SEARCH · PubMed Health

Results for “Norepinephrine”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources

PubMed1999

Modulation of external pancreatic secretion by endogenous norepinephrine: study with a norepinephrine uptake blocker in the rat.

The effect of endogenous catecholamines on pancreatic secretion was analyzed with nisoxetine, a specific norepinephrine uptake blocker, and specific adrenoceptor antagonists in anesthetized acute fistula rats. Nisoxetine was administered alone or with alpha-1 (prazosin), alpha-2 (idazoxan or yohimbine), or beta (propranolol) adrenoceptor antagonists. Pancreatic secretion was measured in basal conditions or after stimulation by 2-deoxy-D-glucose (2DG), electrical vagal stimulation, or acetylcholine. (a) Basal. Nisoxetine alone had no effect. Associated with idazoxan or yohimbine, nisoxetine produced a dose-related stimulation (p < 0.01) of water and electrolyte without changing protein output. Addition of propranolol abolished this stimulation. (b) 2DG. Nisoxetine inhibited 2DG-induced secretion (p < 0.01). Idazoxan or yohimbine suppressed the nisoxetine inhibition of water and electrolyte output (p < 0.01) but had no effect on protein output, which was restored only by adding a mixture of idazoxan, prazosin, and propranolol. (c) Electrical stimulation. Nisoxetine did not modify water and electrolyte but inhibited protein response by 75%. Adding idazoxan to nisoxetine significantly increased (p < 0.01) water and bicarbonate response and partly restored protein response. Water and bicarbonate response was restored by propranolol, whereas protein response was only restored by adding a mixture of idazoxan, prazosin, and propranolol. (d) Nisoxetine did not modify pancreatic response to acetylcholine. In conclusion, endogenous norepinephrine affects the response to vagally mediated effects through several subtypes of adrenoceptors, without changing basal or acetylcholine stimulated secretion.

Acetylcholine↗

PubMed1989

Continuous infusion of tracer norepinephrine may miscalculate unidirectional nerve uptake of norepinephrine in humans.

In order to evaluate uptake kinetics of norepinephrine (NE) in different tissues, a catheterization study was performed in control subjects (n = 6) and patients with enhanced sympathetic nervous activity (cirrhosis, n = 12) during constant intravenous infusion of L[3H]norepinephrine ([3H]NE) for 75 minutes. In spite of a higher NE spillover from kidneys in patients compared with controls (82 vs. 49 ng/min, p less than 0.01), renal extraction ratios of [3H]NE were similar in the two groups (0.33 vs. 0.32, NS), and no significant change was observed during the time of infusion. In contrast, liver-intestine extraction ratios of [3H]NE decreased significantly and equally with infusion time in patients (from 0.57 to 0.44, p less than 0.01) and controls (from 0.59 to 0.46, p less than 0.01). This was observed despite the fact that spillover of NE from this vascular bed was observed only in patients with cirrhosis and not in controls (41 vs. -5 ng/min, p less than 0.02). In the lower limb, net release of NE was similar in patients and controls, and extraction ratios of [3H]NE decreased almost equally with infusion time (from 0.35 to 0.30, p less than 0.01 and from 0.40 to 0.24, p less than 0.1, respectively). Whole-body clearance of [3H]NE decreased over time in patients (-6%, p less than 0.01) and controls (-20%, p less than 0.01), but significant difference was not observed between the groups. We conclude that failure to attain a steady state with respect to [3H]NE removal was demonstrated in areas of large tissue volume relative to blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2002

Comparison of the effects of serotonin selective, norepinephrine selective, and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats.

Previous studies showed that the dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, duloxetine, increases bladder capacity and urethral sphincter electromyographic (EMG) activity in a cat model of acetic acid-induced bladder irritation. The present study aimed to determine the relative importance of 5-HT versus NE reuptake inhibition for mediating these effects by examining drugs that are selective for either the 5-HT or NE system or both. Similar to duloxetine, venlafaxine (0.1 to 10 mg/kg), also a dual serotonin and norepinephrine reuptake inhibitor, produced marked increases in bladder capacity and EMG activity that were reversed by methiothepin (0.3 mg/kg). S-norfluoxetine (0.01 to 10 mg/kg), a serotonin selective reuptake inhibitor, produced small but significant increases in bladder capacity and EMG activity at doses of 3 and 10 mg/kg. Thionisoxetine (0.01 to 3.0 mg/kg), a NE selective reuptake inhibitor, produced no effects on bladder capacity or sphincter EMG activity. Surprisingly, co-administration of thionisoxetine and s-norfluoxetine up to doses of 1 mg/kg of each compound produced no effect on lower urinary tract function. These doses were the maximum that could be administered in combination due to drug-induced emergence of skeletal muscle activity in chloralose-anesthetized animals. These results indicate that there are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that exhibit selective NE and 5-HT reuptake inhibition on lower urinary tract function.

Acetic Acid↗

PubMed2004

Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress.

Cardiac norepinephrine (NE) uptake is reduced in cardiomyopathy. This change is associated with a decrease of NE transporter (NET) receptor and can be reproduced in PC12 cells by extracellular NE. To study whether this effect of NE is mediated via impaired glycosylation and trafficking of NET in the endoplasmic reticulum (ER), we measured the distribution of glycosylated 80-kDa NET and unglycosylated 46-kDa NET in the membrane and cytosolic fractions of PC12 cells. We found that NE decreased glycosylated NET in both membrane and cytosolic fractions and increased cytosolic unglycosylated NET protein. Similar results were produced by tunicamycin and thapsigargin, two agents that induce ER stress by inhibiting N-glycosylation of membrane proteins and disrupting calcium homeostasis, respectively. Also, like the ER stressors, NE not only increased phosphorylation of both the alpha-subunit of eukaryotic initiation factor-2 and its upstream RNA-dependent protein kinase-like ER kinase over 12 h of treatment but also increased ER chaperone molecule glucose-regulated protein 78 and the nuclear transcription factor C/EBP homologous protein. Antioxidants superoxide dismutase and catalase prevented the downregulation of NET proteins and induction of ER stress signals produced by NE but not by tunicamycin or thapsigargin. The results indicate that the downregulation of membrane NET by NE is mediated by decreased N-glycosylation of NET proteins secondary to induction of ER stress pathways by NE-derived oxidative metabolites. Interventions involving the ER stress pathways may provide novel therapeutic strategies for the treatment of sympathetic dysfunction in heart failure.

Animals↗

PubMed2004

Extracellular norepinephrine reduces neuronal uptake of norepinephrine by oxidative stress in PC12 cells.

Cardiac norepinephrine (NE) uptake activity is reduced in congestive heart failure. Our studies in intact animals suggest that this effect on the cardiac sympathetic nerve endings is caused by oxidative stress and/or NE toxic metabolites derived from NE. In this study, we investigated the direct effects of NE on neuronal NE uptake activity and NE transporter (NET), using undifferentiated PC12 cells. Cells were incubated with NE (1-500 microM) either alone or in combination of Cu(2+) sulfate (1 microM), which promotes free radical formation by Fenton reaction for 24 h. NE uptake activity was measured using [(3)H]NE. Cell viability was determined with the use of Trypan blue exclusion and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay, and cellular oxidative stress by dichlorodihydrofluorescein fluorescence and the GSH/GSSG ratio. Cell viability was reduced by NE >100 microM. At lower doses, NE produced oxidative stress and a dose-dependent reduction of NE uptake activity without affecting cell viability significantly. Cu(2+), which has no direct effect on NE uptake activity, potentiated oxidative stress and reduction of NE uptake activity produced by NE. This decrease of NE uptake activity was associated with reductions of NE uptake binding sites and NET protein expression by using the radioligand assay and Western blot analysis, but no changes in NET gene expression. In addition, the free-radical scavenger mannitol, and antioxidant enzymes superoxide dismutase and catalase, reduced oxidative stress and attenuated the reductions of NE uptake activity and NET protein produced by NE/Cu. Thus our results support a functional role of oxidative stress in mediating the neuronal NE uptake reducing effect of NE and that this effect of NE on NET is a posttranscriptional event.

Animals↗

PubMed2006

Chronic stress increases the plasmalemmal distribution of the norepinephrine transporter and the coexpression of tyrosine hydroxylase in norepinephrine axons in the prefrontal cortex.

Norepinephrine (NE) potently modulates the cognitive and affective functions of the prefrontal cortex (PFC). Deficits in NE transmission are implicated in psychiatric disorders, and antidepressant drugs that block the NE transporter (NET) effectively treat these conditions. Our initial ultrastructural studies of the rat PFC revealed that most NE axons (85-90%) express NET primarily within the cytoplasm and lack detectable levels of the synthetic enzyme tyrosine hydroxylase (TH). In contrast, the remaining 10-15% of PFC NE axons exhibit predominantly plasmalemmal NET and evident TH immunoreactivity. These unusual characteristics suggest that most PFC NE axons have an unrecognized, latent capacity to enhance the synthesis and recovery of transmitter. In the present study, we used dual-labeling immunocytochemistry and electron microscopy to examine whether chronic cold stress, a paradigm that persistently increases NE activity, would trigger cellular changes consistent with this hypothesis. After chronic stress, neither the number of profiles exhibiting NET labeling nor their size was changed. However, the proportion of plasmalemmal NET nearly doubled from 29% in control animals to 51% in stressed rats. Moreover, the expression of detectable TH in NET-labeled axons increased from only 13% of profiles in control rats to 32% of profiles in stressed animals. Despite the consistency of these findings, the magnitude of the changes varied across individual rats. These data represent the first demonstration of activity-dependent trafficking of NET and expression of TH under physiological conditions and have important implications for understanding the pathophysiology and treatment of stress-related affective disorders.

Animals↗

PubMed1998

Acute regulation of norepinephrine transport: II. PKC-modulated surface expression of human norepinephrine transporter proteins.

Norepinephrine (NE) transporters (NETs) found in the neuronal plasma membrane mediate the removal of NE from the extracellular space, limiting the activation of adrenoceptors at noradrenergic synapses. Our previous studies with the noradrenergic neuroblastoma SK-N-SH have revealed a muscarinic receptor-triggered regulation of NET surface density and transport capacity, mediated in part by protein kinase C activation. Low abundance of NET proteins in this native cell model, however, preclude direct confirmation of altered trafficking of NET proteins. In our study, we monitored the activity and surface distribution of human NET proteins in transient and stably-transfected cell lines after application of kinase activators and inhibitors. Using hNET stably transfected HEK-293 and LLC-PK1 cells, as well as transiently transfected COS-7 cells, we demonstrate that PKC-activating phorbol esters, beta-PMA or beta-PDBu selectively diminish l-NE transport capacity (Vmax) with little change in NE Km. Effects of phorbol esters are rapid, stereospecific and blocked by protein kinase C inhibitors, staurosporine and bisindolylmaleimide I. As in SK-N-SH cells, beta-PMA induces a reduction in intact cell [3H]nisoxetine binding sites with no change in nisoxetine Kd or total membrane NET density. Cell-surface biotinylation and confocal immunofluorescence techniques confirm that protein kinase C-dependent reductions in NE transport capacity and whole-cell antagonist binding density are accompanied by reductions in cell-surface human NET protein expression. Together these findings argue for kinase-modulated protein trafficking as a potential route for acute regulation of antidepressant-sensitive NE clearance.

Binding Sites↗

PubMed1985

The effect of high-frequency electrical stimulation and norepinephrine on cyclic AMP levels in normal versus norepinephrine-depleted rat hippocampal slices.

Cyclic 3',5'-adenosine monophosphate (cAMP) generation by neuronal activity and norepinephrine (NE) was studied in rat hippocampal slices. High-frequency perforant path stimulation increased cAMP levels 2.5-fold in the dentate gyrus 1 min, but not 30 min, post-stimulation. This increase was abolished by depletion of NE with 6-hydroxydopamine. NE (50 microM) also caused a 3-fold rise in cAMP in whole slices and this stimulation was not altered by NE depletion. These results are consistent with our previous data suggesting that cAMP production is involved in the expression of long-term potentiation and NE-induced long-lasting potentiation in the dentate gyrus.

Animals↗

PubMed1988

Electrophysiological actions of norepinephrine in rat lateral hypothalamus. I. Norepinephrine-induced modulation of LH neuronal responsiveness to afferent synaptic inputs and putative neurotransmitters.

The present studies were conducted as part of an ongoing investigation of the effects of norepinephrine (NE) in neuronal circuits of the mammalian brain. In this report, we describe noradrenergic actions in the lateral hypothalamus (LH), an area which has been implicated in the central integration of cardiovascular regulatory mechanisms, fluid balance and ingestive behaviors. Microiontophoretically applied NE was interacted with extracellularly recorded responses of LH neurons to iontophoretically applied putative neurotransmitters gamma-aminobutyric acid (GABA), acetylcholine (ACh) and glutamate (Glu); and activation of known input pathways from the reticular thalamus (RT) and the lateral preoptic area (LPO). Peri-event histograms of cell responses were computed before, during and after NE microiontophoresis (5-50 nA) and used to quantitatively evaluate monoamine-induced effects on spontaneous and stimulus evoked activity of LH neurons. In 16 of 23 LH neurons, RT-stimulus-induced inhibition was markedly prolonged from a mean of 28.3 +/- 4.8 ms to 44.7 +/- 5.2 ms, during iontophoretic application of NE. In 22 of 38 LH cells, LPO-stimulus-induced excitatory responses were enhanced above control levels during NE administration. In further tests, inhibitory responses of LH cells to iontophoretic pulses of GABA were potentiated during NE administration in 69% (24 of 35) of the cases tested. ACh-induced excitation was potentiated in 9 of 21 cells. In 4 of these cases, otherwise subthreshold doses of ACh caused marked increases in cell firing during the period of NE administration. By contrast, Glu-evoked excitation was antagonized by NE iontophoresis in 65.5% (17 of 26) of LH cells tested. These findings indicate that, as in other noradrenergic target regions of the CNS, NE can facilitate synaptically mediated responses of LH neurons. Taken together these observations suggest that NE may play an important regulatory role in the synaptic transfer of information within LH circuits, and consequently exert considerable influence over the homeostatic functions mediated by this structure.

Acetylcholine↗

PubMed1988

Electrophysiological actions of norepinephrine in rat lateral hypothalamus. II. An in vitro study of the effects of iontophoretically applied norepinephrine on LH neuronal responses to gamma-aminobutyric acid (GABA).

The preceding studies demonstrated that norepinephrine (NE) can consistently augment synaptically mediated (70%) and gamma-aminobutyric acid (GABA)-induced (69%) inhibitory responses of lateral hypothalamic (LH) neurons in vivo. The present experiments further characterized the interactions of NE with LH neuronal responses to GABA in terms of alpha- and beta-receptor mechanisms and demonstrated the utility of the in vitro LH tissue slice preparation as a model for future extra- and intracellular studies of NE modulatory phenomena. Extracellular activity of LH cells was recorded from diencephalic slices (450 microns) incubated in artificial cerebrospinal fluid at 33 degrees C. Interactions between iontophoretically applied NE, isoproterenol (ISO) or phenylephrine (PE) and responses of LH neurons (n = 64) to GABA microiontophoresis were quantitated and characterized using computer-generated ratemeter and histogram records. This analysis revealed two distinct actions of NE on GABA-induced responses of LH neurons. In 8 of 32 cells tested (25%), locally applied NE markedly enhanced inhibitory responses to GABA iontophoresis in a manner identical to that observed in vivo. However, in 20 cells (62.5%), iontophoretic application of NE produced a clear antagonism of GABA responses. NE also exerted dual effects on the background firing rate of LH neurons, causing both inhibition and excitation. Overall, in those cells where NE administration increased spontaneous discharge, it either antagonized or had no effect on GABA-mediated inhibition. In contrast, spontaneous firing rate was never elevated above control levels in those cases where NE potentiated GABA responses. Additional experiments demonstrated that the GABA potentiating actions of the benzodiazepine, flurazepam, were preserved in LH tissue slice preparations. In addition, iontophoretic application of the beta-agonist, ISO, routinely suppressed the spontaneous activity of LH neurons and mimicked the facilitating action of NE on GABA. Likewise, microiontophoretic application of 8-bromo cyclic adenosine monophosphate (AMP) enhanced GABA-induced inhibition of LH firing rate in each of 11 cells tested. On the other hand, local administration of the alpha agonist, PE, routinely produced NE-like antagonism of GABA inhibition along with increases in spontaneous firing rate. Taken together these findings indicate that the commonly observed in vivo phenomena of NE augmentation of GABA and suppression of LH neuron spontaneous firing can be demonstrated in vitro, and most likely result from activation of beta adrenoceptors and subsequent elevation of cyclic AMP levels.(ABSTRACT TRUNCATED AT 400 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1992

Characterization of the norepinephrine uptake system and the role of norepinephrine in the expression of the adrenergic phenotype by quail neural crest cells in clonal culture.

This study investigates the role norepinephrine (NE) may play in regulating the differentiation of quail neural crest cells into sympatho-adrenal cells. Cues originating from the embryonic microenvironment are thought to play an important role during development. It is conceivable that NE has a positive regulatory function because adrenergic expression by quail neural crest cells in clonal culture can be inhibited by NE uptake inhibitors such as desipramine (DMI). This possibility is further supported by the notion that in the avian embryo presumptive adrenergic neural crest cells are likely to encounter catecholamines shortly after they have acquired the NE uptake mechanism. Our present data indicate that neural crest cells in clonal culture express a high affinity NE uptake system that can be inhibited by desipramine. As in the embryo, it appears before noticeable levels of catecholamines are accumulated by neural crest cells, as judged by formaldehyde-induced catecholamine fluorescence (FIF). A comparison of the time course of appearance of different adrenergic markers suggests that immunoreactivity against the biosynthetic enzyme tyrosine hydroxylase (TH) may appear first, and that it is followed very closely by the appearance of detectable levels of dopamine-beta-hydroxylase (DBH) and the NE uptake mechanism. Accumulation of catecholamines (FIF) is observed last. Addition of exogenous NE leads to an increase in adrenergic expression in vitro as judged by an increase in the number of colonies containing FIF-positive cells as well as cells expressing the biosynthetic enzymes TH and DBH. This suggests that exogenous NE can play a positive regulatory role in the differentiation of quail neural crest cells into sympathoadrenal cells.

Animals↗

PubMed1996

Estimating the synaptic concentration of norepinephrine in dentate gyrus which produces beta-receptor mediated long-lasting potentiation in vivo using microdialysis and intracerebroventricular norepinephrine.

Norepinephrine in the hippocampus of urethane anesthetized rats was monitored by microdialysis prior to, and following, an intracerebroventricular injection of 5 micrograms [-]NE in 2 microliters of ACSF. The perforant path evoked potential in dentate gyrus was concurrently monitored by a microelectrode adjacent to the dialysis probe. NE levels 30 x basal values or greater at the recording site were related to long-lasting potentiation of the perforant path-evoked population spike. Increases of 3 x to 6 x basal NE values were not accompanied by any potentiation. NE in the midline ventricles alone did not produce potentiation. These results suggest effective NE concentrations for beta-receptor activation of long-term potentiation would only occur near the NE release site.

Action Potentials↗

PubMed1996

Elevation of either axoplasmic norepinephrine or sodium level induced release of norepinephrine from cardiac sympathetic nerve terminals.

Using dialysis technique, prominent accumulation of norepinephrine (NE) in the myocardial interstitial space was observed under two different conditions: (1) local administration of a monoamine oxidase inhibitor (pargyline, 1, 10 mM), (2) local administration of a Na, K-ATPase inhibitor (ouabain, 10, 100 microM). Further, pretreatment with a vesicle uptake inhibitor (reserpine, 10 microM) augmented these responses. Either condition independently caused endogenous NE release and a brisk increase in dialysate NE levels might occur as a consequence of non-exocytotic release of NE.

Animals↗

PubMed1985

Morphine decreases 3H-norepinephrine release and increases endogenous norepinephrine levels in the isolated cat superior cervical ganglion.

The isolated cat superior cervical ganglion (SCG) was labeled in vitro with either 3H-norepinephrine (3H-NE) or 3H-choline and stimulated through its preganglionic trunk. The release of 3H-NE and 3H-acetylcholine (3H-ACh) elicited by the stimulation was measured under control conditions and in the presence of drugs. The incubation during 30 min with 10 microM morphine lead to a 70% decrease in the amount of 3H-NE released in response to the preganglionic stimulation (10 Hz, 80 V, during 5 min). No further decrease in 3H-NE release was produced by a 10 times higher concentration of morphine. The reduction in 3H-NE release caused by morphine was coincident with a 60% increase in the endogenous content of NE. Both effects of morphine were entirely prevented by an antagonist of opioid receptors, 1.0 microM naltrexone. The opioid antagonist did not modify by itself either the stimulation-induced release of 3H-NE or the endogenous content of NE. The basal efflux of 3H-NE was not altered by morphine. In ganglia labeled with 3H-choline, morphine (10 and 100 microM) did not modify either the basal efflux of 3H-ACh or the release of 3H-ACh evoked by stimulation of the preganglionic trunk (5 Hz, 40 V, during 5 min). These observations suggest that in the cat SCG morphine has a direct action on the dendrites of the postganglionic neuron which store and release NE. The effects of morphine in vitro on 3H-NE release and on the tissue levels of NE may be mediated through the interaction with dendritic opioid receptors.

Acetylcholine↗

PubMed1988

Contribution of adrenal norepinephrine output to increase aortic norepinephrine during carotid sinus reflex activation in anesthetized dogs.

Changes in circulating plasma catecholamine (CA: E, epinephrine; NE, norepinephrine; and DA, dopamine) concentrations in aortic (AO) blood were investigated in relation to variable rates of CA secretion from both adrenal (ADR) glands in response to bilateral carotid artery occlusion (BLCO) in vagotomized dogs anesthetized with sodium pentobarbital. During BLCO (3 min), AO systolic pressure (AP) increased along with significant increases in ADR-CA output, renal venous (RV) CA output, as well as in AO-E and NE concentrations. A ratio of NE:E in ADR venous and AO blood did not exceed 0.42 +/- 0.09 and 1.09 +/- 0.24 upon BLCO, respectively. In contrast, the NE:E ratio in RV blood increased significantly from 5.39 +/- 0.91 to 9.78 +/- 1.31. Following adrenalectomy (ADRX), the increase in AO-NE in response to BLCO was significantly attenuated by approximately 56%, but the increase in RV-NE output was not affected by ADRX. The results show that in vagotomized dogs, NE is co-released with E from the adrenal glands upon BLCO. The data also indicate that the increase in AO-NE concentration was dependent to a similar extent on the simultaneous increases in ADR-NE output and neuronal NE release. We conclude that under conditions where the sympathoadrenal system is activated, circulating plasma NE concentration may be significantly affected by an increase in ADR-NE output. Sympathetic neuronal contributions would, thereby, be overestimated in assessing overall sympathetic nerve activity by measuring circulating NE. NE concentrations in local venous effluent from individual organs may be more reliable estimates of the sympathetic nerve activity.

Adrenal Glands↗

PubMed1993

Alterations in K(+)-evoked release of 3H-norepinephrine and contractile responses in urethral and bladder tissues induced by norepinephrine reuptake inhibition.

The effects of norepinephrine (NE) reuptake inhibition on NE release and contractile responses in lower urinary tract tissues were evaluated using tomoxetine, a selective NE reuptake inhibitor, and imipramine, a nonselective reuptake inhibitor. Although both compounds significantly increased K(+)-evoked release of NE from urethral fragments obtained from rabbits, tomoxetine was at least 10X more potent than imipramine. Tomoxetine significantly enhanced the effects of NE to contract rabbit urethral fragments and to relax carbachol contracted rabbit bladder smooth muscle. Imipramine suppressed the effects of NE on urethral tissue and was less potent than tomoxetine in enhancing bladder responses to NE. These presynaptic and postsynaptic effects of NE reuptake inhibition in lower urinary tract tissues may contribute to the efficacy of imipramine in treating incontinence and represent a new clinical utility for selective and more potent reuptake inhibitors, such as tomoxetine.

Animals↗

PubMed2001

Effects of the selective norepinephrine reuptake inhibitor reboxetine on norepinephrine and serotonin transmission in the rat hippocampus.

Given that norepinephrine (NE) and serotonin (5-HT) neurons are implicated in the mechanisms of action of antidepressant drugs and both project to the hippocampus, the impact of acute and long-term administration of the selective NE inhibitor reboxetine was assessed on CA(3) pyramidal neuron firing in this postsynaptic structure. Cumulative injections of reboxetine (1-4 mg/kg, i.v.) dose-dependently increased the recovery time of the firing of these neurons following iontophoretic applications of NE, but not 5-HT. In rats treated with reboxetine for 2.5 mg/kg/day for 21 days, a robust increase in the recovery time following NE applications was observed, and a small but significant prolongation occurred following 5-HT applications. In controls and reboxetine-treated rats, 1 and 5 Hz stimulations of the afferent 5-HT bundle to the hippocampus, which allows determination of terminal 5-HT(1B) autoreceptor sensitivity, produced similar frequency-dependent decreases in pyramidal neuron firing in both groups. However, after low and high doses of clonidine (10 and 400 microg/kg, i.v.), which assesses alpha(2)-adrenergic auto- and heteroreceptor sensitivity, respectively, only the effect of the high dose of clonidine was attenuated. Interestingly, administration of the selective 5-HT(1A) receptor antagonist WAY 100,635 induced a 140% increase in basal pyramidal neuron firing in reboxetine as compared to saline-treated rats. This increase in tonic activation of postsynaptic 5-HT(1A) receptors might be attributable in part to a desensitization of alpha(2)-adrenergic heteroreceptors, presumably resulting from sustained NE reuptake inhibition. These results indicate that even a selective NE reuptake inhibitor can modulate 5-HT transmission.

Adrenergic Uptake Inhibitors↗

PubMed2001

Phospholipase D activation by norepinephrine is mediated by 12(s)-, 15(s)-, and 20-hydroxyeicosatetraenoic acids generated by stimulation of cytosolic phospholipase a2. tyrosine phosphorylation of phospholipase d2 in response to norepinephrine.

Norepinephrine (NE) stimulates phospholipase D (PLD) through a Ras/MAPK pathway in rabbit vascular smooth muscle cells (VSMC). NE also activates calcium influx and calmodulin (CaM)-dependent protein kinase II-dependent cytosolic phospholipase A(2) (cPLA(2)). Arachidonic acid (AA) released by cPLA(2)-catalyzed phospholipid hydrolysis is then metabolized into hydroxyeicosatetraenoic acids (HETEs) through lipoxygenase and cytochrome P450 4A (CYP4A) pathways. HETEs, in turn, have been shown to stimulate Ras translocation and to increase MAPK activity in VSMC. This study was conducted to determine the contribution of cPLA(2)-derived AA and its metabolites (HETEs) to the activation of PLD. NE-induced PLD activation was reduced by two structurally distinct CaM antagonists, W-7 and calmidazolium, and by CaM-dependent protein kinase II inhibition. Blockade of cPLA(2) activity or protein depletion with selective cPLA(2) antisense oligonucleotides abolished NE-induced PLD activation. The increase in PLD activity elicited by NE was also blocked by inhibitors of lipoxygenases (baicalein) and CYP4A (17-octadecynoic acid), but not of cyclooxygenase (indomethacin). AA and its metabolites (12(S)-, 15(S)-, and 20-HETEs) increased PLD activity. PLD activation by AA and HETEs was reduced by inhibitors of Ras farnesyltransferase (farnesyl protein transferase III and BMS-191563) and MEK (U0126 and PD98059). These data suggest that HETEs are the mediators of cPLA(2)-dependent PLD activation by NE in VSMC. In addition to cPLA(2), PLD was also found to contribute to AA release for prostacyclin production via the phosphatidate phosphohydrolase/diacylglycerol lipase pathway. Finally, a catalytically inactive PLD(2) (but not PLD(1)) mutant inhibited NE-induced PLD activity, and PLD(2) was tyrosine-phosphorylated in response to NE by a MAPK-dependent pathway. We conclude that NE stimulates cPLA(2)-dependent PLD(2) through lipoxygenase- and CYP4A-derived HETEs via the Ras/ERK pathway by a mechanism involving tyrosine phosphorylation of PLD(2) in rabbit VSMC.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗