Modification of the noradrenergic cyclic AMP generating system in the rat limbic forebrain by amphetamine: Role of its hydroxylated metabolites

Summary The cyclic AMP responses to norepinephrine (NE) in slices of the rat limbic forebrain after the administration of (S)-amphetamine and the role of its para- and -hydroxylated metabolites were investigated. The chronic but not acute administration of (S)-amphetamine to rats causes a significant reduction in the sensitivity of the cyclic AMP generating system to NE without changing the basal level of the nucleotide. This change in the sensitivity of the system is not associated with a change in the EC₅₀ value for NE but reflects mainly a decrease in the maximal response. After withdrawal of the drug, the cyclic AMP response to NE returned to control values within 4 days. In vitro, (S)-p-hydroxyamphetamine (POH) and all stereoisomers of p-hydroxynorephedrine (PHN) except (S,R)-PHN enhanced the cyclic AMP response to low concentrations of NE. Since (S,R)-PHN [like the other stereoisomers of PHN and (S)-POH] inhibited in a dose-dependent manner the high affinity uptake of ³H-NE into crude synaptosomal fractions of the limbic forebrain, the results might suggest that the presumably physiological enantiomer of PHN also exerts receptor blocking properties. The inhibition by (S,R)-PHN of the cocaine induced potentiation of the cyclic AMP response to NE supports this supposition. The results provide evidence that the hydroxylated metabolites of (S)-amphetamine, (S)-POH and (S,R)-PHN, modify the action of the parent drug on central noradrenergic function at the level of the NE receptor coupled adenylate cyclase system.     

Effect of acute and chronic treatment of tandamine,a new heterocyclic antidepressant,on biogenic amine metabolism and related activities

Summary The effects of tandamine, a clinically effective heterocyclic antidepressant, administered either acutely (10 mg/kg i.p) or chronically (10 mg/kg i.p. daily for 21 days) on biogenic amine uptake and metabolism in the rat were determined and a comparison with desipramine was made. Tandamine, similarly to desipramine, blocked norepinephrine (NE) uptake in rat brain and heart following both acute and chronic administration. No effect of tandamine on dopamine (DA) or serotonin (5-HT) uptake was observed. Both drugs lowered endogenous brain NE when given chronically but not acutely. In contrast, no such effect on brain DA and 5-HT or heart NE was observed. Tandamine, like desipramine, administered chronically prior to an intraventricular injection of ³H-NE, produced increases in the decline of ³H-NE as indicated by decreased ³H-NE with increased levels of ³H-normetanephrine in brain stem of rats, suggesting an increased turnover of NE. No such effect was observed following acute treatment. Both drugs increased the behavioural effects of L-Dopa following an acute oral administration, with tandamine appearing superior to desipramine at the lower dose examined (10 mg/kg). Tandamine was 57–833 times less effective in binding to rat brain muscarinic receptors than desipramine, imipramine, butriptyline and amitriptyline, respectively. Thus, tandamine affects biogenic amine mechanism following either acute or chronic administration in a fashion similar to desipramine, but unlike desipramine, it exhibits relatively little anticholinergic properties, a further indication of the potential use of tandamine in the treatment of human depression, particularly where an increase in drive is desired.     

Desipramine and some other antidepressant drugs decrease the major norepinephrine metabolite 3,4-dihydroxyphenylglycol-sulphate in the rat brain

Summary The O-methylated and non-O-methylated end metabolites of norepinephrine (NE) in the rat brain were measured to investigate a presumed shift in metabolism of NE from intra- to extraneuronal metabolism by uptake inhibitory antidepressant drugs. Desipramine (DMI), protriptyline and maprotiline in doses from 2.5–20 mg/kg reduced the concentration of the major non-O-methylated NE metabolite 3,4-dihydroxyphenylglycolsulphate (DOPEG-SO₄) in the whole rat brain to about 60–70% of controls, while imipramine, amitriptyline, butriptyline and clorimipramine (20 mg/kg, 21/2 h) caused no significant decrease. The major O-methylated NE metabolite free plus conjugated 3-methoxy-4-hydroxyphenylglycol (total-MOPEG) was almost unaffected by all the drugs 21/2 h after administration. At longer time intervals, however, i.e. 5 h, a high dose of DMI (10 mg/kg, s.c.) decreased total-MOPEG to 75% of controls. DOPEG-SO₄ was decreased by DMI in all brain regions examined: cortex, hippocampus, cerebellum and brain rest. ³H-normetanephrine was increased 1/2h and 1 h after intraventricular injection of ³H-dopamine, and at the same time interval both total-³H-MOPEG and ³H-DOPEG-SO₄ were decreased. Amine storage in granules was not necessary for the action of DMI since DMI retained its metabolite-lowering effects in reserpinized rats. Inhibition of NE uptake in vivo did not induce the expected increase in the major extraneuronal NE metabolite MOPEG, but only the expected decreased in DOPEG-SO₄. The reduction of both the major NE metabolites by DMI suggests a decreased metabolism and turnover of NE.Abbreviations Used NE norepinephrine - DOPEG 3,4-dihydroxyphenylglycol - DOPEG-SO₄ DOPEG sulphate ester - MOPEG 3-methoxy-4-hydroxyphenylglycol - total-MOPEG free plus conjugated MOPEG - DOPAC 3,4-dihydroxyphenylacetic acid - HVA homovanillic acid - NM normetanephrine - DA dopamine - DMI desipramine - MAO monoamine oxidase     

Chronic treatment with desipramine caused a sustained decrease of 3,4-dihydroxyphenylglycol-sulphate and total 3-methoxy-4-hydroxyphenylglycol in the rat brain

Summary The 2 major metabolites of norepinephrine (NE), 3,4-dihydroxyphenylglycol-sulphate (DOPEG-SO₄) and free plus conjugated 3-methoxy-4-hydroxyphenylglycol (total-MOPEG), both their endogenous concentrations and their accumulation from the NE-precursors ³H-tyrosine or ³H-dopamine, were determined in the whole rat brain to assess the effect of chronic treatment with desipramine (DMI), imipramine and amitriptyline. DOPEG-SO₄ was decreased 2 h and 24 h after the last administration of DMI (10 mg/kg twice daily for 4, 10 or 20 days) or imipramine (10 mg/kg twice daily for 10 days). When measured within 24 h after the last dose of DMI or imipramine, several schedules resulted in reduced accumulation of total-³H-MOPEG and ³H-NE, while ³H-NE and MOPEG were unchanged in the remaining schedules. These results indicate that DMI retains its ability to decrease NE-turnover over a period of 20 days of treatment. Forty-eight hours or 72 h after the last administration of desipramine and imipramine an overshoot was observed in NE-metabolism, consisting of increased levels of total-³H-MOPEG and endogenous total-MOPEG; DOPEG-SO₄ was some-times concomitantly increased. The overshoot was more consistent after 20 or 10 days of treatment than after 4 days of treatment. This finding, together with a tendency to partial tolerance to the metabolite decreasing effects of DMI, indicate that adaptive changes occur in the NE system after treatment for 10–20 days with DMI or imipramine.Abbreviations Used NE norepinephrine - DOPEG 3,4-dihydroxyphenylglycol - DOPEG-SO₄ DOPEG sulphate ester - MOPEG 3-methoxy-4-hydroxyphenylglycol - total-MOPEG free plus conjugated MOPEG - DOPAC 3,4-dihydroxyphenylacetic acid - HVA homovanillic acid - NM normetanephrine - DA dopamine - DMI desipramine     

脑室出血后的大鼠脑干组织中去甲肾上腺素含量的变化

目的 通过观察大鼠脑室出血后脑组织中去甲肾上腺素(NE)含量,探讨其在脑室出血中的损伤作用,对诊断疾病、预测病情及预后、指导治疗有着实际的临床意义.方法 将60只大鼠随机分为正常组、假手术组、脑室出血组(IVH组).IVH组取自体动脉血方法制备大鼠原发性脑室出血(PIVH)模型,假手术组大鼠只切开头皮和颅骨钻孔,不做自体动脉血注射.分别在术后5个时间点取脑干组织采用ELISA法检测其含量.结果 IVH组去甲肾上腺素含量在6h、1d、3d与正常组、假手术组比较差异有统计学意义(P＜0.05),从6h开始逐渐升高,1d达最高峰,在注血3d后有下降趋势,但仍高于正常组、假手术组.结论 IVH后,大鼠脑干组织去甲肾上腺素含量增加,因此去甲肾上腺素在脑室出血后脑组织损伤中可能起着重要作用,并对外周组织产生继发性损害,导致病情加重.     

Analysis of Factors that Affect Short-Term Blood Pressure Variability in Patients with Chronic Renal Failure

Recent reports suggest the relationship of short-term blood pressure (BP) variability to cardiovascular target organ damage. In this study, short-term BP variability was assessed as the standard deviation of daytime and nighttime BP in 36 hospitalized patients with chronic renal failure (CRF) who underwent ambulatory BP monitoring. Positive correlations were observed between body mass index (BMI) and daytime systolic and diastolic BP variability, BMI and nighttime diastolic BP variability, cholesterol and daytime systolic BP variability, cholesterol and nighttime systolic and diastolic BP variability, nocturnal decline in BP and nighttime diastolic BP variability, and plasma concentration of norepinephrine (p-NE) and nighttime systolic BP variability. In multivariate linear regression analyses, BMI showed the strongest association with daytime and nighttime diastolic BP variability (p < .005 and p < .05). On the other hand, cholesterol and p-NE were the primary determinants of daytime and nighttime systolic BP variability, respectively (p < .01 and p < .0005). Interestingly, CRF patients with ischemic heart disease (IHD) had significantly increased daytime systolic and diastolic BP variability and nighttime systolic BP variability (p < .05 or less). Furthermore, logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor of IHD in patients with CRF (odds ratio 1.50 [95% confidence interval 1.01 to 2.25]; p < .05). Taken together, short-term BP variability is suggested to be affected by BMI, cholesterol, and p-NE in CRF patients. Furthermore, sympathetic nerve overactivitymay be involved in cardiovascular complications in CRF patients through the increase in nighttime systolic BP variability.     

Treatment of impaired perfusion in septic shock

Severe sepsis and septic shock are relatively common problems in intensive care. The mortality in septic shock is still high, and the main causes of death are multiple organ failure and refractory hypotension. Impaired tissue perfusion due to hypovolemia, disturbed vasoregulation and myocardial dysfunction contribute to the multiple organ dysfunction. Treatment of hemodynamics in septic shock consists of appropriate fluid therapy guided by invasive monitoring combined with vasoactive drugs aiming to correct hypotension and inappropriately low cardiac output. The drug of choice for low vascular resistance is norepinephrine, while insufficient myocardial contractility is commonly treated with dobutamine. The use of norepinephrine seems to be associated with better prognosis as compared to results from the use of dopamine or epinephrine. In septic shock, vasopressin levels are low, and therefore, vasopressin has been advocated as a vasopressor. Its effectiveness and safety have not yet been documented, and so far it is regarded as an experimental treatment. Recent data support the use of corticosteroid, at least in some of the patients with septic shock. Also, activated protein C, a drug with anti-inflammatory and antithrombotic properties, decreases mortality in patients with septic shock.     

糖皮质激素对记忆巩固的作用及其神经机制

背景 糖皮质激素(glucocorticoid,GC)在机体的作用范围比较广泛,对学习记忆也能产生影响. 目的 近年来关于GC增强记忆巩固的神经机制有了进一步的发展,现就近年的进展予以综述. 内容 在人体和动物的众多研究均提示,去甲肾上腺系统的激活在GC影响记忆的机制中发挥重要的作用,谷氨酸及其受体、内源性大麻素也参与其中.GC对记忆巩固的调节主要通过基底外侧杏仁核(the basolateral complex of the amygdale,BLA)及BLA与其他脑区的相互作用而实现,且不同的麻醉药物对应激反应的影响也不相同. 趋向 深入研究GC对人体认知功能的影响,有助于揭示认知功能障碍的发生机制,有利于临床工作者制定有效的预防及治疗方案.     

去甲肾上腺素与哌唑嗪对高血压大鼠动脉平滑肌细胞Na~+-K~+-ATPase活性及mRNA表达的影响

目的观察去甲肾上腺素(NE)及其α1肾上腺素能受体(α1-AR)拮抗剂哌唑嗪(Prazosin)对自发性高血压大鼠(SHR)动脉血管平滑肌细胞Na -K -ATPase活性及mRNA表达的影响。方法采用生化酶学方法和逆转录聚合酶链反应技术,观察不同浓度的NE和哌唑嗪对自发性高血压大鼠血管平滑肌细胞Na -K -ATPase活性和mRNA表达的影响。结果与SHR组比较,NE(10-7mol/L)能减弱Na -K -ATPase活性(3·98±0·14vs7·92±0·19,P<0·01)及Na -K -ATPaseα1-亚单位mRNA的表达(0·863±0·057vs1·307±0·051,P<0·01),单用哌唑嗪对Na -K -ATPase活性及mRNA的表达均无影响(P>0·05)。哌唑嗪(10-7,10-6,10-5mol/L)呈剂量依赖性减弱和阻断NE(10-7mol/L)对Na -K -ATPase活性(4·31±0·24,6·15±0·30,7·52±0·31)及Na -K -ATPaseα1-亚单位mRNA表达(0·857±0·041,1·096±0·055,1·183±0·059)的影响(P<0·01,P<0·05)。结论NE抑制SHRNa -K -ATPase活性和下调Na -K -ATPaseα1-亚单位mRNA表达,可能是通过α1-AR途径介导基因转录的下调。肾上腺素能1型受体拮抗剂哌唑嗪可通过阻断α1-AR途径抑制NE对自发性高血压大鼠血管平滑肌细胞Na -K -ATPase活性和Na -K -ATPaseα1-亚单位mRNA表达的影响。     

Norepinephrine transporter: a candidate gene for initial ethanol sensitivity in inbred long-sleep and short-sleep mice

BACKGROUND: Altered noradrenergic neurotransmission is associated with depression and may contribute to drug abuse and alcoholism. Differential initial sensitivity to ethanol is an important predictor of risk for future alcoholism, making the inbred long-sleep (ILS) and inbred short-sleep (ISS) mice a useful model for identifying genes that may contribute to alcoholism. METHODS: In this study, molecular biological, neurochemical, and behavioral approaches were used to test the hypothesis that the norepinephrine transporter (NET) contributes to the differences in ethanol-induced loss of righting reflex (LORR) in ILS and ISS mice. RESULTS: We used these mice to investigate the NET as a candidate gene contributing to this phenotype. The ILS and ISS mice carry different DNA haplotypes for NET, showing eight silent differences between allelic coding regions. Only the ILS haplotype is found in other mouse strains thus far sequenced. Brain regional analyses revealed that ILS mice have 30 to 50% lower [3H]NE uptake, NET binding, and NET mRNA levels than ISS mice. Maximal [3H]NE uptake and NET number were reduced, with no change in affinity, in the ILS mice. These neurobiological changes were associated with significant influences on the behavioral phenotype of these mice, as demonstrated by (1) a differential response in the duration of ethanol-induced LORR in ILS and ISS mice pretreated with a NET inhibitor and (2) increased ethanol-induced LORR in LXS recombinant inbred (RI) strains, homozygous for ILS in the NET chromosomal region (44-47 cM), compared with ISS homozygous strains. CONCLUSIONS: This is the first report to suggest that the NET gene is one of many possible genetic factors influencing ethanol sensitivity in ILS, ISS, and LXS RI mouse strains.