延髓头端腹外侧区一氧化氮与慢性心力衰竭大鼠心交感传入反射物的关系

为观察延髓头端腹外侧区(rostral ventrolateral medulla,RVLM)一氧化氮(N0)在慢性心力衰竭(chronic heart failure,CHF)大鼠增强的心交感传入反射(cardiac sympathetic afferent reflex,CSAR)中的作用,实验在去压力感受器神经支配的结扎冠状动脉诱发的CHF大鼠和假手术SD大鼠进行,记录电刺激心交感传入神经中枢端前后的血压和肾交感神经活动(renal sympathetic nerve activity,RSNA)变化以评价CSAR。结果显示：(1)CHF大鼠的CSAR显著增强;(2)RVLM微量注射NO合酶(NOS)抑制剂MeTC增强对照组大鼠的CSAR但对CHF大鼠的CSAR无显著影响;(3)RVLM微量注射NO供体S-nitroso-N-acetyl-penicillamine(SNAP)抑制CHF大鼠增强的CSAR;(4)S-methyl-L-thioeitruline（MeTC)仅增强对照组大鼠基础水平的RSNA,而SNAP抑制对照组和CHF大鼠基础水平的RSNA。结果表明RVLM中内源性NO的减少是导致CHF大鼠CSAR增强的重要机制之一。     

失血引起兔肾神经和肾上腺交感神经活动的变化

本文观察了急性失血引起的戊巴比妥钠麻醉兔的肾交感神经活动(RSNA)和肾上腺交感神经活动(AdSNA)的变化。股动脉放血,在10min内使平均动脉压(MAP)下降至5.3kPa。失血过程中RSNA先兴奋后抑制,AdSNA则一直呈兴奋反应,这反应可由动脉压力感受器去神经而消失。失血前和失血后切断迷走神经均可翻转失血引起的RSNA抑制,但不能阻断AdSNA的兴奋反应。静脉注射纳洛酮和延髓腹外侧头端(RVLM)微量注射纳洛酮可翻转失血引起的RSNA抑制,但对AdSNA兴奋反应无显著影响。失血引起心率(HR)和RSNA一样,但不能为纳洛酮所反转。上述结果表明:失血引起的RSNA抑制是由迷走神经传入纤维和阿片肽(尤其是RVLM中的阿片肽)参与所致,而AdSNA的兴奋则与动脉压力感受器传入纤维有关。     

电针诱导心肌缺血大鼠延髓头端腹外侧区nNOS和iNOS差异表达

许多研究表明,延髓头端腹外侧区(rostral ventrolateml medulla,RVLM)的NO/NOS系统参与心血管活动的中枢调节.本实验以结扎Wistar大鼠左冠状动脉前降支法建立急性心肌缺血(acute myocardial ischemia,AMI)动物模型,观察针刺"内关"穴改善AMI大鼠的心功能作用,同时检测大鼠RVLM区神经元型一氧化氮合酶(neuronal nitric oxide synthase,nNOS)和诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)表达的变化,进而探讨针刺治疗AMI的中枢机制.实验观察显示,AMI大鼠心功能各项指标减弱,伴随外周血去甲肾上腺素(norepinephrine,NE)和脑钠肽(brain natriuretic peptide,BNP)水平显著升高,同时RVLM区nNOS阳性神经元数和nNOS mRNA表达升高,而iNOS水平则降低.针刺"内关"穴(Pe 6)(每天30 min,连续5天)改善心功能,降低AMI大鼠血清中NE和BNP的水平,同时升高iNOS并降低nNOS在RVLM的表达.以上结果提示,针刺治疗心肌缺血的同时可以调节iNOS/NO和nNOS/NO在RVLM的变化,这可能与针刺通过调节RVLM区的NO含量进而降低交感传出,从而改善AMI大鼠的心功能有关.     

家兔延髓腹侧表面加压区与压力感受性反射的关系

实验在乌拉坦麻醉、三碘季铵酚制动和人工呼吸的41只家兔进行。电刺激延髓腹侧面加压区(VSMp)引起肾交感神经电活动(RSNA)增强和动脉血压升高。电刺激主动脉神经(AN)则导致RSNA抑制和动脉血压下降。在下列实验条件下,刺激VSMp所致的交感兴奋性效应均不受影响:(1)同时刺激VSMp和AN;(2)刺激AN期间插入VSMp刺激;(3)刺激VSMp期间插入AN刺激。但刺激AN所致的交感抑制性效应却被明显地抑制。提示兴奋VSMp的交感兴奋性效应可调制压力感受性反射的交感抑制性成分,两者之间的动态平衡是维持静态动脉血压水平的基础。     

N-亚硝基左旋精氨酸的心血管效应及其对肾交感神经活动的影响

在麻醉大鼠观察了新型NO合成抑制剂N-亚硝基左旋精氨酸(L-NNA)的血流动力学效应及其对肾交感神经活动的影响,旨在阐明NO在全身动脉血压调节中的可能作用及其作用机制。实验结果如下:(1)静注L-NNA(15 mg/kg)后,平均动脉压(MAP)由9.87±0.80升至14.67±0.53kPa(P<0.001),心率(HR)由317±13减至303±14 bpm(P<0.05),心指数(CI)由9.79±0.83降至7.04±0.41ml/min·100g~(-1)(P<0.05),总外周阻力指数(TPRI)由1.04±0.10升至2.15±0.18 u/100 g(P<0.001),持续30min以上;此效应可被预先注射左旋精氨酸(200 mg/kg)所逆转。(2)在缓冲神经切断的大鼠,i.v.L-NNA时,MAP,CI和TPRI的变化依然存在,而HR则加快,表明神经完整大鼠的HR减慢系压力感受器反射所致。(3)在缓冲神经完整大鼠i.v.L-NNA后,MAP升高,HR减慢,而肾交感神经活动(RSNA)无明显改变。(4)切断缓冲神经后,再i.v.L-NNA时,MAP,HR和RSNA分别增加55.6％、5.1％和34.3％,提示L-NNA可能兴奋交感中枢,而压力感受器反射可掩盖其对RSNA的影响;预先注射左旋精氨酸则可抑制L-NNA的上述效应。根据以上结果似可认为,NO合成抑制剂的血流动力学效应,由两种机制所介导:一是L-NNA抑制外周部位NO的基础性释放,致使血管紧张度增加,进而血压升高;另一是L-NNA兴奋交感中枢,从而引     

中脑导水管周围灰质NO在应激大鼠高血压形成中的作用及其机制探讨

目的：探讨大鼠中脑导水管周围灰质（PAG）内NO在应激性高血压（SIH）发病中的作用。方法：采用电击足底结合噪声建立应激性高血压大鼠模型,NADPH－d组化方法显示PAG内一氧化氮合酶（NOS）阳性神经元的变化,核团微注法和放免法检测PAG内微量注射L－NNA对动物血压和延髓头端腹外侧区（RVLM）内Ach含量的影响。结果：（1）应激性高血压大鼠血压升高,PAG背外侧区NOS阳性神经元数量明显减少,平均灰度值增高,且RVLM内Ach含量也增多。（2）PAG内微量注射L－NNA 100mmol/L 0.1μl后,对照组大鼠的平均动脉压（MAP）升高,RVLM内Ach含量增多,而应激性高血压组大鼠MAP的变化显著小于对照组。结论：应激性高血压大鼠PAG内NOS阳性神经元发生的可塑性变化,可能经RVLM内Ach介导,参与了该病的形成。     

颈动脉注射17β -雌二醇对去缓冲神经大鼠延髓腹外侧头端区神经元放电活动的影响

本研究旨在观察17β-雌二醇(E2)对雄性大鼠延髓腹外侧头端区(RVLM)神经元自发放电活动的影响.在切断双侧缓冲神经的麻醉雄性Sprague-Dawley大鼠上,同步记录血压、心率和RVLM神经元的自发放电活动.颈动脉内注射E2 (10 ng/kg),30个RVLM神经元自发放电单位中有25个单位的放电频率由14.46±0.47降至9.73±0.33 spikes/s (P<0.05),与此同时血压和心率无明显改变.E2的抑制效应在1 min内起效,持续时间长于5 min.雌激素受体拮抗剂tamoxifen (5 mg/kg)不能阻断E2 的抑制效应.预先给予一氧化氮(NO)合酶阻断剂L-NAME (2.7 μg/kg)能明显阻断E2的抑制效应.应用NO供体SIN-1 (0.5 μg/kg)可增强E2的抑制效应.以上结果提示,E2可通过非基因组效应激活RVLM神经元的NOS而引发NO释放,进而抑制其自发放电活动.     

中枢血管紧张素对心血管活动调节作用

血管紧张素(Ang)广泛存在于中枢神经系统和外周组织中,对心血管活动和交感神经活动起重要调节作用。本文介绍了孤束核(NTS)、延髓头端腹侧区(RVLM)、延髓尾端腹侧区(CVLM)和室旁核(PVN)内Ang对心血管活动的影响,Ang对动脉压力感受性反射(ABR)和心交感传入反射(CSAR)的调节作用,肾素-血管紧张素系统的基因敲除研究,以及Ang与高血压和慢性心力衰竭的关系。     

延髓头端腹外侧区血管紧张素Ⅱ对脊髓投射神经元氨基酸递质释放的调节

用脊髓(T8)中间外侧柱(IML)微透析方法结合高效液相色谱(HPLC)技术,研究延髓头端腹外侧区(RVLM)微量注射血管紧张素Ⅱ(ANGⅡ,100pmol,n=11)后脊髓IML氨基酸递质释放的变化.在RVLM区微量注射ANGⅡ(100pmol,n=11),能显著增加(P<0.01)脊髓(T8)内天门冬氨酸(ASP,从4.75±1.01升至8.90±2.28pmol/20μl)和谷氨酸(GLU,从18.99±8.64升至73.88±29.26pmol/20μl)的释放.在同一RVLM部位注射losartan(10nmol,n=8)可以显著抑制注射ANGⅡ引起的GLU释放升高反应(P<0.05).免疫荧光双标记结合共聚焦显微镜观察到RVLM内62%～91%的谷氨酸能神经元呈AT1受体免疫阳性.此结果提示ANGⅡ诱发的脊髓内谷氨酸释放可能来源于RVLM内AT1受体免疫阳性的谷氨酸能脊髓投射神经元.     

内皮素受体拮抗剂波生坦通过降低肾交感神经活性改善间歇性低氧大鼠的高血压

本文旨在观察内皮素受体拮抗剂波生坦对慢性间歇性低氧(chronic intermittent hypoxia,CIH)暴露大鼠血压和肾交感神经活性(renal sympathetic nerve activity,RSNA)的影响,探讨内皮素-1(endothelin-1,ET-1)参与CIH诱发血压升高的交感神经兴奋性机制。24只成年雄性SD大鼠随机分为常氧对照组、CIH组及波生坦组;对照组大鼠暴露于常氧环境,CIH组与波生坦组大鼠暴露于CIH环境3周,其中波生坦组在每天CIH暴露前给予波生坦灌胃(50 mg/kg)。采用BP-2000血压分析系统测定尾动脉收缩压,采用Power Lab信号采集系统记录RSNA以及对苯肾上腺素的压力感受性反射敏感性,采用ELISA法测定大鼠血清中ET-1和去甲肾上腺素(norepinephrine,NE)的含量。结果显示:大鼠血压随CIH暴露时间延长而逐渐升高,在第7、14和21天与对照组相比均具有统计学差异;CIH暴露显著增强大鼠的RSNA,抑制压力感受性反射的敏感性;此外,CIH大鼠血压与血清中ET-1水平呈正相关(r=0.833,P=0.01)。波生坦干预明显降低CIH暴露大鼠的收缩压和RSNA,提高压力感受性反射敏感性,降低血清NE水平。上述结果提示,ET-1参与了CIH诱发血压升高的过程,而波生坦通过降低RSNA改善了CIH诱导的高血压。     

ANG II in the paraventricular nucleus potentiates the cardiac sympathetic afferent reflex in rats with heart failure.

Chronic heart failure (CHF) is characterized by sympathoexcitation, and the cardiac sympathetic afferent reflex (CSAR) is a sympathoexcitatory reflex. Our previous studies have shown that the CSAR was enhanced in CHF. In addition, central angiotensin II (ANG II) is an important modulator of this reflex. This study was performed to determine whether the CSAR evoked by stimulation of cardiac sympathetic afferent nerves (CSAN) in rats with coronary ligation-induced CHF is enhanced by ANG II in the paraventricular nucleus (PVN). Under alpha-chloralose and urethane anesthesia, renal sympathetic nerve activity (RSNA) was recorded. The RSNA responses to electrical stimulation (5, 10, 20, and 30 Hz) of the CSAN were evaluated. Bilateral microinjection of the AT1-receptor antagonist losartan (50 nmol) into the PVN had no significant effects in the sham group, but it abolished the enhanced RSNA response to stimulation in the CHF group. Unilateral microinjection of three doses of ANG II (0.03, 0.3, and 3 nmol) into the PVN resulted in dose-related increases in the RSNA responses to stimulation. Although ANG II also potentiated the RSNA response to electrical stimulation in sham rats, the RSNA responses to stimulation after ANG II into the PVN in rats with CHF were much greater than in sham rats. The effects of ANG II were prevented by pretreatment with losartan into the PVN in CHF rats. These results suggest that the central gain of the CSAR is enhanced in rats with coronary ligation-induced CHF and that ANG II in the PVN augments the CSAR evoked by CSAN, which is mediated by the central angiotensin AT1 receptors in rats with CHF.     

Cardiac sympathetic afferent stimulation augments the arterial chemoreceptor reflex in anesthetized rats.

Chronic heart failure (CHF) is well known to be associated with both an enhanced chemoreceptor reflex and an augmented cardiac "sympathetic afferent reflex" (CSAR). The augmentation of the CSAR may play an important role in the enhanced chemoreceptor reflex in the CHF state because the same central areas are involved in the sympathetic outputs of both reflexes. We determined whether chemical and electrical stimulation of the CSAR augments chemoreceptor reflex function in normal rats. Under anesthesia, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. The chemoreceptor reflex was tested by unilateral intra-carotid artery bolus injection of potassium cyanide (KCN) and nicotine. We found that 1) left ventricular epicardial application of capsaicin increased the pressor responses and the RSNA responses to chemoreflex activation induced by both KCN and nicotine; 2) when the central end of the left cardiac sympathetic nerve was electrically stimulated, both the pressor and the RSNA responses to chemoreflex activation induced by KCN were increased; 3) pretreatment with intracerebroventricular injection of losartan (500 nmol) completely prevented the enhanced chemoreceptor reflex induced by electrical stimulation of the cardiac sympathetic nerve; and 4) bilateral microinjection of losartan (250 pmol) into the nucleus tractus solitarii (NTS) completely abolished the enhanced chemoreceptor reflex by epicardial application of capsaicin. These results suggest that both the chemical and electrical stimulation of the CSAR augments chemoreceptor reflex and that central ANG II, specially located in the NTS, plays a major role in these reflex interactions.     

Inhibition of cardiac sympathetic afferent reflex and sympathetic activity by baroreceptor and vagal afferent inputs in chronic heart failure

Background

Cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic activation and angiotensin II (Ang II) in paraventricular nucleus (PVN) augments the CSAR in vagotomized (VT) and baroreceptor denervated (BD) rats with chronic heart failure (CHF). This study was designed to determine whether it is true in intact (INT) rats with CHF and to determine the effects of cardiac and baroreceptor afferents on the CSAR and sympathetic activity in CHF.

Methodology/Principal Findings

Sham-operated (Sham) or coronary ligation-induced CHF rats were respectively subjected to BD+VT, VT, cardiac sympathetic denervation (CSD) or INT. Under anesthesia, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded, and the CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Either CSAR or the responses of RSNA, MAP and CSAR to Ang II in PVN were enhanced in CHF rats treated with BD+VT, VT or INT. Treatment with VT or BD+VT potentiated the CSAR and the CSAR responses to Ang II in both Sham and CHF rats. Treatment with CSD reversed the capsaicin-induced RSNA and MAP changes and the CSAR responses to Ang II in both Sham and CHF rats, and reduced the RSNA and MAP responses to Ang II only in CHF rats.

Conclusions

The CSAR and the CSAR responses to Ang II in PVN are enhanced in intact CHF rats. Baroreceptor and vagal afferent activities inhibit CSAR and the CSAR responses to Ang II in intact Sham and CHF rats.     

Hydrogen Sulfide in Paraventricular Nucleus Enhances Sympathetic Activity and Cardiac Sympathetic Afferent Reflex in Chronic Heart Failure Rats

Background

Intracerebroventricular infusion of NaHS, a hydrogen sulfide (H₂S) donor, increased mean arterial pressure (MAP). This study was designed to determine the roles of H₂S in the paraventricular nucleus (PVN) in modulating sympathetic activity and cardiac sympathetic afferent reflex (CSAR) in chronic heart failure (CHF).

Methodology/Principal Findings

CHF was induced by left descending coronary artery ligation in rats. Renal sympathetic nerve activity (RSNA) and MAP were recorded under anesthesia. CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. PVN microinjection of low doses of a H₂S donor, GYY4137 (0.01 and 0.1 nmol), had no significant effects on RSNA, MAP and CSAR. High doses of GYY4137 (1, 2 and 4 nmol) increased baseline RSNA, MAP and heart rate (HR), and enhanced CSAR. The effects were greater in CHF rats than sham-operated rats. A cystathionine-β-synthase (CBS) inhibitor, hydroxylamine (HA) in PVN had no significant effect on the RSNA, MAP and CSAR. CBS activity and H₂S level in the PVN were decreased in CHF rats. No significant difference in CBS level in PVN was found between sham-operated rats and CHF rats. Stimulation of cardiac sympathetic afferents with capsaicin decreased CBS activity and H₂S level in the PVN in both sham-operated rats and CHF rats.

Conclusions

Exogenous H₂S in PVN increases RSNA, MAP and HR, and enhances CSAR. The effects are greater in CHF rats than those in sham-operated rats. Endogenous H₂S in PVN is not responsible for the sympathetic activation and enhanced CSAR in CHF rats.     

Superoxide anions in the paraventricular nucleus mediate the enhanced cardiac sympathetic afferent reflex and sympathetic activity in renovascular hypertensive rats

An enhanced cardiac sympathetic afferent reflex (CSAR) is involved in the sympathetic activation in renovascular hypertension. The present study was designed to determine the role of superoxide anions in the paraventricular nucleus (PVN) in mediating the enhanced CSAR and sympathetic activity in renovascular hypertension in the two-kidney, one-clip (2K1C) model. Sinoaortic denervation and vagotomy were carried out, and renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded under anesthesia. The CSAR was evaluated by the response of RSNA to the epicardial application of capsaicin. Superoxide anion levels and NAD(P)H oxidase activity in the PVN increased in 2K1C rats and were much higher in 2K1C rats than in sham-operated (sham) rats after the epicardial application of capsaicin or PVN microinjection of ANG II. In both 2K1C and sham rats, PVN microinjection of the superoxide anion scavenger tempol or the NAD(P)H oxidase inhibitor apocynin abolished the CSAR, whereas the SOD inhibitor diethyldithiocarbamic acid (DETC) potentiated the CSAR. Tempol and apocynin decreased but DETC increased baseline RSNA and MAP. ANG II in the PVN caused larger responses of the CSAR, baseline RSNA, and baseline MAP in 2K1C rats than in sham rats. The effects of ANG II were abolished by pretreatment with tempol or apocynin in both 2K1C and sham rats and augmented by DETC in the PVN in 2K1C rats. These results indicate that superoxide anions in the PVN mediate the CSAR and the effects of ANG II in the PVN. Increased superoxide anions in the PVN contribute to the enhanced CSAR and sympathetic activity in renovascular hypertension.     

Intermedin in the Paraventricular Nucleus Attenuates Cardiac Sympathetic Afferent Reflex in Chronic Heart Failure Rats

Background and Aim

Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide (CGRP) family together with adrenomedullin (AM) and amylin. It has a wide distribution in the central nervous system (CNS) especially in hypothalamic paraventricular nucleus (PVN). Cardiac sympathetic afferent reflex (CSAR) is enhanced in chronic heart failure (CHF) rats. The aim of this study is to determine the effect of IMD in the PVN on CSAR and its related mechanisms in CHF rats.

Methodology/Principal Findings

Rats were subjected to left descending coronary artery ligation to induce CHF or sham-operation (Sham). Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were recorded. CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Acute experiments were carried out 8 weeks after coronary ligation or sham surgery under anesthesia. IMD and angiotensin II (Ang II) levels in the PVN were up-regulated in CHF rats. Bilateral PVN microinjection of IMD caused greater decreases in CSAR and the baseline RSNA and MAP in CHF rats than those in Sham rats. The decrease of CSAR caused by IMD was prevented by pretreatment with AM receptor antagonist AM22-52, but not CGRP receptor antagonist CGRP8-37. Ang II in the PVN significantly enhanced CSAR and superoxide anions level, which was inhibited by PVN pretreatment with IMD or tempol (a superoxide anions scavenger) in Sham and CHF rats.

Conclusion

IMD in the PVN inhibits CSAR via AM receptor, and attenuates the effects of Ang II on CSAR and superoxide anions level in CHF rats. PVN superoxide anions involve in the effect of IMD on attenuating Ang II-induced CSAR response.     

Microinjection of ANG II into paraventricular nucleus enhances cardiac sympathetic afferent reflex in rats

The aims of present study were to determine whether angiotensin II (ANG II) in the paraventricular nucleus (PVN) is involved in the central integration of the cardiac sympathetic afferent reflex and whether this effect is mediated by the ANG type 1 (AT(1)) receptor. While the animals were under alpha-chloralose and urethane anesthesia, mean arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) were recorded in sinoaortic-denervated and cervical-vagotomized rats. A cannula was inserted into the left PVN for microinjection of ANG II. The cardiac sympathetic afferent reflex was tested by electrical stimulation (5, 10, 20, and 30 Hz in 10 V and 1 ms) of the afferent cardiac sympathetic nerves or epicardial application of bradykinin (BK) (0.04 and 0.4 microg in 2 microl). Microinjection of ANG II (0.03, 0.3, and 3 nmol) into the PVN resulted in dose-related increases in the RSNA responses to electrical stimulation. The percent change of RSNA response to 20- and 30-Hz stimulation increased significantly at the highest dose of ANG II (3 nmol). The effects of ANG II were prevented by pretreatment with losartan (50 nmol) into the PVN. Microinjection of ANG II (0.3 nmol) into the PVN significantly enhanced the RSNA responses to epicardial application of BK, which was abolished by pretreatment with losartan (50 nmol) into the PVN. These results suggest that exogenous ANG II in the PVN augments the cardiac sympathetic afferent reflex evoked by both electrical stimulation of cardiac sympathetic afferent nerves and epicardial application of BK. These central effects of ANG II are mediated by AT(1) receptors.     

Involvement of enhanced cardiac sympathetic afferent reflex in sympathetic activation in early stage of diabetes

Cardiac sympathetic afferent reflex (CSAR) is involved in sympathetic activation. The present study was designed to investigate the contribution of enhanced CSAR to sympathetic activation in the early stage of diabetes and the involvement of AT(1) receptors in the paraventricular nucleus (PVN). Diabetes was induced by a single intravenous injection of streptozotocin in rats. Acute experiments were carried out under anesthesia after 3 wk. The CSAR was evaluated by the responses of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) to epicardial application of capsaicin or bradykinin. Sympathetic activity and CSAR were enhanced in diabetic rats. Plasma norepinephrine and angiotensin II were increased, but the transient receptor potential vanilloid 1 (TRPV1) in the left ventricle wall was not significantly increased in diabetic rats. Pericardial injection of resiniferatoxin to desensitize cardiac afferents or PVN microinjection of lidocaine attenuated the CSAR and decreased the RSNA and MAP in diabetic rats. The AT(1) receptor expression in the PVN increased in diabetic rats. Angiotensin II in the PVN caused greater increases in the RSNA and MAP and enhancement in the CSAR in diabetic rats, which were abolished by the losartan pretreatment. Losartan decreased the RSNA and MAP and attenuated the CSAR in diabetic rats but not in control rats. These results indicate that the CSAR is enhanced in the early stage of diabetic rats, which contributes to the sympathetic activation. AT(1) receptors in the PVN are involved in the enhanced CSAR in diabetic rats.     

Endothelin-1 in paraventricular nucleus modulates cardiac sympathetic afferent reflex and sympathetic activity in rats

Background

Cardiac sympathetic afferent reflex (CSAR) is a positive-feedback, sympathoexcitatory reflex. Paraventricular nucleus (PVN) is an important component of the central neurocircuitry of the CSAR. The present study is designed to determine whether endothelin-1 (ET-1) in the PVN modulates the CSAR and sympathetic activity, and whether superoxide anions are involved in modulating the effects of ET-1 in the PVN in rats.

Methodology/Principal Findings

In anaesthetized Sprague–Dawley rats with cervical vagotomy and sinoaortic denervation, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. The CSAR was evaluated by the responses of the RSNA and MAP to epicardial application of capsaicin. Microinjection of ET-1 into the bilateral PVN dose-dependently enhanced the CSAR, increased the baseline RSNA and MAP. The effects of ET-1 were blocked by PVN pretreatment with the ET_A receptor antagonist BQ-123. However, BQ-123 alone had no significant effects on the CSAR, the baseline RSNA and MAP. Bilateral PVN pretreatment with either superoxide anion scavenger tempol or polyethylene glycol-superoxide dismutase (PEG-SOD) inhibited the effects of ET-1 on the CSAR, RSNA and MAP. Microinjection of ET-1 into the PVN increased the superoxide anion level in the PVN, which was abolished by PVN pretreatment with BQ-123. Epicardial application of capsaicin increased superoxide anion level in PVN which was further enhanced by PVN pretreatment with ET-1.

Conclusions

Exogenous activation of ET_A receptors with ET-1 in the PVN enhances the CSAR, increases RSNA and MAP. Superoxide anions in PVN are involved in the effects of ET-1 in the PVN.