic activation in obese rats: role of intrarenal mechanisms

Accumulated evidence indicates that obesity is associated with enhanced sympathetic activation. Chronic sympathetic activation increases the risk of cardiovascular complications and subsequent mortality. The mechanisms linking obesity with sympathetic activation are complex and not completely understood. Gut produced hormone glucagon‐like peptide‐1 (GLP‐1) affects cardiovascular function via regulating blood pressure and sympathetic nerve activity. The aim of the study was to determine the role of intrarenal GLP‐1 mediated renal sympathetic activation in obese rats. In anesthetic Sprague Dawley rats, renal intra‐pelvic infusion of GLP‐1 receptor agonist exendin‐4 increased afferent renal sympathetic nerve activity (A‐RSNA), efferent renal sympathetic nerve activity (T‐RSNA), arterial pressure and heart rate. All the sympathetic and hemodynamic responses to the exendin‐4 infusion were significantly enhanced in high fat diet (HFD, 42% of calories from fat for 12 weeks) induced obese rats. The natriuretic and diuretic effects mediated by intrarenal exendin‐4 infusion was significantly blunted in the obese rats. Furthermore, ablation of renal sympathetic nerves significantly improved the diuretic and natriuretic responses to exendin‐4 infusion in obese rats. We also found significant altered GLP‐1 level and GLP‐1 receptor expression in the kidney of obese rats. The results suggest that altered intrarenal GLP‐1 mediated mechanisms may contribute to the development of obesity‐related high sympathetic activation and obesity hypertension.Support or Funding InformationThe study was supported by the author’s faculty start‐up fund from Sanford School of Medicine of the University of South Dakota Department of Basic Biomedical Sciences.

A selective impairment in the mechanosensitive afferent renal nerve‐mediated sympathoinhibitory reno‐renal reflex contributes to age‐related hypertension

AimThe afferent renal nerves (ARN) mediate reno‐renal reflexes that influence efferent renal sympathetic nerve activity, sodium homeostasis, and blood pressure. These studies tested the hypothesis that impairments in the sympathoinhibitory reno‐renal reflex contribute to age‐related hypertension (HTN).MethodsThree‐month (mo), 8mo, and 16mo male (M) Sprague Dawley (SD) rats on a normal salt (NS; 0.6% NaCl) diet underwent an acute isotonic saline volume expansion (VE; 5% body weight – mechanoreceptor stimulus) or an acute isovolumetric 1M NaCl infusion (20μL/min, 2hr – chemoreceptor stimulus) and mean arterial pressure (MAP), natriuresis (UNaV), and paraventricular nucleus (PVN) neuronal activation (c‐Fos expression) were assessed. Three and 8mo female SD rats also underwent acute VE. N=6/gp.In 3mo, 8mo and 16mo M SD rats, 1) sympathetic tone (plasma and renal norepinephrine [NE] content) or 2) ex vivo ARN activity (substance P [SP] release in response to 1250pM NE [general stimulus] or 450mM NaCl [chemoreceptor stimulus]) were assessed on day 21 of NS or high salt (HS; 4% NaCl) diet. N=6/gp.In 3mo and 16mo M SD rats on a NS diet, MAP and sodium balance were assessed on day 10 after selective ARN ablation (33mM capsaicin) or total bilateral renal denervation (RDNX; 10% phenol). N=6/gp.ResultsAged rats develop HTN (MAP [mmHg] 3mo 124 ± 2 vs 8mo 135 ± 4 vs 16mo 150 ± 3, p<0.05) and exhibit blunted natriuretic and PVN sympathoinhibitory parvocellular neuronal responses to an acute VE (% sodium load excreted 3mo 78 ± 6 vs 8mo 60 ± 7 vs 16mo 22 ± 9, p<0.05; medial parvocellular neuronal activation [c‐fos+ cell count] 3mo 59 ± 4 vs 8mo 42 ± 7 vs 16mo 13 ± 5, p<0.05). There are no sex differences in VE responses in 3 or 8mo rats. The natriuretic and PVN neuronal responses to a 1M NaCl infusion are intact in aged rats.Aged rats exhibit reduced NE‐evoked ARN activity during NS intake and fail to increase NE‐evoked ARN activity during HS intake (SP release [pg/min] 3mo NS 14 ± 2 vs HS 23 ± 4, p<0.05; 8mo NS 8 ± 2 vs HS 6 ± 3, ns; 16mo NS 2 ± 7 vs HS 2 ± 6, ns). Age and diet did not alter 450mM NaCl‐evoked ARN activity.Aged rats exhibit elevated basal plasma and renal sympathetic tone and impaired HS‐evoked suppression of sympathetic tone (renal NE content [pg/mg] 3mo NS 612 ± 36 vs HS 368 ± 32; 8mo NS 835 ± 48 vs HS 722 ± 44, p<0.05; 16mo HS 974 ± 13 vs NS 1019 ± 34, ns).Bilateral RDNX attenuates MAP and improves sodium balance in aged rats (MAP [mmHg] 15mo intact 150 ± 3 vs RDNX 140 ± 2, p<0.05; 24hr sodium balance [mEq] 15mo intact 0.51 ± 0.13 vs RDNX 0.08 ± 0.13, p<0.05). Selective ARN ablation has no impact on MAP or sodium balance.ConclusionsAge‐related HTN is characterized by a selective impairment in the mechanosensitive ARN. We speculate that a decrease in ARN‐mediated sympathoinhibitory reno‐renal reflex activity promotes sympathoexcitation, perhaps due to reduced PVN parvocellular neuronal activity, driving sodium retention and HTN. Critically, RDNX attenuates age‐related HTN and may do so via an improvement in sodium balance.Support or Funding InformationThis work was supported by NIH R56 AG057687, R01 HL139867, R01 HL141406 and 17GRNT33670023 to RDW and NIH F31 DK116501 to AAF.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Peripherally Administered Proinflammatory Cytokines Increase Afferent Renal Nerve Activity in Rat

Inflammation plays an important role in sympathetic activation in cardiovascular diseases. Systemic administration of the proinflammatory cytokines (PICs) tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) increases mean blood pressure (MBP), heart rate (HR) and efferent renal sympathetic nerve activity. However, the renal nerve contains both afferent and efferent fibers. The afferent renal nerve is composed of chemoreceptor and mechanoreceptor fibers, and delivers peripheral signals to the brain that have been reported to increase sympathetic outflow in hypertension and heart failure. The effect of circulating PICs on afferent renal nerve activity (ARNA) has not previously been investigated. The present study sought to determine whether peripherally administered PICs TNF‐α and IL‐1β increase ARNA. Urethane anesthetized male Sprague Dawley rats (300–350 g) underwent an intravenous (IV) or a renal artery injection of TNF‐α or IL‐1β. MBP (mmHg), HR (beats/min) and ARNA (% change from baseline) were continuously recorded for 4–5 hours. IV injection of TNF‐α (500 ng/kg) or IL‐1β (500 ng/kg) significantly (* p<0.01 vs. baseline) increased MBP (20.1 ± 2.2* and 23.4 ± 2.1*, respectively), HR (51.5 ± 6.7* and 58.8 ± 7.1*, respectively) and ARNA (37.2 ± 3.5* and 42.1 ± 3.5*, respectively) with peak responses 20–30 mins after injection. Similarly, renal artery injection of the same doses of TNF‐α or IL‐1β induced increases (*p<0.01 vs. baseline) in MBP (17.0 ± 2.1* and 19.9 ± 2.2*, respectively), HR (45.5 ± 5.6* and 49.3 ± 4.6*, respectively) and ARNA (30.7 ± 3.5* and 38.4 ± 4.5*, respectively) that began within 5–10 mins and peaked at 20–30 mins after the injection. Quantitative real‐time PCR showed high mRNA levels of TNF‐α receptor 1 and IL‐1β receptor in renal cortex and medulla. These data indicate that circulating TNF‐α and IL‐1β can act at the kidney to augment afferent renal nerve activity, suggesting that circulating PICs may activate ARN fibers to elicit a sympathetically mediated pressor response. PIC activation of renal afferent nerves may be an important mechanism contributing to inflammation‐driven sympathetic activation in heart failure and hypertension. These findings provide support for the potential therapeutic benefit of renal afferent denervation.Support or Funding InformationSupported by NIH grant R01 HL139521 (S.G. Wei)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chronic Kidney Disease As a Potential Indication for Renal Denervation.

Renal denervation is being used as a blood pressure lowering therapy for patients with apparent treatment resistant hypertension. However, this population does not represent a distinct disease condition in which benefit is predictable. In fact, the wide range in effectiveness of renal denervation could be a consequence of this heterogeneous pathogenesis of hypertension. Since renal denervation aims at disrupting sympathetic nerves surrounding the renal arteries, it seems obvious to focus on patients with increased afferent and/or efferent renal sympathetic nerve activity. In this review will be argued, from both a pathophysiological and a clinical point of view, that chronic kidney disease is particularly suited to renal denervation.

Autonomic modulation for the management of patients with chronic heart failure.

Dysregulation of the autonomic nervous system in heart failure (HF) has received considerable attention during the past 3 decades, largely because of the well-recognized association between increased sympathetic activity and the elaboration of biologically active molecules, collectively referred to as neurohormones, that help to maintain cardiovascular homeostasis through increased volume expansion, peripheral arterial vasoconstriction, and increased myocardial contractility. However, high and sustained levels of these biologically active molecules (eg, norepinephrine, angiotensin II, aldosterone) are overtly toxic to the heart and circulation.1 These and other insights have led to the clinical use of neurohormonal antagonists, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, and β-blockers to treat patients with HF with a reduced left ventricular ejection fraction (LVEF).1 The effectiveness of these pharmacological agents is predominantly because of their ability to directly antagonize the deleterious effects of excessive sympathetic and renin–angiotensin activation. However, the current guideline-directed medical therapy (GDMT) in patients with HF fails to completely restore normal autonomic balance disrupted as a part of HF pathophysiology. During the last decade, a novel approach has generated widespread interest: modulation of the autonomic nervous system as a result of either a one-time intervention (eg, denervation) or of ongoing active therapy (eg, electric stimulation) as a means of further diminishing the sympathovagal imbalance that develops in HF.2,3 Of note, therapeutic neuromodulation with device-based therapies, either with spinal cord stimulation (SCS) or vagal stimulation (VS), has been used safely in patients with chronic pain, epilepsy, and depression, since the 1980s. As noted above, HF with a reduced LVEF is associated with sustained activation of the sympathetic nervous system that is accompanied by a withdrawal of parasympathetic tone. Impaired arterial baroreflexes have been proposed as an important mechanism that contributes to the sympathovagal imbalance present in HF4 …

Effects of anesthetics on the renal sympathetic response to anaphylactic hypotension in rats.

The autonomic nervous system plays an important role in rat anaphylactic hypotension. It is well known that sympathetic nerve activity and cardiovascular function are affected by anesthetics. However, the effects of different types of anesthesia on the efferent renal sympathetic nerve activity (RSNA) during anaphylactic hypotension remain unknown. Therefore, we determined the renal sympathetic responses to anaphylactic hypotension in anesthetized and conscious rats and the roles of baroreceptors in these responses. Sprague-Dawley rats were randomly allocated to anesthetic groups that were given pentobarbital, urethane, or ketamine-xylazine and to a conscious group. The rats were sensitized using subcutaneously injected ovalbumin. The systemic arterial pressure (SAP), RSNA and heart rate (HR) were measured. The effects of sinoaortic baroreceptor denervation on RSNA during anaphylaxis were determined in pentobarbital-anesthetized and conscious rats. In all of the sensitized rats, the RSNA increased and SAP decreased after antigen injection. At the early phase within 35 min of the antigen injection, the antigen-induced sympathoexcitation in the conscious rats was significantly greater than that in the anesthetized rats. Anaphylactic hypotension was attenuated in the conscious rats compared to the anesthetized rats. The anesthetic-induced suppression of SAP and RSNA was greater in the order ketamine-xylazine >urethane = pentobarbital. Indeed, in the rats treated with ketamine-xylazine, RSNA did not increase until 40 min, and SAP remained at low levels after the antigen injection. The baroreceptor reflex, as evaluated by increases in RSNA and HR in response to the decrease in SAP induced by sodium nitroprusside (SNP), was suppressed in the anesthetized rats compared with the conscious rats. Consistent with this finding, baroreceptor denervation attenuated the excitatory responses of RSNA to anaphylaxis in the conscious rats but not in the pentobarbital-anesthetized rats. RSNA was increased markedly in conscious rats during anaphylactic hypotension. Anesthetics attenuated this antigen-induced renal sympathoexcitation through the suppression of baroreceptor function.

Role of renal sensory nerves in physiological and pathophysiological conditions.

Whether activation of afferent renal nerves contributes to the regulation of arterial pressure and sodium balance has been long overlooked. In normotensive rats, activating renal mechanosensory nerves decrease efferent renal sympathetic nerve activity (ERSNA) and increase urinary sodium excretion, an inhibitory renorenal reflex. There is an interaction between efferent and afferent renal nerves, whereby increases in ERSNA increase afferent renal nerve activity (ARNA), leading to decreases in ERSNA by activation of the renorenal reflexes to maintain low ERSNA to minimize sodium retention. High-sodium diet enhances the responsiveness of the renal sensory nerves, while low dietary sodium reduces the responsiveness of the renal sensory nerves, thus producing physiologically appropriate responses to maintain sodium balance. Increased renal ANG II reduces the responsiveness of the renal sensory nerves in physiological and pathophysiological conditions, including hypertension, congestive heart failure, and ischemia-induced acute renal failure. Impairment of inhibitory renorenal reflexes in these pathological states would contribute to the hypertension and sodium retention. When the inhibitory renorenal reflexes are suppressed, excitatory reflexes may prevail. Renal denervation reduces arterial pressure in experimental hypertension and in treatment-resistant hypertensive patients. The fall in arterial pressure is associated with a fall in muscle sympathetic nerve activity, suggesting that increased ARNA contributes to increased arterial pressure in these patients. Although removal of both renal sympathetic and afferent renal sensory nerves most likely contributes to the arterial pressure reduction initially, additional mechanisms may be involved in long-term arterial pressure reduction since sympathetic and sensory nerves reinnervate renal tissue in a similar time-dependent fashion following renal denervation.

Rebuttal from Markus P. Schlaich, Yusuke Sata and Murray D. Esler.

Extreme positions are rarely useful and almost invariably hinder rather than facilitate progress in clinical science. Dr Jordan (Jordan, 2014) and Dr Paton (Ratcliffe et al. 2014) and their colleagues seem to share this view and, while making a strong case for each of their points, have provided a reasonably balanced appraisal of the evidence surrounding the interventional approaches for resistant hypertension under debate. Importantly, we seem to share common ground in the view that resistant hypertension is a relevant clinical problem, that non-adherence to prescribed medication is common, that alternative and perhaps device-based therapeutic approaches are needed, and that sympathetic overactivity is a major contributor to the pathophysiology of resistant hypertension thereby providing a logical therapeutic target. Our views differ in how this is best achieved. Dr Jordan elegantly reviews the role of baroreflex circuits in long-term blood pressure (BP) control and how electrical carotid sinus stimulation (CCS) may ameliorate resistant hypertension. While highlighting potential advantages of CCS such as the ability of stimulation adjustment, it becomes clear from his pathophysiological considerations that sympathetic inhibition, specifically suppression of efferent renal sympathetic nerve activity, is an important mediator of CCS-induced depressor responses (Iliescu et al. 2012). Why not target the renal nerves directly when this can be achieved safely with catheter-based approaches (Esler et al. 2010; Bhatt et al. 2014)? Carotid body (CB) denervation is the least developed and investigated approach, which does not negate the physiological relevance of chemoreceptor activation and its role in modulation of both sympathetic nerve activity and blood pressure. Dr Paton promotes the concept of CB tonicity driving sympathetic vasomotor activity chronically, particularly in the scenario of hypertension (Paton et al. 2013). Surgical resection of the CB has been performed to alleviate dyspnoea in patients with obstructive airway disease and coincidentally, a BP reduction was observed in a subgroup of hypertensive patients (Nakayama, 1961). Clearly, recent experimental data is more convincing (McBryde et al. 2013). Nevertheless, evidence for a pivotal role of CB-related mechanisms in human resistant hypertension is weak and the concept far from proven. Major concerns that need to be addressed relate to the potential attenuation or loss of hypoxic ventilatory drive and the potentially serious procedural complications. In keeping with the hypothetical ideals for an interventional approach brought forward by Dr Paton, we would argue that renal denervation remains the most promising therapeutic approach despite the recent setback from a suboptimally conducted clinical trial (Bhatt et al. 2014).

Potential Clinical Application of Recently Discovered Brain Mechanisms Involved in Hypertension

Accumulating evidence indicates that central activation of the sympathetic nervous system plays an important role in hypertension.1–8 The aim of this review is to inform clinicians about the involvement of brain mechanisms in clinical hypertension and the applicability of recent findings to clinical practice. Clinicians, particularly cardiologists and nephrologists, are now initiating clinical treatment of hypertension that targets the sympathetic nervous system using novel techniques, such as catheter-based renal denervation and carotid baroreflex activation therapy.9,10 Renal denervation reduces efferent renal sympathetic activity, thereby decreasing renal tubular sodium reabsorption, supporting renal blood flow, and inhibiting the renin–angiotensin–aldosterone system, which has a blood pressure–lowering effect. In addition, it has been proposed that inhibition of central sympathetic outflow via reduced renal afferent input to the brain leads to a long-term reduction in blood pressure.11 Carotid baroreflex activation therapy reduces blood pressure and central sympathetic outflow, and the sympathoinhibitory action lasts for a much longer period than previously thought, without rapid adaptation.12,13 In addition, the currently used antihypertensive drugs are suggested to act on the central nervous system.7,14 The brain is essential for processing and integrating various stimuli from the periphery to maintain blood pressure and fluid homeostasis.1–3 The circumventricular organs, hypothalamus, and brain stem are major brain regions contributing to this function.2 During the past several decades, however, neural mechanisms, such as arterial baroreflex function, have been considered to be involved in short-term blood pressure regulation, but not in long-term blood pressure control (ie, hypertension).1–4 Arterial baroreceptors adapt and thus cannot provide accurate negative feedback signals to the brain to maintain normal arterial pressure. Importantly, surgical removal of the afferent projections of arterial baroreceptors (sinoaortic denervation) results in a transient increase in arterial …

Abstract 538: Prolonged Functional Sympathetic Efferent Denervation Following Ablation of the Renal Nerves in SHR

Renal denervation (RDN) has been shown to be an effective and safe treatment for human resistant hypertension and is considered one of the most promising advances in the field of hypertension. However, the mechanisms mediating the sustained decrease in arterial pressure in response to RDN in humans are unknown. This issue is particularly perplexing, given reports that the depressor effect of RDN in animal models is short lived. The current dogma in the literature is that overtime the efferent sympathetic nerves regrow and so the longevity of the depressor effect of RDN in humans cannot be ascribed to the absence of efferent renal sympathetic nerve activity. We hypothesize that the renal sympathetic nerves regenerate following RDN, and arrive at the target tissues, but the functional response is not fully restored and this contributes to the long-term depressor effect of RDN. Our aim was to examine mean arterial pressure (MAP) and vascular function in spontaneously hypertensive rats (SHR) following RDN. In 10 week old male SHR radiotelemetry probes were implanted to measure MAP. At 12 weeks of age, following 3 days basal MAP recording, sham (n=5) or bilateral RDN (n=5) surgery was performed. MAP was recorded until 24 weeks of age (12 weeks post-RDN). Renal lobar arteries were mounted on a myograph and membrane potential and tension responses to perivascular nerve stimulation assessed. Perivascular nerve stimulation with single pulses at increasing voltage evoked excitatory junction potentials (Ejps) of increasing amplitude in SHR-sham. Ejp amplitude was markedly reduced in arteries from SHR-RDN (P<0.01). Repetitive stimulation (1-8Hz, 5s) evoked slow depolarisation and contraction. At 5Hz 5s, slow depolarisation was 12±2 mV in SHR-shams and 7±2 mV in SHR-RDN (P<0.01), and contractions were smaller than SHR-sham (10 ± 3% vs 22 ± 2% HiK; P<0.01). In conclusion, smaller Ejps suggest that close contacting neuroeffector junctions are not reformed and blunted vasoconstrictor responses indicate neuro-vascular function has only partially returned 12 weeks post-RDN (Fig. 2). Our finding of continued ‘functional’ denervation is compatible with our data that RDN causes a sustained decrease in arterial pressure in SHR.

Renal Sympathetic Denervation and Renal Physiology

The sympathetic nervous system has a profound effect on the kidney's ability to regulate blood pressure and, vice versa, the kidney has an important effect on the overall sympathetic tone. As a result, renal sympathetic nerves are crucial for initiation and the maintenance of systemic hypertension. It is fairly well established that efferent renal sympathetic nerve activity contributes significantly to homeostatic regulation of renal blood flow, glomerular filtration rate, renal tubular epithelial cell solute and water transport, and hormonal release. The afferent nerves from the kidney activate central sympathetic nervous system activity, participate in a reflex control system via reno-renal reflexes and are involved in cardiovascular regulation and pathogenesis of hypertension in CKD patients whose kidney ischemia also seems to play a key role. Sympathetic nerve modulation in hypertension had been considered as a therapeutic strategy long before the advent of modern pharmacological therapies. Renal sympathetic denervation with a percutaneous, catheter-based approach results in significant and sustained blood pressure reduction in patients with resistant hypertension. This procedure has also beneficial effects in multiple organs function. However, renal physiology and the long term observed benefits with the use of renal sympathetic denervation have not completely elucidated.

Mechanisms of cardiovascular actions of urocortins in the hypothalamic arcuate nucleus of the rat

The presence of urocortins (UCNs) and corticotropin-releasing factor (CRF) receptors has been reported in the hypothalamic arcuate nucleus (ARCN). We have previously reported that UCNs are involved in central cardiovascular regulation. Based on this information, we hypothesized that the ARCN may be one of the sites where UCNs exert their central cardiovascular actions. Experiments were done in artificially ventilated, adult male Wistar rats anesthetized with urethane. Unilateral microinjections (30 nl) of UCN1 (0.12-2 mM) elicited decreases in mean arterial pressure (MAP) and heart rate (HR). Maximum cardiovascular responses were elicited by a 1 mM concentration of UCN1. Microinjections of UCN2 and UCN3 (1 mM each) into the ARCN elicited similar decreases in MAP and HR. UCN1 was used as a prototype for the other experiments described below. HR responses elicited by UCN1 were significantly attenuated by bilateral vagotomy. Prior microinjections of NBI-27914 (CRF-1 receptor antagonist) and astressin (CRF-1 receptor and CRF-2 receptor antagonist) (1 mM each) into the ARCN significantly attenuated the cardiovascular responses elicited by UCN1 microinjections at the same site. Microinjections of UCN1 into the ARCN decreased efferent renal sympathetic nerve activity. It was concluded that microinjections of UCN1, UCN2, and UCN3 into the ARCN elicited decreases in MAP and HR. Decreases in MAP, HR, and renal sympathetic nerve activity elicited by UCN1 microinjections into the ARCN were mediated via CRF receptors. Bradycardic responses to UCN1 were mediated via the activation of vagus nerves, and decreases in MAP may be mediated via decreases in sympathetic nerve activity.

Renal Denervation by Ablation with Innovative Technique in Resistant Hypertension

Hypertension is the cause of thousands of deaths annually1, and half of the patients treated present controlled blood pressure (BP)2. Resistant hypertension (RH)is defined when the BP remains above the recommended targets with the use of three antihypertensive drugs with synergistic actions at maximum doses recommended and tolerated, preferably one being a diuretic, or when in use of four or more anti-hypertensive drugs, even with controlled BP3. It is estimated that 12%-15% of persons with hypertension are considered resistant, with high risk of cardiovascular morbidity and mortality4. The pathogenesis of hypertension is multifactorial, but the sympathetic activity plays an important role, especially in patients with resistant hypertension2. Efferent renal sympathetic activity stimulates renin release, increases sodium reabsorption and reduces renal blood flow and may be a mechanism for the development and maintenance of hypertension2. Genetic, behavioral and environmental factors influence increased sympathetic activity in persons with hypertension5. New therapies aiming to reduce sympathetic activity have been developed. Renal Sympathetic Denervation (RSD) by radiofrequency catheter ablation of renal arteries has been shown to control BP in resistant hypertension6,7 and in associated clinical conditions such as sleep destructive apnea8 and insulin resistance9. The main RSD clinical studies used a specific catheter not yet available in Brazil, but the radiofrequency ablation of arrhythmias is a procedure that has been performed by electrophysiologists through appropriate catheters for years in our country. Experimental studies of RSD with catheters used for ablation of arrhythmias indicated the possibility of using these to replace those used in international studies, considering the unavailability of those in our reality. Based on this, for the procedure to be reported, the model used for ablation in children (4 mm tip and 5F), which was proven to be more appropriate, was chosen. The objective of the report is to show the result of the first RSD in our community, with the aid of technology used in cardiac arrhythmias.

787 EFFECTS OF TRANSCATHETER RENAL NERVE ABLATION ON SYMPATHETIC AND NEUROHORMONAL ACTIVITY IN PATIENTS WITH RESISTANT HYPERTENSION

Background: Transcatheter renal nerve ablation is a novel treatment modality to directly and selectively target efferent sympathetic and afferent sensory nerves. Initial clinical trials have demonstrated favorable effects not only on blood pressure control but also on other conditions commonly characterized by sympathetic overdrive, such as insulin resistance, sleep apnea and others. The effects of renal denervation on regional sympathetic nerve activity and neurohormonal activation have not yet been described in detail. Design and methods: A total of 40 patients with resistant hypertension (mean age: 60 ± 8yrs) underwent assessment of regional sympathetic nerve activity using microneurography and/or renal and whole body noradrenaline spillover before and after staged or single session bilateral renal denervation. Renal blood flow and markers of neurohormonal activation were also measured. Results: Renal and muscle sympathetic nerve activity were substantially elevated at baseline and reduced in most patients after renal denervation which was associated with a significant reduction in blood pressure and renovascular resistance. Complementing the reduction in renal NA spillover, plasma renin activity was reduced by 24% and renal plasma flow increased by 11.2%. Data from 10 patients who underwent a staged renal nerve ablation procedure revealed a distinct sympathetic response pattern with an immediate ipsilateral reduction and contralateral increase in renal NA spillover. Prior to the second procedure, renal NA spillover was already reduced bilaterally with the effect being more pronounced after the second procedure. Conclusions: Transcatheter renal nerve ablation is associated with a substantial reduction in efferent renal sympathetic nerve activity and accompanied by favorable changes in systemic and renal hemodynamic and neurohormonal parameters. Reductions in central sympathetic outflow and whole body noradrenaline spillover are likely due to alterations in afferent signaling from the treated kidneys.

Tonic Postganglionic Sympathetic Inhibition Induced by Afferent Renal Nerves?

Other than efferent sympathetic innervation, the kidney has peptidergic afferent fibers expressing TRPV1 receptors and releasing substance P. We tested the hypothesis that stimulation of afferent renal nerve activity with the TRPV1 agonist capsaicin inhibits efferent renal sympathetic nerve activity tonically by a neurokinin 1 receptor-dependant mechanism. Anesthetized Sprague-Dawley rats were instrumented as follows: (1) arterial and venous catheters for recording of blood pressure and heart rate and drug administration; (2) left-sided renal arterial catheter for selective intrarenal administration of the TRPV1 agonist capsaicin (3.3, 6.6, 10, 33*10(-7) m; 10 μL; after 15, 30, 45, and 60 minutes, respectively) to stimulate afferent renal nerve activity; (3) right-sided bipolar electrode for continuous renal sympathetic nerve recording; and (4) specialized renal pelvic and renal artery catheters to separate pelvic from intrarenal afferent activity. Before and after intrarenal capsaicin application, increasing intravenous doses of the neurokinin 1 receptor blocker RP67580 were given. Intrarenal capsaicin decreased integrated renal sympathetic activity from 65.4±13.0 mV*s (baseline) to 12.8±3.2 mV*s (minimum; P<0.01). This sustained renal sympathetic inhibition reached its minimum within 70 minutes and was not directly linked to the transient electric afferent response to be expected with intrarenal capsaicin. Suppressed renal sympathetic activity transiently but completely recovered after intravenous administration of the neurokinin 1 blocker (maximum: 120.3±19.4 mV*s; P<0.01). Intrarenal afferent activity could be unequivocally separated from pelvic afferent activity. For the first time we provide direct evidence that afferent intrarenal nerves provide a tonically acting sympathoinhibitory system, which seems to be rather mediated by neurokinin release acting via neurokinin 1 receptor pathways rather than by electric afferent effects on central sympathetic outflow.

Reflexes from pulmonary arterial baroreceptors in dogs: interaction with carotid sinus baroreceptors

In contrast to the reflex vasodilatation occurring in response to stimulation of baroreceptors in the aortic arch, carotid sinuses and coronary arteries, stimulation of receptors in the wall of pulmonary arteries results in reflex systemic vasoconstriction. It is rare for interventions to activate only one reflexogenic region, therefore we investigated how these two types of reflexes interact. In anaesthetized dogs connected to cardiopulmonary bypass, reflexogenic areas of the carotid sinuses, aortic arch and coronary arteries and the pulmonary artery were subjected to independently controlled pressures. Systemic perfusion pressure (SPP) measured in the descending aorta (constant flow) provided an index of systemic vascular resistance. In other experiments, sympathetic efferent neural activity was recorded in fibres dissected from the renal nerve (RSNA). Physiological increases in pulmonary arterial pressure (PAP) induced significant increases in SPP (+39.1 ± 10.4 mmHg) and RSNA (+17.6 ± 2.2 impulses s(−1)) whereas increases in carotid sinus pressure (CSP) induced significant decreases in SPP (−42.6 ± 10.8 mmHg) and RSNA (−42.8 ± 18.2 impulses s(−1)) (P < 0.05 for each comparison; paired t test). To examine possible interactions, PAP was changed at different levels of CSP in both studies. With CSP controlled at 124 ± 2 mmHg, the threshold, 'set point' and saturation pressures of the PAP–SPP relationship were higher than those with CSP at 60 ± 1 mmHg; this rightward shift was associated with a significant decrease in the reflex gain. Similarly, increasing CSP produced a rightward shift of the PAP–RSNA relationship, although the effect on reflex gain was inconsistent. Furthermore, the responses to changes in CSP were influenced by setting PAP at different levels; increasing the level of PAP from 5 ± 1 to 33 ± 3 mmHg significantly increased the set point and threshold pressures of the CSP–SPP relationship; the reflex gain was not affected. These results indicate the existence of interaction between pulmonary arterial and carotid sinus baroreceptor reflexes; physiological and pathological states that alter the stimulus to one may alter the reflex responses from the other.

Impaired Interaction Between Efferent and Afferent Renal Nerve Activity in SHR Involves Increased Activation of α 2 -Adrenoceptors

Activation of efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), leading to decreases in ERSNA by activation of the renorenal reflexes in the overall goal of maintaining low ERSNA. The renorenal reflex responses to various stimuli are impaired in spontaneously hypertensive rats (SHR). Because renal tissue density of α(2)-adrenoceptors (ARs) is increased in SHR, we examined whether the ERSNA-induced increases in ARNA are impaired in SHR and, if so, the role of α(2)-ARs. The ARNA responses to increases in ERSNA were impaired in SHR, 2390 ± 460%·seconds, versus in Wistar-Kyoto rats, 6620 ± 1690%·seconds. Renal pelvic release of substance P was not altered by 6250 pmol/L norepinephrine (NE) in SHR but was increased by 250 pmol/L NE in Wistar-Kyoto rats, from 5.7 ± 0.7 to 12.5±1.3 pg/min. Renal pelvic administration of the α(2)-AR antagonist rauwolscine enhanced the ERSNA-induced increases in ARNA, 4170 ± 900%·seconds, in SHR but not in Wistar-Kyoto rats. In the presence of rauwolscine, 250 pmol/L NE increased substance P release, from 5.2 ± 0.3 to 11.2 ± 0.8 pg/min, in pelvises from SHR. Because angiotensin II suppresses the activation of renal mechanosensory nerves in SHR, we examined whether losartan improved the ERSNA-induced ARNA responses. Losartan had no effect on the ARNA responses or the NE-induced increases in substance P in SHR. However, losartan+rauwolscine resulted in further enhancement of the responsiveness of the renal sensory nerves to increases in ERSNA and NE in SHR but not in WKY. We conclude that increased activation of renal α(2)-ARs and angiotensin II type 1 receptors contributes to the impaired interaction between ERSNA and ARNA in SHR.

Dietary sodium modulates the interaction between efferent and afferent renal nerve activity by altering activation of α2-adrenoceptors on renal sensory nerves

Activation of efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which then reflexively decreases ERSNA via activation of the renorenal reflexes to maintain low ERSNA. The ERSNA-ARNA interaction is mediated by norepinephrine (NE) that increases and decreases ARNA by activation of renal α(1)-and α(2)-adrenoceptors (AR), respectively. The ERSNA-induced increases in ARNA are suppressed during a low-sodium (2,470 ± 770% s) and enhanced during a high-sodium diet (5,670 ± 1,260% s). We examined the role of α(2)-AR in modulating the responsiveness of renal sensory nerves during low- and high-sodium diets. Immunohistochemical analysis suggested the presence of α(2A)-AR and α(2C)-AR subtypes on renal sensory nerves. During the low-sodium diet, renal pelvic administration of the α(2)-AR antagonist rauwolscine or the AT1 receptor antagonist losartan alone failed to alter the ARNA responses to reflex increases in ERSNA. Likewise, renal pelvic release of substance P produced by 250 pM NE (from 8.0 ± 1.3 to 8.5 ± 1.6 pg/min) was not affected by rauwolscine or losartan alone. However, rauwolscine+losartan enhanced the ARNA responses to reflex increases in ERSNA (4,680 ± 1,240%·s), and renal pelvic release of substance P by 250 pM NE, from 8.3 ± 0.6 to 14.2 ± 0.8 pg/min. During a high-sodium diet, rauwolscine had no effect on the ARNA response to reflex increases in ERSNA or renal pelvic release of substance P produced by NE. Losartan was not examined because of low endogenous ANG II levels in renal pelvic tissue during a high-sodium diet. Increased activation of α(2)-AR contributes to the reduced interaction between ERSNA and ARNA during low-sodium intake, whereas no/minimal activation of α(2)-AR contributes to the enhanced ERSNA-ARNA interaction under conditions of high sodium intake.

Protection of Ischemic Preconditioning on Renal Neural Function in Rats with Acute Renal Failure

We tested whether tolerance induced by ischemic preconditioning (IPC) in kidneys was related to renal nerves. Experimental acute renal failure (ARF) in a rat model was induced for 45 min of left renal arterial occlusion (RAO), followed by 6 or 24 h of reperfusion (ischemic reperfusion (I/R) group). The episode of IPC was four cycles of 4 min of RAO at 11 min intervals and then the I/R injury was treated as above (IPC-I/R group). After 6 h of reperfusion, polyuria was found in the I/R group associated with an enhancement of afferent renal nerve activity (ARNA) and a reflexive decrease in efferent renal nerve activity (ERNA). Changes in nerve responses were related with a reduction in neutral endopeptidase (NEP) activity and an increased release of substance P (SP). After 24 h of reperfusion, the I/R group showed oliguria which was associated with a lower ARNA, hyperactivity of ERNA and a nine-fold increase in SP release due to a further 52% loss in NEP activity. Prior IPC treatment did not affect the changed ischemia-induced excretory and nervous activity patterns during the first 6 h of reperfusion, but normalized both responses in the kidneys 24 h after ischemia. The IPC-mediated protection in oliguric ARF was related to the preservation of NEP activity to only 25% loss that caused an increase of SP amounts of only three-fold and a minor change in neurokinin 1 receptor (NK-1R) activities. Finally, both excretory and sensory responses in oliguric ARF after saline loading were significantly ameliorated by IPC. We conclude that IPC results in preservation of the renal sensory response in postischemic kidneys and has a beneficial effect on controlling efferent renal sympathetic nerve activity and excretion of solutes and water.