• Clinical and Experimental Reproductive Medicine
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• v.40 no.1
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• pp.12-22
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• 2013

Objective: We investigated the norepinephrine transporter (NET) expression in normal and pre-eclamptic placentas and analyzed the invasion activity of trophoblastic cells based on norepinephrine (NE)-NET regulation. Methods: NET and NE expression levels were examined by western blot and enzyme-linked immunosorbent assay, respectively. Trophoblast invasion activity, depending on NE-NET regulation, was determined by NET-small interfering RNA (siRNA) and NET transfection into the human extravillous trophoblast cells with or without NE treatment and invasion rates were analyzed by zymography and an invasion assay. Results: NET mRNA was expressed at a low level in pre-eclamptic placentas compared with normal placentas and NE concentration in maternal plasma increased significantly in pre-eclamptic women compared to normal pregnant women (p<0.05). NET gene upregulation and NE treatment stimulated trophoblast cell invasion up to 2.5-fold (p<0.05) by stimulating matrix metalloproteinase-9 activity via the phosphoinositol-3-kinase/AKT signaling pathway, whereas NET-siRNA with NE treatment reduced invasion rates. Conclusion: NET expression is reduced by inadequate regulation of NE levels during placental development. This suggests that a complementary balance between NET and NE regulates trophoblast cell invasion activities during placental development.

• The Korean Journal of Pharmacology
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• v.27 no.1
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• pp.1-5
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• 1991

We studied changes in the hypothalamic norepinephrine(NE) metabolism in streptozotocin (STZ)-induced diabetic rats by measuring basal NE levels, turnover rate of NE, and in vivo tyrosine hydroxylase activities. Basal NE level did not change significantly upto 4 weeks after the establishment of diabetes with STZ(60 mg/kg, iv). But turnover rate of NE decreased to 62% of control rate(P<0.01), and in vivo tyrosine hydroxylase activities decreased to 32% of control level(P<0.05) at one week of diabetes. From these results, we concluded that, of the three parameters measured, in vive tyrosine hydroxylase activity is the most sensitive index of altered hypothalamic NE metabloism in STZ-induced diabetic rats.

• YAKHAK HOEJI
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• v.22 no.3
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• pp.148-156
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• 1978

An influence of bethanidine (B) onpressor effects of norepinephrine (NE) and tyramine (TR) was investigated in the whole rabbits. B, in a dose 1.0, 3.0 and 5.0 mg/kg, i.v., potentiated significantly the pressor effects of NE and TR. Reserpine and desipramine did not increase the NE effect that had been potentiated by B.B also made little modification of NE effect that had been potentiated by reserpine and desipramine. B increased the NE effect that had been potentiated by tranycypromine and guanethidine. The NE pressor effect potentiated by B was decreased by tranylcypromine, but not influenced by guanethidine. The TR pressor effect potentiated by B was not altered by reserpine and guanethidine, but decreased by desipramine and tranylcypromine. B increased the TR pressor effect that had been potentiated by guanethidine. B, when given after administration of reserpine, tranylcypromine or desipramine, exerted little influence on the TR effect. The mechanism of potentiation of NE and TR pressor effects by B seems to be similar to guanethidine, and the potency of B on the influence of NE and TR effects seems to be greater than guanethidine.

• The Korean Journal of Pharmacology
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• v.32 no.2
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• pp.139-150
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• 1996

The effects of adenosine analogues on the electrically-evoked norepinephrine(NE) release and the influence of ischemia on the effects were studied in the rat hippocampus. Slices from the rat hippocampus were equilibrated with $0.1{\mu}M$ $[^3H]-norepinephrine$ and the release of the labelled product, $[^3H]-NE$, was evoked by electrical stimulation(3 Hz, 2 ms, 5 $VCm^{-1}$ and rectangular pulses for 90 sec), and the influence of various agents on the evoked tritium-outflow was investigated. Ischemia(15min with 95% $N_2$ +5% $CO_2$) increased both the basal and evoked NE release. These increases were abolished by addition of glucose into the superfused medium, and they were significantly inhibited either by $0.3\;{\mu}M$ tetrodotoxin pretreatment or by removing $Ca^{++}$ in the medium. MK-801$(1{sim}10\;{\mu}M)$, a specific NMDA receptor antagonist, and glibenclamide $(1\;{\mu}M)$, a $K^+-channel$ inhibitor, neither alter the evoked NE release nor affected the Ischemia-Induced increases in NE release. However, polymyxin B(0.03 mg), a specific protein kinase C inhibitor, inhibited the effect of ischemia on the evoked NE release. Adenosine and $N^6-cyclopentyladenosine$ decreased the NE release in a dose-dependent manner in ischemic condition, though the magnitude of inhibition was far less than those in normal (normoxic) condition. Also the treatment with $5{\mu}M$ DPCPX, a potent $A_1-adenosine$ receptor antagonist did not affect the ischemia-effect. These results suggest that the evoked-NE release is potentiated by ischemia, and this process being most probably mediated by protein kinase C, and that the decrease of NE release mediated through $A_1-adenosine$ receptor is significantly inhibited in ischemic state.

• Biomedical Science Letters
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• v.15 no.4
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• pp.287-293
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• 2009

Phospholipase D (PLD) is an enzyme hydrolyzing phosphatidylcholine to phosphatidic acid (PA) and choline. We investigated the involvement of PLD1 in the uptake of norepinephrine (NE) in PC12 cells, pheochromocytoma cells. NE uptake was specific in PC12 cells because nomifensine, a specific blocker of NE transporter, blocked NE uptake. Inhibition of PLD function in PC12 cells by the treatment of butanol suppressed the NE uptake. In contrast, overexpression of PLD1 in PC12 cells increased NE uptake efficiently. These results suggest that PLD activity is involved in NE uptake. We explored the action mechanism of PLD in NE uptake. PA phosphatase inhibitor, propranolol, blocks the formation of PKC activator diacylglycerol from PA. Propranolol treatment to PC12 cells blocked dramatically the uptake of NE. Specific PKC inhibitors, GF109203X and Ro31-8220, blocked NE uptake. Taken together, we suggest for the first time that PLD1 activity is involved in NE uptake via the activation of PKC.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.6
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• pp.673-679
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• 1997

It has been generally accepted that glutamate mediates the ischemic brain damage, excitotoxicity, and induces release of neurotransmitters, including norepinephrine(NE), in ischemic milieu. In the present study, the role of nitric oxide(NO) in the ischemia-induced $[^3H]norepinephrine([^3H]NE)$ release from cortex slices of the rat was examined. Ischemia, deprivation of oxygen and glucose from $Mg^{2+}-free$ artificial cerebrospinal fluid, induced significant release of $[^3H]NE$ from cortex slices. This ischemia-induced $[^3H]NE$ release was significantly attenuated by glutamatergic neurotransmission modifiers. $N^G-nitro-L-arginine$ methyl ester(L-NAME), $N^G-monomethyl-L-arginine$ (L-NMMA) or 7-nitroindazole, nitric oxide synthase inhibitors attenuated the ischemia-evoked $[^3H]NE$ release. Hemoglobin, a NO chelator, and 5, 5- dimethyl-L-pyrroline-N-oxide(DMPO), an electron spin trap, inhibited $[^3H]NE$ release dose-dependently. Ischemia-evoked $[^3H]NE$ release was inhibited by methylene blue, a soluble guanylate cyclase inhibitor, and potentiated by 8-bromo-cGMP, a cell permeable cGMP analog, zaprinast, a cGMP phosphodiesterase inhibitor, and S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide generator. These results suggest that the ischemia-evoked $[^3H]NE$ release is mediated by NMDA receptors, and activation of NO system is involved.

• The Korean Journal of Pharmacology
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• v.1 no.1 s.1
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• pp.53-61
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• 1965

Effects of intraventricular norepinephrine (NE) on rabbit blood pressure and heart rate were investigated. 1) Blood pressure was little affected by small doses of NE (below $500{\mu}g$) but showed marked rise by 1 mg. 2) Heart rate was decreased by intraventriccular NE $(200{\sim}500{\mu}g)$. One mg of NE caused less pronounced bradycardia than with smaller doses. The bradycardia could not be observed in vagotomized or atropinized animals. 3) Intraventricular NE potentiated reflexive bradycardia produced by 5-hydroxytryptamine. 4) Cord-sectioned rabbit showed different responses; the smaller doses $(100{\sim}200{\mu}g)$ produced transitory bradycardia and depression of blood pressure, which followed by tachycardia and pressure rise. The transitory bradycardia and depressor effects were not observed in cord-sectioned and vagotomized rabbit. 5) Treatment of animals with reserpine, guanethidine and hexamethonium changed the effects of intraventricular NE on blood pressure, i.e., in these cases the smaller doses of NE caused maked elevation of blood pressure. 6) From these observations it was inferred that central NE caused stimulation of cardioinhibitory and vasomotor center. The former seemed to be more sensitive to NE than the latter. Susceptibility of the vasomotor center to NE seemed to be influenced by peripheral sympathetic tone.

• The Korean Journal of Pharmacology
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• v.5 no.1
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• pp.65-72
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• 1969

After administration of tetrabenazine (TBZ) 40 mg/kg), the pressor and cardioaccelerator responses of rabbits (whole anesthetized and spinal) to norepinephrine and tyramine were studied. The maxmal potentiation of the pressor activity of norepinephrine developed about 10 hours after TBZ administration. At this time the preesor response to tyramine was not decreased. The cardioaccelerator responses to both amines were not significantly altered. The TBZ-induced supersensitivity to norepinephrine was not increased by additional intravenous reserpine, but it was further increased by giving desipramine. Carbachol, given 2 and 6 hours after TBZ administration, inhibited the development of supersensitivity to norepinephrine by TBZ. The TBZ-induced supersensitivity was discussed in relation to reserpine-induced supersensitivity.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.1
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• pp.1-3
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• 2003

To investigate the receptors mediating the regulation of norepinephrine (NE) release in human cerebral cortex slices, we examined the effects of opioid agonists for ${\mu}$-, ${\delta}$-, and ${\kappa}$-receptors on the high potassium (15 mM)-evoked release of [$^3H$]NE. [$^3H$]NE release induced by high potassium was calcium-dependent and tetrodotoxin-sensitive. [$D-Pen^2$, $D-Pen^5$]enkephalin (DPDPE) and deltorphin II (Delt II) inhibited the stimulated release of norepinephrine in a dose-dependent manner. However, Tyr-D-Ala-Gly-(Me)Phe-Gly-ol and U69,593 did not influence the NE release. Inhibitory effect of DPDPE and Delt-II was antagonized by naloxone, naltrindole, 7-benzylidenaltrexone and naltriben. These results suggest that both ${\delta}_1$ and ${\delta}_2$ receptors are involved in regulation of NE release in human cerebral cortex.

• Journal of Nutrition and Health
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• v.26 no.7
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• pp.858-866
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• 1993

S.D.rats were fed with 3.4% tyrosine supplemented diet for 5 days. Tyrosine diet had no effects on brain NE and MHPG-SO4 levels in non-stressed rats. When these animals were given 3 hr-immobilization stress, they responded in a manner that coped better to the stress. This was measured by the increase in brain MHPG-SO4 indicating the increase in norepinephrine turnover by the stressed animals. When rats were stressed, fed basal or high-tyrosine diet, brain tyrosine concentration dropped more than 26% over the non-stress control animals. 3-hr immobilization stress also decreased brain NE levels. However, while the stress resulted in a significant decrease(p<0.05) of brain NE in basal diet, the decrease was not significant in high-TYR diet group. And as the stress index, serum corticosterone, glucose, and free fatty acid concentratons also were assayed. In this study, it was found that high-TYR diet prevented the stress-induced depletion of brain NE and suppressed the rise in serum corticosterone, glucose, and free fatty acid. These results suggest that high-TYR diet increases the coping ability of body to stress.