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PubMedDate not supplied

The role of epinephrine, norepinephrine, and dopamine in blood pressure disturbances in patients with pheochromocytoma.

Fifty-six patients with pheochromocytoma underwent surgery during the 9-year period from 1981 to 1990. These patients were divided into two groups according to whether the dominant plasma concentration was of epinephrine or norepinephrine. Plasma levels of the catecholamines were stratified into three grades at 5 and 10 times the normal upper limit. Pre-operative disturbances of blood pressure, sustained or paroxysmal, and normal blood pressure were highly correlated with the dominantly secreted catecholamine and its plasma concentration. Thirteen patients with high plasma norepinephrine levels (greater than or equal to 10 times normal) had sustained hypertension while 18 patients with moderate to high plasma epinephrine levels (greater than or equal to 5 times normal) had paroxysmal hypertension. In the majority of normotensive patients (12 of 14), plasma catecholamine levels were less than 10 times the upper normal limit. Urinary excretion of dopamine and size of the tumor were analyzed according to these patient groups. In the norepinephrine dominant group, urinary dopamine excretion tended to be proportional to the plasma epinephrine levels and when the patients were normotensive, urinary dopamine excretion decreased. In norepinephrine-secreting patients, urinary dopamine tended to be inversely correlated with the plasma norepinephrine level; however dopamine did not prevent the hypertensive action of norepinephrine. Tumor size showed no correlation with the plasma levels of catecholamine in the moderate to high plasma catecholamine groups. We conclude that the plasma catecholamine type and its level are the most important factors in determining the patterns of blood pressure disturbances of patients with pheochromocytoma.

Adrenal Gland Neoplasms↗

PubMed2003

Pharmacokinetics and pharmacodynamics of dopamine and norepinephrine in critically ill head-injured patients.

OBJECTIVE: To explore the pharmacokinetics and pharmacodynamics of dopamine and norepinephrine. DESIGN: Prospective, controlled, trial. SETTING: Neurosciences critical care unit. PATIENTS: Eight patients with a head injury, requiring dopamine or norepinephrine infusions to support cerebral perfusion pressure (CPP). INTERVENTION: Patients received in randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 70 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 90 mmHg. Data were then acquired using the second agent. Haemodynamic measurements were made during each period and a blood sample was obtained at the end of each study period for analysis of plasma catecholamine concentrations MEASUREMENTS AND RESULTS: Plasma levels of norepinephrine and dopamine were significantly related to infusion rates but did not have a simple linear relationship to haemodynamic parameters. However, there was a significant quadratic relationship between the infusion rate of dopamine and cardiac index (r2=0.431), and systemic vascular resistance index (r2=0.605), with a breakpoint (at which cardiac index reduced and SVRI increased) at a dopamine plasma level of approximately 50 nM/l (corresponding to an infusion rate of approximately 15 microg.kg(-1).min(-1)). CONCLUSIONS: Norepinephrine and dopamine have predictable pharmacokinetics; however, those of dopamine do not fit a simple first-order kinetic model. The pharmacodynamic effects of dopamine and norepinephrine show much inter-individual variability and unpredictability. Plasma levels of dopamine appear to relate to variations in adrenergic receptor effects with break points that reflect expectations from infusion-rate related pharmacodynamics.

Adult↗

PubMed2004

Effect of cerebral perfusion pressure augmentation with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain injury.

OBJECTIVE: To compare the effects of a cerebral perfusion pressure (CPP) intervention achieved with dopamine and norepinephrine after severe head injury. DESIGN: Prospective, controlled, trial. SETTING: Neurosciences critical care unit. PATIENTS: Eleven patients with a head injury, requiring dopamine or norepinephrine infusions to support CPP. INTERVENTION: Cerebral tissue gas measurements were recorded using a multimodal sensor, and regional chemistry was assessed using microdialysis. Patients received in, randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 65 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 85 mmHg. Data were then acquired using the second agent. Haemodynamic measurements and measurements of cerebral physiology were made during each period. MEASUREMENTS AND RESULTS: The CPP augmentation with norepinephrine, but not with dopamine, resulted in a significant reduction in arterial-venous oxygen difference (37+/-11 vs 33+/-12 ml/l) and a significant increase in brain tissue oxygen (2.6+/-1.1 vs 3.0+/-1.1 kPa). The CPP intervention did not significantly affect intracranial pressure. There were no significant differences between norepinephrine and dopamine on cerebral oxygenation or metabolism either at baseline or following a CPP intervention; however, the response to a CPP intervention with dopamine seemed to be more variable than the response achieved with norepinephrine. CONCLUSIONS: If CPP is to be raised to a level higher than 65-70 mmHg, then it is important to recognise that the response to the intervention may be unpredictable and that the vasoactive agent used may be of importance.

Adult↗

PubMed2002

Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex.

RATIONALE: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. OBJECTIVE: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. METHODS: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. RESULTS: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT(2C) receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. CONCLUSION: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.

Animals↗

PubMedDate not supplied

Comparison of heart failure in children with enterovirus 71 rhombencephalitis and cats with norepinephrine cardiotoxicity.

The mechanism of heart failure in patients with enterovirus 71 rhombencephalitis (brain stem encephalitis) remains unknown. Our previous reports hypothesized that a catecholamine storm induced by rhombencephalitis may account for the heart failure. The aim of this study was to develop a novel feline model of norepinephrine cardiotoxicity and compare the resulting heart failure to that in children with enterovirus 71 rhombencephalitis. Nine of 75 children (12%) with enterovirus 71 rhombencephalitis (5 boys and 4 girls; age, 4-28 months; median age, 16 months) were complicated with left ventricular hypokinesia (ejection fraction, 31 +/- 9%). Six cats (weight, 3.03 +/- 0.64 kg) were administered intravenous norepinephrine 30 microg/kg/min for 3 hours. Echocardiography assessed the left ventricular diameter and function before and after the administration of norepinephrine. Pathology studies included hematoxylin and eosin stain and in situ terminal deoxyribonucleotidyl transferase-mediated dUTP nick end-labeling assay. In the feline model, norepinephrine induced significant left ventricular dilatation (end diastolic diameter from 1.18 +/- 0.19 to 1.62 +/- 0.22 cm, p = 0.001; endsystolic diameter from 0.54 +/- 0.09 to 1.36 +/- 0.32 cm, p = < 0.001) and hypokinesia (ejection fraction from 87.5 +/- 4.1 to 35.2 +/- 16.3%, p = 0.001). Heart specimens from 4 patients and six cats showed similar pathology findings, including myocardial hemorrhage, cardiomyocyte apoptosis, and coagulative myocytolysis, which is characterized by sarcoplasmic coagulation, granulation, vacuolization, myofibrillar waving, and disruption. Both groups showed no significant inflammatory reaction. In conclusion, heart failure in patients with enterovirus 71 rhombencephalitis is similar to that in cats with norepinephrine cardiotoxicity. Norepinephrine cardiotoxicity may play a role in the pathogenesis of heart failure in enterovirus 71 rhombencephalitis.

Animals↗

PubMed1982

Response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure.

The activity of the sympathetic nervous system is increased at rest in patients with congestive heart failure. To determine whether this augmentation is carried over during dynamic upright exercise, 14 patients with congestive heart failure were stressed maximally during upright bicycle ergometry. Plasma norepinephrine and epinephrine levels were measured in the basal upright (sitting) posture before and during maximal exercise. The results were compared with those in six healthy control subjects before and during maximal exercise. Plasma norepinephrine increased during exercise from a mean (+/- standard error of the mean) of 650 +/- 95 to 1,721 +/- pg/ml in the group with heart failure. This increase was significantly less (p less than 0.001) than that in the control group (from 318 +/- 36 to 3,230 +/- 418 pg/ml). However, for equivalent levels of total body oxygen consumption (VO2), the group with heart failure had higher levels of plasma norepinephrine than the control group. Plasma epinephrine was similar in the two groups in the basal upright position (92 +/- 18 and 92 +/- 26 pg/ml), but it increased more during exercise in the normal subjects (743 +/- 210 pg/ml) than in the group with heart failure (167 +/- 67 pg/ml) (p less than 0.001). The percent increase in norepinephrine correlated with the percent change in VO2 in the group with heart failure (r = 0.62, p less than 0.02), but the percent change in epinephrine did not. There is, therefore, a disturbance in the sympathetic nervous system during exercise in patients with congestive heart failure. Although norepinephrine increases in such patients to a greater extent than in normal subjects at lower levels of exercise, the extremely high levels of norepinephrine and epinephrine generated by normal subjects during maximal upright exercise do not occur in patients with heart failure.

Adult↗

PubMed1982

Captopril attenuates pressor responses to norepinephrine and vasopressin through depletion of endogenous angiotensin II.

The influence of captopril on pressor responses to exogenously administered vasopressor substances was investigated in normal subjects. Norepinephrine (0.05, 0.1 and 0.2 micrograms/kg . min -1; n = 5), angiotensin II (5, 10 and 20 ng/kg . min -1; n = 5) and vasopressin (2 mU/kg . min -1; n = 5) were infused each for 10 minutes; each infusion was repeated twice. Captopril (50 mg orally) significantly attenuated the pressor response to norepinephrine (0.1 [p less than 0.05], 0.2 [p less than 0.01] micrograms/kg . min -1; n = 7) and to vasopressin (p less than 0.01, n = 5), but not to angiotensin II; these responses were reproducible. Attenuation of the pressor responses to norepinephrine did not occur when a subpressor dose of angiotensin II (ng/kg . min-1) was infused in addition to captopril (n = 5). Infusion of a subpressor dose of bradykinin (0.1 ng/kg . min-1) had no influence on the pressor responses to norepinephrine (n = 5). In the five subjects treated with indomethacin (225 mg/54 hours) captopril still attenuated the pressor responses to norepinephrine. These results suggest that the attenuation by captopril of the pressor responses to norepinephrine and vasopressin might have been due to reduction of endogenous angiotensin II.

Adult↗

PubMed1989

Relation between plasma norepinephrine and response to medical therapy in men with congestive heart failure secondary to coronary artery disease or idiopathic dilated cardiomyopathy.

This study examines the relation between the change in clinical status and the change in plasma norepinephrine concentration in patients with congestive heart failure (CHF) receiving standard medical therapy. Hemodynamic measurements in 11 patients with CHF (ejection fraction 19 +/- 4%) were obtained before and immediately after the administration of digoxin and angiotensin-converting enzyme inhibitors. Patients were then followed for 1 year. Clinical status was determined using the Boston Clinical Heart Failure scoring system. Of the 11 patients, 6 demonstrated significant clinical improvement after therapy, based on the Boston score, over a 1-year period. Five patients did not respond to therapy: 4 died and the remaining patient had worsening CHF. There was no difference between responders and nonresponders in either baseline hemodynamics or acute response to the administration of digoxin and an angiotensin-converting enzyme inhibitor. In the patients who improved, plasma norepinephrine decreased from 706 +/- 235 to 545 +/- 223 pg/ml (p = 0.08) after 1 year of medical therapy. In patients whose CHF worsened or who died, plasma norepinephrine increased from 715 +/- 275 at baseline to 1,237 +/- 671 pg/ml at their last measurement (p = 0.06). Although at baseline the plasma norepinephrine levels were similar in both groups of patients, a significant difference between responders and nonresponders was observed at final follow-up (p less than 0.002). Change in plasma norepinephrine correlated with change in CHF score (r = 0.79, p less than 0.004). Thus, in patients with CHF, serial measurements of plasma norepinephrine correlate with changes in clinical status.

Adult↗

PubMed1988

Ca2+-dependent activation of the malate-aspartate shuttle by norepinephrine and vasopressin in perfused rat liver.

The role of Ca2+ in stimulation of the malate-aspartate shuttle by norepinephrine and vasopressin was studied in perfused rat liver. Shuttle capacity was indexed by measuring the changes in both the rate of production of glucose from sorbitol and the ratio of lactate to pyruvate during the oxidation of ethanol. (T. Sugano et al. (1986) Amer. J. Physiol. 251, E385-E392). Asparagine (0.5 mM), but not alanine (0.5 mM) decreased the ethanol-induced responses. Norepinephrine and vasopressin had no effect on the ethanol-induced responses when the liver was perfused with sorbitol or glycerol. In the presence of 0.25 mM alanine, norepinephrine, vasopressin, and A23187 decreased the ethanol-induced responses that occurred with the increase of flux of Ca2+. In liver perfused with Ca2+-free medium, asparagine also decreased the ethanol-induced responses, but norepinephrine and vasopressin had no effect. Aminooxyacetate inhibited the effects of norepinephrine, A23187, and asparagine. Regardless of the presence or absence of perfusate Ca2+, the combination of glucagon and alanine had no effect on the ethanol-induced responses. Norepinephrine caused a decrease in levels of alpha-ketoglutarate, aspartate, and glutamate in hepatocytes incubated with Ca2+. The present data suggest that the redistribution of cellular Ca2+ may activate the efflux of aspartate from mitochondria in rat liver, resulting in an increase in the capacity of the malate-aspartate shuttle.

Alanine↗

PubMed1984

Interactions of endogenous and exogenous norepinephrine with alpha 2 adrenoceptor binding sites in rat cerebral cortex.

The specific binding of (3H)yohimbine to alpha 2 adrenoceptors in rat cerebral cortex varied significantly with methods of membrane preparation. Membranes prepared in a sucrose containing buffer showed markedly lower Bmax values than those prepared in hypotonic buffer without any change in affinity (Kd) for (3H)yohimbine. Higher concentrations of residual endogenous norepinephrine were found in sucrose prepared membranes. In the presence of exogenous norepinephrine (10(-8), 10(-7) M), membranes prepared in hypotonic buffer showed apparent reduced receptor densities similar to those observed in sucrose prepared cerebral membranes. The presence of exogenous norepinephrine did not produce any apparent change in the overall Kd for (3H)yohimbine. The depression of (3H)yohimbine binding capacities could, in all cases, be reversed by performing incubations in the presence of 200 mM NaCl and 10 microM Gpp(NH)p which synergistically dramatically reduce the affinity of norepinephrine for cerebral alpha 2 adrenoceptors. It is concluded, therefore, that the lower (3H)yohimbine binding capacities in sucrose prepared membranes appears to be due to the occupancy of receptor sites by residual norepinephrine in a pseudo non competitive manner. The reduced affinity of retained endogenous norepinephrine for the alpha 2 adrenoceptor, in the presence of Na+ and guanine nucleotides, would seem to be the cause of the apparent increase in (3H)yohimbine binding sites produced by these modulators in sucrose prepared membranes.

Animals↗

PubMed1987

Effects of calcium depletion on norepinephrine- and A23187-induced stimulation of inositol phosphate formation.

The role of calcium in the stimulation of phosphoinositide (PIn) hydrolysis by norepinephrine and the calcium ionophore A23187 was investigated in chopped cerebral cortex in which the PIns had been labeled previously with ([3H]myo-inositol. The accumulation of the newly formed [3H]inositol phosphate ([3H]IPs) was used as an index of PIn hydrolysis. Norepinephrine produced a concentration-related increase in the accumulation of [3H]inositol-phosphates ([3H]IP), and this effect was only partially antagonized by omission of calcium from the incubation medium. Norepinephrine had relatively little effect on the accumulation of [3H]inositol 1,4-bisphosphate [3H]IP2 and inositol 1,4,5-triphosphate and/or inositol 1,3,4-trisphosphate ([3H]IP3). A23187 also increased the accumulation of [3H]IP but this effect was not antagonized by omission of calcium from the incubation medium. When the tissue had been washed extensively with EGTA, the basal levels of [3H]IP, [3H]IP2 and [3H]IP3 were decreased markedly, and the effects of both norepinephrine and A23187 were antagonized. Addition of calcium back to the depleted tissue led to an increase in the basal level of [3H]IPs as well as restoration of the stimulation produced by norepinephrine and A23187. The calcium threshold for the PIn effect was 0.1 microM. Additional calcium did not affect markedly the stimulation of accumulation of [3H]IP produced by norepinephrine and A23187. The results suggest that there is an absolute calcium requirement for PIn phosphodiesterase which is attained at 0.1 microM Ca2+. A23187 can stimulate the accumulation of [3H]IP perhaps by providing access of another form of the enzyme to artificially high concentrations (millimolar range) of calcium.

Animals↗

PubMed1993

Effects of stimulus intensity on the inhibition by omega-conotoxin GVIA and neomycin of K(+_-evoked [3H]norepinephrine release from hippocampal brain slices and synaptosomal calcium influx.

The effects of various K+ concentrations on the inhibition of [3H]norepinephrine release from rat hippocampal brain slices and evoked synaptosomal 45Ca2+ influx by omega-conotoxin GVIA (omega-CgTx) and neomycin were examined. K+ (15-75 mM) caused a concentration-dependent release of [3H]norepinephrine that was greater than 90% dependent on extracellular calcium. The ability of omega-CgTx to inhibit [3H]norepinephrine release was optimal at 25 mM K+ and was reduced substantially at higher concentrations of K+. omega-CgTx maximally inhibited [3H]norepinephrine release by 49% (15 mM K+), 58% (25 mM K+), 22% (50 mM K+), and 12% (75 mM K+). In contrast, neomycin caused a concentration-dependent and virtually complete inhibition of [3H]norepinephrine release at all concentrations of K+, with IC50 values of 210 microM (15 mM K+), 150 microM (25 mM K+), 450 microM (50 mM K+), and 1500 microM (75 mM K+). omega-CgTx (1 microM) had little effect (10% or less inhibition) on hippocampal synaptosomal 45Ca2+ influx at any concentration of K+, whereas 3 mM neomycin caused at least 75% inhibition of 45Ca2+ influx, with the largest inhibition (96%) occurring at 25 mM K+. The results suggest that increasing stimulus intensity decreases the contribution of N-type voltage-sensitive calcium channels (VSCC) in mediating K(+)-evoked release of [3H]norepinephrine. The comparative absence of omega-CgTx-sensitive synaptosomal 45Ca(2+)-influx sites suggests that N-type calcium channels are a small subset of channels in rat hippocampal synaptosomes. The demonstration that neomycin can inhibit omega-CgTx-sensitive and -insensitive neurotransmitter release and calcium influx suggests that neomycin may block N-type VSCC as well as non-N-type VSCC.

Animals↗

PubMed1996

Induction of uncoupling protein in brown adipose tissue. Synergy between norepinephrine and pioglitazone, an insulin-sensitizing agent.

Insulin resistance and obesity in rodent models of non-insulin-dependent diabetes mellitus have been correlated with ablated or defective brown adipose tissue (BAT) function. The mitochondrial uncoupling protein (UCP) allows BAT to perform its unique role in facultative energy expenditure. In this study, we observed an increase in both BAT mass and the expression of UCP mRNA in BAT from obese diabetic mice and their lean littermates following treatment with the thiazolidinedione pioglitazone, a novel insulin-sensitizing agent. Thus, we wanted to ascertain if pioglitazone directly induces BAT differentiation. We found that treatment for 48 hr with pioglitazone caused a 32-fold increase in UCP mRNA, whereas a 7-hr treatment with norepinephrine caused a 24-fold increase in expression. Cells treated with pioglitazone for 48 hr, with norepinephrine added during the last 7 hr, demonstrated a 59-fold increase in UCP mRNA. However, simultaneous treatment with pioglitazone and repeated treatment norepinephrine for 48 hr yielded a greater than 200-fold increase in UCP mRNA. Examination of UCP protein levels demonstrated a similar time-dependent increase with pioglitazone and/or norepinephrine treatment, as well as a synergistic increase with concurrent pioglitazone and norepinephrine treatment. This study shows that pioglitazone exerts a direct effect on BAT cells in vitro by increasing UCP mRNA and protein levels, and that it also synergizes with norepinephrine perhaps by inducing and stabilizing UCP mRNA and/or preventing proteolysis of UCP protein.

Adipocytes↗

PubMed1984

Brain (Na+,K+)-ATPase and noradrenergic function: recovery of enzyme activity after norepinephrine depletion.

We examined the time course of K+-p-nitrophenylphosphatase and ouabain binding associated with cerebral cortex (Na+,K+)-AT-Pase after depletion of norepinephrine. Norepinephrine depletion by the norepinephrine-selective neurotoxin DSP4 initially reduced the indices of (Na+,K+)-ATPase, with a significant correlation between ouabain binding and tissue norepinephrine levels 16 h after DSP4. Tissue norepinephrine content and DMI binding rapidly declined after DSP4 and remained essentially unchanged for at least 8 weeks. By contrast, the indices of (Na+,K+)-ATPase remained low for about two weeks but then gradually increased, returning to baseline levels by 8 weeks after DSP4. These data indicate that, while usually regulated in part by exposure to norepinephrine, brain (Na+,K+)-ATPase undergoes adaptation to prolonged noradrenergic depletion.

4-Nitrophenylphosphatase↗

PubMed1984

Norepinephrine elicits both excitatory and inhibitory responses from Purkinje cells in the in vitro rat cerebellar slice.

Superfusion of Purkinje neurons in the in vitro rat cerebellar slice with norepinephrine caused increases and decreases of spontaneous Purkinje cell firing. Excitations were evoked by low concentrations of norepinephrine (0.5-10 microM) and by the beta receptor agonist isoproterenol (0.1-5 microM). These excitations were reduced by timolol (1-2 microM), a beta receptor antagonist. Perfusion with higher concentrations of norepinephrine (greater than 16 microM), caused a depression of Purkinje neuron spontaneous activity. This inhibitory response was blocked by the alpha receptor antagonist phentolamine. The alpha 1 selective agonist phenylephrine had no effect on spontaneous activity at concentrations up to 100 microM, but the alpha 2 selective agonist clonidine (1-50 microM) elicited decreases in firing rate. These responses appeared to be due to a direct action on Purkinje cells, because neither the excitation nor the depression of Purkinje neuron activity elicited by norepinephrine was substantially altered when tested in a medium which substantially blocked synaptic transmission within the slice. Under these in vitro conditions, norepinephrine appears to increase the firing rate of Purkinje neurons via an interaction with beta adrenergic receptors, while norepinephrine induced depressions may be linked to alpha adrenergic receptor interactions; both receptors appear to be located directly on the Purkinje neurons.

Action Potentials↗

PubMed1985

Suppression of norepinephrine-elicited feeding by neurotensin: evidence for behavioral, anatomical and pharmacological specificity.

Neurotensin (NT) injected into the paraventricular hypothalamic nucleus (PVN) has been shown to suppress feeding behavior. To investigate whether this suppression generalizes to feeding elicited by norepinephrine injection, rats with bilateral PVN cannulas were injected with NT (3.0 nmol/cannula) or vehicle followed by norepinephrine (20.0 nmol/cannula). Pretreatment with NT caused a 48% reduction in feeding elicited by norepinephrine. To determine whether NT's effect resulted from non-specific behavioral effects or leakage into the periphery, NT (0.25, 1.25 or 6.0 nmol) was injected ipsilateral or contralateral to a unilateral norepinephrine (40.0 nmol) injection. Ipsilateral NT produced a dose-dependent suppression of norepinephrine-elicited feeding which was significantly greater than the effect of contralateral NT, suggesting that NT's effect was at least partially behaviorally and anatomically specific. To investigate the pharmacological specificity of the suppression, rats that ate in response to PVN norepinephrine (40.0 nmol) were given prior injections of NT or one of six NT fragments at 0.25, 1.25, 6.0 or 30.0 nmol. NT and the C-terminal fragments 3-13 and 6-13 caused a dose-dependent suppression of feeding. In contrast, none of the N-terminal fragments (i.e. 1-8, 1-11 or 1-12) were effective. This specificity rules out non-specific changes in parameters such as pH or osmotic pressure and suggests that the anorectic effect may have been mediated by NT receptors.

Animals↗

PubMed1986

Inhibition of fast phase calcium uptake and endogenous norepinephrine release in rat brain region synaptosomes by ethanol.

The effects of ethanol on fast phase calcium (Ca2+) uptake and endogenous norepinephrine release were assessed simultaneously in KCl-depolarized synaptosomes isolated from rat hypothalamus, brainstem and cerebellum. Incubation of brain regional synaptosomes with ethanol resulted in a concentration-dependent inhibition of Ca2+ uptake after 1 s of depolarization. Hypothalamic synaptosomes were most sensitive to the inhibitory effect of ethanol on voltage-dependent Ca2+ uptake and brainstem synaptosomes were least sensitive. Endogenous norepinephrine release from synaptosomes was not altered by addition of ethanol in vitro at any of the concentrations examined (25-200 mM). Chronic ethanol administration resulted in an adaptation to the inhibitory effect of ethanol on Ca2+ uptake into hypothalamic synaptosomes but did not alter the inhibitory effect of ethanol on Ca2+ uptake into brainstem or cerebellar synaptosomes. Fast phase, voltage-dependent norepinephrine release was inhibited by ethanol added in vitro but only in synaptosomes isolated from hypothalami and cerebella of chronically treated animals. Brain regional norepinephrine concentrations were unaltered by chronic ethanol administration. These results suggest that chronic ethanol treatment may alter the coupling of Ca2+ entry with norepinephrine release in some noradrenergic neurons. Effects of ethanol on synaptosomal Ca2+ entry and norepinephrine release differ depending on the brain region.

Animals↗

PubMed1987

Eicosanoid synthesis elicited by norepinephrine in piglet parietal cortex.

We investigated effects of exogenous norepinephrine and isoproterenol on pial arterial diameter and cerebral eicosanoid synthesis in anesthetized newborn pigs. Norepinephrine in artificial cerebrospinal fluid (CSF) constricted pial arteries from 203 +/- 27 micron (X +/- S.E.M.) to 164 +/- 18 micron (20 +/- 2%) (n = 21 vessels from 16 animals) at 10(-4) M. In the same animals, norepinephrine caused the concentration in CSF of 6-keto-prostaglandin F1 alpha to increase from 768 +/- 91 to 1544 +/- 151 pg/ml, thromboxane B2 to increase from 188 +/- 37 to 269 +/- 38 pg/ml, and prostaglandin E2 to increase from 2067 +/- 448 to 6575 +/- 751 pg/ml. Topical application of prostaglandin E2 in CSF to the cortical surface demonstrated that concentrations as low as 10,000 pg/ml were able to dilate pial arteries substantially. Blockade of cyclo-oxygenase activity by indomethacin (5-10 mg/kg, i.v.) potentiated pial arterial constriction to norepinephrine. Topical isoproterenol dilated pial arteries, but isoproterenol did not affect levels of measured eicosanoids in CSF. We conclude that norepinephrine elicits release of prostanoids from the cortical surface, and that these substances limit cerebrovascular constriction to norepinephrine.

Animals↗