Higher Norepinephrine Research Articles

Abnormal plasma monoamine metabolism in schizophrenia and its correlation with clinical responses to risperidone treatment

Abnormalities in plasma monoamine metabolism reflect partly the illness of schizophrenia and sometimes the symptoms. Such studies have been repeatedly reported but have rarely taken both metabolites and parent amines or inter-amine activity ratios into account. In this study, the monoamines, their metabolites, turnovers and between-metabolite ratios in plasma were measured longitudinally in 32 schizophrenic patients treated with risperidone for 6 weeks, to examine possible biochemical alterations in schizophrenia, and to examine the association between treatment responses and psychopathology assessed according to the Positive and Negative Syndrome Scale (PANSS). The results showed lower level of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) in relapsed versus first-episode schizophrenic patients, higher norepinephrine (NE) turnover rate (TR) in undifferentiated in comparison to paranoid schizophrenic patients and relatively higher metabolic activity of dopamine (DA) to serotonin (5-HT) in first-episode versus relapsed schizophrenic patients. Risperidone treatment induced a decrement of plasma DA levels and increments of plasma DOPAC and DA TR in the total group of schizophrenic patients. The turnover rate of 5-HT was was reduced in undifferentiated and relapsed subgroups of schizophrenic patients. The linkages between 5-HT TR, DA/NE relative activity and clinical symptomatology were also identified. These findings are consistent with an involvement of these systems in the pathogenesis of schizophrenia as well as in the responses to treatment, and the usefulness of certain biochemical indices as markers for subgrouping.

Ethnic differences in cardiovascular‐somatosensory interactions and in the central processing of noxious stimuli

Ethnic differences in central sensitization of pain processing and stress-relevant endogenous pain regulatory mechanisms were examined. Forty-four African Americans (AAs; 50% women) and 44 non-Hispanic Whites (nHWs; 50% women) matched for socioeconomic status, were tested for pain responses to the temporal summation of heat pulses and ischemic and cold pain. Resting and stress blood pressure (BP) and norepinephrine (NE) were assessed. AAs had heightened pain responses to all 3 pain tasks relative to nHWs. In nHWs, higher BP and NE were related to reduced pain. In AAs, there was no relationship between BP and pain, but higher NE was related to increased pain. This study provides evidence for ethnic differences in centrally mediated pain and extends prior research demonstrating ethnic differences in endogenous pain regulatory mechanisms. These results have implications for understanding biobehavioral factors contributing to ethnic disparities in clinical pain.

BETA1 (ARG389GLY, SER49GLY)- AND BETA2 (ARG16GLY)-ADRENOCEPTOR POLYMORPHISMS ARE RELATED TO LEFT VENTRICULAR HYPERTROPHY USING ECG IN MIDDLE-AGED, NORMOTENSIVE SUBJECTS: PP.22.358

Objective: Left ventricular hypertrophy (LVH) accompanying elevated sympathetic nervous activity (SNA) is more common in hypertensive and obese people. Elevated SNA is an important mechanism in cardiovascular complications and cardiac morbidity and mortality. β2-adrenoceptor (ADRB2) polymorphisms are closely linked to hypertension and obesity, and β1-adrenoceptor (ADRB1) play roles directly with the heart. We evaluated the relationships between ADRB1 polymorphisms, ADRB2 polymorphisms and LVH. Methods: In 215 nonobese, normotensive Japanese men, ADRB1 polymorphisms (Arg389Gly, Ser49Gly), ADRB2 polymorphisms (Arg16Gly, Gln27Glu), BMI, BP, heart rates (HR), total body fat-mass, waist-to-hip ratio (W/H), plasma norepinephrine (NE), insulin, leptin and ECG were measured. LVH was determined by the Sokolow-Lyon voltage criteria. Results: Twenty-four subjects (11.2%) showed LVH on ECG. Subjects with LVH had higher NE, BP levels and HR compared to those without LVH (all P < 0.05), but BMI, fat-mass, W/H, insulin and leptin were similar. Subjects with LVH had higher frequencies of Gly389 or Gly49 alleles of ADRB1 polymorphisms (χ2 = 49.94, P = 0.002; χ2 = 11.43, P = 0.001, respectively), and Gly16 or Glu27 alleles of ADRB2 polymorphisms (χ2 = 9.59, P = 0.002; χ2 = 3.12, P = 0.059, respectively). Distributions of Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 and Glu27 alleles of ADRB2 were 39.5%, 27.9%, 74.4% and 11.2%, respectively. Subjects with Gly389 or Gly49 had higher frequencies of LVH, higher NE and HR (all P < 0.05), whereas BMI, fat-mass, W/H, BP, insulin and leptin were similar. Subjects with Gly16 had higher frequencies of LVH and greater BMI, fat-mass, systolic BP, NE and insulin compared to those without Gly16 allele (all P < .05). In multiple regression analysis, plasma NE was a significant determinant for systolic BP and LVH in all subjects. Conclusions: Subjects carrying Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 allele of ADRB2 polymorphisms had higher frequency of LVH accompanying high plasma NE. ADRB1 polymorphisms might relate to LVH directly through elevated SNA, but ADRB2 polymorphisms might relate to LVH through obesity and hypertension associated with elevated SNA and insulin resistance.

Norepinephrine-induced nerve growth factor depletion causes cardiac sympathetic denervation in severe heart failure

In severe congestive heart failure (CHF), sympathetic overactivity correlates with the exacerbation of cardiac performance. To test the hypothesis that the cardiac sympathetic nerve density dramatically changes with the acceleration of circulating norepinephrine (NE) concentration, we investigated the temporal association of nerve growth factor (NGF) expression in the heart and cardiac sympathetic nerve density during the development of CHF in the continuous NE-infused rats. The animals were analyzed at 0-, 1-, 3-, 7-, 14-, and 28-day after implantation of osmotic pump at a rate of 0.05 mg/kg/hr. The cardiac performance was temporally facilitated in NE-exposed rats at 3-day in accordance with the sympathetic hyper-innervation induced by the augmentation of NGF mRNA expression in the heart. In NE-treated rats, left ventricular end-diastolic pressure was significantly increased after 7-day and marked left ventricular hypertrophy and systemic fluid retention were observed at 28-day. CHF-induced sympathetic overactivity further increased plasma NE concentration in NE-treated rats and finally reached to 16.1 ± 5.6 ng/ml at 28-day (control level was 0.39 ± 0.1 ng/ml, p < 0.01). In the decompensated CHF rats at 28-day, the NGF mRNA expression was conspicuously reduced concomitant with the obvious nerve fiber loss confirmed by the immunostaining of nerve axonal marker, PGP9.5 and sympathetic neuron marker, tyrosine hydroxylase. This resulted in the attenuated tissue NE contents and the exacerbating cardiac performance. The cardiac sympathetic fiber loss was also confirmed in NE-exposed DBH (dopamine β-hydroxylase)-Cre/Floxed-EGFP (enhanced green fluorescent protein) mice with severe CHF, in which sympathetic nerve could be traced by EGFP. Our results suggest that the cardiac sympathetic nerve density is strictly regulated by the NGF expression in the heart and long-exposure of high plasma NE concentration caused myocardial NGF reduction, following sympathetic fiber loss in severe CHF animals.

The p75 neurotrophin receptor, semaphorins, and sympathetic traffic in the heart

the sympathetic and parasympathetic branches of the autonomic nervous system control cardiac function through the coordinated activity generated by neurons within the intracardiac autonomic ganglia and central nervous system (3). Activation of the sympathetic efferent projections to the heart increases heart rate, modifies the pattern and conduction velocity of the impulse through the heart, and augments both atrial and ventricular contractility while hastening myocardial relaxation. In the vasculature, the sympathetic nervous system (SNS) reduces venous capacitance and constricts resistance vessels, increasing blood pressure. Conversely, the parasympathetic nervous system (PSNS) decreases heart rate and cardiac impulse conduction. More recent evidence has suggested that the PSNS may also affect ventricular function, indirectly by countering β-adrenergic action or directly via inhibition of L-type Ca2+ channels (34). A transient imbalance between these two branches can lead to increased heart rate and blood pressure when cardiac output is increased. When subnormal cardiac PSNS activity concomitant with sympathetic hyperactivation persists, such as after myocardial infarction, this disequilibrium may increase the risk for cardiac adverse events, including arrhythmias, hypertension, cardiac hypertrophy, and, ultimately, heart failure. This condition is called “autonomic neural remodeling” and can greatly contribute to the induction of ventricular fibrillation, thus increasing the patient's susceptibility to sudden cardiac death (41, 47). It is plausible that neurotrophic factors, target organ-secreted proteins essential for the development and differentiation of neurons, are involved in the remarkable neuroplasticity exhibited by the SNS in the adult life, including autonomic remodeling after infarction and/or in the onset and progression of congestive heart failure (17, 30, 32).

Increased Cortisol after Stress is Associated with Variability in Response Time in ADHD Children

PurposeChildren with attention-deficit/hyperactivity disorder (ADHD) often perform poorly during cognitive tests. We sought to evaluate cortisol as potential moderator of performance in mentally challenging tasks in children with ADHD.Materials and MethodsNinety clinic-referred children with ADHD were studied. Cortisol contents in saliva were measured before and after administration of a continuous performance test (CPT).ResultsPre and post CPT cortisol levels were similar in 68 children. Children whose cortisol level increased after testing ( n = 22 ) displayed a significantly longer response time and increased response time variability scores as compared to children who did not display increase of cortisol after the CPT test. Even after controlling for the effects of response time and anxiety, the changes in cortisol levels were associated with effect on response time variability.ConclusionThe patients who showed an increased cortisol level after stress displayed a higher variability in response time than the patients who showed no change or a decreased cortisol level. The result of the current study suggests that stress-induced high norepinephrine (NE) release may accompany poorer attention performance in patients with ADHD.

Evidence of vasopressinergic-noradrenergic mechanisms in depression with above-normal plasma vasopressin concentration with and without psychotic features

Previous studies in the field of melancholic or endogenous depression have resulted in support for a subcategory of depression with above-normal plasma vasopressin (AVP) concentration (ANA). Since an analogous animal model with increased release of above-normal plasma vasopressin exhibits reduced Sympathetic-Nervous-System activity, the present study investigated the plasma norepinephrine concentration and the correlation between plasma norepinephrine and AVP in this ANA depression. As psychotic-melancholic patients may have increased plasma norepinephrine concentration, and noradrenergic activation may stimulate AVP release, potentially confounding effects of psychotic features were also investigated. The data set of the same depressed patient sample that was used before, but limited to those with complete hormonal data (n = 75), was re-analysed. ANA depression (n = 14) had negatively correlating AVP and norepinephrine concentrations. A very small subcategory of ANA depression with psychotic features (n = 3) had high plasma norepinephrine concentration, suggesting that this could be an independent subcategory. This was supported by the combination of relatively low above-normal plasma AVP concentrations with the highest severity scores for depression in this subcategory, which does not correspond with the positive correlation between AVP concentration and severity in non-psychotic ANA depression. The results further support the validity of ANA depression and the analogy with the High Anxiety Behaviour animal model of depression. Further investigations are needed to replicate these findings and to search for genetic and traumatic factors involved.

Are Electrocardiographic Changes in Patients with Acute Subarachnoid Hemorrhage Associated with Takotsubo Cardiomyopathy?

Background: Subarachnoid hemorrhage (SAH) has been associated with electrocardiographic (ECG) changes, arrhythmias, and release of cardiac enzymes. Recently, Takotsubo cardiomyopathies, presenting typical ECG changes and left ventricular (LV) regional wall-motion abnormalities (RWMAs), have been reported and considered to be a result of high norepinephrine (NE) levels. We hypothesized that ST-T-wave changes in patients with SAH may be manifestations of Takotsubo cardiomyopathy and associated with RWMAs. Methods: We instituted consecutive echocardiographic screening of all patients with acute aneurysmal SAH. A standard 12-lead ECG and blood samples for creatine kinase (CK) MB isoenzyme and troponin-T (Tn-T) were obtained. To evaluate sympathetic nervous activity, we obtained blood samples and urine samples for NE. Results: Of 42 patients with acute aneurysmal SAH, 26 had abnormal ECG including rhythm abnormalities. Ten of 12 patients with ST-T-wave changes had severe neurologic deficits, but 1 patient had RWMAs on echocardiography. Another patient with LV dysfunction showed a normal ST-T wave. In patients with ST-T-wave changes, elevated Tn-T (8.3 vs. 3.3%), CK-MB (8.3 vs. 10.0%), plasma and urine NE (16.7 and 33.3% vs. 16.7 and 50.0%), and mortality (8.3 vs. 13.3%) were not significantly higher. All 5 deaths resulted from noncardiac causes. High plasma and urine NE levels were not related to neurologic severity or mortality. Conclusions: Although ECG abnormalities are frequently seen in SAH patients, the incidence of RWMAs is very low. Electrocardiographic manifestations in patients with SAH and Takotsubo cardiomyopathy are similar, but ECG abnormalities in patients with SAH are mostly not related to LV dysfunction.

Intra-individual variability in sleep duration and fragmentation: Associations with stress

Despite growing evidence that there is substantial nightly, intra-individual variability in sleep duration and fragmentation, few studies have investigated the correlates of such variability. The current study examined whether intra-individual variability in sleep parameters was associated with psychosocial and physiological indices of stress, especially among those high in negative affect. Participants were 184 adults aged 46-78 (53% men and 41% Black) in the Pittsburgh SleepSCORE study. Wrist actigraphy was used to estimate sleep duration and fragmentation for nine nights, and overnight samples of urinary norepinephrine were collected for two nights. Stressful life events, depression, and anxiety were also reported. Intra-individual differences exceeded between-person differences in actigraphy-measured sleep duration and fragmentation. Stressful life events were associated with increased nightly variability in duration and fragmentation (ps<.05). Negative affect moderated associations between norepinephrine and variability in sleep, such that the greatest variability in actigraphy measures was among those with both high norepinephrine levels and high negative affect (ps<.05). These data suggest that both psychosocial and physiological stress are related to increased nightly variability in individuals' sleep duration and fragmentation, particularly among those reporting negative emotions. These results may have implications for both sleep and health research.

Relative Efficiencies of Plasma Catechol Levels and Ratios for Neonatal Diagnosis of Menkes Disease

Menkes disease is an X-linked recessive neurodevelopmental disorder resulting from mutation in a copper-transporting ATPase gene. Menkes disease can be detected by relatively high concentrations of dopamine (DA) and its metabolites compared to norepinephrine (NE) and its metabolites, presumably because dopamine-beta-hydroxylase (DBH) requires copper as a co-factor. The relative diagnostic efficiencies of levels of catechol analytes, alone or in combination, in neonates at genetic risk of Menkes disease have been unknown. Plasma from 44 at-risk neonates less than 30 days old were assayed for DA, NE, and other catechols. Of the 44, 19 were diagnosed subsequently with Menkes disease, and 25 were unaffected. Compared to unaffected at-risk infants, those with Menkes disease had high plasma DA (P < 10(-6)) and low NE (P < 10(-6)) levels. Considered alone, neither DA nor NE levels had perfect sensitivity, whereas the ratio of DA:NE was higher in all affected than in all unaffected subjects (P = 2 x 10(-8)). Analogously, levels of the DA metabolite, dihydroxyphenylacetic acid (DOPAC), and the NE metabolite, dihydroxyphenylglycol (DHPG), were imperfectly sensitive, whereas the DOPAC:DHPG ratio was higher in all affected than in all unaffected subjects (P = 2 x 10(-4)). Plasma dihydroxyphenylalanine (DOPA) and the ratio of epinephrine (EPI):NE levels were higher in affected than in unaffected neonates (P = 0.0015; P = 0.013). Plasma DA:NE and DOPAC:DHPG ratios are remarkably sensitive and specific for diagnosing Menkes disease in at-risk newborns. Affected newborns also have elevated DOPA and EPI:NE ratios, which decreased DBH activity alone cannot explain.

Continuum of phenotypes and sympathoadrenal function in premature adrenarche

Premature adrenarche (PA), the early rise in adrenal androgen (AA) production, can manifest with different clinical signs of androgen effect. Premature pubarche defined as appearance of pubic hair before the age of 8/9 years in girls/boys, is the most prominent clinical sign of PA and often erroneously described as a synonym of PA. Our aim was to determine the association of circulating AA concentrations with different prepubertal signs of androgen action (SAA). Secondly, we tested whether adrenomedullary function is altered in children with SAA, as it is in congenital adrenal hyperplasia (CAH) also causing adrenal hyperandrogenism. We examined 73 Finnish prepubertal children with any hyperandrogenic sign(s) having appeared before the age of 8/9 years (girls/boys) (35 with pubic and/or axillary hair=PAH; 38 without=nonPAH), and 98 age- and sex-matched controls. Circulating adrenal steroid and catecholamine concentrations were measured and correlated with clinical parameters. None of the children with SAA had CAH or virilizing tumor. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione concentrations overlapped between the SAA and control children, and they were lower in the nonPAH than PAH group (P<0.01). SAA children had similar plasma epinephrine but higher norepinephrine (NE) concentrations than their controls (mean (95% confidence interval) 1.61 (1.44, 1.77) versus 1.39 (1.30, 1.49) nmol/l, P=0.03). PA forms a continuum with more pronounced increase in circulating androgens in children with PAH than in those without. Some children show SAA with fairly low androgen concentrations. The clinical significance of elevated NE concentrations associated with SAA needs to be confirmed in further studies.

Abstract 5161:β 1 (Arg389Gly, Ser49Gly)- and β2 (Arg16Gly) -adrenoceptor Polymorphisms are Related to Left Ventricular Hypertrophy in Middle-aged, Nonobese, Normotensive Men, but Through Different Mechanisms

Objective: β2-adrenoceptor (ADRB2) polymorphisms are closely linked to hypertension and obesity, and both of them are major cardiac risk. Left ventricular hypertrophy (LVH) is more common in people who have hypertension or obesity. We examined the relationships between ADRB1 and ADRB2 polymorphisms and LVH in nonobese, normotensive subjects. Methods: In 447 middle-aged, normotensive, nonobese men, ADRB1 (Arg389Gly, Ser49Gly) and ADRB2 (Arg16Gly, Gln27Glu) polymorphisms, BMI, BP, heart rates (HR), total body fat-mass, waist-to-hip ratio (W/H), plasma norepinephrine (NE) and ECG were measured after overnight fasting in the supine position. LVH was determined by ECG. Results: Thirty-nine subjects (8.7%) showed LVH on ECG. Subjects with LVH had higher plasma NE and HR compared to those without LVH (both P&lt;.05). Distributions of Gly389 and Gly49 alleles of ADRB1 polymorphisms were 23.5% (Arg/Arg:Arg/Gly:Gly/Gly=270:144:33) and 14.1% (Ser/Ser:Ser/ Gly:Gly/Gly=327:114:6). Thirty-seven subjects with LVH (94.9%) carried Gly389 and Gly49 alleles, especially homozygous for Gly389 or Gly49. Subjects with Gly389 or Gly49 alleles had higher frequencies of LVH (20.9% vs. 0.7%, 30.8% vs. 0.6%). Subjects carrying Gly389 or Gly49 alleles had higher plasma NE and HR (both P&lt;.05), whereas BMI, fat mass, W/H and BP were similar. The Gly16 and Glu27 alleles of ADRB2 polymorphisms were noted in 42.8% (Arg/Arg :Arg/Gly:Gly/Gly=69:245:133) and 36.6% of the subjects (Gln/Gln:Gln/Glu:Glu/ Glu=176:215:56). Twenty-nine subjects with LVH (74.4%) carried Gly16 allele, especially Gly16 homozygous. Subjects with Gly16 allele had higher frequencies of LVH (P&lt;.05), and they had greater BMI, fat mass, W/H, BP, HR and NE compared to those without Gly16 allele (all P&lt;.05). Conclusions: Subjects carrying Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 allele of ADRB2 polymorphism had higher frequency of LVH accompanying high plasma NE. ADRB1 and ADRB2 polymorphisms play important roles in LVH even in nonobese, normotensive subjects. ADRB1 polymorphisms might relate to LVH through heightened sympathetic nerve activity, but ADRB2 polymorphisms might relate to LVH through obesity, hypertension and heightened sympathetic nerve activity.

Perceived Stress and Norepinephrine Predict the Effectiveness of Response to Protease Inhibitors in HIV

In vitro evidence has suggested that increasing levels of norepinephrine (NE) can accelerate HIV replication; however, the importance in a clinical setting has not been tested. The purpose of this study was to determine if perceived stress as well as the stress hormones NE and cortisol would predict the response to starting a new protease inhibitor (PI) prospectively. Perceived stress, urinary cortisol and norepinephrine, CD4 and viral load (VL) were measured in people with HIV before starting a new PI and six months later (an average of three months after starting the new PI) in order to determine CD4 and VL response to the PI. Higher perceived stress significantly predicted lower effectiveness of the new PI in increasing CD4 and decreasing VL controlling for age, duration of new PI, baseline CD4/VL, sexually transmitted diseases (STDs), and gender/ethnic risk groups. Higher norepinephrine, but not cortisol, predicted worse VL response to PIs and, in fact, mediated the relationship between perceived stress and change in VL. Perceived stress and high norepinephrine levels are prospectively associated with a poorer response to starting a new PI. Assessing stress and norepinephrine levels in patients starting on antiretroviral medications might be clinically useful.

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.

High dose norepinephrine-induced apoptosis in cultured rat cardiac fibroblast

Background Prolonged sympathetic activation is damaging to the heart. Recent findings suggest that norepinephrine (NE) may contribute to the apoptotic cardiac cell loss. This study investigated high doses NE apoptotic effect on cardiac fibroblasts (CF) culture and compared the anti-apoptotic effect of α and β (selective and non-selective) adrenergic receptor antagonists. Methods and results Rat CF were cultured in the presence of NE (1 to 100 µM) for 48 h. bax and bcl XL genes expression were measured by real-time quantitative PCR method. Cell viability percentage, apoptotic cell percentage and caspase 3 activity was measured by MTT assay, flow cytometric method and caspase 3 flurogenic assay kit respectively. NE (100 µM) increased bax gene expression by 1.96 ± 0.96 fold while bcl XL gene decreased by 0.53 ± 0.15 fold when compared with the control group ( p < 0.01). The apoptotic cell percentage increased significantly from 5.09 ± 2.94% in control group to 31.48 ± 6.35% ( p < 0.01) with NE and the caspase 3 activity increased from 1432.2 ± 658.8 in the control group to 5162 ± 2028.6 (OD/µg protein, p < 0.05). Addition of carvedilol (non-selective β blocker with α-blockade activity), doxazosin (α blocker), metoprolol (β1 selective blocker) and propranolol (non-selective β blocker) were not capable of inhibiting the apoptotic effect of high dose NE on CF. Conclusion High dose NE has cytotoxic and apoptotic effect on CF. The process involved the activation of caspase 3, up-regulation of pro-apoptotic gene bax and down-regulation of anti-apoptotic gene bcl XL. Both non-selective and selective adrenergic receptor antagonists tested were not capable of inhibiting the apoptotic effect of high dose NE on CF.

Is There a Correlation between Vitamin C Status and Catecholamines Concentrations in Hemodialysis Patients?

It is well established that there is a high incidence of cardiovascular diseases in hemodialysis patients, and involvement of oxidative stress has been hypothesised in these phenomena. Plasma norepinephrine is an independent predictor of many causes of mortality in general, and high norepinephrine levels predict cardiovascular complications in end stage renal disease. The aim of our study was to evaluate the potential link between vitamin C status, a marker of oxidative stress, and catecholamine concentrations before and after hemodialysis sessions. In a prospective study of 16 chronic hemodialysis patients, ascorbyl free radical levels were directly measured using electron spin resonance spectroscopy. These values were expressed with respect to vitamin C concentrations to obtain a direct index of oxidative stress. Vitamin C, epinephrine and norepinephrine were measured by high performance liquid chromatography. The data were examined for correlations between these compounds and clinical parameters including blood pressure and heart rates. In hemodialysis patients, ascorbyl free radical/vitamin C ratios increased significantly after dialysis. No differences were observed for catecholamine concentrations during hemodialysis sessions. In multivariate analysis, the ascorbyl free radical/vitamin C ratio did not correlate with epinephrine or norepinephrine levels. In our study, plasma norepinephrine and ascorbyl free radical/vitamin C ratios were not related among patients with end-stage renal disease. From these findings, we conclude that although these two factors are likely to be involved in the same causal pathway leading to cardiovascular events, it is likely that they seem to be independent.

Plasma Catechols in Familial Dysautonomia: A Long-term Follow-up Study

This study tested whether familial dysautonomia (FD) involves progressive loss of noradrenergic nerves. Plasma levels of catechols, including dihydroxyphenylglycol (DHPG), norepinephrine (NE), dopamine (DA), and DOPA, were measured in 7 adult patients with FD and 50 healthy control subjects. FD patients were re-tested after a mean follow-up period of 13 years. Compared to controls, FD patients had low plasma levels of DHPG (P < 0.001), high DOPA and DA levels (P = 0.01, P = 0.0002), and high NE:DHPG (P < 0.0001), DA:NE (P = 0.0003), and DOPA:DHPG (P < 0.0001) ratios. At follow-up there were no changes in plasma levels of individual catechols; however, there were further increases in DOPA:DHPG ratios (mean 24 +/- 7%, P = 0.01). In FD, plasma catechol profiles are sufficiently stable, at least over a decade, to be used as a biomarker of disease involvement. An increasing DOPA:DHPG ratio suggests slight but consistent, progressive loss of noradrenergic neurons.

Regional and Local Brain Oxygenation During Hemorrhagic Shock: A Prospective Experimental Study on the Effects of Small-Volume Resuscitation With Norepinephrine

Patients with uncontrolled hemorrhage may benefit if resuscitation with large amounts of fluids is replaced by a small volume or vasopressor until surgery. Norepinephrine (NE) is commonly used as a vasopressor to control hypotension. The purpose of this study was to compare the effects of hypertonic-hyperoncotic saline starch solution (HHS) either alone or combined with NE on brain tissue oxygen pressure (PbtO2) and brain oxygen saturation (rSO2) in a model of uncontrolled hemorrhage. After approval of the animal investigation committee, 22 anesthetized pigs underwent simulated penetrating liver trauma. At hemodynamic decompensation, animals were randomly assigned to receive HHS (Hyperhaes; 4 mL/kg; n = 8) with normal saline placebo, low-dose NE (low NE; 500 microg, and 1 microg/kg/min; n = 7), or high-dose NE (high NE; 1,000 microg, and 1 microg/kg/min; n = 7). Bleeding was controlled manually 30 minutes after drug administration. Cerebral perfusion pressure (CePP), PbtO2, and rSO2 decreased with hemorrhage in all groups (baseline vs. decompensation, CePP-HHS, 83 +/- 5 mm Hg vs. 9 +/- 1 mm Hg; low NE, 67 +/- 6 mm Hg vs. 16 +/- 2 mm Hg; high NE, 77 +/- 7 mm Hg vs. 15 +/- 1 mm Hg. PbtO2-HHS, 100% vs. 29%; low NE, 100% vs. 33%; high NE, 100% vs. 27%. rSO2-HHS, 100% vs. 70%; low NE, 100% vs. 76%; high NE, 100% vs. 63%). Therapy with HHS, low NE, and high NE resulted in a comparable increase of CePP, PbtO2, and rSO2, respectively (5 minutes after therapy, CePP-HHS, 29 +/- 3 mm Hg; low NE, 27 +/- 3 mm Hg; high NE, 28 +/- 3 mm Hg. PbtO2-HHS, 207%; low NE, 129%; high NE, 170%. rSO2-HHS, 94%; low NE, 83%; high NE, 87%). Overall survival was six of eight, four of seven, and six of seven, respectively. After uncontrolled hemorrhagic shock, addition of different dosages of NE to HHS, compared with HHS alone, showed no beneficial effect on CePP, rSO2, or PbtO2.

Clinical significance of chemosensitivity in chronic heart failure: influence on neurohormonal derangement, Cheyne–Stokes respiration and arrhythmias

Increased chemosensitivity has been observed in HF (heart failure) and, in order to clarify its pathophysiological and clinical relevance, the aim of the present study was to investigate its impact on neurohormonal balance, breathing pattern, response to exercise and arrhythmic profile. A total of 60 patients with chronic HF [age, 66+/-1 years; LVEF (left ventricular ejection fraction), 31+/-1%; values are means+/-S.E.M.] underwent assessment of HVR (hypoxic ventilatory response) and HCVR (hypercapnic ventilatory response), neurohormonal evaluation, cardiopulmonary test, 24-h ECG monitoring, and assessment of CSR (Cheyne-Stokes respiration) by diurnal and nocturnal polygraphy. A total of 60% of patients had enhanced chemosensitivity. Those with enhanced chemosensitivity to both hypoxia and hypercapnia (i.e. HVR and HCVR), compared with those with normal chemosensitivity, had significantly (all P<0.01) higher noradrenaline (norepinephrine) and BNP (B-type natriuretic peptide) levels, higher prevalence of daytime and night-time CSR, worse NYHA (New York Heart Association) class and ventilatory efficiency [higher VE (minute ventilation)/VCO(2) (carbon dioxide output) slope], and a higher incidence of chronic atrial fibrillation and paroxysmal non-sustained ventricular tachycardia, but no difference in left ventricular volumes or LVEF. A direct correlation was found between HVR or HCVR and noradrenaline (R=0.40 and R=0.37 respectively; P<0.01), BNP (R=0.40, P<0.01), N-terminal pro-BNP (R=0.37 and R=0.41 respectively, P<0.01), apnoea/hypopnoea index (R=0.57 and R=0.59 respectively, P<0.001) and VE/VCO(2) slope (R=0.42 and R=0.50 respectively, P<0.001). Finally, by multivariate analysis, HCVR was shown to be an independent predictor of both daytime and night-time CSR. In conclusion, increased chemosensitivity to hypoxia and hypercapnia, particularly when combined, is associated with neurohormonal impairment, worse ventilatory efficiency, CSR and a higher incidence of arrhythmias, and probably plays a central pathophysiological role in patients with HF.

Norepinephrine-mediated Regulation of 5HT1 Receptor Functioning in Human Platelets

Adaptive changes in serotonergic 5HT1 receptor signalling are believed to underlie the therapeutic effectiveness of antidepressant drugs. Since cells are continuously exposed to neurotransmitters/neuromodulators, spatially and temporally integrated, the responsiveness of a receptor system is dependent upon the physio-pathological state of the cell and the interaction between different neurotransmitters. In the present work, we investigated heterologous regulation of 5HT1 receptors induced by norepinephrine (NE) in human platelets. NE platelet treatment induced a time and concentration dependent 5HT1 receptor desensitisation mediated by both alpha and beta receptors through activation of intracellular protein kinases. In particular NE, through PKC activation, regulated 5HT1 receptor phosphorylation on threonine residues, causing in turn serotonin receptor-G protein uncoupling and functional responsiveness drop. These results suggest that high NE levels (released i.e. during stress disorders) may play an important role in regulating the 5HT1 responsiveness and in controlling effectiveness of drugs acting on these neurotransmitter systems.