Selective Denervation Research Articles

The gastroprotective effect of obestatin on indomethacin-induced acute ulcer is mediated by a vagovagal mechanism.

In order to investigate the role of the vagus nerve in the possible gastroprotective effect of obestatin on the indomethacin-induced acute oxidative gastric injury, Sprague-Dawley rats of both sexes were injected subcutaneously with indomethacin (25 mg/kg, 5% NaHCO3) followed by obestatin (10, 30 or 100 μg/kg). In other sets of rats, surgical vagotomy (Vx) or selective degeneration of vagal afferent fibers by perivagal capsaicin was performed before the injections of indomethacin or indomethacin + obestatin (30 μg/kg). Gastric serosal blood flow was measured, and 4 h after ulcer induction gastric tissue samples were taken for histological and biochemical assays. Obestatin reduced the severity of indomethacin-induced acute ulcer via the reversal of reactive hyperemia, by inhibiting ulcer-induced neutrophil infiltration and lipid peroxidation along with the replenishment of glutathione (GSH) stores, whereas Vx abolished the inhibitory effect of obestatin on blood flow and lipid peroxidation, and worsened the severity of ulcer. On the other hand, serosal blood flow was even amplified by the selective denervation of the capsaicin-sensitive vagal afferent fibers, but obestatin-induced reduction in ulcer severity was not altered. In conclusion, the gastroprotective effect of obestatin on indomethacin-induced ulcer appears to involve the activation of the vagovagal pathway.

Re: One-Year Results with Selective Bladder Denervation in Women with Refractory Overactive Bladder.

Re: One-Year Results with Selective Bladder Denervation in Women with Refractory Overactive Bladder.

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.

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

Clinical and experimental evidence have shown that renal denervation, by removing both the sympathetic and afferent nerves, improves arterial hypertension and renal function in chronic kidney disease (CKD). Given the key role of renal sympathetic innervation in maintaining sodium and water homeostasis, studies have indicated that the total removal of renal nerves leads to impaired compensatory mechanisms during hemodynamic challenges. In the present study, we hypothesized that afferent (or sensory) fibers from the diseased kidney contribute to sympathetic overactivation to the kidney and other target organ, such as the splanchnic region, contributing to hypertension in CKD. We used a method to remove selectively the afferent renal fibers (periaxonal application of 33 mmol/l capsaicin) in a rat model of CKD, the 5/6 nephrectomy. Three weeks after afferent renal denervation (ARD), we found a decrease in mean arterial pressure (∼15%) and normalization in renal and splanchnic sympathetic nerve hyperactivity in the CKD group. Interestingly, intrarenal renin--angiotensin system, as well as renal fibrosis and function and proteinuria were improved after ARD in CKD rats. The findings demonstrate that afferent fibers contribute to the maintenance of arterial hypertension and reduced renal function that are likely to be mediated by increased sympathetic nerve activity to the renal territory as well as to other target organs in CKD.

Contribution of Fat‐derived Sensory Signals to Sympathetic Activation During Obesity‐hypertension

Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Numerous studies have addressed the role of sympathetic nerves in different models of hypertension; however, few have focused on the contribution of afferent nerves innervating the adipose tissue and their role in the development of obesity‐induced hypertension. Thus, the aim of this study was to determine the changes in blood pressure in response to sensory stimulation of the fat pads and the subsequent neuronal activation in brain areas that receive afferent signals from white adipose tissue (WAT). Male C57BL/6J mice were fed low fat diet (LF), regular chow, or high fat diet (HF) for 16 weeks (10%, 18% and 60% Kcal from fat, respectively). First, using radiotelemetry, we determined that mice fed HF display increased mean arterial pressure (MAP), heart rate and sympathetic index compared with LF‐fed mice (p<0.05). The selective afferent denervation of visceral fat using resiniferotoxin (RTX, 20 pmol/ul, 6 sites, 1 ul per site; bilateral) reduced mean arterial pressure (MAP). In addition, capsaicin‐induced increases in MAP were measured in anesthetized mice via carotid catheter. Capsaicin was infused in the intravascular space or skeletal muscle (2 nmol/μl, 8 μl/2 min), and subcutaneous WAT or epidydimal WAT (2 nmol/μl, 8 μl/2 min, 4 sites, bilateral). MAP did not change from baseline after capsaicin infusion into the blood stream via the jugular vein, adjacent skeletal muscle or subcutaneous WAT; whereas the infusion induced a significant increase on MAP in response to epidydimal WAT stimulation (p<0.05). Subcutaneous or epidydimal WAT stimulation with saline solution (0.9% NaCl, 8 μl/2 minutes, 4 sites, bilateral) did not influence baseline MAP in either fat depots. In a different set of mice not subjected to catheter implantation, epidydimal WAT was infused with 0.9% saline (resting, n=4) or capsaicin (n=3–5) for Fos+ cells quantification by immunohistochemistry. We quantified the posterior paraventricular nucleus of the hypothalamus (PVN), magnocellular subdivision of PVN (PaLM), supraoptic nucleus (SON), organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO) and subfornical organ (SFO). HF increased the number of Fos+ cells in the SFO and SON at resting when compared with LF‐fed mice (p<0.05). However, no changes in nonendocrine neurons in the posterior PVN, PaLM, SON, OVLT and MnPO were observed in response to HF at resting. Capsaicin stimulation in epidydimal WAT significantly decreased Fos expression in OVLT and MnPO in HF fed males compared to LF‐fed mice (p<0.05). However, no significant changes were observed in nonendocrine neurons in the posterior PVN, PaLM, SON and SFO in response to diet. Thus, this data shows that adipose tissue‐blood pressure axis response is fat depot‐specific and exacerbated in HF. In addition, although several brain areas are overactivated in response to acute stimulation with capsaicin, the OVLT and MnPO decreased its activation in mice fed a chronic HF.Support or Funding InformationR01 HL135158

Afferent renal nerve input is involved in blood pressure elevation through activation of angiotensin receptor type 1 in hypothalamic paraventricular nucleus in stroke‐prone spontaneously hypertensive rats

BackgroundRenal nerves contain both sympathetic efferent fibers and sensory afferent fibers. Activation of efferent renal nerves increases renin release and renal sodium reabsorption, causing hypertension. However, previous studies suggested that the contribution of afferent renal nerves to blood pressure (BP) regulation may differ among the animal models of hypertension. Activation of brain renin‐angiotensin system, specifically angiotensin receptor type 1 (AT1R), in hypothalamic paraventricular nucleus (PVN), which receives afferent renal input, is crucially involved in BP elevation. Therefore, the aim of this study was to examine whether the afferent renal input contributes to BP elevation through AT1R activation in the PVN in stroke‐prone spontaneously hypertensive rats (SHRSP).MethodsIn chronic experiment, total renal denervation (TRDN), selective afferent renal denervation (ARDN), or sham surgery was performed in male SHRSP at 10 weeks of age, which is the developing phase of hypertension. ARDN was produced by wrapping renal artery and vein with capsaicin‐soaked gauze. Systolic BP was measured by tail‐cuff method at baseline and 2 and 6 days after surgery. In acute experiment, we evaluated the effect of AT1R blockade with losartan in the PVN on pressor response to afferent renal nerve stimulation by intrapelvic infusion of 10 μM capsaicin under anesthesia in male Wistar‐Kyoto rats (WKY) and SHRSP at 10 weeks of age.ResultsSystolic BP was sequentially increased at day 2 and day 6 in sham‐operated SHRSP ([n=4], baseline, 188.3±9.2 mmHg; day 2, 192.1±8.1 mmHg; day 6, 201.1±3.9 mmHg). In both ARDN‐SHRSP and TRDN‐SHRSP, systolic BP was decreased from baseline at day 2 after surgery (ARDN [n=4], baseline, 187.3±10.3 mmHg; day 2, 170.5±5.2 mmHg; p=0.085; TRDN [n=4], baseline, 186.4±5.9 mmHg; day2 145.1±4.2 mmHg; p=0.003), and the decrease in systolic BP was smaller in ARDN‐SHRSP than in TRDN‐SHRSP (ARDN, −16.7±13.2 mmHg; TRDN, ‐ 41.4±10.0 mmHg; p=0.03). Although systolic BP was increased at day 6 compared to day 2 in ARDN‐SHRSP and TRDN‐SHRSP (ARDN, 197.8±14.9 mmHg; TRDN, 185.8±19.3 mmHg), the BP change from baseline to day 6 was smaller in ARDN‐SHRSP and TRDN‐SHRSP compared with sham‐operated SHRSP. We validated TRDN and ARDN by immunohistochemistry and western blotting: in the renal pelvis, both CGRP and tyrosine hydroxylase (a marker for afferent and efferent renal nerves, respectively) were abolished in TRDN‐SHRSP, and CGRP was selectively abolished in ARDN‐SHRSP. In acute experiment, BP elevation induced by afferent renal nerve stimulation was greater in SHRSP than in WKY (Δmean BP, SHRSP [n=4],12.2±4.1 mmHg; WKY [n=4], 6.6±5.4 mmHg; p=0.07). Prior microinjection of losartan into the PVN attenuated the pressor response to afferent renal nerve stimulation in SHRSP (Δmean BP, 1.1±4.4 mmHg, p=0.04 vs before losartan), but not in WKY (Δmean BP, 3.2±6.7 mmHg, p>0.10 vs before losartan).ConclusionNot only efferent renal nerve activation but afferent renal nerve input contributes to development of hypertension in SHRSP. The AT1R activation in the PVN may be involved in its mechanism.

Renal Deafferentation Improves Renal Function and Blood Pressure, but not Cardiac Parameters in an experimental model chronic kidney disease.

Chronic kidney disease is highly prevalent and its mortality is associated with cardiovascular disease. Experimental evidence shows that the renal nerves contribute to arterial hypertension and renal sympathetic hyperactivity worsening the disease; renal denervation has shown renoprotective and cardioprotective effects. However, renal sympathetic innervation plays a fundamental role in renal homeostasis and its removal is associated with impaired compensatory mechanisms during hemodynamic changes. Thus, the aim of this work was to investigate the effects of selective renal denervation of afferent fibers on renal and cardiovascular repercussions in chronic kidney disease (CKD) induced by 5/6 nephrectomy in Wistar rats. The use of animals was approved by the Federal University of São Paulo Animal Care and Use Committee and performed according to the National Institutes of Health guidelines for the conduct of experiments in animals. After five weeks of nephrectomy, denervation of renal afferent fibers with a periaxonal application of 33 mM capsaicin was performed. Cardiovascular and renal function parameters were evaluated three weeks after deafferentation.ResultsCKD induced increase in blood pressure (CTL 113±7.2 × CKD 185±14 mmHg), creatinine plasma levels (CTL 0.5±0.1 × CKD 1.2±0.5 mg/dl) and proteinuria (CTL 14±10 × 300±129 mg/24h). It was also observed an increase in cardiac hypertrophy, reduction in baroreflex sensitivity and in parasympathetic tone after autonomic double blockade. Afferent renal denervation reduced blood pressure (165±21 mmHg), improved creatinine plasma levels (0.8 ±0.2 mg/dl) and proteinuria (178±102 mg/24h). No alterations were observed after deafferentation over baroreflex sensitivity, cardiac hypertrophy and autonomic control to the heart. Together these results suggest that renal deafferentation improves blood pressure and renal function, without, however, improving the cardiac changes found in this CKD model. It is possible that the time expected after deafferentation or the stage of the disease in which it was performed was not sufficient to induce cardiac improvements. Further studies are necessary to elucidate this question.Support or Funding InformationCoordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001; by the São Paulo Research Foundation (FAPESP 18/02671‐3) and by the Brazilian National Research Council (CNPq)

Sympathetic innervation suppresses the autophagic-lysosomal system in brown adipose tissue under basal and cold-stimulated conditions.

The sympathetic nervous system (SNS) activates cAMP signaling and promotes trophic effects on brown adipose tissue (BAT) through poorly understood mechanisms. Because norepinephrine has been found to induce antiproteolytic effects on muscle and heart, we hypothesized that the SNS could inhibit autophagy in interscapular BAT (IBAT). Here, we describe that selective sympathetic denervation of rat IBAT kept at 25°C induced atrophy, and in parallel dephosphorylated forkhead box class O (FoxO), and increased cathepsin activity, autophagic flux, autophagosome formation, and expression of autophagy-related genes. Conversely, cold stimulus (4°C) for up to 72 h induced thermogenesis and IBAT hypertrophy, an anabolic effect that was associated with inhibition of cathepsin activity, autophagic flux, and autophagosome formation. These effects were abrogated by sympathetic denervation, which also upregulated Gabarapl1 mRNA. In addition, the cold-driven sympathetic activation stimulated the mechanistic target of rapamycin (mTOR) pathway, leading to the enhancement of protein synthesis, evaluated in vivo by puromycin incorporation, and to the inhibitory phosphorylation of Unc51-like kinase-1, a key protein in the initiation of autophagy. This coincided with a higher content of exchange protein-1 directly activated by cAMP (Epac1), a cAMP effector, and phosphorylation of Akt at Thr308, all these effects being abolished by denervation. Systemic treatment with norepinephrine for 72 h mimicked most of the cold effects on IBAT. These data suggest that the noradrenergic sympathetic inputs to IBAT restrain basal autophagy via suppression of FoxO and, in the setting of cold, stimulate protein synthesis via the Epac/Akt/mTOR-dependent pathway and suppress the autophagosome formation, probably through posttranscriptional mechanisms.NEW & NOTEWORTHY The underlying mechanisms related to the anabolic role of sympathetic innervation on brown adipose tissue (BAT) are unclear. We show that sympathetic denervation activates autophagic-lysosomal degradation, leading to a loss of mitochondrial proteins and BAT atrophy. Conversely, cold-driven sympathetic activation suppresses autophagy and stimulates protein synthesis, leading to BAT hypertrophy. Given its high-potential capacity for heat production, understanding the mechanisms that contribute to BAT mass is important to optimize chances of survival for endotherms in cold ambients.

Chemical Hip Denervation for Inoperable Hip Fracture.

Hip fracture is a challenging geriatric problem for the health care professionals, especially in patients with multiple comorbidities. In patients with inoperable hip fracture secondary to severe comorbid conditions, the pain can lead to significant challenges in nursing care. With the current understanding of the innervation of hip joint, we are now able to perform selective chemical denervation of the articular branches of femoral and obturator nerves to manage the pain associated with inoperable hip fracture. In this retrospective case series, we analyzed 20 consecutive patients with inoperable hip fracture who received chemical denervation and examined the effect of the denervation on pain and functional outcomes, including the maximally tolerable hip flexion and the ability to sit during their hospital stay. We also assessed the likelihood of being ambulatory as a long-term outcome. The movement-related pain was significantly reduced at 10 minutes postprocedure, on postintervention days 1 and 5 (P values of <.001), and the degree of maximally tolerable hip flexion was doubled at the same time points (P values of <.001, .003, and .002, respectively). Fifty percent of the patients managed to sit within the first 5 days after procedure, and 3 of them managed to walk with aid 4 months after hip denervation. No procedural adverse event was noted. We concluded that this chemical hip denervation could be a safe and effective measure to handle the pain-related and rehabilitation-related challenges as a result of inoperable hip fracture.

Historical view on the pathogenesis and surgical treatment of cervical dystonia

In the past few decades, approaches to surgical treatment of dystonia passed through paradigmatic shift. Intradural upper cervical anterior rhizotomy was replaced by selective peripheral denervation with lesser spectrum of side-effects. Such techniques as microvascular decompression of accessory nerve or spinal cord stimulation for cervical dystonia were abandoned due to lack of proven efficacy. Introducing globus pallidus interna (GPi) DBS in 1990's to treat all types of dystonia, including cervical dystonia, was a fundamental factor. With the growing body of knowledge on the pathophysiology of dystonia, GPi DBS appears to be the most expedient, effective and safe method with limited indications to peripheral destructive procedures.

A Preliminary Study on the Impact of Detrusor Overactivity on the Efficacy of Selective Bladder Denervation for the Treatment of Female Refractory Overactive Bladder

To determine whether the presence of detrusor overactivity (DO) is associated with the 12-week and 12-month clinical outcomes of selective bladder denervation (SBD) in women with refractory overactive bladder (OAB). Prospective single institutional study of refractory OAB females who underwent a urodynamic study and were categorized according to DO status (DO- vs DO+) prior to receiving SBD. Among the 23 patients, 10 were DO- and 13 were DO+. Both groups reported improvement at 12 weeks on the 24-hour pad weight test, in urgency urinary incontinence (UUI) and urgency. At 12 months, both groups still reported improvement in urgency, but only the DO- group reported reduction on the pad weight test and only the DO+ group maintained improvement in the UUI rate. Clinical success (≥50% reduction in UUI) was achieved by all DO- and by 69% of DO+ patients at 12 weeks, and by 60% of DO- and 92% of DO+ patients at 12 months. Treatment benefit (Treatment Benefit Scale ≤2) was reported in 90% of DO- and 85% of DO+ patients at 12 weeks, and in 60% of DO- and 85% of DO+ patients at 12 months. When directly comparing both group outcomes, the only significant difference was the greater reduction of UUI in the DO- group at 12 weeks (-9.0 vs -6.5; P = .045). Refractory OAB females appear to be effectively treated by SBD regardless of baseline DO status. DO status does not seem to be associated with the 12-week and 12-month outcomes of SBD.

Selective denervation of the wrist for chronic pain: a systematic literature review.

Selective denervation of sensory nerve branches to the wrist is a palliative surgical treatment option for patients with chronic wrist pain when preserving the range of motion and function is preferred. Treatment varies from partial isolated denervation of the posterior interosseous nerve to extensive 'complete' denervations. This study aimed to provide an overview of the literature regarding treatment outcomes in the domains of pain, grip strength, patient satisfaction and return to work. MEDLINE (PubMed), EMBASE and Cochrane databases were systematically searched and identified 993 studies, of which 12 were eligible for analysis. Denervation resulted in high 'return to work' rates (up to 94%), patient satisfaction (up to 92%), increased grip strength (7%-64%) and improved average pain scores (36%-92%). Treatment outcomes of both partial and complete denervations were favourable; however, variations in outcomes suggest the need for improving evidence regarding surgical technique and nerve identification.

Selective Carpus Denervation - One of Treatment Options of Madelung Deformity.

Case presentation of 7 years follow up of female patient with wrist arthritis caused by Madelung deformity. As causal treatment remains unknown, the pain reduction by means of selective wrist denervation is one possible option.

Does glucagon-like peptide-1 induce diuresis and natriuresis by modulating afferent renal nerve activity?

Glucagon-like peptide-1 (GLP-1), an incretin hormone, has diuretic and natriuretic effects. The present study was designed to explore the possible underlying mechanisms for the diuretic and natriuretic effects of GLP-1 via renal nerves in rats. Immunohistochemistry revealed that GLP-1 receptors were avidly expressed in the pelvic wall, the wall being adjacent to afferent renal nerves immunoreactive to calcitonin gene-related peptide, which is the dominant neurotransmitter for renal afferents. GLP-1 (3 μM) infused into the left renal pelvis increased ipsilateral afferent renal nerve activity (110.0 ± 15.6% of basal value). Intravenous infusion of GLP-1 (1 µg·kg-1·min-1) for 30 min increased renal sympathetic nerve activity (RSNA). After the distal end of the renal nerve was cut to eliminate the afferent signal, the increase in efferent renal nerve activity during intravenous infusion of GLP-1 was diminished compared with the increase in total RSNA (17.0 ± 9.0% vs. 68.1 ± 20.0% of the basal value). Diuretic and natriuretic responses to intravenous infusion of GLP-1 were enhanced by total renal denervation (T-RDN) with acute surgical cutting of the renal nerves. Selective afferent renal nerve denervation (A-RDN) was performed by bilateral perivascular application of capsaicin on the renal nerves. Similar to T-RDN, A-RDN enhanced diuretic and natriuretic responses to GLP-1. Urine flow and Na+ excretion responses to GLP-1 were not significantly different between T-RDN and A-RDN groups. These results indicate that the diuretic and natriuretic effects of GLP-1 are partly governed via activation of afferent renal nerves by GLP-1 acting on sensory nerve fibers within the pelvis of the kidney.

One-year results with selective bladder denervation in women with refractory overactive bladder.

To report 1-year results with selective bladder denervation (SBD) of the trigone in women with refractory overactive bladder (OAB). In this prospective, international, multicenter case series, women with refractory OAB underwent a single SBD treatment of the bladder subtrigone region using temperature-controlled radiofrequency. Patients were followed for 1 year and evaluated for changes in OAB symptoms and adverse events. Among 35 women, 29 (83%) returned for 1-year follow up. Median symptom reductions based on 3-day bladder diaries were 68% for urgency urinary incontinence ( P < .001), 67% for urinary incontinence ( P < .001), 43% for urgency episodes ( P < .001), 5% for urinary frequency ( P = .19), and 33% for the total urgency and frequency score ( P < .001), with the majority of treatment benefit realized in the first month. Treatment benefit was reported in 72% of patients, the clinical success rate (≥50% reduction in urgency urinary incontinence) was 69%, and the dry rate was 10%. Statistically significant improvements occurred on Symptom Bother and Health-related Quality of Life scales on the Overactive Bladder questionnaire, and on 6 of 9 King's Health Questionnaire domains. Patients with less severe baseline symptoms had similar quality of life improvements as those with more severe baseline symptoms. Device- or procedure-related adverse events were reported in 6 (17%) patients. A single treatment with selective bladder denervation is durable for 1-year in a significant proportion of women with refractory overactive bladder.

Selective Renal Denervation Guided by Renal Nerve Stimulation in Canine.

Renal nerve stimulation (RNS) can result in substantial blood pressure (BP) elevation, and the change was significantly blunted when repeated stimulation after ablation. However, whether RNS could provide a meaningful renal nerve mapping for identification of optimal ablation targets in renal denervation (RDN) is not fully clear. Here, we compared the antihypertensive effects of selective RDN guided by two different BP responses to RNS and explored the nerve innervations at these sites in Kunming dogs. Our data indicated that ablation at strong-response sites showed a more systolic BP-lowering effect than at weak-response sites (P=0.002), as well as lower levels of tyrosine hydroxylase and norepinephrine in kidney and a greater reduction in plasma norepinephrine (P=0.004 for tyrosine hydroxylase, P=0.002 for both renal and plasma norepinephrine). Strong-response sites showed a greater total area and mean number of renal nerves than weak-response sites (P=0.012 for total area and P<0.001 for mean number). Systolic BP-elevation response to RNS before RDN and blunted systolic BP-elevation to RNS after RDN were correlated with systolic BP changes at 4 weeks follow-up (R=0.649; P=0.012 and R=0.643; P=0.013). Changes of plasma norepinephrine and renal norepinephrine levels at 4 weeks were also correlated with systolic BP changes at 4 weeks (R=0.837, P<0.001 and R=0.927, P<0.001). These data suggest that selective RDN at sites with strong BP-elevation response to RNS could lead to a more efficient RDN. RNS is an effective method to identify the nerve-enriched area during RDN procedure and improve the efficacy of RDN.

Re: Six-Month Results of Selective Bladder Denervation in Women with Refractory Overactive BladderS. De Wachter, K. D. Benson, R. R. Dmochowski, E. S. Rovner, E. Versi, L. E. Miller and L. M. Tu J Urol 2019; 201: 573-580.

Re: Six-Month Results of Selective Bladder Denervation in Women with Refractory Overactive BladderS. De Wachter, K. D. Benson, R. R. Dmochowski, E. S. Rovner, E. Versi, L. E. Miller and L. M. Tu J Urol 2019; 201: 573-580.

Selective denervation of the aortic and carotid baroreceptors in rats.

What is the central question of this study? The traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation, which does not permit their individual study in different situations. What is the main finding and its importance? We have described a new surgical approach capable of selective denervation of the arterial (aortic and carotid) baroreceptors, keeping the carotid bodies (chemoreceptors) intact. It is understood that this technique might be a useful tool for investigating the relative role of the baro- and chemoreceptors in several physiological and pathophysiological conditions. Studies have demonstrated that the traditional surgical approach for sino-aortic denervation in rats leads to simultaneous carotid baroreceptor and chemoreceptor deactivation. The present study reports a new surgical approach to denervate the aortic and the carotid baroreceptors selectively, keeping the carotid bodies (peripheral chemoreceptors) intact. Wistar rats were subjected to specific aortic and carotid baroreceptor denervation (BAROS-X) or sham surgery (SHAM). Baroreflex activation was achieved by i.v. administration of phenylephrine, whereas peripheral chemoreflex activation was produced by i.v. administration of potassium cyanide. The SHAM and BAROS-X rats displayed significant hypertensive responses to phenylephrine administration. However, the reflex bradycardia following the hypertensive response caused by phenylephrine was remarkable in SHAM, but not significant in the BAROS-X animals, confirming the efficacy of the surgical procedure to abolish the baroreflex. In addition, the baroreflex activation elicited by phenylephrine increased carotid sinus nerve activity only in SHAM, but not in the BAROS-X animals, providing support to the notion that the baroreceptor afferents were absent. Instead, the classical peripheral chemoreflex hypertensive and bradycardic responses to potassium cyanide were similar in both groups, suggesting that the carotid body chemoreceptors were preserved after BAROS-X. In summary, we describe a new surgical approach in which only the baroreceptors are eliminated, while the carotid chemoreceptors are preserved. Therefore, it is understood that this procedure is potentially a useful tool for examining the relative roles of the arterial baroreceptors versus the chemoreceptors in several pathophysiological conditions, for instance, arterial hypertension and heart failure.

P3‐006: THE CASE FOR CHOLINESTERASE INHIBITION TO MODIFY NEURODEGENERATIVE DISEASES THROUGH THE INTRAMURAL PERIARTERIAL DRAINAGE OF THE CNS (IPAD)

Background Cholinesterase inhibition has been the most successful treatment in neurodegenerative dementias to date. Usually considered to be limited to symptomatic improvement, retrospective data and recent studies suggest disease modifying effects as evidenced by pathologic, imaging and clinical data. The mechanism is unknown, as much of CNS acetylcholine is released extrasynaptically with unclarified activity. We hypothesize that acetylcholine may act by facilitating the clearance of pathologic metabolic by-products through the intramural peri-arterial drainage system (IPAD). Methods A review of the existing animal and human laboratory data regarding the disease modifying effects of cholinesterase inhibition is presented and correlated with emerging clinical and epidemiological data to support or refute this hypothesis. Results Animal and human histopathologic studies have demonstrated that destruction of basal forebrain cholinergic neurons results in accumulation of fibrillar amyloid and functional impairment. Moreover, the IPAD system in mice appears to be impaired by selective chemical cholinergic denervation. Human Studies show that cholinesterase inhibition results in functional improvements in a dose dependent manner, including postponing the need for institutionalization in Alzheimer’s Disease. A human case series demonstrated a reduced cognitive decline in Dementia with Lewy Bodies with higher than usually tolerated doses of cholinesterase inhibitors. Inhibition of muscarinic receptors can identify humans with reduced cholinergic reserve, and correlate with amyloid accumulation. Finally, chronic exposure to muscarinic antagonists may increase risk for developing dementia. Conclusions A fundamental role for acetylcholine in the pathophysiology of neurodegenerative diseases is supported by experimental studies in animals and humans. It is further supported by recent human therapeutic trials and experimental studies in the preclinical stage of AD. Case series and epidemiological data support an association between cholinergic manipulations (in either direction) with the incidence and clinical course of neurodegenerative diseases. The data show strength of association, consistency across species and specificity to the cholinergic system. There is a temporal association between interventions and outcomes as well as dose-response relationships. These findings are all consistent with an emerging mechanistic understanding of CNS protein clearance. Experimental confirmation of the role of acetylcholine in IPAD function is indicated.

Effects of Light-at-Night on the Rat Liver – A Role for the Autonomic Nervous System

Exposure to light at night (LAN) has been associated with serious pathologies, including obesity, diabetes and cancer. Recently we showed that 2 h of LAN impaired glucose tolerance in rats. Several studies have suggested that the autonomic nervous system (ANS) plays an important role in communicating these acute effects of LAN to the periphery. Here, we investigated the acute effects of LAN on the liver transcriptome of male Wistar rats. Expression levels of individual genes were not markedly affected by LAN, nevertheless pathway analysis revealed clustered changes in a number of endocrine pathways. Subsequently, we used selective hepatic denervations [sympathetic (Sx), parasympathetic (Px), total (Tx, i.e., Sx plus Px), sham] to investigate the involvement of the ANS in the effects observed. Surgical removal of the sympathetic or parasympathetic hepatic branches of the ANS resulted in many, but small changes in the liver transcriptome, including a pathway involved with circadian clock regulation, but it clearly separated the four denervation groups. On the other hand, analysis of the liver metabolome was not able to separate the denervation groups, and only 6 out of 78 metabolites were significantly up- or downregulated after denervations. Finally, removal of the sympathetic and parasympathetic hepatic nerves combined with LAN exposure clearly modulated the effects of LAN on the liver transcriptome, but left most endocrine pathways unaffected.Conclusion: One-hour light-at-night acutely affects the liver transcriptome. Part of this effect is mediated via the nervous innervation, as a hepatectomy modulated and reduced the effect of LAN on liver transcripts.