Renal Nerve Stimulation Research Articles

Renal Nerve Stimulation as Procedural End Point for Renal Sympathetic Denervation.

Renal sympathetic denervation (RDN) as treatment option for hypertension has a strong rationale; however, variable effects on blood pressure (BP) have been reported ranging from non-response to marked reductions in BP. The absence of a procedural end point for RDN is one of the potential factors associated with the variable response. Studies have suggested the use of renal nerve stimulation (RNS) to adequately address this issue. This review aims to provide an overview of the clinical and experimental data available regarding the effects of RNS in the setting of RDN. Animal studies have shown that high-frequency electrical stimulation of the sympathetic nerves in the adventitia of the renal arteries elicits an increase in BP and leads to an increased norepinephrine spillover as a marker of increased sympathetic activity and these effects of stimulation were attenuated or blunted after RDN. In a human feasibility study using RNS both before and after RDN, similar BP responses were observed. Moreover, in patients with resistant hypertension, RNS-induced changes in BP appeared to be correlated with 24-h BP response after RDN. These data suggest that RNS is a useful tool to identify renal sympathetic nerve fibers in patients with treatment-resistant hypertension undergoing RDN, and to predict the likely effectiveness of RDN treatments. In acute procedural settings both in animal and human models, RNS elicits increase in BP and HR before RDN and these effects are blunted after RDN. Up to now, there is preliminary evidence that the RNS-induced BP changes predict 24-h ABPM outcome at follow-up in patients with resistant hypertension. Of note, studies are small sized and results of large trials comparing conventional RDN to RNS-guided RDN are warranted.

CRT-600.15 Safety and Performance Of Diagnostic Electrical Mapping of Renal Nerves in Hypertensive Patients and/or Potential Candidates for a Renal Sympathetic Denervation (RDN) Procedure

As the exact location of renal nerves cannot be visualized, renal sympathetic denervation (RDN) remains a so-called blind procedure. The aim to the present study is to assess the safety and feasibility of renal nerve stimulation using the ConfidenHTTM mapping system. The technology could help to

BP.06.05] RENAL NERVE STIMULATION IDENTIFIES AORTICORENAL INNERVATION AND PREVENTS INADVERTENT ABLATION OF PARASYMPATHETIC NERVES DURING RENAL SYMPATHETIC DENERVATION

Objective: Recently we reported the use of renal nerve stimulation (RNS) during renal denervation (RDN) procedures. We hypothesized that electrical stimulation of the sympathetic nerve tissue in the renal artery would lead to an increase in BP and vagal stimulation would cause a decrease in BP. The objective of the current study is to report the different patterns of BP and heart rate responses elicited by RNS prior to RDN. Design and method: Thirty-five patients with drug-resistant hypertension were included. RNS was performed under general anesthesia at four sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP and heart rate changes were monitored. Results: A total of 289 RNS sites in 35 patients were analyzed. An increase in systolic BP of >10 mmHg was regarded as a positive BP response to RNS. This pattern of response was observed in 180 sites (62%). 86 RNS sites (30%) showed an indifferent response with BP changes >10 mmHg. At 13 sites (4.5%) RNS elicited a decrease in BP up to -8 mmHg. However, 10 RNS sites (3.5%) showed a pronounced vagal response with hypotension and sinus arrests ranging between 4224–10272 milliseconds. These sites were distributed among two patients. Conclusions: RNS identified sympathetic and parasympathetic nerve tissue in the renal arteries. RNS can be potentially used to map nerve bundles and guide selective ablation of sympathetic nerve fibers and prevent inadvertent ablation of parasympathetic nerve tissue during RDN.

Renal nerve stimulation for treatment of neurocardiogenic syncope: a review from perspective of commercialization potential.

A strong evidence of outcomes for vasovagal syncope is not easily identified. It would seem reasonable that the proposed Mayo Clinic technology would be reserved for cases with severe recurrent or refractory syncope. However, recurrence levels are relatively low, and while some predictive methods have been proposed, recurrence is also influenced by the interaction that occurs during screening and examinations, i.e. recurrence diminishes once an initial diagnosis has been made. Finally, a key factor in being able to identify suitable patients relates to understanding the relative significance of the vasodepression and cardioinhibitory components-the therapy is best suited to patients that have a significant level of both components. It is probably not needed in patients with mainly cardioinhibitory involvement-data from ISSUE 2 and ISSUE 3 studies suggest that this is a relatively large proportion, particularly with asystolic involvement. The challenge remains in having suitable screening tests to identify the best patients. Tilt table testing has questions concerning its ability to replicate clinical syncope-implantable loop recorders (ILRs) may provide more accurate data but their usage is not yet widely accepted given the costs and invasive nature of the monitor.

Opposite Arterial Pressure Responses to Renal Afferent Nerve Stimulation in Unanesthetized Versus Anesthetized Rats: Implications for the Neural‐Renal Axis and Hypertension

Neural control of the kidney remains a primary focus of treatment of cardiovascular and renal disease, including hypertension (HTN). Moreover, recent studies support a role of renal afferent nerves in the modulation of sympathetic nerve activity (SNA), and in turn, arterial pressure (AP). We recently reported resting afferent nerve activity (ARNA) is elevated in the DOCA‐salt hypertensive rat, and that targeted afferent renal nerve ablation attenuates this model of hypertension (Banek et al. Hypertension 2016). These findings suggest that increased ARNA contributes to the pathogenesis of HTN. Previous investigations of the responses of AP and SNA to renal afferent nerve stimulation have been conducted in anesthetized animals have reported a sympatho‐inhibitory response. The present study was designed to measure the acute AP response to increased ARNA in anesthetized and unanesthetized preparations. Male Sprague Dawley rats (300–400g) underwent acute renal afferent stimulation while under 2% isoflurane anesthesia (ISO; n=12) or in the absence of anesthesia following a cortical decerebration (DEC; n=12). Animals were instrumented to measure AP, heart rate (HR), and ARNA. To activate renal afferent nerves, a ureteral catheterization was performed to perfuse the renal pelvis with vehicle 0.9% saline [VEH] or with the TRPV1‐agonist 50μM capsaicin (CAP). Following instrumentation and a 30‐minute stabilization period, ARNA and cardiovascular responses to VEH or CAP stimulation were recorded. Peak responses in ARNA, AP, and HR were quantified and compared between ISO vs. DEC preparations by a Student's t‐test (α=.05). ARNA responses were calculated as percent change from baseline (%ARNA). Data presented as mean±SEM. There was no difference in resting ∫ARNA, AP, or HR prior to afferent stimulation between ISO and DEC groups. VEH perfusion of the renal pelvis elicited no response in both ISO and DEC groups. In contrast, CAP administration resulted in marked increase in %ARNA that was similar in magnitude in both groups (ISO 214±31% vs. DEC 239±40%). More importantly, whereas the CAP‐induced increase in ARNA elicited a depressor response in ISO rats (−17±6mmHg), CAP evoked an opposing pressor response in DEC rats (+54±9mmHg). These findings suggest the existence of a renal afferent nerve‐dependent sympatho‐excitatory reflex in the rat, and anesthesia may directly interfere in this signaling pathway. It is important to note it is unknown whether this acute reflex translates to long‐term regulation of SNA and AP. While the anatomical and biological mechanisms of this reflex remain rudimentary, further studies are underway to chronically monitor afferent nerve activity and blood pressure in conscious freely moving rats to elucidate this important neural‐renal axis.Support or Funding InformationNIH 5R01HL116476; NIH 2T32HL7741

Renal sympathetic denervation guided by renal nerve stimulation to treat ventricular arrhythmia in CKD patients with ICD.

Chronic kidney disease (CKD) patients on stage 4 present greater risk rates for malignant ventricular arrhythmia events. This study examined patients with CKD in stages 1, 2, 3 and 4, left ventricular dysfunction and automatic implantable cardioverter-defibrillator (ICD). Our goal was to record the appropriate therapies, “Anti-tachycardia Therapy Pacing” (ATP) and shock events during the 18 months of follow-up and compare the incidence and severity of these at different stages of CKD, mainly in patients with CKD stage 4 underwent renal sympathetic denervation (RSD) guided by renal nerve stimulation (RNS). One hundred and fifteen patients were evaluated once every three months till 18 months of follow-up. The arrhythmic events were assessed at each follow-up visit. Comparing the groups, we can see the number of ATP and shock events recorded by ICD during 18 months of follow-up, and differences in the number of therapeutic events between the various stages of CKD. The hazard ratio (HR), 95% confidence interval (CI) and P value for ATP and shock events between all the CKD stages were evaluated by the log-rank/Mantel-Haenszel test. At the 18th month of follow-up, 75% of patients with CKD stage 4 received ATP, and 70% were treated with shock while only 20% of the subjects with CKD stage 4 that were submitted to RSD received ATP and 20% were treated with shock, P<0.0001 and P=0.0002, respectively. In our study, a decline occurred in the incidence of arrhythmias, and therefore, appropriate ICD therapies in advanced stages of CKD, reducing the risk rates for these events in patients with CKD on stage 4 after RSD guided by RNS in comparison to the other CKD stages. Our results suggest that RSD can control the higher incidence of malignant arrhythmias in advanced CKD stages.

Impacts of Renal Sympathetic Activation on Atrial Fibrillation: The Potential Role of the Autonomic Cross Talk Between Kidney and Heart

BackgroundRecent studies have demonstrated that there is a high variability of renal sympathetic nerve density distribution from proximal to distal renal artery segments. The aim of our study was to investigate the roles of renal sympathetic nerve stimulation (RSS) on atrial fibrillation and cardiac autonomic nervous activity.Methods and ResultsTwenty‐eight dogs were randomly assigned to the proximal RSS group (P‐RSS, N=7), middle RSS group (M‐RSS, N=7), distal RSS group (D‐RSS, N=7), and the control group (sham RSS, N=7). RSS was performed using electrical stimulation on the bilateral renal arteries for 3 hours. Effective refractory period and the window of vulnerability were measured at atrial and pulmonary veins sites. Superior left ganglionated plexi (SLGP) and left stellate ganglion (LSG) function and neural activity were determined. C‐fos and nerve growth factor protein expression in the SLGP and LSG were examined. Only P‐RSS (1) caused pronounced blood pressure rises, induced a significant decrease in effective refractory period, and generated a marked increase in cumulative window of vulnerability and effective refractory period dispersion; (2) increased the frequency and amplitude of the neural activity in the SLGP and LSG; (3) increased SLGP and LSG function; and (4) upregulated the level of c‐fos and nerve growth factor expression in the SLGP and LSG.ConclusionsThis study demonstrated that renal sympathetic nerve activation induced by 3 hours of P‐RSS facilitated atrial fibrillation inducibility by upregulating cardiac autonomic nervous activity, suggesting a potential autonomic cross talk between kidney and heart.

Alkaline Phosphatase Inhibitors Attenuate Renovascular Responses to Norepinephrine.

Tissue nonspecific alkaline phosphatase (TNAP) contributes to the production of adenosine by the kidney, and A1-receptor activation enhances renovascular responses to norepinephrine. Therefore, we hypothesized that TNAP regulates renovascular responsiveness to norepinephrine. In isolated, perfused rat kidneys, the TNAP inhibitor l-p-bromotetramisole (0.1 mmol/L) decreased renal venous levels of 5'-AMP (adenosine precursor) and adenosine by 61% (P<0.0384) and 62% (P=0.0013), respectively, at 1 hour into treatment and caused a 10-fold rightward shift of the concentration-response relationship to exogenous norepinephrine (P<0.0001). Similarly, 2 other TNAP inhibitors, levamisole (1 mmol/L) and 2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide (0.02 mmol/L), also right shifted the concentration-response relationship to norepinephrine. The ability of TNAP inhibition to blunt renovascular responses to norepinephrine was mostly prevented or reversed by restoring A1-adenosinergic tone with the A1-receptor agonist 2-chloro-N6-cyclopentyladenosine (100 nmol/L). All 3 TNAP inhibitors also attenuated renovascular responses to renal sympathetic nerve stimulation, suggesting that TNAP inhibition attenuates renovascular responses to endogenous norepinephrine. In control propranolol-pretreated rats, acute infusions of norepinephrine (10 μg/kg/min) increased mean arterial blood pressure from 95±5 mm Hg to a peak of 169±4 mm Hg and renovascular resistance from 12±2 mm Hg/mL/min to a peak of 55±12 mm Hg/mL/min; however, in rats also treated with intravenous l-p-bromotetramisole (30 mg/kg), the pressor and renovascular effects of norepinephrine were significantly attenuated (blood pressure: basal and peak, 93±7 and 146±6 mm Hg, respectively; renovascular resistance: basal and peak, 13±2 and 29±5 mm Hg/mL/min, respectively). TNAP inhibitors attenuate renovascular and blood pressure responses to norepinephrine, suggesting that TNAP participates in the regulation of renal function and blood pressure.

Acute effects of renal sympathetic denervation guided by renal nerve stimulation in CKD patients with ICD

Acute effects of renal sympathetic denervation guided by renal nerve stimulation in CKD patients with ICD

OP.7D.06] RENAL HEMODYNAMIC CHANGES AFTER RENAL DENERVATION

Abstract Stimulation of renal sympathetic nerves causes reduced renal blood flow. To elucidate whether renal denervation (RDN) affects renal perfusion, we analysed renal blood flow of parenchymal areas perfused by arteries that were non-treated versus treated with RDN. In a pilot study 8 patients with treatment-resistant hypertension that had multiple renal arteries in either kidney were included. All patients underwent catheter-based RDN using the Symplicity FlexTM RDN System of the main renal arteries, but not of accessory renal arteries. Renal perfusion was measured noninvasively by magnetic resonance imaging on a 1.5-T scanner with arterial spin labelling before (day-1), after (day + 1) and again after 3 months (3 M) of RDN. Renal parenchyma was divided into areas that were perfused by renal arteries which were treated with RDN versus those areas perfused by accessory renal arteries not treated with RDN. Hence, every patient could serve at its own control with respect to changes of renal blood flow in the same kidney. In addition renal function was assessed by eGFR according CKD-Epi formula. There was an acute increase of renal perfusion in areas supplied by arteries not undergoing RDN (day-1: 242.3 [229.2-263.2] vs. day + 1: 260.0 [243.5-296.6] ml/min/100 g, p = 0.008), which returned to baseline values after 3 M (257.0 [240.5-277.8] ml/min/100 g, p = 0.260). In contrast, renal perfusion did not change in areas supplied by arteries undergoing RDN in acute (day-1: 263.5 [245.9-273.6] vs. day + 1: 256.5 [242.9-273.5] ml/min/100 g, p = 0.953) and 3 M (245.4 [235.5-269.7] ml/min/100 g, p = 0.594). Accordingly, the acute change in renal perfusion between day-1 and day + 1 was significantly greater in parenchymal areas supplied by arteries without compared to areas with RDN (p = 0.014), but not after 3 M. Renal function assessed by eGFR did not change between day-1 and day + 1 (80.3 ± 20 versus 79.8 ± 20 ml/min/1.73m, p = 0.885) as well as after 3 M of RDN (80.8 ± 18 ml/min/1.73m, p = 0.889). Despite an average of 7.0 ± 1.5 antihypertensive drugs, baseline office BP was 157/85mmHg, and was reduced by -11/-7mmHg after 3 M of RDN. Our data indicate an acute increase of renal perfusion in renal parenchymal areas perfused by arteries with intact renal nerves, whereas no change occurred in parenchymal areas perfused by arteries after RDN.

Renal Denervation Improves Exaggerated Sympathoexcitation in Rats With Heart Failure: A Role for Neuronal Nitric Oxide Synthase in the Paraventricular Nucleus.

Renal denervation (RDN) has been postulated to reduce sympathetic drive during heart failure (HF), but the central mechanisms are not completely understood. The purpose of the present study was to assess the contribution of neuronal nitric oxide synthase (nNOS) within the paraventricular nucleus (PVN) in modulating sympathetic outflow in rats with HF that underwent RDN. HF was induced in rats by ligation of the left coronary artery. Four weeks after surgery, bilateral RDN was performed. Rats with HF had an increase in FosB-positive cells in the PVN with a concomitant increase in urinary excretion of norepinephrine, and both of these parameters were ameliorated after RDN. nNOS-positive cells immunostaining, diaphorase staining, and nNOS protein expression were significantly decreased in the PVN of HF rats, findings that were ameliorated by RDN. Microinjection of nNOS inhibitor N(G)-monomethyl l-arginine into the PVN resulted in a blunted increase in lumbar sympathetic nerve activity (11±2% versus 24±2%) in HF than in sham group. This response was normalized after RDN. Stimulation of afferent renal nerves produced a greater activation of PVN neurons in rats with HF. Afferent renal nerve stimulation elicited a greater increase in lumbar sympathetic nerve activity in rats with HF than in sham rats (45±5% versus 22±2%). These results suggest that intact renal nerves contribute to the reduction of nNOS in the PVN, resulting in the activation of the neurons in the PVN of rats with HF. RDN restores nNOS and thus attenuates the sympathoexcitation commonly observed in HF.

Persistent Increase in Blood Pressure After Renal Nerve Stimulation in Accessory Renal Arteries After Sympathetic Renal Denervation

Blood pressure response to renal denervation is highly variable, and the proportion of responders is disappointing. This may be partly because of accessory renal arteries too small for denervation, causing incomplete ablation. Renal nerve stimulation before and after renal denervation is a promising approach to assess completeness of renal denervation and may predict blood pressure response to renal denervation. The objective of the current study was to assess renal nerve stimulation-induced blood pressure increase before and after renal sympathetic denervation in main and accessory renal arteries of anaesthetized patients with drug-resistant hypertension. The study included 21 patients. Nine patients had at least 1 accessory renal artery in which renal denervation was not feasible. Renal nerve stimulation was performed in the main arteries of all patients and in accessory renal arteries of 6 of 9 patients with accessory arteries, both before and after renal sympathetic denervation. Renal nerve stimulation before renal denervation elicited a substantial increase in systolic blood pressure, both in main (25.6±2.9 mm Hg; P<0.001) and accessory (24.3±7.4 mm Hg; P=0.047) renal arteries. After renal denervation, renal nerve stimulation-induced systolic blood pressure increase was blunted in the main renal arteries (Δ systolic blood pressure, 8.6±3.7 mm Hg; P=0.020), but not in the nondenervated renal accessory renal arteries (Δ systolic blood pressure, 27.1±7.6 mm Hg; P=0.917). This residual source of renal sympathetic tone may result in persistent hypertension after ablation and partly account for the large response variability.

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.

Exercise training (ET) in treadmill running reduces oxidative stress and inflammatory signaling of the commissural nucleus of the solitary tract (commNTS) and rostral ventrolateral medulla in rats

Renal sympathetic nerve activity (rSNA) at a low frequencyinfluences handling of sodium and water by the kidneys, without changing renal blood flow and glomerular filtration rate. Accordingly, we have previously demonstrated that renal nerve stimulation increases NHE3mediated sodium reabsorption due to an increased intrarenal reninangiotensin-system (RAS), independent of hemodynamic changes. In the present study, we evaluated how sympathoexcitation accompanied by blood pressure elevation would impact renal function and proximal tubule NHE3 regulation. To this end, we disinhibited the paraventricular nucleus of the hypothalamus (PVN) by microinjecting the antagonist GABA receptor bicuculline in anesthetized Wistar rats. We found that bicuculline injected unilaterallywithin the PVN caused a rapid increase in blood pressure compared with the baseline period (± 45%), which was accompanied by a great increase in urinary volume (more than 300%). This increase in urinary volumewas associatedwith an increase onNHE3 phosphorylation levels, suggesting that the diuretic effect of PVN disinhibition and blood pressure elevation are, at least in part, due to a decrease in NHE3 activity. Ongoing experiments from our laboratory are directed toward investigating the effects of bicuculline within the PVN in other apical sodium transporters along the renal tubule and evaluating the possible role of both systemic and intrarenal RAS in mediating these effects. Supported by CAPES, CNPq and FAPESP.

Exercise training (ET) in treadmill running reduces oxidative stress and inflammatory signaling of the commissural nucleus of the solitary tract (commNTS) and rostral ventrolateral medulla in rats

Renal sympathetic nerve activity (rSNA) at a low frequencyinfluences handling of sodium and water by the kidneys, without changing renal blood flow and glomerular filtration rate. Accordingly, we have previously demonstrated that renal nerve stimulation increases NHE3mediated sodium reabsorption due to an increased intrarenal reninangiotensin-system (RAS), independent of hemodynamic changes. In the present study, we evaluated how sympathoexcitation accompanied by blood pressure elevation would impact renal function and proximal tubule NHE3 regulation. To this end, we disinhibited the paraventricular nucleus of the hypothalamus (PVN) by microinjecting the antagonist GABA receptor bicuculline in anesthetized Wistar rats. We found that bicuculline injected unilaterallywithin the PVN caused a rapid increase in blood pressure compared with the baseline period (± 45%), which was accompanied by a great increase in urinary volume (more than 300%). This increase in urinary volumewas associatedwith an increase onNHE3 phosphorylation levels, suggesting that the diuretic effect of PVN disinhibition and blood pressure elevation are, at least in part, due to a decrease in NHE3 activity. Ongoing experiments from our laboratory are directed toward investigating the effects of bicuculline within the PVN in other apical sodium transporters along the renal tubule and evaluating the possible role of both systemic and intrarenal RAS in mediating these effects. Supported by CAPES, CNPq and FAPESP.

5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats

Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3±1.0, 43.7±2.7 and 66.7±4.0 for 2, 4 and 6Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT1/7 agonist) (0.00000125–0.1μg/kg each) or l-694,247 (5-HT1D agonist; 0.0125μg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists α-methyl-5-HT (5-HT2), 1-PBG (5-HT3), cisapride (5-HT4), AS-19 (5-HT7), CGS-12066B (5-HT1B) or 8-OH-DPAT (5-HT1A) (0.0125μg/kg each). The effect of l-694,247 did not affect the exogenous norepinephrine-induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT1D; 1mg/kg) or l-NAME (nitric oxide; 10mg/kg), but not by indomethacin (COX1/2; 2mg/kg) or glibenclamide (ATP-dependent K+ channel; 20mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT1D receptors via nitric oxide release.

Crosstalk between the renal sympathetic nerve and intrarenal angiotensinII modulates proximal tubular sodium reabsorption.

What is the topic of this review? The sympathetic control of renal sodium tubular reabsorption is dependent on activation of the intrarenal renin-angiotensin system and activation of the angiotensinII type1 (AT1 ) receptor by angiotensinII. What advances does it highlight? Despite the fact that the interaction between the sympathetic nervous system and angiotensinII regarding salt reabsorption is a well-known classical mechanism for the maintenance of extracellular volume homeostasis, the underlying molecular signalling is not clearly understood. It has been shown recently that renal nerve stimulation increases intrarenal angiotensinII and activates the AT1 receptor, triggering a signalling cascade that leads to elevations of Na(+) -H(+) exchanger isoform3-mediated tubular transport. In this short review, the crosstalk between intrarenal angiotensinII and renal nerve activity and its effect on sodium reabsorption is addressed. In this review, we address the importance of the interaction between the sympathetic nervous system and intrarenal renin-angiotensin system in modulating renal tubular handling of sodium and water. We have recently shown that increased Na(+) -H(+) exchanger isoform3 (NHE3) activity induced by renal nerve stimulation (RNS) depends on the activation of the angiotensinII type1 (AT1 ) receptor by angiotensinII (AngII). Low-frequency RNS resulted in higher levels of intrarenal angiotensinogen and AngII independent of changes in blood pressure, the glomerular filtration rate and systemic angiotensinogen. AngiotensinII, via the AT1 receptor, triggered an intracellular pathway activating NHE3 in the renal cortex, leading to antinatriuresis and antidiuresis. Pharmacological blockade of the AT1 receptor with losartan prior to RNS abolished both the functional and the molecular responses, suggesting that intrarenal AngII acting via the AT1 receptor is a major factor for NHE3-mediated sodium and water reabsorption induced by RNS.

Activation of afferent renal nerves modulates RVLM-projecting PVN neurons.

Renal denervation for the treatment of hypertension has proven to be successful; however, the underlying mechanism/s are not entirely clear. To determine if preautonomic neurons in the paraventricular nucleus (PVN) respond to afferent renal nerve (ARN) stimulation, extracellular single-unit recording was used to investigate the contribution of the rostral ventrolateral medulla (RVLM)-projecting PVN (PVN-RVLM) neurons to the response elicited during stimulation of ARN. In 109 spontaneously active neurons recorded in the PVN of anesthetized rats, 25 units were antidromically activated from the RVLM. Among these PVN-RVLM neurons, 84% (21/25) were activated by ARN stimulation. The baseline discharge rate was significantly higher in these neurons than those PVN-RVLM neurons not activated by ARN stimulation (16%, 4/25). The responsiveness of these neurons to baroreflex activation induced by phenylephrine and activation of cardiac sympathetic afferent reflex (CSAR) was also examined. Almost all of the PVN neurons that responded to ARN stimulation were sensitive to baroreflex (95%) and CSAR (100%). The discharge characteristics for nonevoked neurons (not activated by RVLM antidromic stimulation) showed that 23% of these PVN neurons responded to ARN stimulation. All the PVN neurons that responded to ARN stimulation were activated by N-methyl-D-aspartate, and these responses were attenuated by the glutamate receptor blocker AP5. These experiments demonstrated that sensory information originating in the kidney is integrated at the level of preautonomic neurons within the PVN, providing a novel mechanistic insight for use of renal denervation in the modulation of sympathetic outflow in disease states such as hypertension and heart failure.

The role of renal nerves in cardiovascular and renal function in normal and pathophysiological states.

Video slideshow introduction to the Symposium by Symposium Speaker Clive May can be found here. The notion that increased sympathetic nervous system activity is important to trigger and maintain hypertension has been under consideration for decades. It is well known that an increase in renal sympathetic nerve activity (RSNA) stimulates renin secretion, which leads to renal vasoconstriction and increases sodium reabsorption (DiBona & Kopp, 1997), indicating that excessive RSNA will contribute to hypertension. Historically, surgical sympathectomy has been used to improve blood pressure control (Smithwick, 1940; Grimson, 1941). Nevertheless, this procedure was abandoned because of its high operative morbidity and mortality. Recently, however, catheter-based interventional strategies that interrupt the RSNA have shown promising results in providing a better long-term blood pressure control in patients with resistant arterial hypertension (Esler, 2010; Esler et al. 2010). These studies have raised enormous interest in understanding the role of renal nerves in the control of cardiovascular and renal functions. Nevertheless, the mechanisms underlying the initiation and maintenance of sympathoexcitation in pathophysiological conditions and how the renal denervation leads to a long-term reduction of blood pressure are not well understood. The symposium entitled ‘The Role of renal nerves in cardiovascular and renal function in normal and pathophysiological states’, which was held at The First Pan-American Congress of Physiological Sciences, Iguassu Falls, Brazil, 2–6 August 2014, focused on the new advances regarding the importance of efferent and afferent renal fibres on sodium homeostasis and the effects of renal denervation and reinnervation on cardiovascular and kidney functions. Regarding the mechanisms underlying sympathoexcitation in hypertension, the importance of increased oxidative stress in the paraventricular nucleus of hypothalamus and the rostral ventrolateral medulla for the autonomic dysfunction associated with renovascular hypertension was discussed (Campos et al. 2015). The effect of interaction between the sympathetic nervous system and angiotensin II on sodium reabsorption is a well-known classical mechanism for the maintenance of extracellular volume homeostasis; however, the underlying molecular signalling is not clearly understood. Recent data were presented in this symposium to demonstrate that renal nerve stimulation increases intrarenal angiotensin II and activates angiotensin II type 1 receptors, triggering a signalling cascade that leads to elevation of Na+–H+ exchanger isoform 3-mediated tubular transport. The findings enhance our understanding in relation to the interaction and synergism between the sympathetic nervous system and intrarenal angiotensin II actions in normal conditions (Bergamaschi et al. 2015). Additionally, the interaction between the brain and the kidneys to maintain homeostasis is still a matter of debate and was discussed in this symposium. Recent evidences suggest that increased RSNA and renal afferent nerve activity to the brain may contribute to the outcome to the disease, such as hypertension or heart failure (Nishi et al. 2014). During renovascular hypertension, increased afferent signalling from the ischaemic kidney may contribute to the increase in blood pressure. Indeed, in renovascular hypertensive rats submitted to treatment with bone marrow-derived mesenchymal stem cells, an improvement was found in the kidney tissue and function. This was accompanied by a reduction of sympathetic vasomotor activity to the kidneys and a reduction of blood pressure, probably as a consequence of reduced afferents from the diseased kidney (Oliveira-Sales et al. 2015). In another interesting recent study, the time course of the effects of renal denervation was investigated in sheep. In this study, 11 months after catheter-based radiofrequency renal denervation, functional and anatomical evidence of afferent and efferent renal nerve reinnervation were found. Therefore, the mechanism by which catheter-based renal denervation causes a prolonged decrease in blood pressure is not well understood. Further studies are required to address this important issue (Booth et al. 2015). In conclusion, the present symposium discussed new ideas about the mechanisms by which the brain and kidneys communicate and how they interact to maintain cardiovascular and renal homeostasis. Understanding the mechanisms of crosstalk between these two important organs (brain and kidneys) related to the control of blood pressure will probably increase the possibility of finding new strategies for the treatment of cardiovascular and renal diseases. Disclaimer: Supporting information has been peer-reviewed but not copyedited. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Different responses of arterial blood pressure to electrical stimulation of the renal artery in patients with resistant hypertension

SIMPLICITY-HTN 3 revealed several limitations of renal denervation (RDN) for the treatment of resistant hypertension [ [1] Bhatt D.L. Kandzari D.E. O'Neill W.W. D'Agostino R. Flack J.M. Katzen B.T. Leon M.B. Liu M. Mauri L. Negoita M. Cohen S.A. Oparil S. Rocha-Singh K. Townsend R.R. Bakris G.L. SYMPLICITY HTN-3 Investigators: a controlled trial of renal denervation for resistant hypertension. N. Engl. J. Med. 2014; 370: 1393-1401 Crossref PubMed Scopus (1566) Google Scholar ]. One of the main limitations is that the current RDN technique lacks a measurable endpoint. Recently, electrical stimulation of the renal nerves through the ablation catheter introduced in the renal artery before and after RDN was proposed as a promising method in this journal [ 2 Hilbert S. Kosiuk J. Hindricks G. Bollmann A. Blood pressure and autonomic responses to electrical stimulation of the renal arterial nerves before and after ablation of the renal artery. Int. J. Cardiol. 2014; 177: 669-671 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar , 3 Hao Y. Lu Z. Renal denervation: should we still hang in there?. Int. J. Cardiol. 2014; 176: 1255-1256 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar ]. These reports showed that the effect of intra-renal artery electrical stimulation on renal nerves, especially the afferent sensory nerve, before and after ablation, was useful as RDN endpoint. However, the afferent sensory nerve on the lateral side of renal artery might include not only afferent excitatory sympathetic nerve fibers but also inhibitory sympathetic nerve fibers [ [4] Stella A. Weaver L. Golin R. Genovesi S. Zanchetti A. Cardiovascular effects of afferent renal nerve stimulation. Clin. Exp. Hypertens. A. 1987; 9: 97-111 Crossref PubMed Scopus (12) Google Scholar ]. In this report, we present two patients with resistant hypertension who showed opposite arterial blood pressure responses to electrical stimulation before and after RDN.