High Concentrations Of Noradrenaline Research Articles

Noradrenergic ‘Tone’ Determines Dichotomous Control of Cortical Spike-Timing-Dependent Plasticity

Norepinephrine (NE) is widely distributed throughout the brain. It modulates intrinsic currents, as well as amplitude and frequency of synaptic transmission affecting the ‘signal-to-noise ratio’ of sensory responses. In the visual cortex, α1- and β-adrenergic receptors (AR) gate opposing effects on long-term plasticity of excitatory transmission. Whether and how NE recruits these plastic mechanisms is not clear. Here, we show that NE modulates glutamatergic inputs with different efficacies for α1- and β-AR. As a consequence, the priming of synapses with different NE concentrations produces dose-dependent competing effects that determine the temporal window of spike-timing dependent plasticity (STDP). While a low NE concentration leads to long-term depression (LTD) over broad positive and negative delays, a high NE concentration results in bidirectional STDP restricted to very narrow intervals. These results indicate that the local availability of NE, released during emotional arousal, determines the compound modulatory effect and the output of STDP.

Neurotransmitter modulation and supraspinal fatigue

An important aspect of central fatigue is supraspinal fatigue, or fatigue originating from an insufficient output from the motor cortex. One possible underlying mechanism is that this reaction is evoked...

Plasma methoxytyramine: A novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status

BackgroundThere are currently no reliable biomarkers for malignant pheochromocytomas and paragangliomas (PPGLs). This study examined whether measurements of catecholamines and their metabolites might offer utility for this purpose. MethodsSubjects included 365 patients with PPGLs, including 105 with metastases, and a reference population of 846 without the tumour. Eighteen catecholamine-related analytes were examined in relation to tumour location, size and mutations of succinate dehydrogenase subunit B (SDHB). ResultsReceiver-operating characteristic curves indicated that plasma methoxytyramine, the O-methylated metabolite of dopamine, provided the most accurate biomarker for discriminating patients with and without metastases. Plasma methoxytyramine was 4.7-fold higher in patients with than without metastases, a difference independent of tumour burden and the associated 1.6- to 1.8-fold higher concentrations of norepinephrine and normetanephrine. Increased plasma methoxytyramine was associated with SDHB mutations and extra-adrenal disease, but was also present in patients with metastases without SDHB mutations or those with metastases secondary to adrenal tumours. High risk of malignancy associated with SDHB mutations reflected large size and extra-adrenal locations of tumours, both independent predictors of metastatic disease. A plasma methoxytyramine above 0.2nmol/L or a tumour diameter above 5cm indicated increased likelihood of metastatic spread, particularly when associated with an extra-adrenal location. ConclusionPlasma methoxytyramine is a novel biomarker for metastatic PPGLs that together with SDHB mutation status, tumour size and location provide useful information to assess the likelihood of malignancy and manage affected patients.

Giant Cystic Pheochromocytoma Containing High Concentrations of Catecholamines and Metanephrines

A 27-yr-old woman, known with neurofibromatosis type 1 and generalized anxiety disorder, presented with headaches, episodic palpitations, and pallor. Atenolol, started for hypertension by her family doctor, triggered a hypertensive crisis (226/126 mm Hg). Twentyfour-hour urine analysis demonstrated elevated excretion of metanephrine [65.7 ( 1.52; upper limit of reference range) mol/d] and normetanephrine [59.27 ( 1.95) mol/d], and to a lesser extent norepinephrine [2806 ( 569) nmol/d] and epinephrine [1222 ( 149) nmol/d]. Abdominal computed tomography (CT) scan showed a large solid and cystic lesion involving the right adrenal gland (Fig. 1A). 131-I methyliodobenzylguanidine scan showed a right adrenal tumor with prominent peripheral uptake and large central defect (Fig. 1B). After medical preparation with 3 wk of phenoxybenzamine (up to 90 mg/d), propranolol, and preoperative saline loading, the patient appeared clinically adequately blocked. However, anesthetic induction (fentanyl, propofol, lidocaine, and rocuronium) caused a hypertensive crisis (280/170 mm Hg) and prevented surgery. Phenoxybenzamine dosage was increased to 60 mg three times a day, and nifedipine SR 30 mg was added. Intravenous phenylephrine (1 mg) did not affect intraarterial blood pressure, indicating adequate -blockade. The next day, during open adrenalectomy, brittle blood pressure was noted until completion of tumor dissection. A sample of the liquefied tumor center was obtained (Fig. 2). Compared with plasma reference values (1), the cystic fluid contained extremely high concentrations of norepinephrine [65,967 ( 3.4) nmol/liter], epinephrine [51,000 ( 0.8) nmol/liter], dopamine [791.5 ( 0.21) nmol/liter], metanephrine [1,150 ( 0.3) nmol/liter], and normeta-

Measurement of urinary metadrenaline and normetadrenaline by liquid chromatography tandem mass spectrometry for the diagnosis of phaeochromocytoma

Measurement of metadrenalines has been recommended in the investigation of phaeochromocytoma. Urinary assays remain the most common; however, drug interference is still one of the main challenges for analytical systems. We have developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of total urinary normetadrenaline and total urinary metadrenaline, which does not require extraction procedures prior to analysis. Total urinary normetadrenaline and total urinary metadrenaline were individually quantified by electrospray ionization in the multiple-reaction monitoring mode. Deuterated internal standards were used and an acid hydrolysis step was used to convert conjugated metabolites into free metadrenalines. Chromatographic separation was achieved using a Phenomenex Luna 3 micro PFP column followed by analysis on an API 3200 LC-MS/MS. Linearity was exhibited across the calibration range for both normetadrenaline (r = 1, P < 0.0001) and metadrenaline (r = 1, P < 0.0001) with the limit of quantification of 0.05 and 0.02 micromol/L, respectively. Intra-assay imprecision for both normetadrenaline and metadrenaline was less than 5.5% with % coefficient of variations of less than 4%. Inter-assay imprecision was less than 13%. Neither noradrenaline or adrenaline interfere with the assay as determined by the spiking of samples with high concentrations of noradrenaline or adrenaline (P > 0.05). Acceptable analytical performance was seen with comparison to a high-performance liquid chromatography method and on External Quality Assessment returns. An analytically simple and sensitive method has been developed and evaluated for the analysis of total urinary normetadrenaline and total urinary metadrenaline which is now in routine use.

Successful treatment for sympathetic storms in a patient with neuro-Behçet’s disease

Sympathetic storms (SyS) are characterized by hyperactivity of autonomic functions, resulting in episodes of hyperthermia, hypertension, tachycardia, and hyperhidrosis. We show here a patient with neuro-Behçet's disease (NBD) complicated by SyS. Although SyS is well known to occur with brain tumors, trauma, and hydrocephalus, this is the first report to show that SyS is a manifestation of central nervous system involvement in a patient with NBD. High concentrations of norepinephrine (NE) and IL-8 in cerebrospinal fluid reflected the activity of SyS. The patient's symptoms showed almost complete improvement after treatment with corticosteroids and intravenous cyclophosphamide. Also, the concentrations of NE and IL-8 were decreased to normal levels. An awareness of the potential for SyS and adequate immunosuppressant therapy are of importance when dealing with patients with NBD.

Biphasic Modulation of ER-JIN Decalculous Decoction (EJDD) on the Spontaneous Contraction of Porcine Ureteral Smooth Muscle

Background/Purpose. In our previous studies, we showed that ER-JIN Decalculous Decoction (EJDD) could prevent and dissolve experimental bladder calculi. The purpose of this study was further to explore whether EJDD affects the ureteral smooth muscle. Methods. Isolated porcine ureteral smooth muscle was used to investigate the mechamism of EJDD. The smooth muscle was vertically hung in an organ bath comprising 10 mL Kreb's Ringer solution at 37 C with 95% O2 and 5% CO2. Results. Norepinephrine (NE), 5-hydroxytryptamine (5-HT) and PGF(subscript 2a) augmented the frequency and potency of spontaneous smooth muscle contraction in a dose-dependent manner. NE at 1×10^(-4) M and 5-HT at 1×10^(-5) M induced tonic contraction. Spontaneous contraction was inhibited by isoproterenol. EJDD (0.25 to 2 mg/mL) enhanced the frequency and potency of spontaneous contraction in a concentraction-independent manner. EJDD also inhibited the tonic contractions induced by high concentrations of NE and 5-HT. However, the spontaneous contractions induced by NE, 5-HT and PGF(subscript 2a)were inhibited by pretreatment with EJDD. Conclusion. The results suggest that EJDD targets the α, β and 5-HT receptors in islolated procine ureters. The complex effects of EJDD were dependent on endogenous spontaneous contractivity.

Maximal and submaximal treadmill tests in a young adult with fragile-X syndrome

Fragile X syndrome is associated with expansion of a CGG triplet repeat in the FMR1 gene, which abolishes production of the FMRP protein. This abnormality is expressed as a number of neuro-endocrine disorders (the adrenal axis, macroorchidism) and the emergence of significant behavioural stress. Here, we report on the hormonal status of a young adult with fragile X syndrome, with a focus on catecholamine and cortisol changes during a submaximal treadmill test. The patient showed abnormally high epinephrine and norepinephrine concentrations. During a submaximal incremental test, cortisol levels were higher than the laboratory reference range. Although the submaximal incremental test has a significant “stressful” effect, this young adult was able to complete the entire protocol without any maladaptive behaviour or withdrawal.

D-Lactate inhibition of memory in a single trial discrimination avoidance task in the young chick

l-Lactate is a metabolite possibly able to meet some neuronal energy demands. However, a clear role for l-lactate in behaviour remains elusive. Administration of the inactive isomer d-lactate (1.75 mM; ic), immediately post-training, resulted in a persistent retention loss from 40 min post-training when used in conjuction with a single trial discrimination avoidance task designed for the young chick. Furthermore, 1 mM noradrenaline (ic) administered 20 min post-training overcame the retention loss induced by d-lactate. Although not directly demonstrated in the current study, it is plausible that d-lactate inhibited memory processing by competing with l-lactate for uptake into neurons. The time of onset of the retention loss induced by d-lactate is in accord with findings where the action of noradrenaline is inhibited. The successful challenge of d-lactate inhibition by a high concentration of noradrenaline may suggest a relationship by some unidentified mechanism.

Long-term changes in sympathetic innervation in the corpus cavernosum of the STZ-diabetic rat

The noradrenaline (NA) concentration in the rat corpus cavernosum (CC) increased to approximately 350% of control values after about 8 weeks of hyperglycaemia induced by the intraperitoneal injection of streptozotocin (STZ) at 10 weeks of age. These changes were maintained for at least a further 32 weeks of hyperglycaemia and occurred without any significant change in the weight in the tissue. Smaller but significant increases in NA concentration occurred in the glans penis (GP) reaching 150-175% of the control levels during the period of prolonged hyperglycaemia. In contrast, there was no significant change in the NA concentration in the penile urethra. Measurements have also been made that relate to changes in the synthesis and reuptake of NA in the CC during the period during which high NA concentration is maintained. Immunohistochemical studies for the synthetic enzyme tyrosine hydroxylase in the CC indicate that the intensity of staining in the tissue had increased after 10, 20 and 32 weeks of hyperglycaemia, relative to the tissues from control animals. Dilated nerve fibres and engorged endings were present in the CC of the diabetic animals at these times. Reuptake of tritiated NA by the terminal axonal membranes in the CC was raised to 181% of control values after 12 weeks of hyperglycaemia (P<0.05), but later declined to values that are not significantly different from the control levels (after 26 and 64 weeks of hyperglycaemia). There are few studies of the effects of prolonged diabetes on functional aspects of sympathetic postganglionic neurones in the CC, and this paper suggests that the changes described represent remodelling of noradrenergic axonal terminals starting about after 8-10 weeks of hyperglycaemia; this delay in onset of the neuropathic changes is also a feature of type I diabetes in humans.

Dopaminergic and adrenergic toxicities on SK-N-MC human neuroblastoma cells are mediated through G protein signaling and oxidative stress

Dopamine and norepinephrine are neurotransmitters which participate in various regulatory functions of the human brain. These functions are lost in neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. In this study, we used SK-N-MC neuroblastoma cells to investigate the cytotoxicities of high concentrations of dopamine and norepinephrine on neuronal cells. Dopamine, norepinephrine, as well as their corresponding synthetic agonists (SKF38393 and isoproterenol, respectively) triggered SK-N-MC cell death when applied at 50-100 muM persistently for 2 days. This catecholamine-induced cell death appears to be neuronal specific, as demonstrated by their inabilities of triggering apoptosis of A549 lung carcinoma cells and Cos-7 kidney fibroblasts. By pretreating SK-N-MC cells with target-specific inhibitors before administration of catecholamine, components of G protein signaling (i.e. G( s )/cAMP/PKA), monoamine oxidases, nitric oxide synthase, c-Jun N-terminal kinase and oxidative stress were found to be involved in this dopamine/norepinephrine-induced cytotoxicity, which subsequently led to caspase-dependent and -independent apoptotic responses as well as DNA degradation. In contrast, agonists of G( i )-coupled dopamine receptors and adrenergic receptors (quinpirole and UK14,304, respectively) were incapable of triggering apoptosis of SK-N-MC cells. Our results suggest that both G protein (G( s ))-mediated signaling cascade and oxidative stress participate in the dopamine/norepinephrine-induced neuronal apoptosis.

Validation of a behavioral observation tool to assess pig welfare

Accurately measuring and monitoring of animal behavior is an important factor when assessing on-farm animal welfare. First we developed a feasible and simple method aiming at consistently on-farm measuring of pig's behavior. This test should cover a broad range of welfare-related pig behavior. The reaction towards a novel object, startling, tail and ear biting, play and aggressive behavior, stereotypies, coughing, sneezing, skin lesions, defecation, urination and cleanliness of body and pen are included. The development of accurate measures of on-farm behavior first requires the reliability assessment of the procedure. Therefore, the methodology was tested in a first part by three observers scoring simultaneously and independently pre-defined behavioral characteristics of 108 group-housed fattening pigs. The inter-observer repeatability of the measures was calculated using intraclass correlation coefficients, which ranged from 0.7 to 1. In a second part, the objective was to validate the behavioral characteristics against salivary cortisol, urinary epinephrine and norepinephrine and production traits. Salivary cortisol concentrations significantly increased in ear-bitten pigs and in pigs with tail lesions. Growth rate significantly dropped when cortisol levels rose. An age effect was also found. The percentage of animals approaching the novel object is positively correlated with the urinary epinephrine concentration. Pigs defecating during the test showed significantly higher epinephrine levels. Urinary norepinephrine concentration decreased significantly with age. Faster growing animals and animals with tail lesions showed significantly higher levels of norepinephrine. Pen dirtiness and number of animals per pen were associated with higher norepinephrine concentrations. Finally, barrows had higher norepinephrine concentrations than sows.

Impairment of single-trial memory formation by oral methylphenidate in the rat

High synaptic concentrations of dopamine and/or norepinephrine can impair the working memory function of the prefrontal cortex and impede attention and learning. Methylphenidate, a dopamine and norepinephrine transporter blocker known to facilitate these cognitive processes at low doses, was hypothesized to interfere with memory storage at doses that may raise concentrations of these neurotransmitters to systemically disruptive levels. In the present experiments, a dose of 10.0 mg/kg of this drug was administered to female and male Long-Evans rats using a novel oral administration procedure designed to model the normal mode of delivery to humans. It was found to interfere with single-trial memory acquisition in a delayed object recognition test, a spontaneous learning task that involves no appetitive or aversive motivator. The time that the rats spent in overt exploration of the to-be-remembered objects during the acquisition trial was not affected, suggesting that the drug may have impaired processes of memory formation independently of interference with attention.

Low plasma vasopressin/norepinephrine ratio predicts septic shock

To evaluate if low plasma vasopressin and high norepinephrine concentrations predict grave prognosis of sepsis, a prospective sample of consecutive patients visiting the emergency department of a university teaching hospital who met the American College of Chest Physicians criteria of sepsis or severe sepsis was enrolled. Besides septic workup, we measured serum vasopressin and norepinephrine concentrations to correlate the impending outcome. One hundred eighty-two patients aged 27 to 99 years met the inclusive criteria and were classified as those with septic shock (n = 72), severe sepsis (n = 56), and those with sepsis only (n = 54) according to the outcome within 6 hours. Thirty healthy subjects were included as control. The plasma vasopressin level at baseline was significantly lower for those who finally developed septic shock (septic shock group, 3.6 ± 2.5 pg/mL; 95% confidence interval [CI], 3.0-4.2 pg/mL; severe sepsis group, 21.8 ± 4.1 pg/mL, 95% CI, 20.7-22.9 pg/mL; sepsis group, 10.6 ± 6.5 pg/mL, 95% CI, 8.8-12.4 pg/mL, P < .001), whereas the norepinephrine level was highest for the same group (septic shock group, 3650 ± 980 pg/mL, 95% CI, 3420-3880 pg/mL; severe sepsis group, 3600 ± 1000 pg/mL, 95% CI, 3330-3870 pg/mL; sepsis group, 1720 ± 320 pg/mL, 95% CI, 1630-1810 pg/mL). The vasopressin/norepinephrine ratio was significantly lower for the patients with final diagnosis of septic shock ( P < .001). The mean interval between the time of samples drawn and the time of the most severe occurring sequelae was 2.4 ± 0.8 hours. Receiver operating characteristic analysis revealed that the vasopressin/norepinephrine ratio 1 × 10 −3 had a sensitivity of 97% (95% CI, 90%-99%) and a specificity of 85% (95% CI, 78%-91%) for detecting impending septic shock. Low serum vasopressin/norepinephrine ratio can predict impending septic shock.

Autonomic dysfunction in cases of spinal muscular atrophy type 1 with long survival

In Japan, quite a few patients with spinal muscular atrophy type 1 (SMA type 1) survive with mechanical ventilation. Since a patient with SMA type 1 and continuous artificial ventilation exhibited excessive perspiration and tachycardia, we examined the autonomic functions in three cases of SMA type 1, undergoing mechanical ventilation. Two cases exhibited the common sympathetic-vagal imbalance on R–R interval analysis involving 24-h Holter ECG recordings in addition to an abnormality in finger cold-induced vasodilatation. Furthermore, one case showed blood pressure and heart rate fluctuation with the paroxysmal elevation, and a high plasma concentration of norepinephrine during tachycardia. These findings suggest that autonomic dysfunction should be examined in SMA type 1 patients with long survival, although the pathogenesis remains to be clarified.

Major differences in noradrenaline action on lipolysis and blood flow rates in skeletal muscle and adipose tissue in vivo

The regulation of skeletal muscle lipolysis is not fully understood. In the present study, the effects of systemic and local noradrenaline administration on lipolysis and blood flow rates in skeletal muscle and adipose tissue were studied in vivo. First, circulating noradrenaline levels were raised tenfold by a continuous i.v. infusion (n=12). Glycerol levels (an index of lipolysis) were measured in m. gastrocnemius and in abdominal adipose tissue using microdialysis. Local blood flow was determined with the (133)Xe clearance technique and whole-body lipolysis rates assessed with a stable glycerol isotope technique ([(2)H(5)] glycerol). Second, interstitial glycerol levels in m. gastrocnemius, m. vastus and adipose tissue were measured by microdialysis during local perfusion with noradrenaline (10(-8)-10(-6) mol/l) (n=10). Local blood flow was monitored with the ethanol perfusion technique. With regard to systemic noradrenergic stimulation, no change in fractional release of glycerol (difference between tissue and arterial glycerol) was seen in skeletal muscle. In adipose tissue it transiently increased twofold (p<0.0001), and the rate of appearance of glycerol in plasma showed the same kinetic pattern. Blood flow was reduced by 40% in skeletal muscle (p<0.005) and increased by 50% in adipose tissue (p<0.05). After noradrenaline stimulation in situ, a discrete elevation of skeletal muscle glycerol was registered only at the highest concentration of noradrenaline (10(-6) mol/l) (p<0.05). Adipose tissue glycerol doubled already at the lowest concentration (10(-8) mol/l) (p<0.05). In skeletal muscle a decrease in blood flow was seen at the highest noradrenaline concentrations (p<0.05). Lipolysis and blood flow rates are regulated differently in adipose tissue and skeletal muscle. Adipose tissue displays a high, but transient (tachyphylaxia) sensitivity to noradrenaline, leading to stimulation of both lipolysis and blood flow rates. In skeletal muscle, physiological concentrations of noradrenaline decrease blood flow but have no stimulatory effect on lipolysis rates.

Endoluminal pelvic perfusion with norepinephrine causes only minor systemic effects and diminishes the increase in pelvic pressure caused by perfusion

To evaluate the effect of endoluminal norepinephrine (NE) on transport pressures of the normal upper urinary tract of the pig and on plasma levels of NE in relation to possible systemic effects. Six anaesthetized pigs weighing approximately 39 kg were studied. Transparenchymally, two 6-F catheters were introduced into the renal pelvis bilaterally to measure pressure and perfusion. Ultrasonic flow probes recorded renal arterial blood flow, and a transurethral 10-F catheter drained the bladder and monitored diuresis. In all six animals, the bilateral pelvic pressure response was examined at increasing perfusion rates (2, 4, 6, 8, 10 and 15 ml/min) and with increasing doses of NE (0, 5, 50 and 100 microg/ml). Arterial blood samples were analysed for NE, epinephrine and blood glucose. The systemic blood pressure, heart rate and electrocardiogram were registered. At all the investigated concentrations, endoluminal NE significantly diminished the increase in pelvic pressure caused by pelvic perfusion at all flow rates. At the lowest concentration of NE, no significant increase in the plasma level of NE was observed and the blood pressure did not increase. During perfusion with 50 and 100 microg/ml NE, plasma levels of NE increased significantly from 487+/-398 to 1798+/-910 and 2961+/-2093 pg/ml, respectively. This was accompanied by significant rises in mean systolic blood pressure from a baseline value of 95+/-10 mmHg to 111+/-20 and 118+/-23 mmHg, respectively. Heart rate, renal arterial blood flow and plasma levels of epinephrine and glucose did not change. Endoluminal NE diminished the increase in pelvic pressure caused by pelvic perfusion even at concentrations too low to cause significant changes in NE plasma levels or systemic effects. Very high NE concentrations in the perfusion fluid caused increased plasma levels and a modest but significant increase in blood pressure. Administration of endoluminal NE may be useful in upper urinary tract stone treatment and endoscopy.

Catecholamines and 5-Hydroxytryptamine in Tissues of the Rabbit Exocrine Pancreas

Norepinephrine (NE), dopamine (DA), epinephrine (Epi), and 5-hydroxytryptamine (5-HT) all modulate pancreatic exocrine secretion, yet their concentrations in specific tissues of the exocrine pancreas are unknown. Concentrations of catecholamines and 5-HT in rabbit pancreatic ganglia, acini, ducts and ampullae, and arteries and veins were measured using HPLC. Concentrations of NE in ganglia from the head/neck region were significantly higher than those from the body (1620 +/- 220 vs. 778 +/- 179 pmol/mg protein). Acini contained little NE, DA, or 5-HT (9 +/- 2, 0.9 +/- 0.2, 13 +/- 5 pmol/mg protein). Ducts and ampullae contained NE (314 +/- 74 and 156 +/- 24 pmol/mg protein), DA (43 +/- 14 and 13 +/- 4 pmol/mg protein), Epi (63 +/- 29 and 39 +/- 6 pmol/mg protein), and 5-HT (696 +/- 151 and 3563 +/- 288 pmol/mg protein). Arteries and veins contained the highest concentrations of NE (1962 +/- 463 and 736 +/- 80 pmol/mg protein, respectively). Pancreatic ganglia and blood vessels, rather than acini, are the main sites of noradrenergic sympathetic innervation of the rabbit exocrine pancreas. These nerves preferentially target ganglionic transmission in the head/neck versus the body. Serotonergic nerves provide little or no innervation of rabbit pancreatic ganglia or acini.

Sympathetic regulation of glucose uptake by the alpha1-adrenoceptor in human obesity.

To investigate the involvement of alpha1-adrenoceptors in the sympathetic regulation of glucose uptake in human adipocytes. Twenty-four severely obese subjects participated in this study. The microdialysis technique was used to determine interstitial glucose concentration after stimulation of abdominal subcutaneous adipose tissue with the alpha1-agonist norfenefrine, the alpha1,2beta-agonist norepinephrine, and both agents in combination with the alpha1-antagonist urapidil. The effect of beta-adrenoceptor stimulation was assessed by orciprenaline. Changes in local blood flow were determined using the ethanol escape technique. Both norfenefrine and norepinephrine induced a concentration-dependent decrease of interstitial glucose concentration, with a greater decrease observed with norepinephrine. Preperfusion of adipose tissue with urapidil inhibited glucose decrease. The inhibition was overcome with high concentrations of norfenefrine and norepinephrine, respectively. Both adrenergic agents induced tachyphylaxia. Urapidil enhanced extracellular glucose level at high concentration. Blood flow decreased in the presence of norfenefrine and norepinephrine but increased in response to urapidil. The accelerated blood flow due to urapidil was counteracted by norepinephrine and norfenefrine. Orciprenaline decreased interstitial glucose concentration and increased nutritive blood flow. The observed changes in blood flow induced by adrenergic agents were not related to glucose uptake. The stimulatory effect of the sympathetic nerves on glucose uptake in subcutaneous adipose tissue appears to be mediated by the alpha1-adrenoceptor. Norepinephrine enhances glucose entry into adipocytes independently of insulin action. In obese subjects with insulin resistance, the alpha1-adrenergic receptor may provide an important alternative pathway for glucose uptake.

Uptake of serotonin by adult rat corpus callosum is partially reduced by common antidepressants.

The corpus callosum (CC) is the main white matter tract involved in interhemispheric brain communication. We establish that uptake of [3H]5-hydroxytryptamine (5-HT) in CC is partially inhibited by some antidepressants. Slices of the adult rat CC had a high-affinity uptake of 5-HT. About 80% of this uptake was Na+ dependent, with a Michaelis-Menten constant, Km, of 420 +/- 80 nM and a rate of 5-HT uptake, Vmax, of 9.5 +/- 0.8 pmol/mg protein/min. The 5-HT uptake was reduced approximately 60% at pH 5 compared with that at pH 7. Fluoxetine (Prozac) inhibited only 43% of 5-HT uptake in a concentration-dependent manner, with an affinity constant, Ki, of 44.7 +/- 10.0 nM. We also studied the effects of other monoamine uptake inhibitors, all at 10 microM, and found that zimelidine, imipramine, and clomipramine inhibited 5-HT uptake in the CC by approximately 30-40%. The fluoxetine-insensitive 5-HT uptake was not altered by high concentrations of dopamine plus norepinephrine. The present data show that Na(+)-dependent 5-HT uptake occurs in the CC and optic nerve and that this uptake is partially sensitive to antidepressants and probably mediated by the serotonin transporter, which may be relevant during depression.