Kidney Norepinephrine Research Articles

Norepinephrine‐Alpha 2 Adrenergic Receptor Axis is Critical to Long‐Term Sequelae of Ischemic Acute Kidney Injury

ObjectiveUpregulated levels of kidney norepinephrine (NE) have been recognized as a risk factor of development and progression of chronic kidney disease. Our reports showed renal denervation can prevent renal fibrosis and inflammation in renal fibrogenesis models through inhibition of NE‐alpha 2 adrenergic receptors (α2‐ARs) axis. However, the molecular mechanism by which NE‐α2‐ARs axis elicits long‐term sequelae of acute kidney injury (AKI) remains to be elucidated.MethodsBased on our published data, we hypothesized that NE‐α2‐ARs axis mediates its effect through macrophages recruited into ischemic kidneys. In this study, we investigated whether in vivo and in vitro NE‐α2‐AR axis regulates macrophage recruitment, activation and differentiation during the development of chronic kidney disease after ischemia/reperfusion injury (IRI).ResultsRenal bilateral IRI resulted in severe kidney fibrosis in medullary region over 2 weeks with enhanced tissue NE level, persistent tubular injury and massive macrophage infiltration. Inhibition of α2A‐ and/or α2C‐AR subtypes by pharmacological or genetic intervention prevented macrophage accumulation with downregulation of M1 and M2 macrophage markers, reduced levels of macrophage‐released pro‐inflammatory and/or fibrogenic cytokines, resulting in suppression of persistent renal tubular injury and fibrosis progression. In in vitro study using Raw264.7 cells, pharmacological inhibition of α2‐AR blocked macrophage migration to proximal tubule cells exposed to NE. In addition, we demonstrated that NE results in upregulation of both M1 and M2 macrophages.ConclusionsCollectively, NE‐α2‐ARs axis induces long‐term sequelae of ischemic AKI through macrophage recruitment and subsequent activation. Our data suggest that targeting NE‐α2‐ARs axis can be a potential therapeutic strategy to prevent long‐term sequelae of ischemic AKI.Support or Funding InformationThis work was supported by NIH grants DK‐116987, DK‐120533 and American Heart Association (AHA) Grant in Aid 15GRNT25080031 (BJP), AHA postdoctoral fellowship Grant 15POST25130003 (HSJ), and grants (NRF‐2016R1C1B2012080 and NRF‐2019R1F1A1041410) from the National Research Foundation of Korea (JK).

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.

Brain Transforming Growth Factor-β Resists Hypertension Via Regulating Microglial Activation.

Hypertension is the major risk factor for stroke. Recent work unveiled that hypertension is associated with chronic neuroinflammation; microglia are the major players in neuroinflammation, and the activated microglia elevate sympathetic nerve activity and blood pressure. This study is to understand how brain homeostasis is kept from hypertensive disturbance and microglial activation at the onset of hypertension. Hypertension was induced by subcutaneous delivery of angiotensin II, and blood pressure was monitored in conscious animals. Microglial activity was analyzed by flow cytometry and immunohistochemistry. Antibody, pharmacological chemical, and recombinant cytokine were administered to the brain through intracerebroventricular infusion. Microglial depletion was performed by intracerebroventricular delivering diphtheria toxin to CD11b-diphtheria toxin receptor mice. Gene expression profile in sympathetic controlling nucleus was analyzed by customized qRT-PCR array. Transforming growth factor-β (TGF-β) is constitutively expressed in the brains of normotensive mice. Removal of TGF-β or blocking its signaling before hypertension induction accelerated hypertension progression, whereas supplementation of TGF-β1 substantially suppressed neuroinflammation, kidney norepinephrine level, and blood pressure. By means of microglial depletion and adoptive transfer, we showed that the effects of TGF-β on hypertension are mediated through microglia. In contrast to the activated microglia in established hypertension, the resting microglia are immunosuppressive and important in maintaining neural homeostasis at the onset of hypertension. Further, we profiled the signature molecules of neuroinflammation and neuroplasticity associated with hypertension and TGF-β by qRT-PCR array. Our results identify that TGF-β-modulated microglia are critical to keeping brain homeostasis responding to hypertensive disturbance.

Comparison of branch and distally focused main renal artery denervation using two different radio-frequency systems in a porcine model

Anatomic placement of lesions may impact efficacy of radio-frequency (RF) catheter renal denervation (RDN). However, it is unclear if it is necessary to perform treatments post bifurcation with systems that may provide deeper penetration to achieve successful RDN. Sixteen domestic swine (n=16) were randomly assigned to 4 groups: 1) 8 lesions created in the branch arteries using the Spyral catheter (SP8); 2) 8 lesions created in the branch arteries plus 4 lesions created in the main artery using the SP catheter (SP12); 3) 8 lesions created in the main artery using the EnligHTN catheter with the distal position as close as possible to the bifurcation (EN8); and 4) 12 lesions created in the main artery using the EN catheter with the distal position as close as possible to the bifurcation (EN12). Each arm showed statistically significant changes in kidney norepinephrine (NE, ng/g) between treated kidneys vs. untreated contralateral control. There were no statistically significant differences in tissue NE% reductions across each arm based on catheter, anatomic location, & number of lesions (p=0.563): EN8 -74±34%, EN12 -95±3%, SP8 -76±16%, SP12 -82±17% (p=0.496). A total of 46 lesions were measured for lesion depth: EN main (3.3±2.8mm) vs. SP branch (2.0±1.0mm, p=0.039), SP main (2.9±1.6mm) vs. SP branch (p=0.052), and EN main vs. SP main (p=0.337). Distally-focused main renal artery treatment using the EN system appears to be equally efficacious in reducing tissue NE levels compared with SP treatment in the branches plus main renal arteries, advocating for device-specific procedure execution.

Sympathoinhibitory Effect of Radiofrequency Renal Denervation in Spontaneously Hypertensive Rats With Established Hypertension.

Radiofrequency ablation of the renal arteries (RF-ABL) has been shown to decrease blood pressure (BP) in drug-resistant hypertensive patients who receive antihypertensive drug therapy. However, there remain questions regarding how RF-ABL influences BP independent of drug therapy and whether complete renal denervation is necessary to maximally lower BP. To study these questions, we examined the cardiovascular, sympathetic, and renal effects produced by RF-ABL of the proximal renal arteries in spontaneously hypertensive rats (SHR) with established hypertension. SHR were instrumented (telemetry) for measurement of systolic/diastolic BP (SBP/DBP). Rats then underwent Sham-ABL or RF-ABL adjacent to the renal ostium and BP was recorded for 8 weeks. Changes in sympathetic activity, 24-hour water/sodium excretion, and levels of urinary angiotensinogen (AGT), plasma renin activity, and kidney renin content (KRC) were measured in SHR. Compared with Sham-ABL, RF-ABL produced a sustained decrease in BP. At 8 weeks, SBP/DBP was 171±6/115±3 and 183±4/129±3mm Hg for RF-ABL and Sham-ABL SHR, respectively. Correlating with the reduction in BP, RF-ABL significantly decreased the low frequency/total and low frequency/high frequency of BP variability and attenuated the hypotensive response to chlorisondamine. Kidney norepinephrine levels were markedly decreased at 8 weeks in RF-ABL vs. Sham-ABL SHR. There were no group differences in 24-hour sodium/water excretion or urinary AGT excretion rate (6 weeks) or plasma renin activity or KRC (8 weeks). In other studies, concurrent RF-ABL plus surgical denervation initially decreased BP to a greater level than RF-ABL alone, but thereafter the reduction in BP between groups was not different. In hypertensive SHR, bilateral RF-ABL of the proximal renal arteries produced a sustained decease in sympathetic activity and BP without changes in sodium/water excretion or activity of the systemic/renal renin-angiotensin system.

Abstract 106: Hypothalamic PVN GαI2 Protein-mediated Renal Nerve Dependent Sympathoinhibition Facilitates Suppression of NCC Activity and a Salt-resistant Phenotype

Aim: We hypothesize hypothalamic paraventricular (PVN) specific Gαi2 proteins, which are up-regulated in the PVN during increased sodium intake, mediate global and renal sympathoinhibition to facilitate suppression of the activity of the sodium chloride cotransporter (NCC) and salt-resistance in the Sprague Dawley rat. Methods: Groups of intact or bilateral renal denervated (RDNX) salt-resistant Sprague-Dawley rats received a bilateral PVN infusion of a scrambled (SCR) or Gαi2 oligodeoxynucleotide (ODN-300ng/side/day) and a normal 0.4% (NS) or high 8% NaCl (HS) diet for 7-days. On day-7 24h Na+ balance was assessed - in sub-groups MAP, plasma norepinephrine (NE) content, kidney NE content and NCC activity (peak natriuresis to iv bolus hydrochlorothiazide (HCTZ)) was assessed (N=6/gp/study). Results: In SCR ODN infused rats HS-intake evoked a significant 3-fold site-specific increase in PVN Gαi2 proteins and suppressed plasma NE content (plasma NE [nmol/L] SCR NS 72±4 vs HS 40±5, P&lt;0.05), endogenous kidney NE content (NE [pg/m] SCR NS 586±36 vs HS 496±41, P&lt;0.05) and NCC activity (peak ΔUNaV to HCTZ [μeq/min] SCR NS 10.6±0.8 vs HS 7±1, P&lt;0.05) without impacting sodium homeostasis or MAP. ODN-mediated PVN Gαi2 down-regulation caused renal nerve-dependent hypertension (MAP [mmHg] Gαi2 NS 126±2, Gαi2 HS 147±2, Gαi2 HS + RDNX 131±3 P&lt;0.05) sodium retention (24h Na+ balance [meq] Gαi2 NS 0.6±0.3, Gαi2 HS 2.3±0.4, Gαi2 HS + RDNX 0.8±0.3 P&lt;0.05), global and renal sympathoexcitation (plasma NE [nmol/L] Gαi2 NS 67±7, Gαi2 HS 105±11, Gαi2 HS + RDNX 74±6 P&lt;0.05; kidney NE content [pg/mg] Gαi2 NS 614±48 vs HS 823±59, P&lt;0.05) and a failure to suppress NCC activity (peak ΔUNaV to HCTZ [μeq/min] Gαi2 NS 10.2±2, Gαi2 HS 14.7±2, Gαi2 HS + RDNX 7.6±2, P&lt;0.05). Conclusion: PVN Gαi2 protein-gated pathways represent a sodium sensitive CNS mechanism acting to regulate renal nerve-dependent sodium excretion via, in part, actions upon the activity of the NCC. Based on recent studies by other groups we speculate the regulation of NCC in this setting is mediated by the actions of NE released from efferent renal nerves on renal adrenoceptors to impact the signal transduction network that regulates NCC expression.

Renal sympathetic nerve denervation using intraluminal ultrasound within a cooling balloon preserves the arterial wall and reduces sympathetic nerve activity.

Circumferential ablation of renal sympathetic nerves using catheter-based ultrasound energy was studied in a preclinical in vivo model. The aim was to investigate the benefit of cooling the arterial wall and the extent of renal nerve injury based on histopathology, and to correlate the injury with kidney norepinephrine levels. Computer simulations of the ultrasound transducer within the cooling balloon demonstrated a circumferentially uniform heating profile. In vivo characterisation was performed in 10 normotensive pigs. Nine were treated bilaterally with ultrasound and survived for seven days (n=8) or were sacrificed acutely (n=1). Acutely, TTC staining of the renal arteries treated with ultrasound energy in the presence of cooling demonstrated viable tissue consistent with preservation of the arterial medial layer. Histological studies demonstrated no endothelial injury and minimal to no injury to the media of the renal arterial wall at seven days. Overall, circumferential nerve damage with up to 76% of nerve bundles affected within 7.5 mm of the arterial lumen was observed. Kidney norepinephrine (NEPI) levels were significantly reduced in all animals compared to a non-treated control animal (n=1) and correlated with the degree of nerve damage. A greater reduction in NEPI and a greater percentage of affected nerves was observed in arteries treated with two or three bilateral ultrasound emissions. Catheter-based ultrasound delivered within a cooling balloon is effective at targeting the majority of the renal nerves circumferentially, resulting in significantly decreased kidney NEPI levels without damaging the arterial wall in a porcine model.

Microglia participate in neurogenic regulation of hypertension.

Hypertension is associated with neuroinflammation and increased sympathetic tone. Interference with neuroinflammation by an anti-inflammatory reagent or overexpression of interleukin-10 in the brain was found to attenuate hypertension. However, the cellular mechanism of neuroinflammation, as well as its impact on neurogenic regulation of blood pressure, is unclear. Here, we found that hypertension, induced by either angiotensin II or l-N(G)-nitro-l-arginine methyl ester, is accompanied by microglial activation as manifested by microgliosis and proinflammatory cytokine upregulation. Targeted depletion of microglia significantly attenuated neuroinflammation, glutamate receptor expression in the paraventricular nucleus, plasma vasopressin level, kidney norepinephrine concentration, and blood pressure. Furthermore, when microglia were preactivated and transferred into the brains of normotensive mice, there was a significantly prolonged pressor response to intracerebroventricular injection of angiotensin II, and inactivation of microglia eliminated these effects. These data demonstrate that microglia, the resident immune cells in the brain, are the major cellular factors in mediating neuroinflammation and modulating neuronal excitation, which contributes to the elevated blood pressure.

Renal protective effect and mechanism of continuous infusion of norepinephrine in rat with early stage sepsis

Objective To investigate the protective effect and possible mechanisms of continuous infusion of norepinephrine in kidney of septic rats in the early stage. Methods Thirty healthy male SD rats of SPF level were randomly divided into five groups.Rats in control group were given intraperitoneal injection of saline and began a continuous infusion of saline (1 ml/h). Rats in LPS group and the intervention group (low-dose, medium-dose and high-dose norepinephrine group) were given intraperitoneal injection of LPS 10 mg/kg.LPS group began a continuous infusion of saline (1 ml/h) while low, medium and high dose groups began continuous infusion of different norepinephrine solution [(0.06, 0.3, 0.6 μg/(kg·min)]. Rats were sacrificed after 24 hours infusion.We detected serum inflammatory cytokines [tumor necrosis factor(TNF)-α, interleukin(IL)-1β, IL-6 and IL-10] in 2 h and 6 h by ELISA.Rat serum CRP, Cr and BUN, ,swelling and membrane potential of kidney mitochondria and oxidative stress-related indicators were tested in 24 h. We also observed renal pathologic changes by electronic microscopy and biopsy. Results Compared with the control group, serum levels of TNF-α [(2 203.3±1 028.7) pg/ml], IL-1β [(2 214.5±457.0) pg/ml], IL-6 [(7 784.7±248.2) pg/ml] and IL-10 [(1 076.1±368.4) pg/ml] were statistically higher in LPS group in 2 h (P<0.05); CRP [(0.35±0.24) mg/L], Cr [(30.8±11.5) μmol/L], BUN [(7.7±1.8) mmol/L], NO [(1 057.4±172.9) μmol/gprot] were statistically higher (P<0.01), membrane potential of kidney mitochondria (0.046 4±0.018 5) decreased statistically (P<0.01). Compared with LPS group, serum levels of TNF-α [(506.8±301.7) pg/ml], IL-1β [(415.6±178.0) pg/ml], and IL-10 [(381.7±171.0) pg/ml] significantly decreased in low-dose group in 2 h (P<0.05), BUN [(5.2±1.4) mmol/L] decreased (P<0.05), mitochondrial membrane potential (0.347 4±0.152 6) increased in 24 h (P<0.05); serum levels of TNF-α [(323.9±227.9) pg/ml], IL-1β [(700.0±246.2) pg/ml], and IL-10 [(282.6±134.4) pg/ml] significantly decreased statistically in medium-dose group in 2 h (P<0.05), CRP [(0.17±0.08) mg/L] decreased statistically (P<0.01), mitochondrial membrane potential (0.377 5±0.143 7) increased in 24 h (P<0.05); serum levels of TNF-α [(378.7±89.8) pg/ml], IL-1β [(945.7±264.4) pg/ml] significantly decreased in high-dose group in 2 h (P<0.05), CRP [(0.19±0.12) mg/L] and Cr [(23.2±3.4) μmol/L] decreased in 24 h (P<0.05). Mitochondrial matrix coated fuzzy, vacuoles and coagulation were found in LPS group by electronic microscopy examination.Interstitial edema, monocyte-macrophage infiltration, glomerular shrinkage, tubular epithelial cell swelling, empty bubble degeneration were found in LPS group by microscopy examination.Pathological damage was alleviated in medium-dose group. Conclusion Continuous infusion of norepinephrine plays a protective role on renal function in rats with sepsis in the early stage.The intervention protect rat kidney by reducing levels of inflammatory cytokines, oxidative stress and mitochondrial damage. Key words: Sepsis; Acute kidney injury; Norepinephrine; Cytokines; Mitochondria; Oxidative stress

Hypothalamic PVN Gαi2 protein‐mediated regulation of renal NE turnover and sodium homeostasis: implications for the pathophysiology of salt‐sensitive hypertension (860.23)

Aim: These studies examined the direct role of PVN Gαi2 proteins, which are up‐regulated during high‐salt intake in Sprague‐Dawley (SD) rats, in the regulation of water &amp; electrolyte homeostasis, MAP and CNS/renal norepinephrine (NE) levels during high salt‐intake.Methods: Groups of male SD rats received a bilateral PVN infusion of a scrambled (S) or Gαi2 oligodeoxynucleotide (ODN‐300ng/side/day) and a 7‐day normal 0.4% (NS) or high 8% NaCl (HS) diet. On day‐7 24h Na+ balance was assessed. In sub‐groups MAP, estimated blood volume (EBV), estimated plasma volume (EPV), plasma NE levels and PVN and kidney NE turnover were assessed (N=6/gp/study).Results: In S infused rats HS did not alter sodium homeostasis (24h Na+ balance [meq] NS 0.7±0.3 vs HS 0.9±0.3), MAP (MAP [mmHg] NS 126±3 vs HS 127±3) or EBV and EPV. In S infused rats HS intake suppressed plasma NE content (plasma NE [nmol/L] NS 72±4 vs HS 40±5, P&lt;0.05), kidney NE content (NE [pg/mg] NS 586±36 vs HS 496±31, P&lt;0.05) and NE turnover in the PVN. HS intake in rats receiving a Gαi2 infusion evoked sodium retention (24h Na+ balance [meq] NS 0.6±0.2 vs HS 2.5±0.4 P&lt;0.05), hypertension (MAP [mmHg] NS 127±3 vs HS 146±4, P&lt;0.05) and increased blood and plasma volume (EPV [ml] NS 10.9±0.4 vs HS 11.8±0.4, P&lt;0.05; EBV [ml] NS 21.1±0.5 vs HS 22.4±0.3, P&lt;0.05). In Gαi2 infused rats HS intake increased plasma NE content (plasma NE (NE [nmol/L]; NS 67±7 vs HS 105±11, P&lt;0.05), kidney NE content (NE [pg/mg] NS 614±48 vs HS 823±59, P&lt;0.05) and kidney NE turnover (NE turnover rate [pg/mg/hr] NS 7.5±0.6 vs HS 20.3±1, P&lt;0.05) while suppressing PVN NE turnover.Conclusion: Impairment of PVN Gαi2 signal transduction during high salt‐intake results in dysregulation of renal NE content and turnover. This imbalance likely drives sodium &amp; fluid retention stimulating the development of hypertension. These data highlight the interaction between the CNS and kidney, and the role of the sympathetic nervous system, in the long‐term regulation of MAP.Grant Funding Source: Support by R01HL107330 &amp; K02HL112718A1

Radiofrequency renal nerve denervation decreases blood pressure, sympathetic activity and renal norepinephrine content in spontaneously hypertensive rats (875.16)

Radiofrequency renal denervation (RF‐RDN) decreases blood pressure (BP) in patients with drug‐resistant hypertension. This study investigated the effects of RF‐RDN on sympathetic activity and BP (Systolic, SBP; Diastolic, DBP) in SHR. Methods Nineteen‐week old male SHR were instrumented with telemetry probes for chronic measurement of BP and BP variability (BPV). After 1‐week, control BP was measured in rats for 3 days. The next day SHR (n=6/group) were anesthetized and randomly received either bilateral Sham‐RDN or RF‐RDN of the renal arteries (Biosense Webster Stockert 70 generator and RF‐probe). BP was then measured in SHR for 8 weeks. Results Following RF‐RDN, SBP/DBP was significantly decreased the day after (153±8/102±4 mmHg) and throughout the post‐RDN study (4‐week SBP/DBP, 173±7/120±5; 8‐weeks, 171±6/116±4 mmHg) compared to pre‐RDN control levels (SBP/DBP, 187±9/130±5 mmHg). RF‐RDN significantly decreased the low frequency component of BPV in SHR with the peak attenuation observed at 8 weeks (LF/HF 2.2±0.2 vs 0.9±0.2); this correlated with a blunting of the hypotensive response to i.p. chlorisondamine in RF‐RDN rats. Finally, at the end of week 8, kidney norepinephrine (NE) levels in RF‐RDN rats (left, 10±10; right, 0.0±0.0 ng/g kidney) were dramatically decreased compared with levels from sham SHR (left, 130±10; right, 110±10 ng/g kidney). Conclusions These data demonstrate that in hypertensive SHR, bilateral RF‐RDN of the renal arteries decreases BP in part by chronic inhibition of sympathetic neural pathways and a decrease in renal tissue NE levels.Grant Funding Source: Biosense Webster grant IIS‐175 to DRK and FS; NIH NIGMS P20 GM103514 to DK

Radiofrequency renal nerve ablation decreases blood pressure in SHR accompanied by increased urinary sodium excretion (857.4)

We have shown that radiofrequency catheter ablation of the renal arteries (RF‐RDN) decreases blood pressure (BP) in spontaneously hypertensive rats (SHR). Here, we studied the effects of RF‐RDN on changes in water and sodium excretion and urinary angiotensinogen levels in SHR with established hypertension. Methods Nineteen‐week old male SHR were instrumented with telemetry probes for measurement of BP. After 1‐week, control BP was measured. The next day SHR randomly received either bilateral Sham‐RDN (n=5) or RF‐RDN (n=6) of the renal arteries (Biosense Webster Stockert 70 generator and RF‐probe). BP (Systolic, SBP; Diastolic, DBP) was then measured for 2 weeks. Rats were then placed in metabolic cages for collection of urine and measurement of 24‐hr water and sodium balance. Results BP was significantly decreased in RF‐RDN SHR (2 weeks; ΔSBP, ‐12±5; ΔDBP, ‐9±4 mmHg) as compared to sham SHR (2 weeks; ΔSBP, ‐2±2; ΔDBP, 2±2 mmHg). RF‐RDN SHR increased urinary sodium excretion (RF‐RDN, 0.33±0.02; Sham, 0.25±0.03 mEq/day) and food intake (RF‐RDN 21±1; Sham 17±1 g/day). However, there were no significant differences between groups in 24‐hr daily water (RF‐RDN, 21±1; Sham, 19±2 ml) or sodium balance (RF‐RDN, 0.59±0.04; Sham, 0.48±0.06 mEq), or urinary angiotensinogen, protein and creatinine excretion rates. At the end of week 2, kidney norepinephrine levels in RF‐RDN rats (left, 0±0; right, 10±10 ng/g kidney) were markedly decreased compared with levels from sham SHR (left, 130±10; right, 110±10 ng/g kidney). Conclusions These data demonstrate that in hypertensive SHR, bilateral RF‐RDN produces an increase in urinary sodium excretion, which may potentially contribute to the concurrent decrease in BP.Grant Funding Source: Biosense Webster IIS‐175 to DRK &amp; FS; P30 GM103337 to LGN; P20 GM103514 to DRK

Renal Sympathetic Denervation Suppresses De Novo Podocyte Injury and Albuminuria in Rats With Aortic Regurgitation

The presence of chronic kidney disease is a significant independent risk factor for poor prognosis in patients with chronic heart failure. However, the mechanisms and mediators underlying this interaction are poorly understood. In this study, we tested our hypothesis that chronic cardiac volume overload leads to de novo renal dysfunction by coactivating the sympathetic nervous system and renin-angiotensin system in the kidney. We also examined the therapeutic potential of renal denervation and renin-angiotensin system inhibition to suppress renal injury in chronic heart failure. Sprague-Dawley rats underwent aortic regurgitation and were treated for 6 months with vehicle, olmesartan (an angiotensin II receptor blocker), or hydralazine. At 6 months, albuminuria and glomerular podocyte injury were significantly increased in aortic regurgitation rats. These changes were associated with increased urinary angiotensinogen excretion, kidney angiotensin II and norepinephrine (NE) levels, and enhanced angiotensinogen and angiotensin type 1a receptor gene expression and oxidative stress in renal cortical tissues. Aortic regurgitation rats with renal denervation had decreased albuminuria and glomerular podocyte injury, which were associated with reduced kidney NE, angiotensinogen, angiotensin II, and oxidative stress. Renal denervation combined with olmesartan prevented podocyte injury and albuminuria induced by aortic regurgitation. In this chronic cardiac volume-overload animal model, activation of the sympathetic nervous system augments kidney renin-angiotensin system and oxidative stress, which act as crucial cardiorenal mediators. Renal denervation and olmesartan prevent the onset and progression of renal injury, providing new insight into the treatment of cardiorenal syndrome.

Programming of hypertension: the nervous kidney

two decades after Barker and coworkers ([2][1]) described an inverse epidemiological relationship between birth weight and risk of adult cardiovascular morbidity, including hypertension, the pathophysiology of prenatally programmed hypertension remains incompletely understood. Experimental models

Catecholamines in turkeys with inbred cardiomyopathy

Abstract Patients with heart failure often have increased adrenergic nervous system activity. However, since the role of catecholamines in the development of inherited dilated cardiomyopathy is not totally clear, this study was designed to examine catecholamines in turkeys with inbred dilated cardiomyopathy (DCM). Plasma and tissue (heart, aorta, and kidney) catecholamines were measured in DCM and normal turkeys at ages 1, 10, 30, and 60 days, with echocardiograms and intra-arterial pressure obtained at 60 days. DCM turkeys weighed less than controls at all ages. At 60 days, cardiac dysfunction was evident by hypotension, cardiac dilatation, and decreased shortening fraction. Unlike other models of heart failure, cardiac norepinephrine was not depleted in DCM birds, and in fact was higher than controls at ages 10 and 30 days. Kidney norepinephrine was also equal to or greater than control birds, and both cardiac and kidney dopamine were present in normally low concentrations. In 60 day old DCM birds, reduced shortening fraction correlated with lower mean arterial pressure ( r = 0.77, P

Catecholamines in turkeys with alcohol-induced cardiomyopathy.

Although alcoholic cardiomyopathy has been difficult to reproduce in animals, turkeys fed 5% ethanol develop a dilated congestive cardiomyopathy. We therefore used this model to examine the adrenergic response to left ventricular dysfunction induced by alcohol. In normal turkeys, norepinephrine in kidneys decreased markedly with age from 1 day to 2 mo, with a similar but less dramatic decrease in cardiac norepinephrine. By 2 mo, chronic alcohol ingestion depleted cardiac norepinephrine compared with controls (217 +/- 22 vs. 316 +/- 41 ng/g, P < 0.05), even though cardiac norepinephrine is relatively low in turkeys compared with many other animals and humans. Norepinephrine in aorta was also decreased with alcohol administration, but kidney norepinephrine was unaffected. Dopamine was unaltered in any of the organs studied. Plasma norepinephrine is normally high in turkeys with arterial levels greater than venous (2,898 +/- 746 vs. 1,987 +/- 531 pg/ml at 2 mo). Venous plasma norepinephrine did not differ from control (2,595 +/- 547 pg/ml) after 2 mo of alcohol. Thus, as in humans, cardiomyopathy in alcohol-fed turkeys is associated with reduced cardiac norepinephrine, but unlike humans with cardiomyopathy, circulating norepinephrine remains normal.

Prenatal exposure to nicotine impairs nervous system development at a dose which does not affect viability or growth

Prenatal exposure to high doses of nicotine (greater than 6 mg/kg/day) via maternal infusions has been shown to impair nervous system development and to decrease viability and growth. In the current study, we have examined the effects of infusing pregnant rats with 2 mg/kg of nicotine per day from gestational days 4 through 20. At this lower dose, there was neither interference with maternal weight gain nor any increase in resorption rate. Intrauterine and postnatal growth was maintained at normal or supranormal rates in the exposed offspring. Nevertheless, sufficient nicotine penetrated the fetal brain to cause persistent alterations in [3H]nicotine binding sites, abnormalities of cellular development [assessed by measurements of ornithine decarboxylase (ODC) activity and deoxyribonucleic acid (DNA)], and impairment of development of peripheral noradrenergic projections (assessed by kidney norepinephrine levels); in each case, the neural alterations were virtually equivalent to those obtained previously at the higher, growth-suppressant dosage. These findings indicate that growth impairment alone is insufficient to predict the adverse effects of nicotine on development.

Tissue norepinephrine concentration in spontaneously diabetic Chinese hamsters.

There is some controversy concerning a possible effect of diabetes mellitus on the sympathetic nervous system in humans with spontaneous diabetes mellitus and in animals with experimental diabetes mellitus. In this study we compared the tissue norepinephrine (NE) concentration of normal and diabetic Chinese hamsters in the untreated state and after treatment with insulin. Diabetes resulted in a 128% increase in the NE concentration of the kidney in female but not male hamsters. The NE concentration was increased in the liver (133%) and in the cerebral cortex (118%) of both male and female hamsters. There was no significant increase in the NE concentration of hypothalamus, acinar pancreas, pancreatic islets, or heart of diabetic hamsters. Three days of insulin therapy reduced the elevated NE concentration in kidney, liver and cerebral cortex of diabetic hamsters to the levels found in normal hamsters. However, insulin therapy of normal hamsters did not reduce the tissue NE concentration of the kidney, liver, and cerebral cortex below the normal levels found in these animals. Insulin therapy reduced the hypothalamic concentration of NE in both diabetic and normal hamsters. The increase in kidney NE concentration in female diabetic hamsters was not due to a reduction in renal size, for the kidneys of both female and male diabetic hamsters were larger than those of normal hamsters. When synthesis of NE was inhibited with alpha-methyltyrosine, there was a comparable rate of fall in the tissue NE concentration in the four experimental groups, suggesting that the increased tissue NE concentration in the tissues of diabetic hamsters was not due to a decreased rate of disappearance of this compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered tyrosine and tryptophan metabolism during hypothermic hibernation in the 13-lined ground squirrel ( Spermophilus tridecemlineatus)

(1) Tyrosine and tryptophan metabolism in brain and peripheral tissues were studied in hypothermic hibernating and normothermic nonhibernating 13-lined ground squirrels (Spermophilus tridecemlineatus). (2) In the hypothermic hibernating state, there were significant elevations of brain stem tyrosine, norepinephrine, and dopamine levels; forebrain norepinephrine and dopamine levels; and cerebellum norepinephrine and tyrosine levels. (3) On the other hand, plasma norepinephrine levels were significantly decreased in hypothermic hibernating squirrels while plasma tyrosine levels were increased. Kidney norepinephrine levels were significantly increased in hypothermic hibernating squirrels, while kidney tyrosine levels were decreased. Total plasma tryptophan and free plasma tryptophan were significantly reduced in hypothermic hibernating squirrels. Hepatic tyrosine aminotransferase Km and Vmax were decreased in hypothermic hibernating squirrels, while tryptophan 2,3-dioxygenase activity was not altered. Plasma and liver albumin were increased in hypothermic hibernating squirrels, while plasma and liver total protein were not altered. (4) These results demonstrate that significant changes in tyrosine and tryptophan metabolism occur in both central and peripheral tissues with concomitant alterations in metabolites during hypothermic hibernation in 13-lined ground squirrels.

Renal nerves and the pathogenesis of angiotensin-induced hypertension.

The present study examined the role of the renal nerves in the development of hypertension produced by chronic infusion of angiotensin II in the conscious rat. The animals were divided into four groups, and a unilateral nephrectomy was performed. The remaining kidney was denervated in two groups, whereas in the other two groups of animals the nerves were left intact. Four days later either angiotensin II (83 ng/min) or saline infusions were begun through subcutaneously implanted osmotic minipumps. The rats were subsequently studied for 14 days. The results indicate that renal denervation significantly attenuated the pressor response to angiotensin II for approximately 6 days. Following this period, there was no difference in blood pressure between the innervated and denervated rats infused with angiotensin II, as both groups attained a hypertensive level of 170 to 180 mm Hg, which was 60 to 70 mm Hg above the blood pressure of the control rats infused with saline. Kidney norepinephrine content was reduced 95% by the denervation procedure and by 40% following infusion of angiotensin II into rats with intact renal nerves. These data demonstrate that, while the renal nerves appear to play a modulatory role in the development of the hypertension, they are not essential for the pathogenesis to occur nor do they determine the final level of hypertension achieved following chronic infusion of angiotensin II in the rat.