Change of central noradrenergic system in Alzheimer's disease

The abnormality of the central noradrenergic system in Alzheimer's disease has two cases: decrease or increase. The former is easy to be understood, because it is resulted from the outstanding forfeit of the noradrenergic neurons in the nucleus locus ceruleus (nLC); but the noradrenalin concentration does not change and enen increase, it seems to disagree with the loss of the noradrenergic neurons in the nLC. This article put emphasis on it, enumerated the related evidence and analyzed the possible causes. At present time, the drugs to increase noradrenalin is used mostly in clinic. This paper summarized it and put forth our own opinions.     

烟碱对大鼠心电图的影响

烟碱对心率的作用具有阶段性,初期引起心率短暂性减弱,紧接着发生瞬时增加。为进一步确定烟碱对大鼠心脏的作用,对描记烟碱作用后大鼠心电图进行分析,发现烟碱能引起大鼠心电图显示较长的QT间期,增加了PR间期及T波面积,与肾上腺素或去甲肾上腺素引起的QT间期延长相似,且能被M受体阻断剂阿托品所阻断,说明烟碱能够诱导局部释放乙酰胆碱或者作用于部分副交感神经控制的毒蕈碱受体。     

Urinary catecholamine and metanephrine to creatinine ratios in healthy dogs at home and in a hospital environment and in 2 dogs with pheochromocytoma

BACKGROUND: Measurement of high concentrations of urine catecholamines and metanephrines is useful in diagnosing pheochromocytoma in humans. Stress increases catecholamine excretion in urine. HYPOTHESIS: Stress of a hospital visit increases urinary catecholamine and metanephrine excretion in dogs. ANIMALS: Fourteen clinically normal dogs, 2 dogs with pheochromocytoma. METHODS: Voided urine samples were collected by the owners 7 days before (t-7), during the hospital visit immediately after diagnostic procedures (t0), as well as 1 (t1) and 7 days (t7) after the hospital visit. Urine catecholamine and metanephrine concentrations were measured using high-pressure liquid chromatography and expressed as ratios to urine creatinine concentration. RESULTS: In client-owned dogs epinephrine and norepinephrine ratios at t0 were significantly higher compared with ratios at t7. Metanephrine and normetanephrine ratios at t-7, t0, and t1 did not differ significantly from each other; however, at t7 they were significantly lower compared to values at t-7. In staff-owned dogs no significant differences were detected among the different collecting time points for any variable. Metanephrine and normetanephrine ratios were significantly higher in client-owned dogs compared to staff-owned dogs at t-7, t0, and t1 but not at t7. CONCLUSIONS AND CLINICAL IMPORTANCE: Stress associated with a hospital visit and with the sampling procedure causes increases in urine catecholamine and metanephrine excretion. Urine collection for the diagnosis of pheochromocytoma probably should take place at home after adaptation to the sampling procedure.     

Alterations of cardiac sympathetic norepinephrine transporter expression in rats with volume overload

AIM: To determine the alterations of myocardial 1-adrenergic receptor (1-AR) and cardiac sympathetic norepinephrine transporter (NET) mRNA expression, which is upstream modulator of 1-AR, in rats with longterm volume overload (VOL). METHODS: Left ventricular systolic (LVSP) and end diastolic pressure (LVEDP) of rats with VOL induced by aortacaval fistula operation and control group were measured at 314,30and 60d after the operation, the mRNA at the time points was measured by RT-PCR and Northern blot analysis and quantified by densitometry. RESULTS: The cardiac sympathetic NET specific expression is in the cardiac sympathetic ganglia. Be compared with the control group, LVSP of VOL rats decreased most dramatically by 24% (P<0.05) at 3 d, after that LSVP increased gradually and were higher than control group at 60d. LVEDP increased initially compared with the control (P<0.05), the latter recovered to the control levels. RT-PCR and Northern blot showed that in VOL rats the NET mRNA did not decreased significantly from 3to 30d, and decreased remarkably at 60d after the operation (P<0.05). The pattern of 1-AR mRNA expression were similar to the NET. CONCLUSION: The results suggest decreased levels of NET mRNA may contribute to cardiac sympathetic dysfunction in heart failure due to longterm VOL, which may lead to decreased myocardial 1-AR mRNA. We conclude that the normal NET mRNA expression may play a critical role to maintain sensitivity of 1-AR to adrenergic stimuli and cardiac contractility.     

Norepinephrine attenuates injury of vascular endothelial cells induced by LPS

AIM: To investigate the effects of norepinephrine (NE) on vascular endothelial cell damage induced by lipopolysaccharides (LPS). METHODS: Human umbilical vein endothelial cells (HUVEC-12) were cultured with LPS at 100 mg/L to establish the cell damage model. Real-time PCR and Western blot were used to determine the expressions of VE-cadherin at mRNA and protein levels. The levels of TNF-α, IL-1β, IL-2 and IL-10 in culture supernatant were measured by ELISA. The reactive oxygen species (ROS) production in the endothelial cells was detected by ROS assay kit. RESULTS: LPS decreased both mRNA and protein levels of VE-cadherin accompanied by increased levels of TNF-α, IL-1β, IL-2 and intracellular ROS, and decreased level of IL-10 in the endothelial cells. NE reversed the expression of VE-cadherin at mRNA and protein levels under the condition of LPS treatment in a dose-dependent manner, and also alleviated the intracellular oxidative stress. CONCLUSION: NE reverses the endothelial damage induced by LPS, which may be related to the up-regulation of VE-cadherin level and the decreases in oxidative stress and inflamatory mediators.     

Effect of asymmetric dimethylarginine on blood pressure and renal function in sympathectomized spontaneously hypertensive rats

AIM: To investigate the effect of asymmetric dimethylarginine (ADMA) on blood pressure and renal function in sympathectomized spontaneously hypertensive rats (SHR). METHODS: The neonatal SHR were sympathectomized by guanethidine monosulfate. Systolic and diastolic blood pressure was monitored by tail-cuff method. Urine excretion of norepinephrine (NE) was measured by metabolic cage collection. The levels of ADMA and NE in the kidneys were analyzed by HPLC. Nitric oxide (NO) content in SHR kidney was detected by colorimetry. The protein expression of endothelial nitric oxide synthase (eNOS) was determined by Western blot. Glomerular filtration rate (GFR) was examined to evaluate the renal function. RESULTS: Neonatal chemical sympathectomy produced significant decreases in urinary NE excretion, renal NE and ADMA contents, and systolic and diastolic blood pressure compared with the sympathetically intact SHR (P<0.05). Moreover, the level of NO content and protein expression of eNOS in the kidneys were significantly increased (P<0.05). However, no significant difference was observed in microalbumin, urinary sodium excretion and GFR between the sympathetically intact SHR and the sympathectomized SHR. CONCLUSION: Inhibition of sympathetic nervous system affects blood pressure by reducing the release of ADMA and NE, and increasing NO synthesis and eNOS expression. The regulation of ADMA generation by sympathetic nervous system does not influence renal function.     

Effects of norepinephrine on the activity of NF-κB in cardiomyocytes

AIM: To study the effects and mechanisms of norepinephrine (NE) on the activity of nuclear factor-kappa B (NF-κB) in cardiomyocytes. METHODS: Using the cultured neonatal rat cardiac myocytes, the levels of reactive oxygen species and the nuclear DNA binding activity of NF-κB were measured in cardiomyocytes before and after stimulated with NE alone, NE+prazosin+propranolol, and NE+vitamin E, respectively. RESULTS: NE increased significantly the levels of reactive oxygen species and NF-κB activity in cardiac myocytes. These effects of NE were attenuated by vitamin E pretreatment, as well as prazosin and propranoloe. CONCLUSION: The effects of NE on cardiomyocytes might be exerted partly through NF-κB activation, associated with NE-induced overproducion of reactive oxygen species via the adrenergic receptor pathway.     

Nuclear calcium oscillation in cultured neonatal rat myocytes

AIM: To determine whether nuclear Ca²⁺ is independently regulated from the cytosolic Ca²⁺ and nuclear Ca²⁺ oscillation induced by many modulating factors in cultured rat neonatal myocytes and its mechanism. METHODS: Rat neonatal cardiac myocytes were cultured, and fluo-4/AM was loaded as calcium probe. The changes of cytosolic and nuclear Ca²⁺ were observed by confocal laser microscopy. RESULTS: Calcium fluorescent intensity oscillated slightly in myocardiocytes and the average intensity was much higher in the nucleus than that in the cytosole. Ca²⁺ oscillation in nucleus and cytosole induced by norepinephrine, isoproperenol, ATP were completely blocked by Ca²⁺-ATPase antagonist thapsigargin (10^-6 mol/L),L-type Ca²⁺ channel blocker verapermil (500 μmol/L) and KCl (20 mmol/L). Ca²⁺-ATPase antagonist thapsigargin completely blocked the propagation of Ca²⁺ waves and simutaneouly induced a temporary Ca²⁺ increase followed by a magnificient drop and loss of response to norepinephrine. CONCLUSIONS: The results suggested that generation and maintenance of calcium oscillation both in cytosole and nucleus depended on extracellular Ca²⁺ influx, membrane potential, Ca²⁺ release and uptake of cytosolic and nuclear calcium stores. The difference between cytosolic calcium and nuclear calcium indicated that calcium regulating system relatively independent of cytosole may exist in nucleus.