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PubMed1995

Norepinephrine as a morphogen?: its unique interaction with brown adipose tissue.

Norepinephrine is normally considered a neurotransmitter mediating acute metabolic effects in target cells. However, analysis of the regulation of the recruitment process in brown adipose tissue has indicated that norepinephrine may interact with this tissue in such a way that it could be considered a morphogen for this tissue. Besides stimulating the acute thermogenic processes, norepinephrine can induce the expression of tissue-specific proteins such as the uncoupling protein, induce expression of non-tissue specific proteins necessary of the thermogenic processes (e.g. lipoprotein lipase) and repress the expression of non-essential proteins (e.g. subunit c of the ATP-synthase). Upon chronic adrenergic stimulation, the general differentiation state of the tissue is advanced, indicating that the expression of factors with a more general effect on brown adipocyte differentiation is also under adrenergic control. It may even be discussed that norepinephrine may be involved early in the embryonal determination process directing cell clones into this line. The molecular basis for these effects of norepinephrine are only poorly known at present, but adrenergic effects on the expression level of many transcription factors, such as C/EBPalpha, C/EBPbeta, and PPARgamma 2, have been noted. These collective recruitment effects of norepinephrine are well suited to allow the tissue to grow or atrophy in response to the physiological needs of the organism.

Adipose Tissue↗

PubMedDate not supplied

[Studies of DNP protein dissociation in the presence of norepinephrine].

Calf thymus DNP dissociation was studied by sepharose 2B gel-chromatography as well as by oxyapatite ion-exchange chromatography. The degree of dissociation was estimated by protein content in the chromatography peaks. Intact DNP and DNP incubated with norepinephrine were filtered simultaneously through two identical columns. In the presence of norepinephrine a partial deproteinization was observed. This effect has some specificity, namely, it was considerably lower in the presence of tyrosine, and was absent when the norepinephrine structure was changed. On the basis of the available data on the norepinephrine ability to form chelatic complexes with polyvalent metals and comparing the deproteinizing effect of norepinephrine and EDTA it was assumed that the norepinephrine dissociating effect was due to its binding with cations incorporated into the DNP complex structure.

Animals↗

PubMed1998

Pertussis toxin modification of PC12 cells lowers cytoskeletal F-actin and enhances norepinephrine secretion: involvement of protein kinase C and protein phosphatases.

We have investigated the relationship between norepinephrine secretion and cytoskeletal F-actin in rat phaeochromocytoma PC12 cells. Stimulation of PC12 cells with extracellular ATP or high K+ caused both the release of norepinephrine and a decrease in F-actin. The stimulation of secretion and the decrease in F-actin were dependent on extracellular Ca2+. The addition of Ca2+ to digitonin-permeabilized PC12 cells also stimulated norepinephrine release and decreased F-actin. Modification of PC12 cells with pertussis toxin caused a 35% decrease in F-actin, and it enhanced ATP-stimulated and K+ stimulated norepinephrine secretion from intact cells and Ca(2+)-dependent norepinephrine secretion from permeabilized cells. After down regulation of protein kinase C, pertussis toxin still enhanced secretion, but it had no effect on F-actin indicating that the effect of pertussis toxin on F-actin was dependent on protein kinase C activity. The addition of okadaic acid, an inhibitor of serine/threonine protein phosphatases, to PC12 cells caused a decrease F-actin, but it had no effect on ATP-stimulated or K(+)-stimulated norepinephrine secretion. After down regulation of protein kinase C, much higher concentrations of okadaic acid were need to decrease F-actin. The similarity between the effects of pertussis toxin and low concentrations of okadaic acid suggest that the effect of pertussis toxin on cytoskeletal F-actin in PC12 cells may result from an inhibition of protein phosphatase 2A.

Actins↗

PubMed1998

Time-dependent changes in norepinephrine-induced left ventricular dysfunction and histopathologic condition.

BACKGROUND: Intense activation of the sympathetic nervous system or administration of high concentrations of catecholamines diminishes myocardial contractility and produces infarct-like lesions throughout the heart. This study was conducted to determine whether norepinephrine-induced left ventricular (LV) dysfunction reverses with time and whether the histopathologic condition and the cardiac dysfunction produced by high doses of norepinephrine are causally related. METHODS: Norepinephrine, 10 microg bolus followed by 2.5 microg/kg/min for 90 minutes, was administered to conscious New Zealand white rabbits. Control rabbits (n=8) received saline solution. LV function was evaluated either immediately (n=7), on day 4 (n=8), or on day 10 (n=7) after norepinephrine treatment. Transverse sections from the left ventricle were then prepared for light microscopic study. RESULTS: Animals studied immediately after norepinephrine treatment demonstrated severe LV dysfunction and a decrease in global LV compliance. In contrast, LV function and compliance were normal in rabbits studied on day 4, but tissue sections from the left ventricle showed diffuse areas of inflammation. By day 10 the inflammatory process had progressed, and substantial collagen deposition had occurred. LV systolic function was normal, but a decrease in LV compliance was evident at this time. CONCLUSIONS: The normal LV systolic function on days 4 and 10 in spite of multiple foci of inflammation suggests (1) that norepinephrine-induced LV systolic dysfunction is reversible and (2) that the histologic derangements and the LV dysfunction are not causally related.

Animals↗

PubMedDate not supplied

[Daily excretion of epinephrine and norepinephrine in acute phase of cerebral ischemia].

The aim of the study was to assess the relation between urinary excretion of epinephrine and norepinephrine, and stroke severity, prognosis and standard biochemical investigations in acute phase of ischaemic stroke. The study was done on the material of 36 patients (17 women and 19 men, aged 41-89 years, mean: 69 +/- 13 years) admitted to the stroke unit of the Neurology Department within 24 hours (mean: 7.7 hours), after the first ever ischaemic stroke affecting the territory of the internal carotid artery circulation, confirmed by CT. Patients with the history of diabetes mellitus, cardiac insufficiency and infection on admission were excluded from the study. The 24-hour urine collection for catecholamines (epinephrine and norepinephrine) was done on the first and third day of hospitalization. An even single increased daily excretion of epinephrine (> 10 micrograms/24 hr) was found in 21 and norepinephrine (> 50 micrograms/24 hr) in 10 of 36 patients. No correlation between daily excretion of epinephrine and norepinephrine was found. Statistical analysis revealed a significant relation between norepinephrine, but not epinephrine, and neurological deficit, prognosis and some biochemical parameters of investigated patients. Patients with increased daily excretion of norepinephrine showed worse neurological deficit (p < 0.01), greater mortality assessed on the 30-th and 90-th day of stroke (p < 0.05) and increased plasma glucose, sedimentation rate, white blood cells count, creatinine kinase activity as well as microalbuminuria and decreased plasma kalium concentration.

Acute Disease↗

PubMed1976

Effect of variations in adrenocortical function on dopamine beta-hydroxylase and norepinephrine in the brain of the rat.

The effect of adrenalectomy and corticosterone treatment on dopamine beta-hydroxylase (DBH) activity, catecholamine content and norepinephrine formation and metabolism were studied in the hypothalamus and other parts of the brain of male rats. Two days after adrenalectomy, there was a decrease in DBH activity in the hypothalamus and the brain stem but no change in norepinephrine or dopamine content. Conversion of intraventricularly administered tritiated dopamine to tritiated norepinephrine was slightly increased and norepinephrine was metabolized at a more rapid rate than normal. Corticosterone in a dose of 100 mg/kg increased DBH activity but decreased hypothalamic norepinephrine and copamine content. In adrenalectomized rats, smaller, more physiological doses of corticosterone did not change DBH activity or catecholamine content. The fact that norepinephrine formation and metabolism were increased at the same time that DBH activity in vitro was decreased suggests that DBH is not rate-limiting in adrenergic neurons in the hypothalamus, or that a change in the in vitro activity of the enzyme was not accompanied by a parallel change in its activity in vivo.

Adrenal Cortex↗

PubMed1971

Effects of L-dopa on norepinephrine metabolism in the brain.

Rats received intracisternal [(3)H]norepinephrine and, after 5 min, intraperitoneal L-dopa (100 mg/kg); they were killed at intervals during the subsequent 24 hr. Their brains were assayed for norepinephrine, L-dopa, S-adenosylmethionine, and [(3)H]norepinephrine and its metabolites. Rats that received L-dopa had markedly lower brain concentrations of S-adenosylmethionine and of O-methylated metabolites of [(3)H]norepinephrine than controls. An increase (15-40%) in brain norepinephrine content and accelerated turnover of brain norepinephrine was also observed in the animals receiving L-dopa. These changes were all transient, lasting about 1 hr and coinciding with the period when appreciable amounts of L-dopa were detectable in the brain.

Animals↗

PubMed1983

Developmental changes in response of dog isolated ventricular myocardium to norepinephrine.

There are maturational changes of myocardial function and response to inotropic agents. Because of incomplete myocardial sympathetic innervation, neonatal myocardium may be more sensitive to norepinephrine than is adult myocardium. We tested this hypothesis by using isolated trabecular muscle from two groups of puppies and from adult dogs. The muscles were exposed to norepinephrine at concentrations of 1 x 10(-10) to 1 x 10(-4) M, and indices of isometric and isotonic contraction were measured. Active tension and maximum rate of contraction increased in all age groups with norepinephrine. Adult dogs were more sensitive than puppies to the arrhythmogenic effect of norepinephrine. Although there was no strictly significant difference statistically, there appeared to be an age-related increase in the dose at which 50% of the maximum effect of the drug was achieved (ED50). Total contraction time, time to peak tension, and relaxation time decreased with increasing concentrations of norepinephrine in older puppies and in adults but not in newborn puppies. Thus, there are significant age-related differences in response to norepinephrine.

Journal Article↗

PubMed1985

Receptor (norepinephrine), P-site (2',5'-dideoxyadenosine), and calcium-mediated inhibition of prostaglandin and forskolin-activated cyclic AMP-generating systems in human platelets.

Prostaglandin D2, 2-chloroadenosine, forskolin and combinations of these agents increase cyclic AMP-levels in intact human platelets. The inhibition of activated cyclic AMP-generating systems by 1) alpha2-adrenergic receptor-mediated hormonal input (norepinephrine), 2) a P-site agent (2',5'-dideoxyadenosine) and 3) a divalent cation (calcium) were examined: 1) Norepinephrine produces non-competitive inhibition of both forskolin and prostaglandin D2(PGD2)-stimulated cyclic AMP-accumulation in intact human platelets. The Ki values for norepinephrine versus forskolin, PGD2 and 2-chloroadenosine are similar in magnitude, while the Ki versus a forskolin-PGD2 combination is approximately 10-fold greater. Onset of inhibition by norepinephrine of the PGD2-response is several fold faster than for the forskolin-response. When platelets stimulated by the forskolin and PGD2 combination are exposed to norepinephrine, there is a transient increase in levels of cyclic AMP due to the potentiation of a minor beta-adrenergic component. This stimulation is followed by inhibition. 2) 2',5'-Dideoxyadenosine produces a non-competitive inhibition of the forskolin-response with a Ki of 110 microM. The inhibition of the PGD2-response by 2',5'-dideoxyadenosine is competitive with a Ki of 6-13 microM, while inhibition of the forskolin-PGD2 response has a Ki of 30 microM. Onset of inhibition by 2',5'-dideoxyadenosine is identical for forskolin or PGD2-stimulated platelets. There is a lag period for inhibition of platelets stimulated with the forskolin-PGD2 combination. The PGD2-forskolin combination appears to stabilize the cyclic AMP-generating system of platelets against inhibition by either norepinephrine or 2',5'-dideoxyadenosine. 3) Calcium ions cause a similar inhibition of cyclic AMP-generation in intact platelets, regardless of the type of stimulation.

Adenylyl Cyclase Inhibitors↗

PubMed2000

Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders.

BACKGROUND: The etiology of depressive illness has been linked with brain monoaminergic neuronal dysfunction, yet the development of sensitive markers of endogenous depression has proven difficult. METHODS: Using catheters placed in an internal jugular vein, we estimated the release of brain monoamine neurotransmitters in 19 healthy volunteers and in 9 patients with nonbipolar depressive illness refractory to medication at rest and following intravenous desipramine hydrochloride. Venoarterial plasma concentration gradients were used to quantify the amount of neurotransmitters stemming from the brain. Cerebral oxidative metabolism was assessed concurrently from measurements of oxygen and carbon dioxide gas exchange via the process of regional indirect calorimetry. RESULTS: The brains of these patients exhibited reduced venoarterial norepinephrine (4.0 +/- 2.7 nmol/L vs 0.7 +/- 1.3 nmol/L) and homovanillic acid concentration gradients (8.3 +/- 7.8 nmol/L vs 3.1 +/- 1.9 nmol/L), and used an energy source other than glucose. Internal jugular 5-hydroxyindoleacetic acid concentration gradients were not reduced in the patients with depressive illness. While both the reduction in norepinephrine turnover and the defect in cerebral metabolism were normalized following pharmacological blockade of the norepinephrine transporter with desipramine, paradoxically it was the brain's turnover of dopamine that bore a significant relation to the patients' clinical status (r(s) = 0.79, P =.02). The positive nature of this relationship remains difficult to reconcile. CONCLUSIONS: In accordance with the monoamine hypothesis, a deficit in brain norepinephrine and dopamine exists in patients with depressive illness. Moreover, the brains of these patients use an energy source other than glucose, a situation that is normalized following the acute pharmacological blockade of the norepinephrine transporter with the tricyclic antidepressant, desipramine.

Adult↗

PubMed1993

Fluoxetine and desipramine selectively attenuate 2'-NH2-MPTP-induced depletions in serotonin and norepinephrine.

We recently reported that the novel MPTP analog 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP) administered to C57BL/6 mice produced substantial decreases in forebrain serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine, with negligible effects on brain dopamine or dopamine metabolites. In the present report, we confirm and extend our original results to include dose-response data and the effect of selective uptake inhibition on the levels of monoamine neurotransmitters in various regions of the mouse brain following treatment with 2'-NH2-MPTP. In a dose-ranging study, 2'-NH2-MPTP (10 mg/kg x 4) produced a 25-30% reduction in frontal cortex 5-HT, 5-HIAA, and norepinephrine. When 4 x 20 mg/kg 2'-NH2-MPTP was administered, 70-75% reductions in 5-HT, 5-HIAA, and norepinephrine in both frontal cortex and hippocampus were seen 1 week after treatment. No changes in dopamine were found in striatum or in any of the other brain regions examined at either dose. Doses of 40 and 60 mg/kg were lethal shortly after a single injection. In mice receiving either fluoxetine or desipramine (10 mg/kg) prior to 2'-NH2-MPTP (20 mg/kg x 4), decreases in 5-HT and norepinephrine, respectively, were significantly attenuated by approximately 30-40%. These data suggest that 2'-NH2-MPTP acts in a dose-dependent manner and that the serotonergic and noradrenergic uptake systems are involved in the mechanism by which 2'-NH2-MPTP causes selective deficits in cortical and hippocampal 5-HT and norepinephrine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2005

Dopamine and norepinephrine transporter-dependent c-Fos production in vitro: relevance to neuroadaptation.

Cocaine, methylphenidate and other drugs that block dopamine transport indirectly promote immediate early gene expression, via dopamine-mediated activation of D1 dopamine receptors. Increased expression of the immediate early gene (IEG) c-fos, initiates a cascade of intracellular events that may underlie neuroadaptive changes following repeated exposure to the drugs. We investigated whether substrates (dopamine, norepinephrine) of the human dopamine (hDAT) and norepinephrine (hNET) transporters can directly induce c-Fos protein in HEK-293 (HEK) cells transfected with the hDAT and hNET and whether PKC modulators affect this process. Dopamine and norepinephrine robustly induced c-Fos immunofluorescence in both hDAT and hNET cells, but not in untransfected HEK-293 cells, demonstrating that catecholamine-induced c-Fos induction was DAT- and NET-dependent. The PKC activator PMA induced c-Fos in hDAT, hNET and HEK cell lines indicating that PKC stimulated c-Fos independent of transporters. The PKC inhibitor bisindolylmaleimide I (BIS) significantly increased c-Fos expression in hDAT cells, but not in hNET or HEK-293 cells, suggesting that inhibition of DAT-mediated phosphorylation results in c-Fos induction. BIS pretreatment abolished norepinephrine-induced c-Fos expression hNET but not dopamine-induced c-Fos induction in hDAT cells. In conclusion, induction of c-Fos by dopamine and norepinephrine requires the presence of hDAT and hNET but the contributions of hDAT and hNET to c-Fos induction is distinguishable on the basis of differing responses to a PKC inhibitor. These findings present a cell system and methodology for investigating the potential contribution of monoamine transporters to pre-synaptic neuroadaptation.

Adaptation, Physiological↗

PubMed1997

Placental norepinephrine transporter development in the ovine fetus.

The placenta has been shown to be a site of expression of several of the monoamine membrane uptake transporters. However, the development and relative contribution of transport-dependent mechanisms to placental catecholamine clearance in vivo have not been demonstrated. These studies were designed to determine the development of the placental norepinephrine transporter (NET) and the relative contribution of transport dependent mechanisms to whole body and placental catecholamine clearance. Norepinephrine clearance and production rate were determined in 122 +/- 1 day gestation chronically catheterized fetal sheep. Placental clearance was shown to account for over 40 per cent of total intrauterine clearance and, of the clearance in the placenta, nearly 50 per cent was uptake, transport-dependent as shown by specific pharmacologic blockade. NET transport expression was examined by measurement nisoxetine binding in placenta and compared with binding in the frontal cortex of fetal, newborn and adult animals. Nisoxetine is a selective ligand for the norepinephrine transporter. Nisoxetine binding was 20-fold greater in placenta than in frontal cortex. Placental transporter binding decreased modestly in between 99 days gestation and term (145 days) but did not change in frontal cortex. These results suggest that expression of the norepinephrine transporter in the placenta is associated with a significant capacity for neurotransmitter re-uptake in utero. Given the high fetal norepinephrine production rate, this capacity is important for fetal homeostasis. This site of transporter expression may be important in the pathogenesis of derangements in catecholamine production in the fetus and in the adverse effects on the fetus of drugs, such as cocaine, which block catecholamine re-uptake.

Animals↗

PubMed1995

Differential in vivo regulation of mRNA encoding the norepinephrine transporter and tyrosine hydroxylase in rat adrenal medulla and locus ceruleus.

To investigate the regulation of norepinephrine transporter mRNA in vivo, we analyzed the effects of reserpine on its expression in the rat adrenal medulla and locus ceruleus. First, PCR was used to clone a 0.5-kb rat cDNA fragment that exhibits 87% nucleotide identity to the corresponding human norepinephrine transporter cDNA sequence. In situ, the cDNA hybridizes specifically within norepinephrine-secreting cells, but in neither dopamine nor serotonin neurons, suggesting strongly it is a partial rat norepinephrine transporter cDNA. Reserpine, 10 mg/kg administered 24 h premortem, decreased steady-state levels of norepinephrine transporter mRNA in the adrenal medulla by approximately 65% and in the locus ceruleus by approximately 25%, as determined by quantitative in situ hybridization. Northern analysis confirmed the results of the in situ hybridization analysis in the adrenal medulla but did not detect the smaller changes observed in the locus ceruleus. Both analyses showed that reserpine increased tyrosine hydroxylase expression in the adrenal medulla and locus ceruleus. These results suggest that noradrenergic neurons and adrenal chromaffin cells can coordinate opposing changes in systems mediating catecholamine uptake and synthesis, to compensate for catecholamine depletion.

Adrenal Medulla↗

PubMed2003

Orthostatic intolerance is not necessarily related to a specific mutation (Ala457Pro) in the human norepinephrine transporter gene.

BACKGROUND: Orthostatic intolerance (OI) is a syndrome characterized by lightheadedness, palpitations, fatigue, blurred vision, dizziness, chest discomfort, cognitive impairment, and occasionally syncope. These symptoms usually occur after upright posture and are associated with tachycardia and high plasma concentrations of norepinephrine. It has been proposed that a mutation in exon 9 of the norepinephrine transporter gene (Ala457Pro), resulting in more than 98% loss of function compared with the wild type, might provide a pathogenetic mechanism to explain the clinical symptoms of patients with OI. METHODS: We studied 46 young men from military service who had sought medical advice because of dizziness while standing. Every patient underwent a tilt-table test, with monitoring of blood pressure, heart rate, and plasma catecholamines in supine position and during 30 minutes of standing. Fourteen patients showing the full-blown OI syndrome (30 bpm increase in heart rate and 600 pg/mL plasma norepinephrine levels while standing) underwent direct DNA sequencing of exon 9 of the norepinephrine-transporter gene. RESULTS AND CONCLUSIONS: The specific mutation (Ala457Pro) was not detected in any of the 14 OI patients. Based on these findings, we doubt that this specific genetic transport defect is a frequent cause of the impaired uptake of norepinephrine in OI patients. Its routine determination will therefore not be helpful to establish the clinical diagnosis of OI.

Adolescent↗

PubMed2002

Inhibition of norepinephrine uptake in patients with major depression treated with paroxetine.

OBJECTIVE: The study examined whether paroxetine inhibits the human norepinephrine transporter in addition to the human serotonin (5-HT) transporter in patients with major depressive disorder. METHOD: In an open-label, parallel-group, forced-titration study, 52 outpatients with DSM-IV major depressive disorder and a baseline Montgomery Asberg Depression Rating Scale score > or =20 were randomly assigned to treatment with paroxetine (to 60 mg/day) or desipramine (to 30 mg/day) in a 3-to-1 ratio, respectively. Norepinephrine and 5-HT transporter function were assayed by using human transporter transfected cells in the presence of serum collected at baseline and the end of each treatment week. Data from 36 patients were analyzed. RESULTS: Paroxetine decreased norepinephrine uptake to 73% of control (27% inhibition) at an average serum concentration of 100 ng/ml and 57% of control (43% inhibition) at 200 ng/ml. Uptake of 5-HT was decreased to less than 15% (greater than 85% inhibition) of control at these paroxetine concentrations. Desipramine decreased norepinephrine uptake to near maximal 15% of control (85% inhibition) at 100 ng/ml. Uptake of 5-HT was decreased to 82% of control (18% inhibition) at 100 ng/ml and 49% of control (51% inhibition) at 500 ng/ml. CONCLUSIONS: Paroxetine, currently classified as a selective 5-HT reuptake inhibitor, can act as a 5-HT/norepinephrine uptake inhibitor in vivo. The clinical significance of this action on norepinephrine uptake is currently unknown, but this action may contribute to the broad therapeutic efficacy of paroxetine in the treatment of depression, panic disorder, social anxiety disorder, posttraumatic stress disorder, and generalized anxiety disorder.

Adult↗

PubMed2000

Regulation of the human norepinephrine transporter by cocaine and amphetamine.

Certain antidepressant and psychostimulant drugs block the uptake of norepinephrine from the synaptic cleft by inhibiting norepinephrine transporter (NET) function. The effects of chronic occupation of the NET by these drugs on NET expression are poorly understood. We previously described down-regulation of the NET in cultured cells after continuous exposure to the tricyclic antidepressant desipramine. Here, the effects of structurally unrelated NET ligands, cocaine and amphetamine, on levels of NET and on NET function in HEK-293 cells transfected with human NET cDNA were investigated. All drug exposures were followed by incubation in drug-free media before harvesting and assays. Exposure of intact cells to cocaine for 3 days did not significantly affect the B(max) or K(D) of [(3)H]nisoxetine binding to NET in membrane homogenates, and did not alter levels of NET immunoreactivity or NET mRNA. In contrast, incubation of cells with amphetamine significantly reduced [(3)H]nisoxetine binding to NET and levels of NET immunoreactivity in a time-dependent manner, although levels of NET mRNA appeared to be unaffected. Exposures to cocaine or amphetamine resulted in significant reductions of [(3)H]norepinephrine uptake, although the magnitude of the reduction produced by amphetamine was much greater than cocaine. [(3)H]Nisoxetine binding to NET and NET protein levels were also reduced by exposure of cells to high concentrations of norepinephrine, although norepinephrine exposures were accompanied by changes indicative of cellular toxicity. Cocaine and amphetamine have distinctly different effects on NET expression after continuous exposure. The ability of only certain drugs to down-regulate the NET may provide clues to the unique therapeutic effects of antidepressants that are NET ligands.

Amphetamine↗

PubMed2003

Increased MIBG uptake after transfer of the human norepinephrine transporter gene in rat hepatoma.

UNLABELLED: The transport of MIBG by the human norepinephrine transporter (hNET) seems to be the critical step in the treatment of MIBG-concentrating tumors. Therefore, we investigated whether the accumulation of MIBG may be induced by retroviral transfection of the hNET gene in Morris hepatoma cells. METHODS: A bicistronic retroviral vector for the transfer of the hNET coding sequence and the hygromycin resistance gene was generated. Morris hepatoma cells (MH3924A) were infected with the respective retroviral particles, and hNET-expressing cell lines MHhNEThyg1 to MHhNEThyg9 were obtained through hygromycin selection. The uptake of (3)H-norepinephrine or (131)I-MIBG and the efflux of (131)I-MIBG were determined in transfected and wild-type cells. In addition, the (131)I-MIBG distribution was monitored in nude mice and rats bearing wild-type and hNET-expressing hepatomas. RESULTS: hNET-expressing hepatoma cell lines accumulated up to 36 times more norepinephrine than did wild-type cells and 8 times more than did hNET-expressing neuroblastoma cell line SK-N-SH. The addition of nisoxetine, a selective inhibitor of noradrenaline uptake, inhibited norepinephrine uptake. Maximal (131)I-MIBG accumulation was observed 2 h after incubation and was followed by 43% efflux within 4 h after the (131)I-MIBG-containing medium had been removed. In vivo experiments performed with nude mice bearing both hNET-expressing and wild-type tumors showed a 10-fold-higher accumulation of (131)I-MIBG in transfected tumors than in wild-type tumors. The ex vivo calculations revealed doses of 605 and 75 mGy in hNET-expressing and wild-type tumor tissues, respectively. CONCLUSION: Transduction of the hNET gene enables Morris hepatoma cells to accumulate norepinephrine and MIBG. However, the retention of MIBG is brief; therefore, the absorbed dose of radiation in vivo is not expected to be therapeutically effective.

3-Iodobenzylguanidine↗