Arterial Sympathetic Nerve Research Articles

Clinical Effect of Renal Arterial Sympathetic Radiofrequency Ablation on Secondary Hypertension.

Sympathetic hyperactivity is one of the main mechanisms of secondary hypertension. Reducing renal sympathetic activity through surgery can effectively reduce blood pressure. Many cases have shown that renal denervation (RDN) can selectively block renal artery sympathetic nerve activity to control refractory hypertension. This surgery is a minimally invasive surgery, and the risk of surgery-related adverse events is significantly reduced compared with surgery. Therefore, the purpose of this study is to explore the efficacy of radiofrequency ablation of renal artery sympathetic nerve in the treatment of secondary hypertension. Eight patients with secondary hypertension diagnosed by the cardiovascular department of our hospital and treated with RDN were followed up for 3-18 months, of which 5 cases were followed up for more than 12 months and 8 cases were followed up for more than 3 months. Eight patients were treated with radiofrequency ablation of renal artery catheter. The parameters such as preoperative blood pressure, antihypertensive drugs, organ function, intraoperative ablation resistance, power, time, and temperature were determined. The related changes of blood pressure, antihypertensive drugs, and visceral function and the occurrence of side effects at 1 week and 1, 3, 6, and 12 months after operation were related to the operation. In conclusion, RDN has a significant clinical effect in the treatment of refractory hypertension, with stable postoperative blood pressure drop, reduced drug dosage, and less side effects.

P105 Endocrine, autonomic and vascular function in children with Sleep Disordered Breathing

Abstract SDB is a risk factor for cardiovascular disease and co-exists with chronic endocrine disorders such as type II diabetes and metabolic syndrome. Children with SDB have increased blood flow velocity, an indicator of reduced vascular compliance and early vascular aging. Increased blood flow velocity is positively associated with sympathetic activity, increased arterial sympathetic nerve fibre density and endothelial damage. Whether changes in endocrine function occur concomitantly with altered autonomic and vascular function in children with SDB was assessed. Thirty six children scheduled for tonsillectomy underwent overnight polysomnography (SDB severity), pupil light reflex (autonomic function), fasting brachial artery blood flow assessment (vascular function - Doppler Ultrasound). Leptin and Ghrelin - both hormonal markers associated with sympathetic activity were measured in urine using ELISA and serum using MagPlex. The following dimensions of the dorsal lingual artery (tonsil) were measured – medial thickness, medial area, smooth muscle cell number/layers. We observed a positive correlation between serum and urine leptin and ghrelin concentrations. Increased blood flow velocity and arterial medial thickness were both associated with increased serum and urine leptin and ghrelin concentrations. Pupil light reflex was negatively associated with serum leptin and ghrelin levels. OAHI was positively correlated with leptin and ghrelin concentration (urine and serum) but not blood flow velocity. Blood flow velocity was inversely correlated with SpO2 nadir (REM). Our findings suggest that SDB has a global effect on the autonomic, vascular and endocrine systems.The impact of untreated paediatric SDB on the development of comorbidities in later life needs urgent attention.

Abstract 14842: Brain Fibroblast Growth Factor Receptor 4 Stimulation is Involved in High Phosphate Diet-Induced Skeletal Muscle Reflex Overactivation in Rats

An increasing number of studies have reported a deleterious role of inorganic phosphate (Pi) in promoting hypertension. Previously, we have shown high Pi diet-induced excessive pressor and sympathetic responses to muscle contraction in otherwise normal rats, which were primarily mediated by an overactive exercise pressor reflex (EPR), a reflex arising from contracting muscle. However, the mechanism underlying these abnormalities generated by excess Pi intake remains unclear. Dietary Pi is known to increase release of bone-derived fibroblast growth factor (FGF) 23 to regulate Pi homeostasis. Evidence suggests that FGF23 and FGF receptors (FGFRs) are also present in the central nervous system. The aim of this study was to determine the role of brain FGFRs in mediating augmented EPR activity induced by dietary Pi excess. Accordingly, we assessed cerebrospinal fluid FGF23 levels in Sprague-Dawley rats fed either a normal 0.6% Pi diet (NP) or a high 1.2% Pi diet (HP) for 12 weeks. To determine the role of central FGFRs in mediating the EPR, we measured mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) responses to hindlimb muscle contraction before and after intracerebroventricular (ICV) administration of either a selective FGFR4 inhibitor BLU9931 or a FGFR1/2/3 inhibitor AZD4547 in decerebrate NP and HP animals. Cerebrospinal fluid FGF23 levels were significantly higher in HP rats compared to NP rats (8.3±0.9 vs. 7.2±0.8 pM, P<0.01). ICV BLU9931 injection markedly attenuated (all P<0.01) the heightened MAP (Δ=41±14 vs. 20±14 mmHg) and RSNA (Δ=112±70 vs. 65±46 %) responses to EPR activation in HP animals, but did not significantly affect the responses in NP animals (ΔMAP=11±3 vs. 7±4 mmHg, ΔRSNA=21±17 vs. 15±5 %). MAP and RSNA responses to EPR stimulation were unchanged by ICV AZD4547 administration in NP or HP rats. In conclusion, our data demonstrate a novel action of central FGFR4 inhibition by reducing the high Pi diet-mediated skeletal muscle reflex overactivation. Importantly, the results implicate that activation of brain FGFR4 may lead to sympathetic dysregulation contributing to the abnormal hypertensive responsiveness after excess Pi consumption.

A Pilot Study of Perioperative External Circumferential Cryoablation of Human Renal Arteries for Sympathetic Denervation

PurposeCryoablation, which induces cellular death without extensive tissue damage, has been extensively used to denervate the myocardium. However, periadventitial external circumferential application of cryotherapy to denervate the renal artery sympathetic nerves has, to our knowledge, never been tested in humans. The main aim of this study was to examine the safety and potential effects of cryotherapy on ambulatory blood pressure levels and other outcomes that are indirectly related to sympathetic tone, including pulse-wave velocity, central pulse pressure, and glucose levels.Materials and Methods Five patients who underwent the denervation of the renal arteries during open surgery of the abdominal aortic aneurysm and four controls who did not undergo denervation during the surgery were enrolled. An argon-powered cryotherapy catheter (Cardioblate; Medtronic Inc., USA) was applied periadventitially to each renal artery in the five patients and then activated by infusion with liquid nitrogen for 1 minute.ResultsNo cryoablation-related complications occurred in the five consecutive patients. Their ambulatory blood pressures 3 to 5 months after surgery did not demonstrate any general blood pressure-reducing effects, but two patients responded favorably with the reduction of antihypertensive medication and decreased 24-hour blood pressure. The patients’ mean HbA1C levels decreased from 5.9±0.78% to 5.6±0.71% (P=0.042).ConclusionThis pilot study suggests that periadventitial cryoablation during open surgery can be used in the study of renal denervation in humans, as it had no complications in five patients in this study. The effectiveness of cryoablation for treating hypertension should be proven in a phase II clinical trial.

P3573Different contribution of sympathetic nerve activity to pulse wave velocity and arterial velocity pulse index in healthy subjects

Abstract Background Pulse Wave Velocity (PWV) is associated with the net effect of arterial stiffness and sympathetic nerve activity. Recent study demonstrated the significant relationship between PWV and muscle sympathetic nerve activity (MSNA). Arterial Velocity pulse Index (AVI) is a newly developed parameter, which could evaluate vascular reflected wave, regardless of aortic form. Vascular reflected wave is considered to be associated with sympathetic nerve activity, however little is known about the relationship between AVI and MSNA. Purpose The purpose of this study was to evaluate the relationship between AVI or PWV and MSNA in healthy subject. Method 21 healthy subjects were included in this study. AVI was measured by NAS-1000 (Nihon Koden, Japan), calculated from the time series of occlusive cuff pressure in the left upper arm. Brachial-ankle PWV (baPWV) was measured by BP-203RPEIII (Omron Healthcare, Japan). MSNA was recorded from left peroneal nerve by microneurography using tungsten microelectrode. All measurements were performed in the same day morning. Results The mean age was 31+5 years and body mass index (BMI) 22.5+3.0 kg/m2. In regression analysis, baPWV was significantly associated with age (r=0.64 P<0.05) but not with MSNA or BMI. AVI was significantly associated with MSNA (r=0.73, P<0.05) but not with age and BMI. Conclusion We found that different contribution of MSNA to baPWV and AVI and revealed that AVI was associated with MSNA in healthy subjects. These results suggest that AVI could reflect sympathetic nerve activity compared to baPWV.

Novel choline analog 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol produces sympathoinhibition, hypotension, and antihypertensive effects.

The search for new drugs remains an important focus for the safe and effective treatment of cardiovascular diseases. Previous evidence has shown that choline analogs can offer therapeutic benefit for cardiovascular complications. The current study investigates the effects of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032) on cardiovascular function and cholinergic-nitric oxide signaling. Synthesized LQFM032 (0.3, 0.6, or 1.2mg/kg) was administered by intravenous and intracerebroventricular routes to evaluate the potential alteration of mean arterial pressure, heart rate, and renal sympathetic nerve activity of normotensive and hypertensive rats. Vascular function was further evaluated in isolated vessels, while pharmacological antagonists and computational studies of nitric oxide synthase and muscarinic receptors were performed to assess possible mechanisms of LQFM032 activity. The intravenous and intracerebroventricular administration of LQFM032 elicited a temporal reduction in mean arterial pressure, heart rate, and renal sympathetic nerve activity of rats. The cumulative addition of LQFM032 to isolated endothelium-intact aortic rings reduced vascular tension and elicited a concentration-dependent relaxation. Intravenous pretreatment with L-NAME (nitric oxide synthase inhibitor), atropine (nonselective muscarinic receptor antagonist), pirenzepine, and 4-DAMP (muscarinic M1 and M3 subtype receptor antagonist, respectively) attenuated the cardiovascular effects of LQFM032. These changes may be due to a direct regulation of muscarinic signaling as docking data shows an interaction of choline analog with M1 and M3 but not nitric oxide synthase. Together, these findings demonstrate sympathoinhibitory, hypotensive, and antihypertensive effects of LQFM032 and suggest the involvement of muscarinic receptors.

Anatomic Conformation of Renal Sympathetic Nerve Fibers in Living Human Tissues

Renal denervation using radiofrequency catheter ablation is known to eliminate the renal sympathetic nerve and to lower blood pressure in patients with resistant hypertension. We sought to investigate the detailed anatomic conformation of the peri-renal arterial sympathetic nerve fibers with living human specimens. Peri-renal arterial tissue was harvested from patients undergoing elective radical or simple nephrectomy. Digital images of each section from the distal arterial bifurcation to the proximal margin were obtained and analyzed after immunohistochemical staining with anti-tyrosine hydroxylase antibodies. A total of 3,075 nerve fibers were identified from 84 sections of peri-renal arterial tissue from 28 patients (mean age 62.5 ± 10.2 years, male 68%). Overall, 16% of nerve fibers were located at distances greater than 3 mm from the endoluminal surface of the renal artery. The median distance from the arterial lumen to the nerve fibers of the proximal, middle, and distal renal arterial segments was 1.51 mm, 1.48 mm, and 1.52 mm, respectively. The median diameter of the nerve fibers was 65 μm, and there was no significant difference between the segments. A substantial proportion of the sympathetic nerve fibers were located deeper in the peri-arterial soft tissue than in the lesion depth created by the conventional catheter-based renal sympathetic denervation system.

A4020 Reduction of Blood Pressure Immediately After Renal Artery Adventitia Stripping During Total Nephroureterectomy

Objectives: Two men on antihypertensive therapy underwent unilateral radical nephroureterectomy for cancer of the renal pelvis. Methods: When the renal artery adventitia was stripped and cauterized just before renal artery ligation, hemodynamic monitoring revealed a gradual decrease of blood pressure in both patients. Results: This was presumably due to removal of renal artery sympathetic nerves, similar to the mechanism of catheter-based renal sympathetic denervation, although anesthesia, fluid infusion, and/or mesenteric traction may have had an influence. Conclusion: A similar strategy involving thoracolumbar sympathectomy was reported about 50 years ago. The clinically significant blood pressure reduction in these patients suggests renal denervation is effective.

Abstract 106: Central Angiotensin II Mediates Neurogenic Hypertension Through Post-Translational Regulation of Neuronal Nitric Oxide Synthase in the Paraventricular Nucleus of the Hypothalamus

Activation of renin-angiotensin- system, nitric oxide (NO) bioavailability and subsequent sympathoexcitation plays a pivotal role in the pathogenesis of many cardiovascular diseases including hypertension. Previously we have shown Ang II enhances PIN (a protein inhibitor of nNOS: neuronal nitric oxide synthase, known to dissociate nNOS dimers into monomers) mediated ubiquitination of nNOS in the PVN of rats with heart failure. To further elucidate the mechanism by which Ang II increases sympathetic outflow by regulating PIN mediated nNOS ubiquitination, we used Sprague-Dawley rats (250-300 g) subjected to intracerebroventricular infusion of Ang II (20 ng/min, 14days, 0.5μl/h) through osmotic mini-pumps and NG108-15 hybrid neuronal cell line treated with Ang II as an in vitro model. Ang II infusion increased baseline mean arterial pressure (126 ± 9* vs. 84 ± 4 mmHg) and renal sympathetic nerve activity (20.5 ± 2.3* vs. 6.4 ± 1.9 % of Max. Activity). Ang II infusion increased the expression of PIN (1.36 ± 0.04* Ang II vs. 0.81 ± 0.02 Veh) with a concomitant 52% decrease in dimeric nNOS and PIN-Ub conjugates (0.73 ± 0.04* Ang II vs. 1 ± 0.03 Veh) in the PVN. Further, Ang II-mediated increase in PIN expression(0.67±0.06* CHX AngII vs. 0.40±0.08 CHX 0h) was independent of CHX (protein synthesis inhibitor) mediated decrease in PIN expression (0.41±0.06* CHX AngII vs. 0.19±0.04 CHX 4h) suggesting Ang II-mediated post-translational stabilization of PIN. Substrate-dependent ligase assay in cells transfected with pCMV-(HA-Ub)8 vector revealed a reduction of HA-Ub-PIN conjugates after Ang II and proteasome inhibitor lactacystin (LC) treatment (4.5 ± 0.6* LC Ang II vs. 9.2 ± 2.2 LC). TUBE (Tandem Ubiquitin-Binding Entities) assay showed decrease PIN-Ub conjugates in Ang II-treated cells (0.82 ± 0.12* LC Ang II vs. 1.23 ± 0.05 LC) while AT1R blocker Losartan(Los) treatment diminishes the Ang II-mediated stabilization of PIN (1.21 ± 0.07 LC Los vs. 1.14 ± 0.04* LC AngII Los). Taken together, our studies suggest that increased central levels of Ang II contribute to the enhanced expression of PIN leading to reduced expression of the dimeric form of nNOS, thus diminishing the inhibitory action of NO on pre-autonomic neurons in the PVN resulting in an increase in sympathetic outflow.

Effects of the bioactive peptides Ile-Pro-Pro and Val-Pro-Pro upon autonomic neurotransmission and blood pressure in spontaneously hypertensive rats.

The bioactive peptides Ile-Pro-Pro (IPP) and Val-Pro-Pro (VPP) are believed to improve blood pressure and arterial function. To gain a better understanding of the mechanisms underlying the action of these peptides, we investigated their effects upon autonomic neurotransmission and blood pressure in spontaneously hypertensive rats (SHR). Both IPP and VPP caused a significant reduction in cutaneous arterial sympathetic nerve activity (CASNA) and reduced mean arterial pressure (MAP); however, both of these effects were eliminated following sub-diaphragmatic vagotomy. On the other hand, captopril, an angiotensin-converting enzyme inhibitor, reduced MAP without changing CASNA, and maintained this hypotensive effect following vagotomy. Moreover, the effects of IPP and VPP upon CASNA were observed following gastric administration but not by duodenal administration. These results suggest that IPP and VPP reduce CASNA via the stomach and afferent vagus nerve, thus causing reductions in MAP in SHR.

Renal artery sympathetic nerve radiofrequency denervation.

Arterial hypertension is one of the most common chronic diseases in the western world, affecting more than 25% of the adult population. The aim of this study was to assess changes in arterial blood pressure (BP) levels in hypertensive patients, after ablation of nerve terminals in renal arteries, using radiofrequency energy during 24 months of follow-up. Thirty-two patients with diagnosed resistant hypertension (20 men and 12 women) underwent percutaneous catheter-based renal denervation of nerve terminals in renal artery walls. Mean BP value before ablation was [mm Hg]: systolic 174.92, diastolic 99.73 and pulse pressure 75.19. After procedure reduction value of BP was reported [mm Hg]: systolic 146.78; diastolic 87.14, pulse pressure 59.64 at 24-month follow-up (p < 0.05 for all). 30% of patients had systolic BP ≤ 140 mm Hg, 67% had diastolic BP ≤ 90 mm Hg, and optimum BP values ≤ 140/90 mm Hg were observed in 30% of patients. In our cohort of patients, percutaneous renal artery ablation procedure effectively reduces systolic, diastolic BP and pulse pressure. No adverse events during 24 months of follow-up were noted. These results were comparable with available data from SIMPLICITY I and II trials.

Hypotensive effects of renal denervation in spontaneously hypertensive rat based on ultrasonic contrast imaging

BackgroundSympathetic nerves-fire rate is generally enhanced in some types of hypertension models. Renal sympathetic denervation(RSD) by the radiofrequency ablation was used to treat the hypertension has achieved curative effect.HTN-1 and HTN-2 trial reported catheter-based renal denervation may cause substantial and sustained blood-pressure reduction in patients with resistant hypertension. However, recent controlled HTN-3 trial questioned the BP lowering effect of Renal denervation treatment. The controversial results maybe arised from the incompleted RSD which implemented inside the renal artery. Now renal denervation therapy for resistant hypertension is in attractive and controversial status. Our aim is to define the hyotensive value of complete renal denervation in adult spontaneous hypertensive rats. MethodsMale spontaneous hypertensive rats(SHR) aged 12 weeks were randomly selected for either unilateral renal artery sympathetic nerves ablation (URSNA), or conventional technique of renal denervation (CRD), or bilateral renal artery sympathetic nerves ablation (BRSNA) and sham operation. Blood pressure, sodium and water balance,serum reninangiotensin II and Norepinephrine concentration were measured during 20 weeks after renal denervation operation. Internal diameters of renal arteries and renal blood flow rate was tested by ultrasonic contrast imaging. ResultsThe continued increased blood pressure in SHR was delayed and significantly reduced by conventional renal denervation over a period of 8 weeks. Both the bilateral and unilateral renal sympathetic nerve ablation procedure did not prevent the development of hypertension in SHR. The attenuation of hypertension was accompanied with the increase of urinary sodium excretion and depression of rennin angiotensin system (RAS). ConclusionsWe concluded that renal denervation may not be an effective therapeutic method in the long-term control of hypertension in adult SHR.

Abstract 035: Differential Effects of Bardet-biedl Syndrome 1 Gene Deletion From Agouti-related Peptide Neurons

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive human disorder associated with several clinical features including obesity and hypertension. We previously demonstrated that Bbs1 gene deletion from the central nervous system caused obesity and hypertension in mice highlighting the importance of neuronal BBS proteins for energy homeostasis and cardiovascular regulation. Here, we investigated the role of Bbs1 gene in the orexigenic agouti-related peptide (AgRP) neurons. We crossed Bbs1 fl/fl mice with AgRP Cre mice and confirmed Cre recombinase activity in AgRP neurons using td-Tomato reporter mice. Interestingly, female AgRP Cre /Bbs1 fl/fl mice developed profound obesity as indicated by the increased body weight (46.8±2.0 g vs control littermates, 35.5±1.9 g at 25 weeks of age). In contrast, body weight of male AgRP Cre /Bbs1 fl/fl mice (48.5±1.2 g) was similar to the controls (46.7±1.2 g). There was no change in the expression of hypothalamic genes regulating food intake (AgRP, proopiomelanocortin and neuropeptide Y) in AgRP Cre /Bbs1 fl/fl mice relative to controls. Next, we assessed the consequence on arterial pressure (AP) and sympathetic nerve activity (SNA) of ablating the Bbs1 gene from AgRP neurons. Interestingly, deletion of the Bbs1 gene in AgRP neurons did not recapitulate the hypertension phenotype of BBS as indicated by the lack of difference in mean AP (107±5.0 vs 106±5.2 mmHg in controls) and heart rate (597±23.5 vs 589±16.4 in control). However, conscious renal SNA was significantly higher in AgRP Cre /Bbs1 fl/fl mice relative to controls (114±10 vs 78±6 spikes/sec, p&lt;0.05). In addition, the depressor effect of ganglionic blockade (hexamethonium) was higher in AgRP Cre /Bbs1 fl/fl mice (-64.4±10 vs -55.8±8.3 mmHg in control). Finally, we used wire myography to measure mesenteric artery vascular function and found impairment in acetylcholine induced relaxation in AgRP Cre /Bbs1 fl/fl mice (Max. relaxation: 78 ± 6% vs 26 ± 9% in controls; p&lt;0.05), but no changes in the relaxation evoked by sodium nitroprusside, suggesting endothelial, but not smooth muscle, dysfunction. These findings demonstrate that Bbs1 gene in AgRP neurons is critical for energy homeostasis, renal sympathetic outflow and vascular endothelial function.

CaV2.3 Mediate ATP Release from Rat Tail Artery Sympathetic Nerves

Peripheral sympathetic nerves are essential for regulating homeostatic control of target organs, such as the tone of blood vessels, and many details of the molecular organization of peripheral sympathetic nerve varicosities remain to be defined. Unlike central synapses, peripheral varicosities typically exhibit co-transmission of multiple neurotransmitters. Several lines of evidence show co-transmission of the sympathetic transmitters norepinephrine (NE) or ATP is mediated by the preferential association of separate pools of vesicles with CaV2.1 and CaV2.2 isoforms that provide the Ca2+ entry for vesicle release. CaV2.3 is a closely related channel that has been studied in several central synapses, but its role in peripheral sympathetic nerves is largely unknown. Using confocal microscopy to study perivascular nerves, we previously found that ATP and NE are stored in segregated pools of vesicles. Further, we found that CaV2.3 are expressed in rat tail perivascular sympathetic nerves and that they co-localize with vesicles expressing the vesicular nucleotide transporter (VNUT) that loads ATP into vesicles rather than vesicle harbouring the NE-transporting vesicular monoamine translocase 2 (VMAT2). We now report one of the first functional characterizations of CaV2.3 in perivascular nerves. We assessed the functional role of CaV2.3 in field-stimulated isometric force generated by rat tail arteries in response to pulse-number ramps (3-100 pulses, 20 Hz). Inhibition of vasoconstriction with the CaV2.3 blocker SNX-482 (250 nM) mimicked the effect of blocking smooth muscle P2X receptors with suramin while blocking α-adrenergic receptors with phentolamine productive a distinct inhibitory profile. These functional tests were corroborated by immuno-fluorescence microscopy showing that CaV2.3 immunoreactivity correlated with the sensitivity of individual blood vessels to suramin and SNX-482.

Abstract 13295: Interaction Between Neural and Peripheral Effects of Intravenous Guanfacine in Determining Arterial Pressure and Sympathetic Nerve Activity

Introduction: Guanfacine is a selective α 2A -adrenergic agonist and suppresses sympathetic nerve activity (SNA) by acting on the central nervous system. In the use of intravenous guanfacine in animal experiments, however, arterial pressure (AP) does not necessarily fall much even when SNA is markedly suppressed. Hypothesis: Intravenous guanfacine may act on peripheral α-adrenergic receptors to increase AP at a given SNA. Methods: To separately assess the neural and peripheral effects of intravenous guanfacine, an open-loop analysis of the carotid sinus baroreflex was performed in 7 anesthetized Wistar-Kyoto rats. Carotid sinus pressure was changed from 60 to 180 mmHg in a staircase manner while steady-state SNA and AP were measured. Effects of intravenous guanfacine (100 μg/kg, bolus) on the baroreflex response was examined. Results: As shown in the figure, the neural arc of the baroreflex approximated a sigmoid curve. Guanfacine reduced the response range of the neural arc from 89.8±2.2% to 32.9±10.9% (P&lt;0.01) and the minimum SNA from 11.6±1.9% to 2.4±1.2% (P&lt;0.01). The peripheral arc of the baroreflex approximated a straight line. Guanfacine increased the intercept from 67.6±7.1 to 92.8±8.5 mmHg (P&lt;0.01) without significantly affecting the slope of AP versus SNA. The operating point of the baroreflex was determined from the intersection between the neural and peripheral arcs on the baroreflex equilibrium diagram (denoted by a double circle). The operating-point SNA decreased from 47.5±6.0% to 13.6±3.9% (P&lt;0.01) whereas the operating-point AP was not decreased significantly (from 114.7±4.3 to 109.0±7.1 mmHg). Conclusions: The operating-point AP and SNA are determined through the interaction between the neural and peripheral effects of intravenous guanfacine. While the operating-point SNA was significantly decreased, the operating-point AP was relatively maintained via the peripheral effect.

Pressor threshold of muscle metaboreflex is modulated during unloading of carotid baroreceptors in humans

Static and dynamic exercise are accompanied by increases in arterial blood pressure, heart rate and sympathetic nerve activity. It is thought that the activation of the muscle metaboreflex is one of major mechanisms for evoking the pressor responses during heavy intensity exercise [1]. It has been shown that the arterial baroreflex buffers the muscle metaboreflex-mediated pressor responses [2]. However, it is unknown whether the carotid baroreflex modifies muscle metaboreflex function in humans. Therefore, the purpose of this study was to investigate the effects of unloading of carotid baroreceptors on threshold and gain of the muscle metaboreflex in humans.

Abstract 083: Metabolic and Cardiovascular Effects of BBS1 Ablation From the POMC-containing Neurons

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive disorder associated with several features including obesity and hypertension. Deletion of Bbs genes globally, in the nervous system or in the leptin receptor-expressing cells recapitulated many of the BBS phenotypes including obesity and hypertension. Here, we assessed the effect of ablating the Bbs1 gene from the neurons expressing proopiomelanocortin (POMC) neurons. Breeding Bbs1 flox mice with POMC Cre mice created mice deficient in Bbs1 gene only in the POMC-positive neurons (visualized by tdTomato expression). Importantly, POMC Cre /Bbs1 fl/fl mice display an obesity phenotype as indicated by the increased (P&lt;0.05) body weight (48.6±1.7 vs 34.9±0.8 g in controls) and fat pads (3.3±0.3 vs. 0.7±1.1 g for inguinal fat, 2.1±0.2 vs. 0.4±0.05 g for perirenal fat, 3.3±0.3 vs. 0.8±0.3 g for reproduction fat and 0.4±0.02 vs. 0.2±0.02 g for brow fat) associated with increased (P&lt;0.05) food intake (3.79.±0.14 vs. 2.97±0.15 g in controls) in 25 weeks old mice. POMC Cre /Bbs1 fl/fl mice displayed decreased (P&lt;0.05) O 2 consumption (2.6±0.03 vs. 3±0.04 mL O 2 /100g/min in controls) and heat production (8.0±0.09 vs. 9.2±0.13 kcal/kg/hr in controls). These results indicate that hyperphagia and decreased energy expenditure contribute to the development of obesity in POMC Cre /Bbs1 fl/fl mice. Next, we assessed the consequence on arterial pressure (AP) and sympathetic nerve activity (SNA) of ablating the Bbs1 gene from POMC neurons. Interestingly, deletion of the Bbs1 gene in POMC neurons did not recapitulate the hypertension phenotype of BBS as indicated by the slight, but not significant increase in mean AP (116±4.7 vs 109±6.1 mmHg in controls). However, conscious renal SNA was significantly higher in POMC Cre /Bbs1 fl/fl mice relative to controls (132.4±11 vs 74.3±4.2 spikes/sec, P&lt;0.05). Finally, the depressor effect of ganglionic blockade (hexamethonium) was exaggerated in POMC Cre /Bbs1 fl/fl mice (-68.6±4.4 vs -45.2±9.4 mmHg in control, P=0.017). These findings demonstrate that Bbs1 gene in the POMC neurons is critical for energy homeostasis, but not for arterial pressure regulation.

Abstract P620: Renal Nerve Denervation Modulates GABA-ergic Input into Paraventricular Nucleus of the Hypothalamus and Exerts a Long Term Antihypertensive Effect in Hypertensive Mice Associated with Chronic Kidney Disease

Background: Sympathoexcitation plays an important role in the pathogenesis of hypertension with chronic kidney disease (CKD). In hypertension, the paraventricular nucleus of the hypothalamus (PVN) in the brain controls the sympathetic outflow through GABA-ergic mechanisms. The renal nerve denervation (RDN) exerts a certain long term antihypertensive effect; however the precise mechanism is not fully elucidated. We aimed to clarify whether RDN modulates sympathetic outflow through GABA-ergic mechanisms in the PVN in hypertensive mice with CKD. Methods and Results: In 5/6-nephrectomized ICR-mice (Nx) at 4-weeks after nephrectomy, systolic BP (SBP) was significantly increased (vs. Sham, 143±2 vs. 109±2mmHg, n=12-24, p&lt;0.01), accompanied by sympathoexcitation (urinary norepinephrine (uNE): vs. Sham, 424±26 vs. 226±17μg/24hrs, n=12-24, p&lt;0.01). We performed RDN or sham operation and divided into 3 groups (Sham-sham, Nx-sham, and Nx-RDN, n=12 for each). At 2-weeks after RDN, SBP was significantly decreased (123±2 vs. 136±2 mmHg, n=12 for each, p&lt;0.01), and urinary sodium excretions were increased (0.64±0.04 vs. 0.47±0.03 mmol/24hrs, n=8 for each, p&lt;0.01) in Nx-RDN compared with those in Nx-sham. The uNE levels were not different between two groups. At 6-weeks after RDN, SBP was kept decreasing (125±1 vs. 140±3 mmHg, n=12 for each, p&lt;0.01) and uNE levels were also decreased (386±32 vs. 541±35 μg/24hrs, n=12 for each, p&lt;0.01) in Nx-RDN compared with those in Nx-sham. The urinary sodium excretions were not different between two groups. Bicuculline (GABA-A receptor antagonist, 50pmol) microinjection into PVN increased mean arterial pressure (MAP) and lumbar sympathetic nerve activity (LSNA) in all groups. The pressor responses and the change in LSNA were significantly attenuated in Nx-sham (vs. Sham-sham, [[Unable to Display Character: &amp;#8710;]]MAP/baseline MAP [%], 33±4 vs. 66±6 %; [[Unable to Display Character: &amp;#8710;]]LSNA (%baseline), 57±7 vs. 112±8 %, p&lt;0.01, n=6 for each), but were enhanced in Nx-RDN at 6-weeks after RDN (vs. Nx-sham, [[Unable to Display Character: &amp;#8710;]]MAP/baseline MAP [%], 60±6 vs. 33±4 %; [[Unable to Display Character: &amp;#8710;]]LSNA (%baseline), 94±5 vs. 57±7 %, p&lt;0.05, n=6 for each). Conclusion: These data indicate that augmented GABA-ergic input into PVN induced by RDN, at least in the late phase, is involved in antihypertensive action in hypertensive mice with CKD.

Evaluation of the ventricular systolic function in dogs with pulmonary artery hypertension after transcatheter renal sympathetic denervation

Objective To evaluate the effects of transcatheter renal sympathetic denervation (RSD) on the cardiac systolic function of dogs with pulmonary arterial hypertension(PAH) using two-dimensional speckle tracking imaging(2D-STI). Methods Twenty two dogs were divided in to three groups: control group (n=7), PAH group (n=8), PAH+ RSD group(n=7). Pulmonary artery hypertension models were made by monocrotaline injection in PAH group and PAH+ RSD group, while bilateral renal artery sympathetic nerve were also ablated in PAH+ RSD group. Meanwhile, sham operation treatment were made in the control group and PAH group. The changes of blood pressure and cardiac indicies of ultrasound were observed before and after 8 weeks respectively. Then the left ventricular(LV) lateral strain, septal strain (IVS LS) and right ventricular(RV) strain were calculated. In the apical 4-chamber view, time from QRS onset to peak systolic strain in each the six segments of the LV and RV were measured and standard deviation of the time to peak longitudinal strain of six segments(LVTsl-6SD and RVTsl-6SD) were calculated. LV twist degree were obtained from LV rotation curve in basal and apical short-axis planes. Results After 8 weeks, there was no difference in the mean strain of LV lateral wall among the three groups, while the mean strain of RV lateral wall and septal were higher in PAH+ RSD group than the PAH group [(18.91±0.86)% % vs 16.34±1.36)%, P<0.001; (18.39±1.03)% vs (17.02±1.00)%, P<0.001, respectively]. Compared with PAH group, LVTsl-6SD and RVTsl-6SD of PAH+ RSD group decreased significantly [(25.45±3.59)ms vs (40.40±2.83)ms, P<0.001; (34.16±2.81)ms vs (51.98±3.64)ms, P<0.001, respectively]. The LV twist degree of PAH+ RSD group increased significantly[(10.47±0.73)° vs (8.46±1.06)°, P<0.001]. Conclusions RSD can reduce the influence of pulmonary artery hypertension on cardiac systolic function. Key words: Echocardiography; Hypertension, pulmonary; Renal sympathetic nerve; Catheter ablation; Ventricular function, left

Upregulation of Orexin Receptor in Paraventricular Nucleus Promotes Sympathetic Outflow Through Non‐selective Cation Channel in Obesity

AbstractElevated sympathetic outflow contributes to hypertension in obesity. Orexins importantly regulates autonomic function. Presently we determined the role of orexin in the paraventricular (PVN) nucleus of hypothalamus in controlling sympathetic outflow in obese Zucker rats (OZRs) and lean Zucker rats (LZRs). Orexin A microinjection into PVN significiantly dose‐dependently elevated arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) manner in anesthetized OZRs than LZRs, which eliminated by SB‐334867, orexin receptor 1 receptor (OX1R) antagonist, but not TCS‐OX2‐29, OX2R antagonist. Furthermore, SB‐334867 reduced basal ABP and RSNA in OZRs but not LZRs. Compared with LZRs, OX1R expression in PVN was significantly higher in OZRs, while no difference for OX2R. OX1R immunoreactivity was positive in retrogradely labeled PVN‐spinal neurons. Compared with LZRs, the basal firing rate in the PVN‐spinal neurons was higher in OZRs, and orexin A excited firing activity in PVN‐spinal neurons in OZRs, which eliminated by SB334867. SB334867 also decreased basal firing activity of these neurons in OZRs. In addition, orexin A induced larger currents in PVN spinal neurons in OZRs. These data suggest that upregulation of OX1R in the PVN promotes hyperactivity of PVN presympathetic neurons and sympathetic outflow in obesity.This work was supported by National Institutes of Health (Grants MH096086 to D.‐P. L.) and National Natural Sciences Foundation of China (31271223 and 31071002).