Unilateral Renal Denervation Research Articles

The Total Denervation of the Ischemic Kidney Induces Differential Responses in Sodium Transporters' Expression in the Contralateral Kidney in Goldblatt Rats.

The Goldblatt model of hypertension (2K-1C) in rats is characterized by renal sympathetic nerve activity (rSNA). We investigated the effects of unilateral renal denervation of the clipped kidney (DNX) on sodium transporters of the unclipped kidneys and the cardiovascular, autonomic, and renal functions in 2K-1C and control (CTR) rats. The mean arterial pressure (MAP) and rSNA were evaluated in experimental groups. Kidney function and NHE3, NCC, ENaCβ, and ENaCγ protein expressions were assessed. The glomerular filtration rate (GRF) and renal plasma flow were not changed by DNX, but the urinary (CTR: 0.0042 ± 0.001; 2K-1C: 0.014 ± 0.003; DNX: 0.005 ± 0.0013 mL/min/g renal tissue) and filtration fractions (CTR: 0.29 ± 0.02; 2K-1C: 0.51 ± 0.06; DNX: 0.28 ± 0.04 mL/min/g renal tissue) were normalized. The Na+/H+ exchanger (NHE3) was reduced in 2K-1C, and DNX normalized NHE3 (CTR: 100 ± 6; 2K-1C: 44 ± 14, DNX: 84 ± 13%). Conversely, the Na+/Cl- cotransporter (NCC) was increased in 2K-1C and was reduced by DNX (CTR: 94 ± 6; 2K-1C: 144 ± 8; DNX: 60 ± 15%). In conclusion, DNX in Goldblatt rats reduced blood pressure and proteinuria independently of GRF with a distinct regulation of NHE3 and NCC in unclipped kidneys.

Hemorrhage Magnitude Correlates with Sympathetic Vasomotion in Conscious Rabbits

Each year, over 1.8 million people die from hemorrhagic shock, and the median time from onset to death is only two hours, making early recognition and prompt action the cornerstone of management. The sympathetic nervous system is the most rapid physiological hemodynamic compensatory mechanism, and we have developed a novel measure of sympathetic vascular control called sympathetic vasomotion which could serve as an early marker of hemorrhage. We performed unilateral renal denervation on six rabbits and instrumented these rabbits with bilateral renal flow probes and arterial pressure telemeters to allow for measurement of sympathetic vasomotion. After a two-week recovery period, the rabbits then underwent controlled blood withdrawal via an auricular arterial catheter. The differences in admittance gain and phase shift occurrence between the innervated and denervated kidneys increased significantly before any other hemodynamic changes. Over the first 15 minutes of hemorrhage, the differences in admittance gain and phase shift correlated with hemorrhage magnitude (r = 0.69 and 0.63, respectively), whereas the differences in coherence did not. The sum of the admittance gain and phase shift differences showed a slightly higher correlation with hemorrhage magnitude (r = 0.71). This data suggests that some features of sympathetic vasomotion may be useful as a biomarker for diagnosing early-stage normotensive hemorrhage and assessing treatment response. Further studies are needed to evaluate the utility of sympathetic nervous system monitoring in clinical contexts. Supported by NIH P01 HL62222 and NIH F30 HL118974. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Renal Glucose Release after Unilateral Renal Denervation during a Hypoglycemic Clamp in Pigs with an Altered Hypothalamic Pituitary Adrenal Axis after Late-Gestational Dexamethasone Injection.

Previously, we demonstrated in pigs that renal denervation halves glucose release during hypoglycaemia and that a prenatal dexamethasone injection caused increased ACTH and cortisol concentrations as markers of a heightened hypothalamic pituitary adrenal axis (HPAA) during hypoglycaemia. In this study, we investigated the influence of an altered HPAA on renal glucose release during hypoglycaemia. Pigs whose mothers had received two late-gestational dexamethasone injections were subjected to a 75 min hyperinsulinaemic-hypoglycaemic clamp (<3 mmol/L) after unilateral surgical denervation. Para-aminohippurate (PAH) clearance, inulin, sodium excretion and arterio-venous blood glucose difference were measured every fifteen minutes. The statistical analysis was performed with a Wilcoxon signed-rank test. PAH, inulin, the calculated glomerular filtration rate and plasma flow did not change through renal denervation. Urinary sodium excretion increased significantly (p = 0.019). Side-dependent renal net glucose release (SGN) decreased by 25 ± 23% (p = 0.004). At 25 percent, the SGN decrease was only half of that observed in non-HPAA-altered animals in our prior investigation. The current findings may suggest that specimens with an elevated HPAA undergo long-term adaptations to maintain glucose homeostasis. Nonetheless, the decrease in SGN warrants further investigations and potentially caution in performing renal denervation in certain patient groups, such as diabetics at risk of hypoglycaemia.

Angiotensin II inhibition increases diuresis during acute sympathetic activation in intact and denervated kidneys in rats with chronic myocardial infarction.

We examined urine excretion during primary acute sympathetic activation (PASA) in Wistar-Kyoto rats with myocardial infarction (MI). The rats underwent unilateral renal denervation (RDN) 7weeks after coronary artery ligation. 4-10days later, an acute experiment was performed under anesthetized conditions (n = 8 rats). Isolated carotid sinus pressure was changed stepwise from 60 to 180mmHg, and the relationship between the arterial pressure (AP) and the normalized urine flow (nUF, urine flow normalized by the body weight) was examined. After obtaining the control data, an angiotensin II type 1 receptor blocker telmisartan (2.5mg/kg) was intravenously administered. The effects of RDN, telmisartan, and heart weight (biventricular weight) on the relationship between AP and nUF were examined using multiple regression analyses. Regarding the slope of nUF versus AP (nUFslope), the constant term of the regression was positive (0.315 ± 0.069 μL·min-1·kg-1·mmHg-1), indicating that nUF increased with AP. The heart weight had a negative effect on nUFslope (P < 0.05), suggesting that the severity of MI was associated with the impairment of urine excretion. Telmisartan increased nUFslope by 0.358 ± 0.080 μL·min-1·kg-1·mmHg-1 (P < 0.001), whereas RDN had no significant effect on this parameter. The results indicate that unilateral RDN was unable to abolish the effect of the renin-angiotensin system on urine excretion during PASA. Circulating or locally produced angiotensin II, rather than ongoing renal sympathetic nerve activity, played a dominant role in the impairment of urine excretion during PASA in rats with chronic MI.

Open-loop analysis on sympathetically mediated arterial pressure and urine output responses in spontaneously hypertensive rats: effect of renal denervation

Primary acute sympathetic activation (PASA) causes a subsequent arterial pressure (AP) elevation. In this case, an antidiuretic effect via the renal innervation and pressure diuresis can act antagonistically on the kidneys. We examined the effect of PASA on urine output in spontaneously hypertensive rats (SHR) 4–7 days after unilateral renal denervation (RDN) (n = 9). The slope of the plot of urine flow versus AP was positive (0.120 ± 0.031 μL min−1 kg−1 mmHg−1) on the intact side, but it was less than 1/3 of the slope observed previously in normotensive Wistar–Kyoto rats (WKY). RDN did not normalize the slope of urine flow versus AP (0.179 ± 0.025 μL min−1 kg−1 mmHg−1, P = 0.098 versus the intact side). The urine flow at the operating point of the AP tended to be greater on the denervated than the intact side (29.0 ± 1.8 vs. 25.3 ± 1.9 μL min−1 kg−1, P = 0.055). The percent increase (17.2 ± 7.2%) was not different from that observed previously in WKY. Although high-resting sympathetic nerve activity is prerequisite for maintaining hypertension in SHR, the effect of sympathetic innervation on the urine output function was not greater than that in WKY.

Open-loop analysis on sympathetically mediated arterial pressure and urine output responses in rats: effect of renal denervation

Primary acute sympathetic activation (PASA) can increase arterial pressure (AP). Under this situation, the kidneys may receive mutually opposing influences from sympathetic activation: a direct anti-diuretic effect via the renal innervation and pressure diuresis. We examined whether PASA would reduce urine output regardless of the AP elevation. We also examined the impact of renal denervation (RDN) on urine output during PASA. The experiment was performed on rats 3 to 9 days after unilateral RDN (n = 10). Under anesthesia, systemic sympathetic nerve activity (SNA) was varied over a wide range via the carotid sinus baroreflex. The slope of urine flow versus SNA was positive (0.252 ± 0.052 μL·min−1·kg−1· %−1) on the intact side, and it was greater on the denervated side (0.331 ± 0.069 μL·min−1·kg−1· %−1, P < 0.05). In conclusion, urine output change was an effect of elevated AP during PASA. Nevertheless, RDN was able to augment pressure diuresis during PASA.

1196Transvascular pace-capture of aorticorenal ganglia provides a testable procedural endpoint for transcatheter renal artery denervation and identifies a novel therapeutic ablation target for denervation

Abstract Background Transcatheter renal denervation procedures often produces incomplete renal denervation and inconsistent antihypertensive effect. The lack of an intraprocedural method for renal sympathetic nerve function assessment has precluded a rational and physiologically based approach to ensure adequate denervation has been achieved at the time of the procedure. Purpose To demonstrate that it is possible to localise aorticorenal ganglia via transvascular pacing to provide: 1) a testable procedural endpoint for transcatheter renal denervation and, 2) a novel ablation target for renal denervation. Methods High frequency pacing in the inferior vena cava and aorta, invasive blood pressure measurements and renal angiography was performed in sheep (N=19) to identify ARG pace-capture sites by concurrent hypertensive and renal vasoconstrictive responses. Group A (N=5) underwent ink injection labelling at the ARG pace-capture site for histological verification; Group B (N=6) received unilateral irrigated radiofrequency ablation of ARG pace-capture sites and assessment of renal innervation at 1week post-procedure; and Group C (N=8) had ARG pacing performed prior to and 2–3 weeks after unilateral transcatheter microwave renal denervation. Results ARG pace-capture responses were observed at paired discrete sites in the posterior IVC and anterolateral aorta approximately 40mm above the ipsilateral renal artery. Pacing elicited a mean arterial blood pressure change of 22.2 [IQR 15.5–34.3] mmHg, p&lt;0.001, together with ipsilateral renal vasoconstriction with main renal artery calibre change of −0.42mm [IQR −0.64mm to −0.24mm] measured with quantitative coronary analysis (QCA), p&lt;0.0001, and branch renal artery median pixel density index change −10.4% [IQR −22.7% to −3.0%], p=0.003. Contralateral renal arterial vasoconstriction was not observed consistently at either the main or branch renal artery level. Sympathetic ganglionic tissue was observed at ARG pace-capture sites, and ganglion ablation caused significant ipsilateral renal denervation with a median hilar functional sympathetic nerve area reduction of 51% [IQR 24%–52%], p=0.043, and renal cortical norepinephrine reduction of 54% [IQR 36%–59%], p=0.043. Circumferential renal denervation resulted in immediate and sustained abolition of ARP pacing induced renal vasoconstriction and significant ipsilateral renal denervation. Conclusion Localisation of ARG using transvascular pacing is feasible with pace-capture demonstrated by concurrent hypertensive and ipsilateral renal arterial vasoconstrictive responses. Abolition of ARG pacing induced renal arterial vasoconstriction may indicate successful renal sympathetic denervation, providing a physiological procedural endpoint to guide transcatheter renal denervation. Additionally, ablation of ARG could provide an alternative or adjunctive method for renal denervation. Acknowledgement/Funding University of Sydney; Western Sydney Local health District; National Health and Medical Research Council of Australia; National Heart Foundation (Au)

1197The development and validation of a novel transcatheter microwave renal denervation system

Abstract Background Clinical studies of transcatheter radiofrequency renal denervation for treating hypertension have been hampered by the lack of consistent denervation efficacy. Microwave energy is well suited to renal denervation due to its capacity to spare vascular structures due to cooling from adjacent blood flow while enabling deep perivascular heating. Purpose We aimed to: 1) develop a transcatheter microwave system capable of safely delivering deep and circumferential perivascular renal nerve ablation, and 2) demonstrate the feasibility, short-term efficacy and safety of transcatheter microwave renal denervation. Method A novel 7F transcatheter microwave denervation system was designed, built, and iteratively prototyped in vitro and in 15 sheep. A histological grading system for microwave induced renal arterial and renal nerve injury was devised. The microwave denervation system was validated in an additional 9 sheep, which underwent unilateral renal denervation. Up to 2 microwave ablations were delivered to each artery with maximum power at 100–110W for 480s. Sheep were euthanised at 2–3 weeks post procedure. Gross microscopic histological examination as well as renal tissue norepinephrine content was analysed. Results Catheter deployment and ablation was successful in all 19 targeted vessel segments and ablation produced substantial circumferential perivascular injury; median ablation lesion area &gt;395 (IQR 251–437) mm2, depth 17.1 (IQR 15.8–18.4) mm, length 16 (IQR 12–20) mm, without collateral visceral injury. Limiting power to 100W minimised arterial injury, while maintaining a deep circumferential perivascular ablation. At microwave ablation sites, a total of 292 nerve fascicles were identified, median distance from the renal artery of 4.2mm (IQR 2.1–8.8mm), of which 249 (85%) had sustained thermal injury with 128/249 (51%) showing grade 3–4 (moderate to severe) injury. Microwave denervation reduced median functional sympathetic nerve surface area at the renal hilum on anti-tyrosine hydroxylase staining by 100% (IQR 87%-100%), p=0.0039, and median renal cortical norepinephrine content by 83% (IQR 76%–92%), p=0.0078, compared to the paired control kidney. Conclusion Transcatheter microwave ablation can produce deep circumferential perivascular ablations over a long segment of the renal artery without significant arterial or collateral visceral injury to provide effective renal denervation. Clinical translation may enable more consistent and complete transcatheter renal denervation and antihypertensive efficacy. Acknowledgement/Funding University of Sydney; Western Sydney Local health District; National Health and Medical Research Council of Australia; National Heart Foundation (Au)

Transcatheter microwave ablation can deliver deep and circumferential perivascular nerve injury without significant arterial injury to provide effective renal denervation.

Clinical studies of transcatheter radiofrequency renal denervation for treating hypertension have been hampered by the lack of consistent denervation efficacy. We aimed to demonstrate the short-term efficacy and safety of transcatheter microwave renal denervation. A novel 7F microwave system was validated in a sheep model of unilateral renal denervation. Up to two microwave ablations were delivered to each artery with maximum power at 100-110 W for 480 s. Catheter deployment and ablation was successful in all 19 targeted vessel segments, and ablation produced substantial circumferential perivascular injury; median ablation lesion area greater than 395 [interquartile range (IQR) 251-437] mm, depth 17.1 (IQR 15.8-18.4) mm, length 16 (IQR 12-20) mm, without collateral visceral injury. Limiting power to 100 W minimized arterial injury, while maintaining a deep circumferential perivascular ablation. Microwave denervation reduced median functional sympathetic nerve surface area at the renal hilum on antityrosine hydroxylase staining by 100% (IQR 87-100%, P = 0.0039), and median renal cortical norepinephrine content by 83% (IQR 76-92%, P = 0.0078), compared to the paired control kidney at 2-3 weeks postprocedure. Transcatheter microwave ablation can produce deep circumferential perivascular ablations over a long segment of the renal artery without significant arterial or collateral visceral injury to provide effective renal denervation.

Blunted diuretic and natriuretic responses to acute sodium loading early after catheter-based renal denervation in normotensive sheep.

Catheter-based renal denervation (RDN) was introduced as a treatment for resistant hypertension. There remain critical questions regarding the physiological mechanisms underlying the hypotensive effects of catheter-based RDN. Previous studies indicate that surgical denervation reduces renin and the natriuretic response to saline loading; however, the effects on these variables of catheter-based RDN, which does not yield complete denervation, are largely unknown. The aim of this study was to investigate the effects of catheter-based RDN on glomerular-associated renin and regulation of fluid and sodium homeostasis in response to physiological challenges. First, immunohistochemical staining for renin was performed in normotensive sheep (n = 6) and sheep at 1 wk (n = 6), 5.5 mo (n = 5), and 11 mo (n = 5) after unilateral RDN using the same catheter used in patients (Symplicity). Following catheter-based RDN (1 wk), renin-positive glomeruli were significantly reduced compared with sham animals (P < 0.005). This was sustained until 5.5 mo postdenervation. To determine whether the reduction in renin after 1 wk had physiological effects, in a separate cohort, Merino ewes were administered high and low saline loads before and 1 wk after bilateral RDN (n = 9) or sham procedure (n = 8). After RDN (1 wk), the diuretic response to a low saline load was significantly reduced (P < 0.05), and both the diuretic and natriuretic responses to a high saline load were significantly attenuated (P < 0.05). In conclusion, these findings indicate that catheter-based RDN acutely alters the ability of the kidney to regulate fluid and electrolyte balance. Further studies are required to determine the long-term effects of catheter-based RDN on renal sodium and water homeostasis.

Transvascular Pacing of Aorticorenal Ganglia Provides a Testable Procedural Endpoint for Renal Artery Denervation

ObjectivesThis study sought to develop a method to assess renal sympathetic nerve function through localization and pacing of aorticorenal ganglia (ARG). BackgroundTranscatheter renal denervation procedures often fail to produce complete renal denervation because of the lack of a physiological procedural endpoint. MethodsHigh-frequency pacing was performed in the inferior vena cava and aorta in sheep (n = 19) to identify ARG pace-capture sites. Group A (n = 5) underwent injection at the ARG pace-capture site for histological verification, group B (n = 6) underwent unilateral irrigated radiofrequency ablation of ARG pace-capture sites and assessment of renal innervation at 1 week post-procedure; and group C (n = 8) underwent ARG pacing before and 2 to 3 weeks after unilateral microwave renal denervation. ResultsARG pace-capture responses were observed at paired discrete sites above the ipsilateral renal artery eliciting a change in mean arterial blood pressure of 22.2 (interquartile range [IQR]: 15.5 to 34.3 mm Hg; p < 0.001) with concurrent ipsilateral renal arterial vasoconstriction, change in main renal artery diameter of −0.42 mm (IQR: −0.64 to −0.24 mm; p < 0.0001), and without consistent contralateral renal vasoconstriction. Sympathetic ganglionic tissue was observed at ARG pace-capture sites, and ganglion ablation led to significant ipsilateral renal denervation. Circumferential renal denervation resulted in immediate and sustained abolition of ARP pacing-induced renal vasoconstriction and significant ipsilateral renal denervation. ConclusionsTransvascular ARG pace-capture is feasible and recognized by concurrent hypertensive and ipsilateral renal arterial vasoconstrictive responses. Abolition of ARG pacing-induced vasoconstriction may indicate successful renal sympathetic denervation and serve as a physiological procedural endpoint to guide transcatheter renal denervation.

Laparoscopic-based perivascular unilateral renal sympathetic nerve denervation for treating resistant hypertension: a case report

A 38-year-old man with a history of resistant hypertension for more than 10 years underwent laparoscopic-based perivascular unilateral renal sympathetic nerve denervation in 2012. After the operation, the patient’s blood pressure has been controllable while the antihypertensive drug intake has decreased over 6 years. Laparoscopic-based perivascular unilateral renal sympathetic nerve denervation may be a potentially feasible and effective option in treating patients with resistant hypertension.

A PROCEDURAL ENDPOINT FOR CIRCUMFERENTIAL RENAL ARTERY DENERVATION? ABOLITION OF PACING INDUCED RENAL ARTERY VASOCONSTRICTION

Renal arterial vasoconstriction from high renal sympathetic tone may allow intraprocedural arterial vasodilation to serve as a renal denervation endpoint. 8 sheep underwent unilateral microwave renal artery denervation after attempts to identify and repetitively pace the ipsilateral aorticorenal

TRANSCATHETER MICROWAVE ABLATION CAN PRODUCE DEEP CIRCUMFERENTIAL PERIVASCULAR ABLATION AND EFFECTIVE RENAL DENERVATION WITHOUT SIGNIFICANT ARTERIAL INJURY

Radiofrequency renal denervation does not have consistent and durable efficacy. Microwave denervation may enable circumferential perivascular ablation while the renal arterial wall is protected by cooling blood flow. 9 sheep underwent unilateral renal denervation using a novel microwave catheter

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

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

PP.LB02.15] RENAL DENERVATION NORMALIZES SYMPATHETIC VASOMOTOR ACTIVITY AND PRODUCES DIFFERENTIAL EFFECTS ON THE ARTERIAL BARORECEPTOR FUNCTION IN THE GOLDBLATT RENOVASCULAR HYPERTENSION

Objective: Sympathetic nerve activity is increased in renovascular hypertension. Renal denervation has shown promise in the treatment of patients with resistant hypertension to drug therapy, although the mechanisms underlying reduction in blood pressure remains uncertain. The aim of this study was to evaluate the effects of unilateral renal denervation (H+DnX) on efferent post-ganglionic sympathetic nerve activity to renal (rSNA) and lumbar (lSNA) sympathetic nerves in Goldblatt hypertensive rats (2K1C). Design and method: The baroreceptor sensitivity to rSNA, lSNA, heart rate (HR) and the cardiovascular autonomic function (by power spectral density analysis) were evaluated ten days after renal denervation. Denervation of clipped kidney (DnX – all visible bundles nerves were dissected – 10% phenol) was performed 5 weeks after clipping (gap width 0.2 mm). The rSNA and barorreceptor reflex control to rSNA was performed in the innervated contralateral kidney. Results: Ten days after DnX, blood pressure (BP) was significantly reduced (16%) in the 2K1C rats compared to 2K1C undenervated (H). DnX normalized rSNA (CT: 110 ± 8, n = 14; 2K1C:150 ± 8, n = 12; 2K1C DnX:89 ± 7, pps n = 8) and lSNA (CT: 137 ± 8, n = 8; 2K1C: 202 ± 7, n = 11; 2K1C DnX:131 ± 7, pps n = 8) in the 2K1C rats. DnX significantly improved the baroreceptor function for rSNA (CT: −2.3 ± 0.2, n = 11; 2K1C: −0.7 ± 0.1, n = 8; 2K1C DnX: −1.5 ± 0.2, pps/mmHg n = 5) and tachycardic response (CT: −3.9 ± 0.5, n = 7; 2K1C: −1.9 ± 0.1, n = 8; 2K1C DnX: −3.3 ± 0.4, bpm/mmHg n = 8), but not for lSNA in 2K1C rats. Furthermore, DnX significantly increased the high frequency (HF) component (CT: 1.4 ± 1, n = 10; 2K1C: 3.4 ± 2 n = 9; 2K1C DnX: 7.6 ± 3, ms2 n = 9) but not the very low frequency (VLF) and low frequency (LF) components (VLF = CT: 2.7 ± 1, n = 10; 2K1C: 13 ± 7, n = 9; 2K1C DnX: 9 ± 5, ms2 n = 8 / LF = CT: 2 ± 0.6, n = 9; 2K1C: 5 ± 3, n = 11; 2K1C DnX: 6 ± 4, ms2 n = 9) which remained elevated in the 2K1C rats. Conclusions: The results show that renal denervation normalized sympathetic vasomotor activity and increased the HF component of spectral analysis accompanied by a non uniform improvement in the arterial baroreceptor function. Whether the baroreceptor function sensitivity improvement induced by DnX is a cause or a consequence of BP reduction remains to be determined. Supported by FAPESP and CAPES.

Uninephrectomy-Induced Lipolysis and Low-Grade Inflammation Are Mimicked by Unilateral Renal Denervation.

Uninephrectomy (UniNX) in rats on a fixed food intake leads to increased lipolysis and a low-grade inflammation with an increased subset of circulating cytokines. Because UniNX ablates renal nerves on the side of the removed kidney, we tested the contribution of unilateral renal denervation in the phenotype of UniNX. We compared Sham-operated controls, left nephrectomy (UniNX) and unilateral left kidney denervation (uDNX) in rats 4 weeks after surgery. uDNX did not affect kidney weight and function. In general, the uDNX phenotype was similar to the UniNX phenotype especially for lipolysis in fat pads and increased low-grade inflammation. uDNX led to decreased fat pad weight and increased hormone sensitive lipase and adipocyte triglyceride lipase mRNA levels in epididymal and inguinal adipose tissue, as well as increased circulating lipolysis markers β-hydroxybutyrate and glycerol. Measured circulating hormones such as leptin, T3 and insulin were similar amongst the three groups. The lipolytic cytokines interferon-gamma and granulocyte macrophage colony stimulating factor were increased in the circulation of both uDNX and UniNX groups. These two cytokines were also elevated in the spleen of both groups, but contrastingly they were decreased in fat pads, liver, and kidneys. Both uDNX and UniNX similarly increased noradrenaline content in fat pads and spleen. Melanocortin 4 receptor mRNA levels were increased in the brains of both uDNX and UniNX compared to Sham and may contribute to increased tissue noradrenaline levels. In addition, the farnesoid x receptor (FXR) may contribute to changes in tissue metabolism and inflammation, as anti-inflammatory FXR was decreased in the spleen but increased in other tissues in uDNX and UniNX compared to Sham. In summary, both uDNX and UniNX in rats promote metabolic and immunological alterations by mechanisms that seem to implicate modification of unilateral renal nerve pathways as well as central and peripheral neural pathways.

Complex reinnervation pattern after unilateral renal denervation in rats.

Renal denervation (DNX) is a treatment for resistant arterial hypertension. Efferent sympathetic nerves regrow, but reinnervation by renal afferent nerves has only recently been shown in the renal pelvis of rats after unilateral DNX. We examined intrarenal perivascular afferent and sympathetic efferent nerves after unilateral surgical DNX. Tyrosine hydroxylase (TH), CGRP, and smooth muscle actin were identified in kidney sections from 12 Sprague-Dawley rats, to distinguish afferents, efferents, and vasculature. DNX kidneys and nondenervated kidneys were examined 1, 4, and 12 wk after DNX. Tissue levels of CGRP and norepinephrine (NE) were measured with ELISA and mass spectrometry, respectively. DNX decreased TH and CGRP labeling by 90% and 95%, respectively (P < 0.05) within 1 wk. After 12 wk TH and CGRP labeling returned to baseline with a shift toward afferent innervation (P < 0.05). Nondenervated kidneys showed a doubling of both labels within 12 wk (P < 0.05). CGRP content decreased by 72% [3.2 ± 0.3 vs. 0.9 ± 0.2 ng/gkidney; P < 0.05] and NA by 78% [1.1 ± 0.1 vs. 0.2 ± 0.1 pmol/mgkidney; P < 0.05] 1 wk after DNX. After 12 wk, CGRP, but not NE, content in DNX kidneys was fully recovered, with no changes in the nondenervated kidneys. The use of phenol in the DNX procedure did not influence this result. We found morphological reinnervation and transmitter recovery of afferents within 12 wk after DNX. Despite morphological evidence of sympathetic regrowth, NE content did not fully recover. These results suggest a long-term net surplus of afferent influence on the DNX kidney may be contributing to the blood pressure lowering effect of DNX.

Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptor.

Recent data suggest that exercise training (ExT) is beneficial in chronic heart failure (CHF) because it improves autonomic and peripheral vascular function. In this study, we hypothesized that ExT in the CHF state ameliorates the renal vasoconstrictor responses to hypoxia and that this beneficial effect is mediated by changes in α1-adrenergic receptor activation. CHF was induced in rabbits. Renal blood flow (RBF) and renal vascular conductance (RVC) responses to 6 min of 5% isocapnic hypoxia were assessed in the conscious state in sedentary (SED) and ExT rabbits with CHF with and without α1-adrenergic blockade. α1-adrenergic receptor expression in the kidney cortex was also evaluated. A significant decline in baseline RBF and RVC and an exaggerated renal vasoconstriction during acute hypoxia occurred in CHF-SED rabbits compared with the prepaced state (P < 0.05). ExT diminished the decline in baseline RBF and RVC and restored changes during hypoxia to those of the prepaced state. α1-adrenergic blockade partially prevented the decline in RBF and RVC in CHF-SED rabbits and eliminated the differences in hypoxia responses between SED and ExT animals. Unilateral renal denervation (DnX) blocked the hypoxia-induced renal vasoconstriction in CHF-SED rabbits. α1-adrenergic protein in the renal cortex of animals with CHF was increased in SED animals and normalized after ExT. These data provide evidence that the acute decline in RBF during hypoxia is caused entirely by the renal nerves but is only partially mediated by α1-adrenergic receptors. Nonetheless, α1-adrenergic receptors play an important role in the beneficial effects of ExT in the kidney.

Unilateral renal sympathetic denervation may reduce blood pressure in patients with refractory hypertension

A 52-year-old Caucasian woman with essential resistant and refractory hypertension despite optimal medical therapy, including 6 different antihypertensive drugs was referred for the catheter-based renal denervation. Due to unfavourable anatomy because of non-critical fibromuscular dysplasia on the right renal artery, renal denervation of only the left renal artery was performed. Before and after the renal denervation, the patient’s blood pressure was monitored by &lt;em&gt;office&lt;/em&gt; measurements and ambulatory blood pressure measurements (ABPM). Before the procedure, the mean &lt;em&gt;office&lt;/em&gt; blood pressure was 157/98 mmHg; at ABPM, the mean blood pressure values were 145/94 mmHg. At 6 months of follow-up, the mean &lt;em&gt;office&lt;/em&gt; blood pressure was 134/90 mmHg and 121/76 mmHg at ABPM. In latest 12 months of follow-up, &lt;em&gt;office&lt;/em&gt; and ABPM blood pressure were 125/80 and 127/80 mmHg respectively. This unique case suggests that unilateral renal denervation may be effective in lowering blood pressure in patients with refractory hypertension and unfavorable renal arteries anatomy.