Endogenous Norepinephrine Desensitizes α1D-Adrenoceptors in Cultured Rat Aorta

Desensitization is a process characterized by the loss of cellular response to an agonist when this is present for a long time. α1D-adrenergic receptor (α1D-AR) desensitization is important since this receptor is involved in the contraction of large caliber arteries, such as the aorta. The aim of this research was to evaluate the desensitization of α1D-AR due to the endogenous release of norepinephrine in cultured rat aorta. Wistar rat aorta was incubated for 2 h or 24 h in DMEM at 37°C, and then subjected to isometric tension and the action of added norepinephrine, in concentration-response curve (CRC). In some experiments, BMY-7378 (α1D-AR antagonist) or 5-methylurapidil (α1A-AR antagonist) was used to identify the α1-AR involved in the response, or BMY-7378 to protect the α1D-AR from desensitization. Results showed that α1D-AR was desensitized when the aorta was incubated for 24 h, since the CRC to exogenous norepinephrine showed lower maximal contraction and the curve was displaced to the right, indicating that the receptor involved in contraction was not the α1D-AR, as compared to the aorta incubated 2 h. The receptor stimulated by norepinephrine at 24 h was neither the α1A-AR, as shown by the lack of displacement of the curve by 5-methylurapidil, but rather it seems that α1B-AR is inducing contraction. When the aorta was incubated with BMY-7378 for 24 h, the α1D-AR antagonist protected the receptor from desensitization. Endogenous norepinephrine desensitizes α1D-AR in the cultured aorta, and the α1D-AR is protected by BMY-7378.

Norepinephrine transporter (NET) is expressed in cardiac sympathetic ganglia of adult rat

The sympathetic nervous system plays a cardinal role in regulating cardiac function through releasing the neurotransmitter norepinephrine (NE). In comparison with central nervous system, the molecular mechanism of NE uptake in myocardium is not clear. In present study, we proved that in rat the CNS type of NE transporter (NET) was also expressed in middle cervical-stellate ganglion complex (MC-SG complex) which is considered to control the activity of heart, but not expressed in myocardium. The results also showed that NET expression level in right ganglion was significantly higher than in the left, rendering the greater capacity of NE uptake in right ventricle, a fact which may contribute to the maintenance of right ventricular function under pathologic state.

The norepinephrine transporter gene is associated with the retardation symptoms of major depressive disorder in the Han Chinese population

The norepinephrine transporter plays an important role in the pathophysiology and pharmacological treatment of major depressive disorder. Consequently, the norepinephrine transporter gene is an attractive candidate in major depressive disorder research. In the present study, we evaluated the depression symptoms of subjects with major depressive disorder, who were all from the North of China and of Hart Chinese origin, using the Hamilton Depression Scale. We examined the relationship between two single nucleotide polymorphisms in the norepinephrine transporter, rs2242446 and rs5569, and the retardation symptoms of major depressive disorder using quantitative trait testing with the UNPHASED program, rs5569 was associated with depressed mood, and the GG genotype may be a risk factor for this; rs2242446 was associated with work and interest, and the TT genotype may be a risk factor for loss of interest. Our findings suggest that rs2242446 and rs5569 in the norepinephrine transporter gene are associated with the retardation symptoms of depression in the Hart Chinese population.

Effects of electro-acupuncture on brain tissue norepinephrine contents in a morphine withdrawal anxiety mouse model

BACKGROUND： Following morphine withdrawal, anxiety is associated with abnormal norepinephrine content change. However, increasing blood lactic acid content can induce anxiety or panic in patients with anxiety disorder or endogenous opioid peptide functional disorder. OBJECTIVE： This study was designed to observe the effects of electro-acupuncture, at the ＂Sanyinjiao＂ point （SP 6）, on brain tissue norepinephrine and blood lactic acid content in anxiety-model mice after morphine withdrawal. DESIGN： A randomized controlled animal experiment. SETTING： This study was performed in the Laboratory of Acupuncture, Electro-acupuncture ＆ Tuina College, Chengdu University of Traditional Chinese Medicine, from June to September 2001. MATERIALS： A total of 50 healthy Kunming male mice were provided by the Laboratory Animal Center of Chengdu University of Traditional Chinese Medicine. The protocol was performed in accordance with ethical guidelines stated in the Guide for the use and care of laboratory animals, approved by the Committee on the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources Commission on Life Sciences, National Research Council, China （1985）. Experimental reagents and equipment used were as follows： morphine hydrochloride （Lot No. 930503, Shenyang No.1 Pharmaceutical Factory, China）, norepinephrine （Sigma Chemical Company, USA）, fluorospectrophotometer （RF-510, Shimadzu Corporation, Japan）, Han electro-acupuncture apparatus （WQ 1002, No. zun （91）-227270-588, Beijing Anlong Photoelectricity-Technique Company, China）, and T-maze （self-made）. METHODS： A total of 50 mice were randomly divided into 5 groups, with 10 mice in each group： blank control, T-maze, model, model ＋ electro-acupuncture, and electro-acupuncture groups. Establishment of anxiety model after morphine withdrawal： the mouse hot plate assay was used to detect the activity of morphine. The median effective dose of morphine, 2.95 mg/kg, was defined as the base. Mice were subcutaneously administered morphine, 3 times a day, for 4 days successively （initially 2.95 mg/kg, then increased day by day, as described below）. Interventions： In the model ＋ electro-acupuncture group, after model induction, mice were subjected electro-acupuncture at bilateral ＂Sanyinjiao＂ （SP6） points using a Han electro-acupuncture apparatus with sparse-dense waves and frequency of 2-100 Hz, once a day, for 6 days. In the model group, after anxiety-model induction, mice were subjected to fixation as same as model ＋ electro-acupuncture group within 6 days of model induction. In the electro-acupuncture group, the anxiety model was not induced and mice were subjected to fixation, electro-acupuncture and the T-maze test. In the T-maze group, the anxiety model was not induced and mice were subjected to fixation. The T-maze test was performed in the 4 groups after experiment. In the blank control group, the anxiety model was not induced and mice were subjected to fixation only. MAIN OUTCOME MEASURES： Brain tissue norepinephrine content of morphine-withdrawal anxiety mice was detected by fluorospectrophotometry after 6 days of electro-acupuncture. Blood lactic acid content was detected by visible spectrophotometry. RESULTS： A total of 50 mice were included in the final analysis. Brain norepinephrine content was significantly greater in the model group compared to the T-maze, blank control, electro-acupuncture and model ＋ electro-acupuncture groups, （P 〈 0.05-0.01）. Brain norepinephrine content was similar between the model ＋ electro-acupuncture and the blank control groups （P 〉 0.05）. There was no significant difference in blood lactic acid content among the groups （P 〉 0.05）. CONCLUSION： Electro-acupuncture lowers brain norepinephrine content but does not influence peripheral blood lactic acid content in morphine-withdrawn, anxiety-modeled mice. These results demonstrate that anxiety-inhibiting effects of electro-acupuncture, after morphine withdrawal, might be related to regulation of norepinephrine release.

Biochemical properties of norepinephrine as a kind of neurotransmitter secreted by bone marrow-derived neural stem cells induced and differentiated in vitro

BACKGROUND： It has been proved by many experimental studies from the aspects of morphology and immunocytochemistry in recent years that bone marrow stromal cells （BMSCs） can in vitro induce and differentiate into the cells possessing the properties of nerve cells. But the functions of BMSCs-derived neural stem cells（NSCs） and the differentiated neuron-like cells are still unclear. OBJECTIVE： To observe whether bone marrow-derived NSCs can secrete norepinephrine （NE） under the condition of in vitro culture, induce and differentiation, and analyze the biochemical properties of BMSCs-derived NSCs. DESIGN： A non-randomized and controlled experimental observation SETTING ： Institute of Neuromedicine of Chinese PLA, Zhujiang Hospital, Southern Medical University MATERIALS： This experiment was carried out in the Institute of Neuromedicine of Chinese PLA, Zhujiang Hospital, Southern Medical University. The bone marrow used in the experiment was collected from 1.5- month-old healthy New Zealand white rabbits. METHODS： This experiment was carried out in the Institute of Neuromedicine of Chinese PLA, Zhujiang Hospital, Southern Medical University. The bone marrow used in the experiment was collected from 1.5 month-old healthy New Zealand white rabbits. BMSCs of rabbits were isolated and performed in vitro culture, induce and differentiation with culture medium of NSCs and differentiation-inducing factor, then identified with immunocytochemical method. Experimental grouping： ①Negative control group： L-02 hepatic cell and RPMI1640 culture medium were used. ② Background culture group： Only culture medium of NSCs as culture solution was added into BMSCs to perform culture, and 0.1 volume fraction of imported fetal bovine serum was supplemented 72 hours later. ③Differentiation inducing factor group： After culture for 72 hours, retinoic acid and glial cell line-derived neurotrophic factors were added in the culture medium of BMSCs and NSCs as corresponding inducing factors. The level of NE in each group was detected on the day of culture and 5, 7, 14 and 20 days after culture with high performance liquid chromatography （HPLC）. The procedure was conducted 3 times in each group.Standard working curve was made according to the corresponding relationship of NE concentration and peak area. The concentration of NE every 1×10^7 cells was calculated according to standard curve and cell counting. MAIN OUTCOME MEASURES ： The level of NE of cultured cells was detected with HPLC; immunocytochemistrical identification of Nestin and neuron specific nuclear protein was performed. RESULTS： ① On the 14^th day after cell culture, BMSCs turned into magnus and round cells which presented Nestin-positive antigen, then changed into neuron-like cells with long processus and presented neuron specific nuclear protein -positive antigen at the 20^th day following culture. ② The ratio of NE concentration and peak area has good linear relationship, and regression equation was Y=1.168 36＋0.000 272 8X,r=-0.998 4. Coefficient variation （CV） was 〈 5% and the recovery rate was 92.39%（ Y referred to concentration and X was peak area）.③NE was well detached within 10 minutes under the condition of this experiment. ④ NE was detected in NSCs and their culture mediums, which were cultured for 7, 14 and 20 days respectively, but no NE in BMSCs, NSCs-free culture medium and L-02 hepatic cell which were as negative control under the HPLC examination. Analysis of variance showed that the level of NE gradually increased following the elongation of culture time （P 〈 0.01 ）. No significant difference in the level of NE existed at the same time between differentiation inducing factor group and basic culture group（P 〉 0.05）. CONCLUSION ： BMSCs of rabbits can proliferate in vitro and express Nestin antigen; They can differentiate into neuron-like cells, express specific neucleoprotein of mature neurons, synthesize and secrete NE as a kind of neurotransmitter.

Clinical trials comparing norepinephrine with vasopressin in patients with septic shock:A meta-analysis

Background: To compare the mortality rates and benefits of norepinephrine and vasopressin in patients with septic shock. Methods: PubMed, EMBASE, and the Cochrane Library database were searched from database inception to December 2013. We selected randomized controlled trials in adults with septic shock and compared norepinephrine with vasopressin. After assessing the heterogeneity of treatment effects across trials using the I2 statistic, we used a fixed effects model(P≥0.1) and expressed the results as risk ratios(RRs) for dichotomous outcomes or as standardized mean differences(SMDs) for continuous data with 95% confidence intervals(CIs). Meta-analysis was conducted using Review Manager 5.1 software.Results: Seven trials(n=2323) met the inclusion criteria. Overall, the mortality rate in these seven trials was 36.2%(840/2323). There was no difference in mortality following the use of norepinephrine or vasopressin(RR 1.07; 95%CI 0.97-1.20; P=0.19). Compared to norepinephrine, vasopressin had no significant effect on heart rate(HR)(SMD 0.21; 95%CI-0.08-0.50; P=0.15), mean arterial pressure(MAP)(SMD 0.15; 95%CI-0.15-0.44; P=0.33), cardiac index(CI)(SMD-0.10; 95%CI-0.64-0.44; P=0.73), systemic vascular resistance index(SVRI)(SMD 0.15; 95%CI-0.39-0.70; P=0.58), oxygen delivery(DO2)(SMD-0.06; 95%CI-0.62-0.49; P=0.82), oxygen consumption(VO2)(SMD 0.03; 95%CI-0.52-0.59; P=0.91) or lactic acid(SMD 0.07; 95%CI-0.23-0.36; P=0.66). No significant heterogeneity was found in these comparisons(P≥0.1).Conclusions: There is not sufficient evidence to prove conclusively that norepinephrine is superior to vasopressin in terms of mortality and hemodynamics. The effects of norepinephrine and vasopressin on patients with septic shock require further study in large randomized controlled trials.

Effect of Higher Mean Arterial Pressure with Norepinephrine on Tissue Oxygenation and Perfusion in Patients of Septic Shock

The current survival sepsis guideline proposes the use of vasopressors and fluid resuscitation to maintain the mean arterial pressure (MAP) ≥ 65 mmHg. Titrating catecholamine infusion to achieve higher MAP has been demonstrated to improve tissue oxygenation, microcirculation, renal function and overall outcome of the patient in some studies and literature on actual hemodynamic goals is scarce. AIM: To study the influence of two MAP on tissue oxygenation and perfusion parameters in patients of septic shock on norepinephrine infusion. SUBJECT AND MATERIALS: Forty adult patients with the diagnosis of septic shock were enrolled. In all patients norepinephrine was titrated to first stabilize the MAP at 65 ± 5 mmHg (Set I), followed by MAP of 85 ± 5 mmHg (Set II). Heart rate (HR), Central venous oxygen saturation (SCVO2), Transcutaneous partial pressure of oxygen (PtcO2) by TCM 400/TINA (using miniature Clark electrode), Arterial partial pressure of oxygen(PaO2), PtO2/PaO2 ratio, Urine output and Serum Base deficit were recorded in each Set after 2 hrs of stabilization. RESULTS: There was a significant increase in transcutaneous partial pressure of oxygen PtcO2 (p tO2/PaO2 (p < 0.0001), ScvO2 (p < 0.0001), urine output (p < 0.006) on increasing the MAP from 65mmHg to 85mmHg. Serum base deficit also improved (p < 0.0001). CONCLUSION: Higher MAP with norepinephrine is associated with better perfusion, oxygenation parameters in patients with established septic shock. These findings suggest that there is improvement in tissue oxygenation parameters using escalating doses of norepinephrine to achieve higher MAP without inherent adverse

Effect of the Melatonin on Morning Blood Pressure Surge and Norepinephrine Endovenous Infusion in Healthy Volunteers

Melatonin, the pineal gland hormone, has been considered as a central hypotension factor. However their roles in the regulation of the human blood pressure and its possible use as antihyper-tensive drug have not been fully determined. The objective of this trial was to determine the effect of melatonin on blood pressure morning increase and a peripheral vasoconstriction challenge in healthy volunteers. Twelve healthy male volunteers were included in a prospective, comparative, randomized, crossover trial in which changes on blood pressure (BP) and heart rate (HR) after the first morning orthostatism and endovenous norepinephrine (NE) infusion were measured one hour after the administration of placebo (PL) or 10 mg of melatonin in double blind conditions. Melatonin blunted the effects of the first orthostatism on BP and HR. Melatonin also reduces the pressor effect of NA. One concludes that melatonin has central and peripheral hypotensive effects that support a potential role of this hormone in cardiovascular therapeutics.

Sympathetic stimulation with norepinephrine may come at a cost

Norepinephrine(NE;also known as noradrenaline)is the body’s primary adrenergic neurotransmitter which belongs to the catecholamine family.Norepinephrine has pharmacologic effects on theα1(Suita et al.,2015),α2(Schwartz,1997),β1,β2 andβ3(Tsukada et al.,2003)adrenoceptors.In the brain,norepinephrine increases arousal and alertness,promotes vigilance,enhances formation and retrieval of memory,and focuses attention.It also increases restlessness and anxiety.In the remainder of the body,norepinephrine increases heart rate and blood pressure,triggers the release of glucose from energy stores,increases blood flow to skeletal muscle and increases muscle contraction,reduces blood flow to the gastrointestinal system and its motility and lastly,inhibits voiding of the bladder(Goldstein,2010).This last point is particularly interesting in the context of this perspective piece.

Val 70, Phe 72 and the last seven amino acid residues of C-terminal are essential to the function of norepinephrine transporter

The norepinephrine transporter(NET) is a member of the Na+/Cl- dependent neurotransmitter transporter family and constitutes the target of several clinically important antidepressants. To delineate the critical amino acid residues and the function of C-terminal in regulating transport activity of NET, here we constructed two site mutants (V70F, F72V; V70I, F72V) and one C-terminal truncated mutant (△611-617). The wild type and mutants of NET were expressed in Xenopus oocytes by injection of their cRNA. We found that all of these mutants lost their transport activity. These results indicate that the amino acid residues of V70 and F72 3 and the last seven amino acids of C-terminal are essential to the transport activity of NET.

Effects of 5-HT and norepinephrine on the neuronal activities of the nucleus tractus solitarii in medullary slices

The relationship between 5-HT receptor and α-adrenoceptor was investigated inrat medullary slice preparations.In 57 nucleus tractus solitarii(NTS)neurons,47(82.5%)responded to both serotonin(5-HT)and norepinephrine(NE).After synapse transmissionwas blocked by perfusion of artificial cerebrospinal fluid(ACSF)with low calcium andhigh magnesium,5 in 8 neurons were still sensitive to both 5-HT and NE.On the otherhand,3 in 5 neurons responding only to 5-HT or NA were sensitive to both 5-HT andNE after the synapse transmission blockage.In some neurons which exhibited excitatoryor inhibitory responses to 5-HT or NE alone,the responses were inversed when perfusedwith 5-HT and NE in combination.These results suggest that there may exist aninhibitory interaction between 5-HT receptors and α-adrenoceptors in NTS and that most5-HT and α-adrenoceptors coexist in the same NTS neurons.

Effects of norepinephrine on dorsomedial hypothalamic nucleus of rat before and after synaptic blockade

Extracellular discharges of neurons in the dorsomedial nucleus（DMN）were recordedwith glass microelectrode from rat hypothalamic slices.The firing frequency decreased in 77 andincreased in 48 units during the addition of norepinephrine into the bath(NE,2×10-5 mol/L)of160 units when the slices were perfused with artificial cerebrospinal fluid （ACSF）.Most of theseresponses could be antagonized by Yohimbine(YOH,2×10-5～4×10-5 mol/L).Nevertheless,when the perfusion fluid was changed,i.e.,with low Ca2+-high Mg2+ ACSF（CM-ACSF）whichcould block the chemical synaptic transmission,26 out of 35 units were inhibited by NE and only1 unit excited.The inhibition could he blocked by YOH. A very significant difference（P【0.01）was seen between the data obtained in ACSF and those in CM-ACSF.Furthermore,all NE-inhibited units in ACSF were also NE-inhibited in CM-ACSF,but the majority of NE-excited u-nits in ACSF changed into NE-inhibited or NE-unresponsive in CM-ACSF.The results suggestedthat NE produced a direct inhibitory effect on neurons in DMN which was mediated by the post-synaptic alpha 2 adrenergic receptors.

Effects of Testosterone on Norepinephrine Release in Isolated Rat Heart

The effects of testosterone on norepinephrine release were investigated in the isolated rat hearts.Sprague-Dawley male rats (n=120) were randomized to testosterone and control groups.The rats in testosterone group were perfused with modified Krebs-Henseleit buffer containing different concentrations of testosterone (0.1,1.0,10.0,and 100.0 nmol/L,respectively).Myocardial ischemia was induced by globally stopping the perfusion flow.Exocytotic norepinephrine release was induced by electrical field stimulation at 5 V (effective voltage) and 6 Hz (pulse width of 2 ms) for 1 min.The overflow of norepinephrine was determined by high pressure liquid chromatography and electrochemical detec-tion (HPLC-EC).Following acute ischemia,testosterone (1.0,10.0 and 100.0 nmol/L) significantly re-duced norepinephrine release (P<0.01),and the norepinepherine overflow was similar between the con-trol and 0.1 nmol/L testosterone group (P>0.05).Electrical stimulation of the ventricle evoked norepi-nepherine release,and this was diminished by the perfusion with testosterone at the concentrations of 1.0,10.0 and 100.0 nmol/L (P<0.01).It is suggested that testosterone suppresses ischemia-and electri-cal stimulationinduced norepinepherine release in the isolated rat hearts.

Effects of Norepinephrine on Renal Cortical and Medullary Blood Flow in Atherosclerotic Rabbits

Objective The aim of this study was to explore the effect of norepinephrine(NE)on renal cortical and medullary blood flow in atherosclerotic rabbits without renal artery stenosis.Methods Atherosclerosis was induced in 21 New Zealand white rabbits by feeding them a cholesterol-rich diet for 16 weeks.Thirteen healthy New Zealand white rabbits were randomly selected as controls.After atherosclerosis induction,standard ultrasonography was performed to confirm that there was no plaque or accelerated flow at the origin of the renal artery.Contrast-enhanced ultrasound(CEUS)was performed at baseline and during intravenous injection of NE.The degree of contrast enhancement of renal cortex and medulla after the injection of contrast agents was quantified by calculating the enhanced intensity.Results The serum nitric oxide(NO)level in atherosclerotic rabbits was higher than that in healthy rabbits(299.6±152 vs.136.5±49.5,P<0.001).The infusion of NE induced a significant increase in the systolic blood pressure(112±14 mmHg vs.84±9 mmHg,P=0.016)and a significant decrease in the enhanced intensity in renal cortex(17.78±2.07 dB vs.21.19±2.03 dB,P<0.001)and renal medulla(14.87±1.82 dB vs.17.14±1.89 dB,P<0.001)during CEUS.However,the enhanced intensity in the cortex and medulla of healthy rabbits after NE infusion showed no significant difference from that at baseline.Conclusion NE may reduce renal cortical and medullary blood flow in atherosclerotic rabbits without renal artery stenosis,partly by reducing the serum NO level.

Analysis of the 5' flanking sequence of the human norepinephrine transporter gene

The human norepinephrine transporter(NET) gene was cloned and structurally analyzed. The far 5’ fragment containing exon 1 (a non-coding exon) and exon 2 was sequenced. The transcription start site of the gene in human brain stem tissue was determined by primer extension analysis. It was found that the gene could be transcribed from multiple starting points. The 5’ flanking sequence contains a proximal G-C rich region, one possible GSG elemeflt and several SP1 sites. However it does not contain TATA box and CAAT box motifS. Gel shift analysis with nuclear extracts from different tissues of mouse shows that the G-C rich region may be involved in tissue specific expression of the gene.

Mechanisms of Depressor Effect of Norepinephrine Injected into Subnucleus Commissuriu of Nucleus Solitarius Tractus in Rabbits

This experiment aimed to investigate the effect of adrenergic system in the subnucleus commissuriu of nucleus solitrius tractus (CNTS) on renal nerve discharges. Norepinephrine (NE) was microinjected into the CNTS of rabbits and mean arterial blood pressure (MAP) and renal nerve discharges (FRND) were synchronously recorded. The results indicated that (1) microinjection of norepinephine into the CNTS of rabbit could significantly attenuate the frequency of renal nerve discharge, and at the same time decrease markedly the mean arterial pressure. (2) Microinjection of 0.3 nmol yohimbin into CNTS had no significant influence on FRND and MAP, but could attenuate and even reverse the effects of NE on FRND and MAP. These results suggest that microinjection of NE into CNTS may activate the alpha-adrenorecptor located in CNTS and secondarily produce a depressor effect by attenuating the activity of peripheral sympathetic nervous system.

Molecular cloning and structural analysis of human norepinephrine transporter gene(NETHG)

A cDNA molecule encoding a major part of the hu-man Norepinephrine transporter(hNET) was synthesized by means of Polymerase Chain Reaction(PCR) technique and used as a probe for selecting the human genomic NET gene. A positive clone harbouring the whole gene was ob-tained from a human lymphocyte genomic library through utilizing the "genomic walking" technique. The clone, des-ignated as phNET, harbours a DNA fragment of about 59 kb in length inserted into BamH Ⅰ site in cosmid pWE15.The genomic clone contains 14 exons encoding all amino acid residues in the protein. A single exon encodes a dis-tinct transmembrane domaill, except for transmembrane domain 10 and 11, which are encoded by part of two ex-ons respectively, and exon 12, which encodes part of do-main 11 and all of domain 12. These results imply that there is a close relationship between exon splicing of a gene and structural domains of the protein, as is the case for the human γ-aminobutyric acid transporter(hGAT) and a number of other membrane proteins.

Unmasking lower gastrointestinal bleeding under administration of norepinephrine

BACKGROUND Bleeding in the gastrointestinal tract is common and transarterial embolization enables the clinician to control gastrointestinal bleeding.Contrast extravasation is a prerequisite for successful embolization.Provocative angiography is helpful in the detection of elusive bleeding.AIM We performed a retrospective analysis of angiographic treatment in patients with lower gastrointestinal hemorrhage and initially negative angiographies,as well as the role of norepinephrine(NE)in unmasking bleeding.METHODS We analyzed 41 patients with lower gastrointestinal bleeding after angiography who had undergone treatment over a period of 10 years.All patients had a positive shock index and needed intensive care.RESULTS In three of four patients,angiography disclosed the site of bleeding when NE was used during the procedure for hemodynamic stabilization.CONCLUSION We suggest that angiography performed after the administration of NE in unstable patients with gastrointestinal bleeding and an initially negative angiography has the potential to unmask bleeding sites for successful embolization.However,this statement must be confirmed in prospective studies.

Kinetics of Norepinephrine- and Serotonin-Induced BDNF Release in Cultured Embryonic Hippocampal Neurons

The primary neurotransmitters targeted by currently used antidepressants, such as duloxetine, venlafaxine and fluoxetine, are serotonin and norepinephrine, which also are released in significant amounts in the central nervous system in response to sympathetic nervous system activation. In cultured hippocampal neurons, we have previously shown that norepinephrine induces increased expression of brain-derived neurotrophic factor (BDNF), the PI-3 K/Akt, MAPK pro-survival pathways, the BDNF receptor, TrkB, a transcription factor, and cyclic AMP response element binding protein (CREB). In the present study, we extend these findings of increased BDNF expression to its kinetics of release into the surrounding media. We also evaluate these two cell survival pathways, TrkB and CREB, in response to application of serotonin and/or norepinephrine. Serotonin elicits an earlier, but brief expression and release of BDNF, whereas norepinephrine elicits a more delayed and sustained release of BDNF. In response to both norepinephrine and 5-HT, the presence of BDNF in lysates and subsequent release into the media is significantly increased out to 4 h, as is PI-3 K/Akt activation. Together, these two neurotransmitters increase BDNF expression and release covering the entire 8 h continuum evaluated. The results of this study provide further evidence for a G protein-coupled receptor and a crosstalk-to-TrkB receptor with transactivation signaling across pathways.

Changes of norepinephrine and tumor necrosis factor in submandibular gland of rats with sympathetic nerve injury and the protective effect of 17 beta-estradiol

BACKGROUND： Recent researches have indicated that estrogen has extensive neuroprotective effects. So some studies designed ovariectomized animal models and administrated with estrogen, so as to verify its neuroprotective effects. OBJECTIVE： To observe the effect of 17 beta-estradiol on the content of norepinephrine （NE） and level of tumor necrosis factor （TNF） in submandibular glands of rats with sympathetic nerve injury, and analyze the dose-dependence and pathway of action. DESIGN： A randomized control animal study SETTINGS： Department of Hand Surgery, the 252 Hospital of Chinese PLA; Department of Hand Surgery Union Hospital affiliated to Tongji Medical College, Huazhong University of Science and Technology. MATERIALS： Fifty healthy female Wistar rats were randomly divided into 5 groups with 10 rats in each group： sham-operated group, ovariectomy＋6-OHDA＋saline group, ovariectomy＋6-OHDA＋17β-estradiol 50, 200 and 500 μg/kg groups. METHODS： The experiments were carried out in Tongji Medical College, Huazhong University of Science and Technology between October 2005 and March 2006. Bilateral ovaries were only exposed but not resected for the rats in the sham-operated group, but bilateral ovaries were resected in all the other groups. In the ovariectomy＋6-OHDA＋176-estradiol 50, 200 and 500 μg/kg groups, the rats were administrated with intraperitoneal injection of 6-OHDA （8 mg/kg）, and then immediately given 176-estradiol of corresponding dosages respectively, once a day for 10 days continuously. Rats in the sham-operated group and ovariectomy＋6-OHDA＋saline group were administrated with saline of the same volume. After administration, 5 rats in each group were killed to determine the NE contents in bilateral submandibular glands with high performance liquid chromatography-electrochemical detector （HPLC-ECD）, and the other 5 rats were used to determine the TNF levels in submandibular glands with enzyme-linked immunosorbant assay. MAIN OUTCOME MEASURES： The NE contents and TNF levels in submandibular glands of rats in each group were observed. RESULTS： All the 50 rats were involved in the analysis of results. （1） The NE content was obviously lower in the ovariectomy＋6-OHDA＋saline group than in the sham-operated group [（1 035±196）, （1 823±314） ng/g, P 〈 0.05], there were no significant differences between the ovariectomy＋6-OHDA＋17β-estradiol 50 μg/kg group and ovariectomy＋6-OHDA＋saline group [（1 004±253）, （1 035±196） ng/g, P 〉 0.05], but obviously higher in the ovariectomy＋6-OHDA＋17β-estradiol 200 and 500 μg/kg groups than in the ovariectomy＋6-OHDA＋saline group [（1 487±268）, （1 939±274）, （1 035±196） ng/g, P 〈 0.05]. （2） The TNF level was obviously higher in the ovariectomy＋6-OHDA＋saline group than in the sham-operated group [（3.498±0.792）, （1.893±0.533） ng/g, P 〈 0.05], there were no significant differences between the ovariectomy＋ 6-OHDA＋17β-estradiol 50 μg/kg group and ovariectomy＋6-OHDA＋saline group [（3.328 ±0.712）, （3.498±0,792） ng/g, P 〉 0.05], but obviously lower in the ovariectomy＋6-OHDA＋17β-estradiol 200 and 500 μg/kg groups than in the ovariectomy＋6-OHDA＋saline group [（2.639±0.438）, （2.016±0.619）, （3.498＋0.792） ng/g, P 〈 0.05]. CONCLUSION： Estrogen has obvious protective effect dose-dependently on 6-OHDA induced chemical sympathetic nerve terminal injury in rats, and it may play its protective role by reducing TNF level and ameliorating inflammatory reaction.