Chemical Stimulation of Renal Tissue Induces Sympathetic Activation and a Pressor Response via the Paraventricular Nucleus in Rats

Sympathetic activation and the kidney play critical roles in hypertension and chronic heart failure.The role of the kidney in sympathetic activation is still not well known.In this study,we revealed an excitatory renal reflex(ERR)in rats induced by chemical stimulation of the kidney that regulated sympathetic activity and blood pressure.The ERR was induced by renal infusion of capsaicin,and evaluated by the changes in renal sympathetic outflow,blood pressure,and heart rate.Renal infusion of capsaicin dose-dependently increased the contralateral renal sympathetic nerve activity,mean arterial pressure,and heart rate.Capsaicin in the corticomedullary border had greater effects than in the cortex or medulla.Intravenous infusion of capsaicin had no significant effects.The effects of renal infusion of capsaicin were abolished by ipsilateral renal denervation,but were not affected by bilateral sinoaortic denervation.Renal infusion of capsaicin increased the ipsilateral renal afferent activity.The ERR was also induced by renal infusion of bradykinin,adenosine,and angiotensin II,but not by ATP.Renal infusion of capsaicin increased c-Fos expression in the paraventricular nucleus(PVN)of hypothalamus.Lesion of neurons in the PVN with kainic acid abolished the capsaicin-induced ERR.These findings indicate that chemical stimulation of kidney causes an excitatory reflex,leading to sympathetic activation,pressor response,and accelerated heart rate.The PVN is an important central nucleus in the pathway of the ERR.

Angiotensin Type 1 Receptors and Superoxide Anion Production in Hypothalamic Paraventricular Nucleus Contribute to Capsaicin-Induced Excitatory Renal Reflex and Sympathetic Activation

Chemical stimulation of the kidney increases sympathetic activity and blood pressure in rats.The hypothalamic paraventricular nucleus(PVN)is important in mediating the excitatory renal reflex(ERR).In this study,we examined the role of molecular signaling in the PVN in mediating the capsaicin-induced ERR and sympathetic activation.Bilateral PVN microinjections were performed in rats under anesthesia.The ERR was elicited by infusion of capsaicin into the cortico-medullary border of the right kidney.The reflex was evaluated as the capsaicin-induced changes in left renal sympathetic nerve activity and mean arterial pressure.Blockade of angiotensin type 1 receptors with losartan or inhibition of angiotensin-converting enzyme with captopril in the PVN abolished the capsaicin-induced ERR.Renal infusion of capsaicin significantly increased NAD(P)H oxidase activity and superoxide anion production in the PVN,which were prevented by ipsilateral renal denervation or microinjection of losartan into the PVN.Furthermore,either scavenging of superoxide anions or inhibition of NAD(P)H oxidase in the PVN abolished the capsaicin-induced ERR.We conclude that the ERR induced by renal infusion of capsaicin is mediated by angiotensin type 1 receptor-related NAD(P)H oxidase activation and superoxide anion production within the PVN.

Enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with heart failure induced by adriamycin

Our previous studies have shown that the cardiac sympathetic afferent reflex is enhanced in rats with chronic heart failure （CHF） induced by coronary artery ligation and contributes to the over-excitation of sympathetic ac- tivity. We sought to determine whether sympathetic activity and cardiac sympathetic afferent reflex were en- hanced in adriamycin-induced CHF and whether angiotensin II （Ang II） in the paraventricular nucleus （PVN） was involved in enhancing sympathetic activity and cardiac sympathetic afferent reflex. Heart failure was induced by intraperitoneal injection of adriamycin for six times during 2 weeks （15 mg/kg）. Six weeks after the first injec- tion, the rats underwent anesthesia with urethane and a-chloralose. After vagotomy and baroreceptor denervation, cardiac sympathetic afferent reflex was evaluated by renal sympathetic nerve activity and mean arterial pressure （MAP） response to epicardial application of capsaicin （1.0 nmol）. The response of MAP to ganglionic blockade with hexamethonium in conscious rats was performed to evaluate sympathetic activity. The renal sympathetic nerve activity and cardiac sympathetic afferent reflex were enhanced in adriamycin rats and the maximum depres- sor response of MAP induced by hexamethonium was significantly greater in adriamycin rats than that in control rats. Bilateral PVN microinjection of angiotensin II （Ang II） caused larger responses of the cardiac sympathetic afferent reflex, baseline renal sympathetic nerve activity and MAP in adriamycin rats than control rats. These re- sults indicated that both sympathetic activity and cardiac sympathetic afferent reflex were enhanced and Ang II in the PVN was involved in the enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with adriamycin-induced heart failure.

Visit-to-Visit Blood Pressure Variability Are Associated with an Imbalance between Sympathetic and Parasympathetic Tone in Hypertensive Patients

Greater fluctuations in office blood pressure increase the risk of stroke and blood pressure volatility is an important risk factor for cardiovascular events. Effects of sympathetic and parasympathetic nerve on blood pressure regulation are well known, however, those on visit-to visit variation remains unclear. Aim of this study is to clarify the contribution of sympathetic and parasympathetic balance on blood pressure fluctuation. Methods: We enrolled 23 outpatients with essential hypertension. We measured blood pressure, and pulse rate at clinic 14 times in a row and calculated coefficient of variance (CV) as visit-to-visit variability. The velocity of pupil contraction, miosis (VC) and dilation, mydriasis (VD) was determined from pupillary function test. Results: Systolic blood pressure and diastolic blood pressure were not significantly correlated with VC, VD and VD/VC. Heart rate was not correlated with VC and VD, but significantly correlated with VD/VC. CV of systolic blood pressure, diastolic blood pressure and heart rate were not significantly correlated with VC or VD. Ratio of VD to VC significantly negative correlated with CV of blood pressure, diastolic blood pressure, and heart. Value of VD was significantly correlated with value of VC. Conclusion: Visit-to-visit variability of blood pressure and heart rate is not related with sympathetic or parasympathetic tone independently but augmented by the impaired sympathetic and parasympathetic balance.

Deterioration in Hemodynamics Reaction, Baroreflex Sensitivity, Sympathetic Nerve Activity and Redox State of Thoracic Aorta in the Experimental Model of Nitrate Tolerance and Its Pharmacological Correction

Continuous treatment with organic nitrates causes nitrate tolerance and provides evidence for a relationship between mitochondrial complex 1 activity and mitochondrial aldehyde dehydrogenase-2 (ALDH-2) with disturbances of the hemodynamics reaction during nitroglycerin (NTG) tolerance (NTGT). The purpose of this study was the evaluation of efficacy of original oxidized form NAD-containing drug, NADCIN®, on hemodynamic reactions, baroreflex sensitivity (BRS) and reflex control of splanchnic sympathetic nerve activity (SSNA), level of redox-potential, activity of ALDH-2 and superoxide anion generation in aortic tissue in rat model of NTGT. Five groups (7 - 9 each) of male Wistar rats, including control, acute i.v. NTG (150 mcg/kg) administration, NTG tolerance NTGT treatment with NADCIN® 8 mg/kg and methylene blue (MB, 2.5 mg/kg) were used. NTGT in rats was accompanied with the greatly attenuation of hemodynamics reaction, BRS, the decreasing of the ability to reflex control of SSNA without pronounce overexpression of endothelin-1 in vessels (aorta). In NTGT rats i.v. NTG along induced less hypotensive reactions and alterations in heart period vs single NTG treated group, more expressively decreased BRS (-34%) and reflex control of SSNA (-18%). NADCIN® significantly inhibits tolerance-inducing properties of the prolonged nitroglycerin infusion (max decrease of blood pressure response to nitroglycerin injection, % of normal controls: NTGT 51.2%, NADCIN® 91.6%, MB 55.8%). NADCIN® in NTGT rats after NTG i.v. administration increased reduced BRS (+37.8%, p < 0,05), reflex control of SSNA (+29.4%, p < 0.05) and reversed the decreasing of NAD/NADH ratio, ALDH-2 activity and decreasing in superoxide generation in thoracic aortic tissue. Thus, course treatment with NADCIN® of NTGT rats restores hemodynamics changes, BRS and SSNA throughout the increasing of redox-potential NAD/NADH and cessates the NTGT developing.

Cardiovascular dysfunction following spinal cord injury

Both sensorimotor and autonomic dysfunctions often occur after spinal cord injury（SCI）. Particularly, a high thoracic or cervical SCI interrupts supraspinal vasomotor pathways and results in disordered hemodynamics due to deregulated sympathetic outflow. As a result of the reduced sympathetic activity, patients with SCI may experience hypotension, cardiac dysrhythmias, and hypothermia post-injury. In the chronic phase, changes within the CNS and blood vessels lead to orthostatic hypotension and life-threatening autonomic dysreflexia（AD）. AD is characterized by an episodic, massive sympathetic discharge that causes severe hypertension associated with bradycardia. The syndrome is often triggered by unpleasant visceral or sensory stimuli below the injury level. Currently the only treatments are palliative - once a stimulus elicits AD, pharmacological vasodilators are administered to help reduce the spike in arterial blood pressure. However, a more effective means would be to mitigate AD development by attenuating contributing mechanisms, such as the reorganization of intraspinal circuits below the level of injury. A better understanding of the neuropathophysiology underlying cardiovascular dysfunction after SCI is essential to better develop novel therapeutic approaches to restore hemodynamic performance.

Endovascular denervation(EDN):From Hypertension to Non-Hypertension Diseases

Recently,the use of endovascular denervation(EDN)to treat resistant hypertension has gained significant attention.In addition to reducing sympathetic activity,EDN might also have beneficial effects on pulmonary arterial hypertension,insulin resistance,chronic kidney disease,atrial fibrillation,heart failure,obstructive sleep apnea syndrome,loin pain hematuria syndrome,cancer pain and so on.In this article we will summarize the progress of EDN in clinical research.

Effects of Obstructive Sleep Apneas on Endothelial Function and Autonomic Modulation in Adult Man

Objective To study the effects of obstructive sleep apneas on endothelial function and autonomic modulation. Methods From June 2009 to June 2011, male patients with obstructive sleep apnea hypopnea syndrome (OSAHS) were consecutively enrolled in this study. Patients with an apnea/hypopnea index (AHI) of greater than 15 and without previous treatment for OSAHS were included as Group OSAHS and obese subjects with an AHI of less than 5 were included as non-OSAHS controls (Group Control). Electrocardiography and beat-to-beat blood pressure were continuously recorded from the radial artery by applanation tonometry which was synchronized with polysomnography recording. Endothelial function was measured by arterial augmentation index (AAI). Spectral analysis of heart rate variability (HRV) and blood pressure variability (BPV) were computed for cardiac parasympathetic modulation (high frequency power, HF); sympathetic modulation (low frequency power, LF), sympathovagal balance (LF/HF power of R-R variability, LF/HF) and BPV sympathetic modulation (BPV LF) in normalized units [total power of the components/(total power-very LF power)×100]. Results Finally, 27 moderate-severe OSAHS patients and 22 non-OSAHS obese controls were recruited in the Group OSAHS and Group Control, respectively. In Group OSAHS, the age was 43.3±9.3 year-old, body mass index (BMI) was 36.8±8.7 kg/m 2 ; in Group Control, the age was 42.9±8.6 year-old, BMI was 34.4±7.9 kg/m 2 ; there were no significant differences in age and BMI between the Group OSAHS and Group Control (all P>0.05). The baseline AAI (12.5%±2.2% vs. 8.2%±2.1%) and BPV LF (68.3%±13.5% vs. 61.1%±11.7%) of the Group OSAHS were significantly higher than those of the Group Control (all P<0.05). And after overnight sleep, systolic BP (143.7±14.2 vs. 132.8±13.3 mm Hg), diastolic BP (87.7±7.7 vs. 78.6±5.5 mm Hg), HRV LF (69.7%±14.4% vs. 64.3%±12.1%), HRV LF/HF (3.7±2.0 vs. 2.3±1.3) and BPV LF (77.8%±15.6% vs. 68.3%±13.5%) of the Group OSAHS were significantly increased (all P<0.001), while HRV HF was significantly decreased (21.1%±9.3% vs. 27.5%±10.3%, P<0.05) from baseline.Conclusions The baseline endothelial function and autonomic modulation are impaired in OSAHS patients, which happened prior to hypertension and other cardiovascular complications. And the load effects of overnight obstructive breathing events could induce blood pressure and sympathetic activity increasing in the morning in OSAHS patients without acute aggravation in endothelial dysfunction.

肾脏去神经技术:历史,现状和前景（英文）

Renal denervation is a new technique approved effective for resistant-hypertension treatment.The common renal denervation system consists of a generator and a flexible catheter.During this minimally invasive procedure,the interventionalist uses a steerable catheter with a radio frequency(RF)energy electrode tip.The RF energy is delivered to the renal artery via standard femoral artery access.A series of 2-minute ablation are delivered in each renal artery to distroy the nerves system.The procedure does not involve a permanent device implant.By deactivating the renal nerves,and therefore reducing sympathetic nerve transmission,a significant and reliable reduction in blood pressure could be achieved.In this review,potential complications and future sights of renal denervation are also discussed.

Valves replacement operation in treatment of electrical storm induced by rheumatic valves disease

Objective： To present a case of electrical storm （ES） in a female patient with rheumatic valve disease. Methods： A female patient with severe rheumatic valve disease suffered an unexpected ES. She received more than 50 electrical shocks for repeated cardiac arrests due to ES over 16 hours. Then she received beta-blocking agent treatment and had an operation of double valves replacement. Results： ES was suppressed by sympathetic blockade with beta-receptor blocker and finally disappeared after the double pathological valves had been replaced. Conclusion： Increased sympathetic activity plays an important role in the genesis of electrical storm and sympathetic blockade may effectively suppress ES. However, the most important thing in the treatment of ES is to identify and eliminate the underlying cause of ES.

Influence of stress on the expression of bcl-2/bax protein in spontaneously hypertensive rats

Objective To explore the influence of stress induced increased sympathetic nerve activity on cardiomyocyte apoptosis and on the development of congestive heart failure. Methods 45 male, 16 week old spontaneously hypertensive rats (SHRs) were studied, in which 6 as controls. After the 6 controlled SHRs were examined by echocardiography, they were anesthetized and killed by decapitation. The other 39 were divided into the stress group (n=20) and the control group (n=19), and both groups were observed from 16 week old to 36 week old. In the stress group, binding-stress model was used. Till 36 week, all animals were echocardiographied, weighed and killed as described above. Cardiac bcl 2 and bax protein were quantified by western blot. Circulating catecholamine and angiotensin II (Ang II) were detected by radioimmunoasssy. Results Left ventricular volume (P< 0.05), left ventricular mass (P< 0.05) and the ratio of ventricular mass to body weight were higher in 36 week than those of the 16 week SHRs, whereas the volumes of eject fraction (EF) manifested the trend of decline, P< 0.05, binding stress for 20 weeks made this trend significantly, P< 0.05. With the increase of age, the serum norepinephrine (NE), epinephrine (E) and Ang II increased, suggesting that the binding-stress triggered the activity of central sympathetic nerve system. The cardiac bcl 2 protein was higher in 36 week than 16 week, P >0.05, whereas the bax protein increased significantly with the increase of age, P< 0.05, and so was the ratio of bax to bcl 2, P< 0.05. Conclusions The model of binding stress can effectively activate central sympathetic system, thus and mimic the neuroendocrine states. From 16 to 36 week, the process of cardiac apoptosis aggravated and the increased sympathetic activity would exacerbate rather than relieve this trend.

Specific acupuncture stimulation of Shenshu(BL23)affects sympathetic nervous activity-associated plasma renin concentration changes

OBJECTIVE:To examine whether specific stimulation of Shenshu(BL23)affects sympathetic nervous activity(SNA)-associated plasma renin concentration(PRC).METHODS:Eight healthy volunteers participated in three pattern conditions in random order:control(Cont),stimulation of Shenshu(BL23),and stimulation of sham point(Sham).All participants were initially in the supine position for>60 min,and then remained in the standing position during the experimental procedure to increase SNA.An electrocardiogram was used to calculate low frequency/high frequency(LF/HF)ratio;blood was collected to analyze PRC.RESULTS:The LF/HF ratio was significantly increased in the standing position when compared with the supine position(P<0.01).There was no difference in LF/HF ratio during or after stimulation of Shenshu(BL23)in the standing position when compared with before the stimulation in the supine position;however,the LF/HF ratio was significantly increased in Cont and Sham conditions(P<0.01).There was no difference in PRC after stimulation of Shenshu(BL23)in the standing position when compared with before the stimulation in the supine position;however,there was a significant increase in PRC in the Cont and Sham conditions(Cont P<0.05,Sham P<0.01).CONCLUSION:Our results demonstrated that specific acupuncture stimulation of Shenshu(BL23)in the standing position decreased SNA-associated PRC,which was not observed during acupuncture stimulation of the sham point.

Efficacy of regional renal nerve blockade in patients with chronic refractory heart failure

Background Increased renal sympathetic nerve activity can result in diuretic resistance in patients with chronic congestive heart failure. We investigated the effect of regional renal nerve blockade on the patients with chronic refractory heart failure and diuretic resistance. Methods Eighteen patients with chronic refractory heart failure were enrolled （mean age （64＋11） years）. The patients were randomly divided into two groups （renal nerve blockade group and standard therapy group, n=9 each）. Renal nerve blockade was performed by percutaneous injection of local anaesthetic under computed tomographic guidance. Heart rate, mean arterial blood pressure, plasma and urine electrolytes, neurohormones, factional excretion of sodium （FENa）, 24-hour urine volume were monitored at baseline and the first 24 hours after therapy. Dyspnea and oedema were also evaluated. The major adverse cardiovascular events （MACE）, plasma brain natriuretic peptide （BNP） level and left ventricular ejection fraction （LVEF） were compared between the two groups during the 3-12 months follow-up period. Results No complication was observed during the acute phase of renal nerve blockade. After renal nerve blockade, the 24-hour urine volume and FENa were significantly increased, while the level of plasma rennin, angiotensin II, aldosterone BNP and atrial natriuretic peptide as well as dyspnea and oedema were significantly reduced in renal nerve blockade group compared with baseline and standard therapy group. During three to 12 months of follow-up, the rate of MACE and plasma BNP level were significantly lower, while LVEF was significantly higher in renal nerve blockade group than those in standard therapy group. Conclusion Regional renal nerve blockade may be a safe and effective treatment for patients with chronic refractory heart failure.