清醒大鼠室旁核灌流谷氨酸受体阻断剂对压力感受性反射的影响

目的:探讨下丘脑室旁核(PVN)内谷氨酸参与压力感受性反射中枢调节的神经化学机制。方法:在清醒大鼠,用脑部微量透析法和高效液相色谱法观察静脉注射苯肾上腺素诱发压力感受性反射对PVN区谷氨酸含量的影响;NMDA受体阻断剂MK-801或非NMDA受体阻断剂CNQX直接灌流PVN区并诱发压力感受性反射,进一步探讨PVN区谷氨酸对压力感受性反射的作用。结果:①静脉注射苯肾上腺素诱发压力感受性反射时,PVN内的谷氨酸含量迅速升高到注射前的384.82%±91.77%(P<0.01)。②PVN区灌流谷氨酸受体阻断剂MK-801或CNQX,同时诱发压力感受性反射,其血压升值明显减少,心率降值明显增加(P<0.01),压力感受性反射的敏感性(△HR/△MAP)明显增加(P<0.01)。结论:PVN内的谷氨酸可能通过离子型谷氨酸受体参与压力感受性反射的中枢调节,而且此调节作用可能是抑制性的。     

心房钠尿肽的中枢性心血管和肾效应

在麻醉大鼠观察了颈动脉、脊髓蛛网膜下腔和侧脑室内注射心房钠尿肽(Atrial natri-uretic peptide,ANP)后,血压,心率或/和尿量、尿钠和尿钾的变化,并观察了 ANP 对血管紧张素Ⅱ(AGⅡ)中枢效应的影响。结果如下:(1)在大鼠头部交叉循环条件下,经受血鼠颈总动脉内注射α-人心房钠尿多肽(α-human atrial natriurctic polypeptide,α-hANP)(15μg/kg)后,受血鼠平均动脉压(MAP)无改变,而供血鼠的 MAP 降低,⊿MAP为-2.4±0.84kPa(-18±6.3mmHg,P<0.05),(2)脊髓蛛网膜下腔注射心房肽,Ⅱ(AtriopeptinⅡ,APⅡ)(5μg/kg)对血压、心率和尿量无明显影响;(3)侧脑室注射 APⅡ(20μg/kg)后血压和心率无显著改变,尿量仅在注射后第30至50min 时显著增加,而尿钠无改变;(4)侧脑室注射 AGⅡ(1μg/kg),血压升高,⊿MAP 为1.3±0.17kPa(10±1.3mmHg,n=10,P<0.001)。注射1h 后,尿量增加106%(P<0.01),尿钠增加642%(P<0.01);(5)事先侧脑室注射 APⅡ(20μg/kg),2min 后再注入 AGⅡ(1μg/kg),AGⅡ的中枢升压效应不受影响,⊿MAP为1.5±0.25kPa(11±1.9mmHg,n=7,P<0.01),而尿量和尿钠的增值明显减小。以上结果表明,ANP 难于透过血脑脑脊血屏障,可能与其分子量较大有关。在静脉注射 ANP 所致降压效应中,似无中枢机制的参与。ANP 对 AGⅡ     

侧脑室注射心房钠尿肽对大鼠室旁核单位放电的影响

本实验利用微电极技术在大鼠下丘脑共记录到118个自发放电单位,其中84个位于室旁核(PVN)内,34个位于 PVN 邻近部位。侧脑室注入心房钠尿肽(ANP)后,受其影响的 PVN神经元和 PVN 邻近部位神经元,分别有91%(P<0.005)和71%(P>0.05)表现为自发放电频率减少;侧脑室注入高渗 NaCl 溶液则分别使64.7%(P<0.005)和61.1%(P>0.05)的神经元自发放电频率增加。结果表明,侧脑室注入 ANP 对 PVN 神经元自发放电活动具有明显的抑制作用。     

大鼠侧脑室注射高渗盐水引起血压上升过程中心房钠尿肽和血管升压素的变化

为研究中枢渗透压刺激升压的机制,在大鼠侧脑室内给予高滲人工脑脊液,记录颈动脉压和心率变化,给药10min 后,用放射免疫法测定血浆、下丘脑和垂体中的心房钠尿肽和升压素。结果表明:中枢给予高渗人工脑脊液后,血浆中升压素水平明显增加,心房钠尿肽没有明显改变,下丘脑和垂体中的心房钠尿肽含量增加,而升压素含量下降。     

血管紧张素Ⅱ、心房钠尿肽Ⅲ和血管升压素对大鼠脑片室旁核神经元放电活动的影响

在28个脑片观察了血管紧张素Ⅱ(AGⅡ)、心房钠尿肽Ⅲ(ANPⅢ)和血管升压素(AVP)三种多肽对101个下丘脑室旁核(PVN)神经元单位电活动的影响。脑片灌流AGⅡ(10~(-7)mol/L,3 min)后,28/50个单位(56.0％)放电频率明显增加,5/50个单位(10.0％)放电频率降低,17/50个单位(34.0％)无明显反应。AGⅡ对PVN放电单位的兴奋和抑制作用均可为AGⅡ受体阻断剂saralasin(10~(-6)mol/L)所阻断。脑片灌流ANPⅢ(10~(-7)mol/L,3 min)后,16/26个单位(61.5％)放电频率明显降低,1/26个单位(3.9％)放电频率增加,9/26个单位(34.6％)无明显反应。脑片灌流AVP,(10~(-7)mol/L,3min)后,19/25个单位(76.0％)放电频率明显增加,1/25个单位(4.0％)放电频率降低,5/25个单位(20,0％)无明显反应。在观察这三种多肽对同一PVN神经元的作用时,4个单位对AGⅡ和AVP均产生兴奋反应;2个单位对AGⅡ呈兴奋和被ANPⅢ所抑制;7个单位对AVP呈兴奋,而对ANPⅢ为抑制,未见到既对AGⅡ和AVP呈兴奋,又为ANPⅢ所抑制的单位。结果提示:AGⅡ,ANP和AVP三种多肽都能影响PVN神经元的自发电活动,PVN可能是神经内分泌和植物性功能调节的中枢整合部位之一。     

中枢氧化应激抑制高血压大鼠压力感受性反射功能

目的:观察中枢氧化应激对压力反射功能的影响,探讨自发性高血压大鼠(SHR)压力反射敏感性降低的中枢机制。方法:24周龄雄性SHR和正常大鼠在乌拉坦和α-氯醛糖混合麻醉下,静脉注射苯肾上腺素(PE)和硝普钠(NP)诱发动脉压力感受性反射,以心率变化与血压变化的比值代表压力反射敏感性(BRS)。侧脑室给予超氧化物歧化酶(SOD)拟似剂tempol和SOD抑制剂DETC,检测给药前后BRS变化。结果:高血压大鼠BRS明显低于正常大鼠(P<0.01),侧脑室应用Tempol明显改善高血压大鼠BRS(P<0.05),但不影响正常大鼠BRS;而DETC则衰减两组大鼠BRS(P<0.05),对正常大鼠BRS抑制作用更明显。高血压大鼠下丘脑丙二醛(MDA)含量明显高于正常大鼠(P<0.01),但总抗氧化能力、总SOD、CuZn-SOD、过氧化物酶(CAT)等活性均明显低于正常大鼠(P<0.05)。结论:高血压大鼠压力反射功能减弱与中枢氧化应激有关,脑内抗氧化酶活性降低和抗氧化能力下降可能导致中枢氧化应激。     

一肾一包型高血压大鼠动脉压力反射敏感性的变化

本文用苯肾上腺素和硝普钠改变血压,同步记录心动周期,用平均动脉血压-心动周期关系为指标,研究了 Grollman一肾一包型肾性高血压大鼠动脉压力感受性反射敏感性(Ar-terial baroreflex sensitivity,ABS)的变化。实验分为三组:Grollman 高血压组,假手术组和正常组,手术后三周进行实验,结果如下:Grollman 高血压组的 ABS 明显低于假手术组(P<0.01);侧脑室注射150μg Captopril 后,Grollman 高血压组和假手术组的 MAP都下降,但 Grollman 组更明显(注射35 min 时,P<0.01 Fig.1),注射后35到60 min时,假手术组的 MAP 已趋稳定水平,而 Grollman 组仍有下降趋势。注射后60 min 时高血压组的 ABS 比注射前60 min 值明显增加,而假手术组的增加不明显(Fig.2)。此外向正常动物 i.v.c.注射8μg 血管紧张素Ⅱ,MAP 显著增加但 ABS 则显著下降。上述结果提示在Grollman 肾性高血压形成期,ABS 下降,这可能与中枢血管紧张素Ⅱ含量的增加有关。     

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。     

侧脑室注射Orexins对大鼠摄食的影响及机制

目的:探讨侧脑室注射orexins(食欲素)、NPY(神经肽Y)、MCH(黑色素聚集激素)和甘丙肽对大鼠摄食的影响及其机制。方法:将成年雄性Wistar大鼠随机分为对照组、侧脑室注射组和室旁核(PVN)注射组。通过套管将orexin-A、orexin-B、NPY、MCH和甘丙肽分别注射至侧脑室和PVN内,随后测量大鼠食物摄入量,并检测PVN、弓状核(ARC)和VMH内c-fos的表达。结果:与对照组比较,侧脑室注射NPY、MCH和orexin-B 2 h后,大鼠摄食量显著增多(P0.05)。相较于orexin-B和MCH,NPY对摄食的影响更显著(P0.05)。与NS对照组比较,侧脑室注射甘丙肽和orexin-A 1 h后,大鼠摄食量显著增多(P0.05)。与NS对照组比较,侧脑室注射orexin-A可显著增加c-fos在PVN和ARC中的表达,在VMH中效应较弱(P0.05)。与NS对照组比较,PVN注射NPY能显著增加大鼠2 h摄食量(P0.05),PVN注射orexin-A能显著增加大鼠2 h和4 h摄食量(P0.05)。结论:orexins与可促进大鼠摄食,此效应可能通过下丘脑参与摄食调控中枢PVN和ARC而实现的。     

心力衰竭状态下的动脉压力感受器反射

心力衰竭是以心脏泵血功能降低（心输出量减少）为始动因素的临床综合征。心输出量降低首先引起动脉压力感受性反射失负荷,进而通过迷走-交感机制加快心率;同时,支配血管床的交感传出活动增强,进而增加总外周阻力。本文主要论述在心力衰竭状态下压力感受性反射在循环功能异常调控中的作用机制。本综述及我们近年的研究表明：（1）在心力衰竭状态下压力感受性反射功能明显减弱;（2）中枢血管紧张素Ⅱ和活性氧在压力感受性反射功能失调中发挥关键作用;（3）心交感传入刺激和化学感受性反射能抑制压力感受性反射;（4）适当的运动可以部分纠正异常的心血管反射活动。     

Effect of a new V1 antagonist (OPC-21268) on vascular action of vasopressin in cultured rat vascular smooth muscle cells.

The effect of 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl-3,4-dihydro-2(1 H)- quinolinone) (OPC-21268) on vascular action of arginine vasopressin (AVP) was examined in cultured rat vascular smooth muscle cells (VSMC) by the measurement of cytosolic free calcium concentration [( Ca2+]i) and the AVP V1 receptor study. The preincubation of cells with OPC-21268 for 10 min inhibited the AVP-induced mobilization of [Ca2+]i in a dose-dependent manner but did not affect the angiotensin II-induced mobilization of [Ca2+]i. The receptor study revealed that OPC-21268 blocks the binding of AVP to the receptor in VSMC in a similar way to the V1 structural antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)-2-O-methyltyrosine]AVP: d(CH2)5Tyr(Me)AVP. Lineweaver-Burk plot showed that OPC-21268 is the competitive AVP V1 receptor antagonist. These results therefore indicate that OPC-21268 specifically blocks the vascular action of AVP mediated through the competitive inhibition of AVP binding to the receptors in VSMC.     

Key amino acids of vasopressin V1a receptor responsible for the species difference in the affinity of OPC-21268

A non-peptide, vasopressin V1a receptor-selective antagonist, OPC-21268, exhibited a markedly higher affinity for the rat V1a receptor (Ki = 380 nM) than for the human V1a receptor (Ki = 140 microM). To delineate the region responsible for the high affinity binding of OPC-21268 for the rat V1a receptor, we have constructed a series of chimeric human and rat V1a receptors, and examined the chimeric and point-mutated receptors by competitive radioligand binding analysis. The results showed that the transmembrane domain (TMD) VI-VII of the vasopressin V1a receptor, in particular the amino acid residue Ala-342 in TMD VII, is the major component conferring the rat-selective binding of OPC-21268 to the V1a receptor.     

V1-receptor mediated GSH efflux by vasopressin from rat hepatocytes.

Vasopression increases sinusoidal efflux of GSH in the perfused rat liver. The mechanism of this effect was studied in the perfused rat liver and in isolated rat hepatocytes. Vasopressin stimulated GSH efflux in both systems and a V1-receptor antagonist (OPC-21268) significantly inhibited the effect of vasopressin suggesting that vasopressin stimulates GSH efflux from rat hepatocytes via V1-receptor.     

Central interaction of the brain atrial natriuretic polypeptide (ANP) system and the brain renin-angiotensin system in ANP secretion from heart--evidence for possible brain-heart axis

To elucidate the involvement of the brain renin-angiotensin system and the brain atrial natriuretic polypeptide (ANP) system in the regulation of ANP secretion from the heart, the effects of intracerebroventricular administration of angiotensin II and ANP on the plasma ANP level were examined in conscious unrestrained rats. The intracerebroventricular administration of angiotensin II at doses of 100 ng and 1 microgram significantly enhanced ANP secretion induced by volume-loading with 3-mL saline infusion (peak values of the plasma ANP level: control, 220 +/- 57 pg/mL; 100 ng angiotensin II, 1110 +/- 320 pg/mL, p less than 0.01; 1 microgram angiotensin II, 1055 +/- 60 pg/mL, p less than 0.01). The intracerebroventricular injection of angiotensin II at the same doses alone had no significant effect on the basal plasma ANP level. The enhancing effect of central angiotensin II on ANP secretion induced by volume-loading was significantly attenuated by pretreatment with the intravenous administration of the V1-receptor antagonist of vasopressin or with the intracerebroventricular administration of phentolamine. The intracerebroventricular administration of alpha-rANP(4-28) (5 micrograms) had no significant influence on the basal plasma ANP level; however, it significantly attenuated central angiotensin II potentiating effect of volume-loading induced ANP secretion. These results indicate that the brain renin-angiotensin system regulates ANP secretion via the stimulation of vasopressin secretion and (or) via the activation of the central alpha-adrenergic neural pathway, and that the brain ANP system interacts with the brain renin-angiotensin system in the central modulation of ANP secretion from the heart.(ABSTRACT TRUNCATED AT 250 WORDS)     

Xylazine activates oxytocinergic but not vasopressinergic hypothalamic neurons under normal and hyperosmotic conditions in rats

Role of central alpha2-adrenoceptors in the regulation of hypothalamic magnocellular cells was studied under hyperosmotic challenge elicited by hypertonic saline (HS). Rats pretreated with receptor agonist, xylazine (XYL), were injected intraperitoneally with different (low: 0.375, moderate: 0.75, high: 1.5 M) HS 30 min later. The activity of the paraventricular (PVN) and supraoptic (SON) vasopressin and oxytocin perikarya was established by Fos-dual-immunohistochemistry 60 min after HS administration. Results showed that 1/XYL is a potent stimulus for oxytocin but not vasopressin magnocellular cells under basal and weak hyperosmotic conditions 2/highHS completely overlaps the effect of XYL. In addition, XYL partially suppressed Fos expression in the parvocellular PVN cells activated by highHS. The data suggest that alpha2-adrenoceptors may play an important role in the regulation of oxytocinergic PVN and SON neurons under basal and weak hyperosmotic conditions and that alpha2-adrenoceptors may also participate in the control of PVN parvocellular cells under intense osmotic challenge.     

Difference between intracarotid and intravenous infusions of angiotensin II on baroreflex sensitivity and vasopressin release in conscious rats

A carotid infusion of angiotensin (AII) (10 ng/kg/min) has been found to increase significantly higher mean arterial pressure (MAP) and produces significantly lower bradycardia than AII intravenous infusions at the same dose and rate. Besides, i.v. administration of AII elicits greater impairment on baroreflex sensitivity than carotid infusion of AII does. On the other hand, vasopressin vascular receptor blockade did not modify the baroreflex sensitivity either in the carotid or in the i.v. infusions of AII, and plasma AVP measurements did not change significantly in any group. It clearly indicates that neither AVP nor baroreflex impairment plays any role on the pressor action of AII intracarotid infusions at a low dose. The present results further suggest that baroreflex impairment in rats may unlikely be located in the region irrigated by the carotid artery.     

下丘脑室旁核加压素能神经元参与电针刺激对实验性...

It has been demonstrated in animal model of somatic pain that hypothalamic paraventricular nucleus (PVN) participates in acupuncture analgesia, probably by mediation of vasopressin release. The role of PVN in acupuncture analgesia for experimental visceral pain in rats was further investigated in the present study. Experimental results demonstrated that electroacupuncture could inhibit the writhing response, produced by intraperitoneal injection of antimonium potassium tartrate and this inhibitory effect could be enhanced by electrical stimulation of PVN, but decreased by electrolytical lesion of PVN, intracerebroventricular injection of vasopressin antiserum (14 microliters) or the vasopressin antagonist, d(CH2)5Tyr(Me)-AVP (500 ng/5 microliters). Intraperitoneal administration of the latter drug (10 micrograms/kg), however, was ineffective. The above experimental results suggest that vasopressinergic neurons in PVN also participate in the inhibition of visceral pain by electroacupuncture.     

Central effects of atrial natriuretic peptide on plasma catecholamines, vasopressin, renin and beta-endorphin and on renal excretory functions in the dog

Atrial natriuretic peptide (ANP) has been identified in the central nervous system and its participation in regulation of various regulatory brain functions has been postulated. To elucidate whether central ANP influences endocrine systems related to blood pressure regulation and renal excretory functions, effects of infusion of ANP at a rate of 120 ng.min-1 into the third cerebral ventricle on plasma level of epinephrine (E), norepinephrine (NE), renin, vasopressin and beta-endorphin as well as on excretion of urine, sodium, potassium (UKV) solutes and free water (CH2O) were investigated in conscious dogs. Significant decrease of plasma E from 77.6 +/- 7.0 to 62.1 +/- 4.8 pg.ml-1 and of NE from 345.5 +/- 20.7 to 286.4 +/- 15.0 pg.ml-1 was found at the end of 30 min lasting ANP infusion. Significant elevation of PRA and UKV and a decrease in CH2O were found 60 min after ANP infusion. No significant changes in other variables were found. In time control experiments plasma hormones concentration and renal excretory functions were not significantly influenced. The results suggest that central ANP may affect the sympatho-adrenal outflow.     

Clonidine and morphine increase atrial natriuretic peptide secretion in anesthetized rats

In order to determine whether the activity of central alpha 2-adrenergic and opioid receptors influence plasma atrial natriuretic peptide (ANP) levels, clonidine and morphine were infused into the lateral cerebral ventricle for 45 min in anesthetized Sprague-Dawley rats. The central administration of a low dose of clonidine (10 ng/min) caused a significant increase in plasma ANP without changing arterial blood pressure or central venous pressure. Pretreatment with yohimbine (5 micrograms/min) completely blocked the effect of clonidine. Central infusion of morphine (100 ng/min) also elevated plasma ANP levels and naloxone (5 micrograms/min) blunted this effect. Intravenous infusion of the same dose of clonidine or morphine did not affect plasma ANP levels. Moreover, the effect of clonidine on plasma ANP was partially blocked by pretreatment with naloxone (5 micrograms/min). These results suggest that central alpha 2-adrenergic and opioid receptors may be involved in ANP secretion.     

Inhibition of sympathetic responses at birth in sheep by lesion of the paraventricular nucleus

Birth is characterized by a surge in sympathetic outflow, heart rate (HR), mean arterial blood pressure (MABP) and circulating catecholamines. The paraventricular nucleus (PVN) of the hypothalamus is an important central regulatory site of sympathetic activity, but its role in the regulation of sympathoexcitation at birth is unknown. To test the hypothesis that the PVN regulates sympathetic activity at birth, experiments were performed in chronically instrumented near-term (137- to 142-day gestation, term 145 days) sheep before and after delivery by cesarean section. Stereotaxic guided electrolytic lesioning of the PVN (n = 6) or sham lesioning (n = 6) was performed 48 h before study. At 30 min after birth, renal sympathetic nerve activity (RSNA) increased 128 +/- 26% above fetal values in the sham-lesioned animals (P < 0.05). In contrast, at a similar time point, RSNA decreased to 52 +/- 12% of the fetal value in the PVN-lesioned animals. Lesioning of the PVN did not affect the usual postnatal increases in MABP and epinephrine levels although HR failed to rise above fetal values. ANG II but not arginine vasopressin or norepinephrine levels increased in PVN-lesioned animals after birth, whereas all three hormones increased (P < 0.05) in sham-lesioned animals. Fetal and newborn HR baroreflex responses were similar in both groups. However, the usual postnatal attenuation of baroreflex-mediated inhibition of RSNA was blunted in the PVN-lesioned group. The results of this study demonstrate that ablation of the PVN abolishes sympathoexcitation with birth at near-term gestation. The PVN may play a critical role in physiological adaptation at birth.