血浆多种神经肽与缺血性脑血管病相关性研究

目的 :探讨血浆多种神经肽在缺血性脑血管病中的作用。方法 :采用放射免疫法检测 112例不同类型缺血性脑血管病患者血浆降钙素基因相关肽 (CGRP)、内皮素 (ET)、心房利钠肽 (ANP)、神经肽 Y(NPY)、神经降压肽(NT)水平。结果 :急性脑梗死 CGRP、 NT较对照组降低 (P<0 .0 5 ) ,ET、 ANP、 NPY均较对照组升高 (P<0 .0 1) ,病情重者较轻者变化更显著 (P<0 .0 1) ,椎动脉供血不足组 CGRP、 ET、 ANP、 NPY均较对照组升高 (P<0 .0 1) ,脑动脉硬化组 ET较对照组升高 ,NT较对照组降低 (P<0 .0 5 ) ,其他神经肽变化不显著。结论 :神经肽参与了缺血性脑血管病病理生理过程 ,其改变可作为早期判断缺血性脑血管病严重程度指标之一     

急性脑梗死后血浆NO、NOS、ET含量的动态变化及尼莫地平对其影响

目的　观察急性脑梗死 (ACI)后血浆一氧化氮 (NO)、一氧化氮合成酶 (NOS)、内皮素 (ET)含量的动态变化 ,以及尼莫地平治疗后对其影响。方法　ACI患者 110例 ,随机分成尼莫地平组 (5 0例 ) (在常规治疗基础上用尼莫地平 )和常规治疗组 (6 0例 )。在发病后不同时点动态观察血浆NO、NOS、ET含量 ,并设 5 0例脑动脉硬化患者为对照组。结果　脑梗死后血浆ET含量显著升高 ,直至恢复期 ;NO、NOS先增高后下降 ;尼莫地平组和常规组比较ET有显著差异 (P <0 .0 1) ,NO、NOS差别不显著 (P >0 .0 5 )。结论　NO、NOS、ET参与并影响了ACI后复杂的病理生理过程 ;尼莫地平部分通过对ET含量的影响发挥其对脑梗死的治疗作用     

长期饮酒脑缺血大鼠血浆NPY、CGRP、ET含量的测定

目的 探讨长期饮酒对脑缺血大鼠血浆中神经肽Y(NPY)、降钙素基因相关肽(CGRP)、内皮素(ET)含量的影响。方法 选用180～200g雄性Wistar大鼠50只，分为饮水组与饮酒组，饮酒组以7．2％酒精喂养100d，制作长期饮酒模型，后将两组用线拴法制作脑缺血模型，在缺血前、缺血1h、3h、6h分别取血，用放免法测定NPY、CGRP、ET。结果 各时间段饮酒组NPY含量明显高于饮水组P％0．05，缺血3h时，两组血浆NPY含量明显升高，于6h逐渐下降；各时间段饮酒组CGRP均低于饮水组P％0．01，饮水组于缺血3h、饮酒组于缺血1h时，血浆中CGRP明显下降；饮酒组血浆ET于缺血前及缺血1h明显高于饮水组P％0．05，饮水组于缺血3h、饮酒组于缺血1h血浆ET明显升高。结论 脑梗死超早期伴有血浆NPY、CGRP、ET的动态改变，长期饮酒可加重这些变化．增加血浆中缩血管物质的含量减少舒血管物质的含量，进一步减少脑部血液供应。     

缺血性脑卒中患者血浆内皮素和血浆降钙素基因相关肽的研究

目的探讨血浆内皮素(ET)和血浆降钙素基因相关肽(CGRP)在缺血性脑卒中损伤过程中的变化.方法应用放射免疫分析法测定血浆ET和CGRP水平.结果脑梗死患者的血浆ET明显高于对照组(P＜0.05～0.01),脑梗死患者血浆CGRP明显低于对照组(P＜0.01).结论 ET和CGRP与缺血性脑血管病的病理改变有密切关系.     

不同病期脑梗死患者血浆脂酰氢过氧化物和维生素E水平的变化

目的　探讨血浆脂质过氧化物与抗氧化物在缺血性脑梗死不同病期的变化及其意义。方法　采用紫外及可见分光光度法测定 4 8例脑梗死不同病期患者血浆脂酰氢过氧化物 (AHP)和维生素E的含量并与正常人比较。结果　脑梗死急性期组患者 (19例 )血浆AHP水平显著升高 ,血浆维生素E水平显著降低 ,与正常对照组比较差异均有显著性 (P <0 0 1,P <0 0 5 ) ;恢复期组患者 (17例 )血浆AHP水平明显下降 ,与急性期组比较差异有显著性 (P <0 0 1) ,而血浆维生素E水平未见明显回升 ;后遗症期组 (12例 )患者血浆AHP水平与恢复期组比较差异无显著性 (P >0 0 5 ) ,血浆维生素E水平与急性期组比较无显著提高 (P >0 0 5 )。结论　对缺血性脑梗死患者应常规监测血中过氧化脂质及抗氧化物含量 ,抗氧化治疗可能有利于脑梗死患者的康复和预防脑卒中的复发。     

急性颅脑损伤患者TNF、ET及CGRP含量变化及意义

目的本文旨在探讨急性颅脑损伤患者血浆和脑脊液中肿瘤坏死因子（TNF）、内皮素（ET）、降钙素基因相关肽（CGRP）的变化与临床意义。方法49例急性颅脑损伤患者和31例正常对照组，采用放射免疫分析法（RIA）动态测定血浆及脑脊液TNF、ET、CGRP含量，比较颅脑损伤组和对照组中TNF、ET、CGRP的变化。结果颅脑损伤患者急性期血浆及脑脊液TNF、ET含量显著升高；CGRP含量显著降低，且与伤情轻重程度明显相关；TNF、ET与CGRP呈负相关，TNF、ET与CGRP在血浆及脑脊液中具有相似的变化趋势。结论血浆及脑脊液TNF、ET水平增高和CGRP水平降低可能是急性颅脑损伤继发性病理生理损害的重要因素之一；TNF及ET受体拈抗剂可成为治疗颅脑损伤的有效途径；血浆及脑脊液TNF、ET、CGRP动态含量，可作为判断急性颅脑损伤患者预后的重要指标。     

急性脑血管病患者血浆t-PA、PAI-1水平的临床意义研究

目的 探讨急性脑血管病患者血浆组织型纤溶酶原激活物（tissue-type plasminogen activator,t-PA）及纤溶酶原激活物抑制剂-1（plasminogen activator inhibitor-1,PAI-1）抗原含量的变化规律。方法 运用酶联免疫吸附法（enzyme-linked immunosorbent assay,ELISA）法测定2007年10月至2008年9月78例急性脑出血、脑梗死和短暂性脑缺血发作（transient ischemic attack,TIA）患者血浆t-PA及PAI-1抗原含量水平,并与同期22例健康对照组进行比较。结果 与对照组比较,脑出血组血浆t-PA水平明显升高、PAI-1水平降低（P均<0.001）;脑梗死组血浆t-PA及PAI-1水平均较对照组明显升高（P均<0.001）;TIA组血浆t-PA水平低于对照组（P=0.006）,PAI-1水平升高（P<0.001）。结论 急性脑血管病患者存在纤溶活性的异常。     

依达拉奉对高血压脑出血患者SPECT、血浆ET、CGRP的影响

目的观察依达拉奉对高血压脑出血患者SPECT值、血浆ET、CGRP的影响,探讨依达拉奉治疗脑出血可能的机制。方法采用SPECT、放射免疫法分别对依达拉奉治疗组40例和常规治疗组40例及正常对照组30例的脑血流值,血浆ET、CGRP值进行检测分析。结果①入院时(0d)依达拉奉治疗组与常规组SPECT、ET、CGRP值比较,P>0.05,差异无统计学意义。②入院后(1、3、5d)依达拉奉治疗组与常规组SPECT、ET、CGRP值比较,P<0.05;常规组与正常对照组比较,P<0.01。差异有统计学意义。③ET与SPECT显著负相关(0.05水平);CGRP与SPECT显著正相关(0.01或0.05水平);ET与CGRP显著负相关(0.05水平)。结论依达拉奉通过降低血浆ET值,升高CGRP及SPECT值,对对高血压脑出血导致的脑损伤有一定保护作用。     

急性脑卒中并多脏器功能衰竭患者NO和SOD测定的临床意义

目的 :通过检测急性脑卒中和卒中并多脏器功能衰竭 (MOF)患者一氧化氮 (NO)及超氧化物歧化酶(SOD) ,以了解自由基对上述疾病变化和预后的临床意义。方法 :分别测定 2 8例脑出血 ,2 6例脑梗死 ,30例急性脑卒中并MOF及 2 5例健康者对照组血浆NO及SOD含量。结果 :急性脑出血、脑梗死组、卒中并MOF组血浆NO明显高于对照组 (P <0 0 1) ,SOD明显低于对照组 (P <0 0 1) ,卒中并MOF死亡组NO含量明显高于存活组 ,SOD明显低于存活组。结论 :氧自由基参与急性脑卒中和急性脑卒中并MOF的病理生理过程 ,故血中NO及SOD的动态变化可作为判断病情发展及预后的指标     

亚低温治疗对蛛网膜下腔出血继发性血管痉挛及脑脊液和血浆内皮素、降钙素基因相关肽的影响

目的 探讨亚低温治疗对蛛网膜下腔出血(SAH)继发性血管痉挛及脑脊液和血浆内皮素(ET)、降钙素基因相关肽(CGRP)水平的影响.方法 56例SAH患者随机分成亚低温组和对照组,两组在常规治疗的基础上,亚低温组增加局部亚低温治疗;检测两组入院时及治疗7 d、14 d脑脊液和血浆ET、CGRP水平,并比较两组脑血管痉挛的发病情况.结果 (1)脑脊液、血浆ET水平治疗7 d时亚低温组较对照组显著降低(均P＜0.05);14 d时差异更显著(均P＜0.01);两组CGRP水平治疗第7 d时降至最低,后渐升高,亚低温组较对照组变化幅度小,差异有统计学意义(P＜0.05～0.01).(2)亚低温组脑血管痉挛发病率为6.67%,较对照组的30.77%明显减少(P＜0.05).结论 亚低温治疗减少了SAH患者脑脊液和血浆中ET水平上升幅度及CGRP水平下降幅度,从而降低脑血管痉挛的发生率.     

Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V(1a), V(1b) and V(2) receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V(1b) receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V(1a) agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V(2) /V(1a) antagonist, conivaptan and the V(2) antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V(1a), V(1b) and V(2) antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.     

The incretin hormones GIP and GLP-1 in diabetic rats: effects on insulin secretion and small bowel motility

Abstract  Incretin hormones often display inhibitory actions on gut motility. The aim of this study was to investigate if altered responsiveness to glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) as regards insulin release and small bowel motility could bring further clarity to the pathophysiology of diabetes in the Goto-Kakizaki (GK) rat. The isolated perfused pancreas was studied in male GK and Wistar rats (controls) under euglycemic and hyperglycemic conditions. Glucose-dependent insulinotropic peptide (10 nmol L⁻¹) or GLP-1 (10 nmol L⁻¹) were added to the medium and perfusate was collected and analysed for insulin. Moreover, GK and Wistar rats were supplied with bipolar electrodes in the small bowel and myoelectric activity was recorded during intravenous administration of GIP (1–400 pmol kg⁻¹ min⁻¹) or GLP-1 (0.1–20 pmol kg⁻¹ min⁻¹). Finally, tissue was collected from GK and Wistar rats for RNA extraction. Under euglycemia, GIP and GLP-1 stimulated the initial insulin response by 10-fold in GK rats ( P  < 0.05). At later hyperglycemia, the insulin response to GIP and GLP-1 was blunted to about one-third compared with controls ( P  < 0.05). In the bowel GLP-1 was about 2.6–16.7 times more potent than GIP in abolishing the migrating myoelectric complex in the GK and control rats. Polymerase chain reaction (PCR) showed GIP and GLP-1 receptor gene expression in pancreatic islets and in small bowel. The initially high, but later low insulin responsiveness to stimulation with GIP and GLP-1 along with inhibition of small bowel motility in the GK rat indicates a preserved incretin response on motility in diabetes type 2.     

Effects of bombesin and gastrin-releasing peptide on memory processing

We have previously shown that feeding mice immediately following training enhances memory retention and that one of the gastrointestinal hormones released during a meal, cholecystokinin, also enhances retention after peripheral administration. In the studies reported here we demonstrate that another gastrointestinal peptide, gastrin-releasing peptide (GRP), enhances retention after peripheral administration, as does its amphibian counterpart, bombesin. GRP_14–27 had the same effect as the intact peptide, while GRP_1–16 was ineffective at enhancing retention. The dose-response curves showed a characteristic inverted U-shape with high doses of both GRP and bombesin being amnestic. The effect of both peptides was time-dependent and both reversed amnesia induced by the anticholinergic, scopolamine. I.c.v. administration of the peptides required higher doses to produce an effect on memory retention. suggesting that the effect was mediated predominantly through a peripheral mechanism. Doses of the peptides that enhanced memory retention after peripheral administration failed to increase serum glucose, suggesting that glucose modulation was not the mechanism by which GRP and bombesin modulate memory processing. Vagotomy inhibited the memory-enhancing effects of both GRP and bombesin, suggesting that these peptides produced their effect by stimulating ascending vagal pathways. These studies, together with our previous study with cholecystokinin, suggest the existence of a gastrointestinal hormonal system, which is activated by the passage of food through the intestine, that enhances memory retention.     

Comparative distribution of bombesin/GRP- and substance-P-like immunoreactivities in rat hypothalamus

Immunohistochemical localization of bombesin/gastrin-releasing peptide ( GRP )-like immunoreactivity (BN/ GRP -LI) and substance P-like immunoreactivity (SP-LI) in consecutive sections of rat hypothalamus was studied. Bombesin/ GRP -like immunoreactivity in the hypothalamus was partially characterized by gel filtration chromatography followed by radioimmunoassay. In the hypothalamus, SP-LI was more widely distributed than BN/ GRP -LI. Only the anterior and medial parvocellular parts of the nucleus paraventricularis and the nucleus suprachiasmaticus contained numerous cell bodies which exhibited BN/ GRP -LI. Neurons in these areas did not exhibit SP-LI. In contrast, cell bodies exhibiting SP-LI were numerous in the nucleus preopticus medialis and lateralis, nucleus anterior, nucleus ventromedialis and dorsomedialis, nucleus lateralis, nucleus arcuatus, and nucleus premamillaris ventralis and dorsalis. Only occasional cell bodies in these areas exhibited BN/ GRP -LI. It is concluded that the neuronal systems in the hypothalamus containing BN/ GRP -LI and SP-LI are separate, though the terminal fields in many areas overlap. Two peaks of BN/ GRP -LI were detected after gel filtration chromatography from extracts of the rat nucleus paraventricularis. The high molecular weight form coeluted with synthetic GRP (1-27), and the small molecular weight form eluted after synthetic bombesin. Thus, the endogenous BN/ GRP -LI is probably not authentic bombesin.     

Localization of natriuretic peptide-activated guanylate cyclase mRNAs in the rat brain

Physiological actions of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are elaborated by membrane-bound natriuretic peptide receptors (NPRs). These receptors possess intracellular guanylate cyclase domains that mobilize cyclic guanosine monophosphate upon binding of peptide. Two distinct NPR subtypes have been described in brain: the NPR-A selectively binds ANP, whereas NPR-B exhibits high affinity for CNP. To define further the potential domains of ANP and CNP action in brain, the present study used in situ hybridization histochemistry to map NPR-A and NPR-B mRNA-expressing cell populations. Significant levels of neuronal NPR-A mRNA expression were observed only in the mitral cell layer of the olfactory bulb, medial habenula, subfornical organ, and area postrema. Expression of NPR-A mRNA was observed in forebrain white matter tracts, suggesting synthesis in glial cells. In contrast, NPR-B mRNA was widely expressed throughout the neuraxis. In the telencephalon, signal was abundant throughout limbic cortex and neocortex, olfactory bulb, hippocampus, and amygdala. Intense NPR-B mRNA hybridization was observed in preoptic-hypothalamic neuroendocrine circuits and in motor nuclei of cranial nerves. Intermediate expression of NPR-B mRNA was observed in brainstem nuclei controlling autonomic function. Labeling for NPR-B but not NPR-A mRNA was observed in pituicytes in the neural lobe of the pituitary and in scattered cells of the anterior pituitary. These results suggest that CNP is the primary biologically active natriuretic peptide in brain. In contrast with NPR-B, NPR-A appears to be expressed largely in restricted cell populations containing high levels of ANP and in circumventricular organs. These data implicate the NPR-A in autoregulation of ANP neurons and central registration of cardiac ANP release. © 1996 Wiley-Liss, Inc.     

Synchronised expressions of LPXRFamide peptide and its receptor genes: seasonal, diurnal and circadian changes during spawning period in grass puffer

Among the RFamide peptide family, the LPXRFamide peptide (LPXRFa) group regulates the release of various pituitary hormones and, recently, LPXRFa genes were found to be regulated by photoperiod via melatonin. As a first step towards investigating the role of LPXRFa on reproductive function in grass puffer (Takifugu niphobles), which spawns in semilunar cycles, genes encoding LPXRFa and its receptor (LPXRFa-R) were cloned, and seasonal, diurnal and circadian changes in their absolute amounts of mRNAs in the brain and pituitary were examined by quantitative real-time polymerase chain reaction. The grass puffer LPXRFa precursor contains two putative RFamide peptides and one possible RYamide peptide. LPXRFa and LPXRFa-R genes were extensively expressed in the diencephalon and pituitary. The expression levels of both genes were significantly elevated during the spawning periods in both sexes in the brain and pituitary, although they were low in the spawning fish just after releasing eggs and sperm. The treatment of primary pituitary cultures with goldfish LPXRFa increased the amounts of follicle-stimulating hormone β- and luteinising hormone β-subunit mRNAs. In the diencephalon, LPXRFa and LPXRFa-R genes showed synchronised diurnal and circadian variations with one peak at zeitgeber time 3 and circadian time 15, respectively. The correlated expression patterns of LPXRFa and LPXRFa-R genes in the diencephalon and pituitary and the possible stimulatory effects of LPXRFa on gonadotrophin subunit gene expression suggest the functional significance of the LPXRFa and LPXRFa-R system in the regulation of lunar-synchronised spawning of grass puffer.     

Secretion of natriuretic peptides caused by an epileptic attack

OBJECTIVE: To describe clinical features of a patient with secretions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) during an epileptic attack. PATIENT: A 65-year-old woman experienced frequent bouts of polyuria, pyrexia and general fatigue after several years of a cerebral contusion involving the left fronto-temporal lobe caused by a traffic accident. Her urine output and urinary sodium excretion increased, and plasma ANP and BNP concentrations were markedly high during each attack. Electroencephalography (EEG) showed serial seizure discharge in the left anterior temporal region during the attacks, indicative of epileptic focus. CONCLUSION: ANP and BNP secretions probably were triggered by epileptic stimulation on the diencephalon beyond the focus.     

The effects of aging and chronic fluoxetine treatment on circadian rhythms and suprachiasmatic nucleus expression of neuropeptide genes and 5‐HT1B receptors

Age‐related changes in circadian rhythms, including attenuation of photic phase shifts, are associated with changes in the central pacemaker in the suprachiasmatic nucleus (SCN). Aging decreases expression of mRNA for vasoactive intestinal peptide (VIP), a key neuropeptide for rhythm generation and photic phase shifts, and increases expression of serotonin transporters and 5‐HT_1B receptors, whose activation inhibits these phase shifts. Here we describe studies in hamsters showing that aging decreases SCN expression of mRNA for gastrin‐releasing peptide, which also modulates photic phase resetting. Because serotonin innervation trophically supports SCN VIP mRNA expression, and serotonin transporters decrease extracellular serotonin, we predicted that chronic administration of the serotonin‐selective reuptake inhibitor, fluoxetine, would attenuate the age‐related changes in SCN VIP mRNA expression and 5‐HT_1B receptors. In situ hybridization studies showed that fluoxetine treatment does not alter SCN VIP mRNA expression, in either age group, at zeitgeber time (ZT)6 or 13 (ZT12 corresponds to lights off). However, receptor autoradiographic studies showed that fluoxetine prevents the age‐related increase in SCN 5‐HT_1B receptors at ZT6, and decreases SCN 5‐HT_1B receptors in both ages at ZT13. Therefore, aging effects on SCN VIP mRNA and SCN 5‐HT_1B receptors are differentially regulated; the age‐related increase in serotonin transporter sites mediates the latter but not the former. The studies also showed that aging and chronic fluoxetine treatment decrease total daily wheel running without altering the phase of the circadian wheel running rhythm, in contrast to previous reports of phase resetting by acute fluoxetine treatment.     

Evaluation of the role for prolactin-releasing peptide in prolactin secretion induced by ether stress and suckling in the rat: comparison with vasoactive intestinal peptide

Prolactin (PRL)-releasing peptide (PrRP) is a recently discovered hypothalamic peptide possessing a specific stimulatory action on PRL secretion. In this study, we examined whether PrRP plays a role in mediating ether stress- and suckling-induced PRL secretion in rats through administering anti-PrRP antisera intracerebroventricularly. For comparison, we also tested the effect of anti-vasoactive intestinal peptide (VIP) antisera on the hormonal responses, since VIP is another candidate for a physiological PRL-releasing factor. The immunoneutralization of VIP, but not of PrRP, led to a significant suppression of PRL responses to both ether and suckling. These results suggest that PrRP may not play a significant role, or at least play a much weaker role than VIP, in mediating PRL release induced by ether stress and suckling in the rat.