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Comparison of norepinephrine, dopamine and dobutamine combined with enteral nutrition in the treatment of elderly patients harboring sepsis.
Zhou, WJ, Cui, JK, Liu, M, Shang, XK, Ding, SS
Pakistan journal of pharmaceutical sciences. 2021;(3):957-961
Abstract
The present study was performed in order to investigate the safety and efficacy of different vasoactive drugs combined with enteral nutrition in terms of treating elderly patients with sepsis. A total of 75 elderly patients with sepsis treated with enteral nutrition in our hospital were randomly divided into three groups: group A (n = 25), group B (n = 25) and group C (n = 25). The three groups were treated with dopamine, dobutamine and norepinephrine respectively. One week after treatment, the therapeutic effects of the three groups were compared, the vascular elastic indexes, hemodynamic indexes and levels of inflammatory factors of the three groups were measured. After treatment, the clinical effective rate of group C was evidently higher than that of group A and group B. The vascular elasticity coefficient and stiffness coefficient in group C were significantly lower than those in group A and group B, and the arterial compliance in group C was significantly higher than that in group A and group B (P < 0.05). The levels of MAP and PVRI in group C were significantly higher than those in group A and B, and the levels of CI, CVP and HR in group C were significantly lower than those in group A and group B (P < 0.05). Norepinephrine elicited greater effects in terms of improving hemodynamic indexes, vascular elasticity and reducing the level of inflammatory factors compared with dopamine and dobutamine in elderly patients harboring sepsis.
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Norepinephrine release may play a critical role in the Warburg effect: an integrative model of tumorigenesis.
Fitzgerald, PJ
Neoplasma. 2020;(5):947-957
Abstract
Many cancer cells share the property of carrying out markedly elevated rates of glycolysis to generate energy even in the presence of sufficient oxygen, and this is known as the Warburg effect. In recent years, there has been a resurgence of interest in the Warburg effect, as the field of oncology has amassed evidence that cellular metabolism may play a prominent role in many neoplasms. Largely in the past decade, another prominent and perhaps surprising factor has emerged in the cancer literature: the catecholamine molecules, epinephrine (adrenaline) and norepinephrine (noradrenaline), appear to play a role in tumorigenesis and metastasis. The drug propranolol, which blocks beta adrenergic receptors, may be therapeutic in human angiosarcoma, melanoma, and ovarian cancer. The current paper synthesizes these older and more recent findings, in an attempt to unify the major factors that contribute to tumorigenesis. This paper suggests that in addition to the direct interaction of catecholamine signaling with genetic risk factors (including mutagenesis), it interacts with environmental factors such as hypertension, obesity, unhealthy dietary components, physical inactivity, substance abuse, and mental or emotional stress, to promote the Warburg effect by facilitating glucose availability through suppression of pancreatic insulin release. Further, it proposes that many cancer cells synthesize and release catecholamines to activate their own receptors in an autocrine fashion. In summary, catecholamines are an important "new" factor in cancer that may interface with both genetics and environmental factors to alter the Warburg effect and modulate tumorigenesis.
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The "Sick-but-not-Dead" Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases.
Goldstein, DS
Seminars in neurology. 2020;(5):502-514
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Abstract
The catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases-pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the "sick-but-not-dead" phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with ("quinonizes") α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases.
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Endocrine responses during CPAP withdrawal in obstructive sleep apnoea: data from two randomised controlled trials.
Thiel, S, Haile, SR, Peitzsch, M, Schwarz, EI, Sievi, NA, Kurth, S, Beuschlein, F, Kohler, M, Gaisl, T
Thorax. 2019;(11):1102-1105
Abstract
The aim of this investigation was to elucidate the effect of CPAP withdrawal on neurometabolic and cardiometabolic markers in patients with obstructive sleep apnoea. We evaluated 70 patients (mean age 61±10 years, 82% men) treated with CPAP in two 2-week, parallel, randomised controlled trials. CPAP withdrawal resulted in elevated 3,4-dihydroxyphenylglycol, norepinephrine and cortisol after 2 weeks of CPAP withdrawal; however, no statistically significant changes of the renin-angiotensin-aldosterone system (RAAS) determinants were documented. In summary, CPAP withdrawal may be more prominently linked to short-term increases in sympathetic activation than hypothalamic-pituitary-adrenal axis or RAAS activation. ClinicalTrials.gov Identifier: NCT02493673 and NCT02050425.
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Association Between Norepinephrine Levels and Abnormal Iron Status in Patients With Chronic Heart Failure: Is Iron Deficiency More Than a Comorbidity?
Moliner, P, Enjuanes, C, Tajes, M, Cainzos-Achirica, M, Lupón, J, Garay, A, Jimenez-Marrero, S, Yun, S, Farré, N, Cladellas, M, et al
Journal of the American Heart Association. 2019;(4):e010887
Abstract
Background Mechanisms underlying iron homeostasis dysregulation in patients with chronic heart failure remain unsettled. In cardiomyocyte models, norepinephrine may lead to intracellular iron depletion, but the potential association between catecholamines (sympathetic activation markers) and iron metabolism biomarkers in chronic heart failure is unknown. Methods and Results In this cross-sectional analysis, we studied the association between plasma norepinephrine levels and serum iron status biomarkers indicating iron storage (ferritin), iron transport (transferrin saturation), and iron demand (soluble transferrin receptor) in a prospective cohort of 742 chronic heart failure patients (mean age, 72±11 years; 56% male). Impaired iron status was defined as ferritin <100 μg/L or transferrin saturation <20%. Impaired iron status was observed in 69% of patients. In multivariate models, greater norepinephrine levels were associated with impaired iron transport (transferrin saturation <20%, odds ratio=2.28; 95% CI [1.19-4.35]; P=0.013), but not with impaired iron storage (ferritin <100 μg/L, odds ratio=1.25; 95% CI [0.73-2.16]; P=0.415). Norepinephrine was a significant predictor of increased iron demand (soluble transferrin receptor, standardized β-coefficient=0.12; P=0.006) and low transferrin saturation (standardized β-coefficient=-0.12; P=0.003). However, norepinephrine levels were not associated with iron or ferritin levels ( P>0.05). Adjusted norepinephrine marginal means were significantly higher in patients with impaired iron status compared with those with normal iron status (528 pg/mL [505-551] versus 482 pg/mL [448-518], respectively; P=0.038). Conclusions In chronic heart failure patients, increased sympathetic activation estimated with norepinephrine levels is associated with impaired iron status and, particularly, dysregulation of biomarkers suggesting impaired iron transport and increased iron demand. Whether the relationship between norepinephrine and iron metabolism is bidirectional and entails causality need to be elucidated in future research.
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Oxidative burst and Dectin-1-triggered phagocytosis affected by norepinephrine and endocannabinoids: implications for fungal clearance under stress.
Buchheim, JI, Hoskyns, S, Moser, D, Han, B, Deindl, E, Hörl, M, Biere, K, Feuerecker, M, Schelling, G, Choukèr, A
International immunology. 2018;(2):79-89
Abstract
A prolonged stress burden is known to hamper the efficiency of both the innate and the adaptive immune systems and to attenuate the stress responses by the catecholaminergic and endocannabinoid (EC) systems. Key mechanisms of innate immunity are the eradication of pathogens through phagocytosis and the respiratory burst. We tested the concentration-dependent, spontaneous and stimulated (via TNFα and N-formylmethionine-leucyl-phenylalanine) release of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMNs) in vitro in response to norepinephrine (NE) and AM1241, a pharmacological ligand for the EC receptor CB2. We evaluated phagocytosis of Dectin-1 ligating zymosan particles and tested the cytokine response against Candida antigen in an in vitro cytokine release assay. Increasing concentrations of NE did not affect phagocytosis, yet stimulated ROS release was attenuated gradually reaching maximum suppression at 500 nM. Adrenergic receptor (AR) mechanisms using non-AR-selective (labetalol) as well as specific α-(prazosin) and β-(propranolol) receptor antagonists were tested. Results show that only labetalol and propranolol were able to recuperate cytotoxicity in the presence of NE, evidencing a β-receptor-mediated effect. The CB2 agonist, AM1241, inhibited phagocytosis at 10 µM and spontaneous peroxide release by PMNs. Use of the inverse CB2 receptor agonist SR144528 led to partial recuperation of ROS production, confirming the functional role of CB2. Additionally, AM1241 delayed early activation of monocytes and induced suppression of IL-2 and IL-6 levels in response to Candida via lower activity of mammalian target of rapamycin (mTOR). These findings provide new insights into key mechanisms of innate immunity under stressful conditions where ligands to the sympatho-adrenergic and EC system are released.
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Renal effects of norepinephrine-induced variations in mean arterial pressure after liver transplantation: A randomized cross-over trial.
Skytte Larsson, J, Bragadottir, G, Redfors, B, Ricksten, SE
Acta anaesthesiologica Scandinavica. 2018;(9):1229-1236
Abstract
BACKGROUND Acute kidney injury is commonly seen after liver transplantation. The optimal perioperative target mean arterial pressure (MAP) for renal filtration, perfusion and oxygenation in liver recipients is not known. The effects of norepinephrine-induced changes in MAP on renal blood flow (RBF), oxygen delivery (RDO2 ), glomerular filtration rate (GFR) and renal oxygenation (=renal oxygen extraction, RO2 Ex) were therefore studied early after liver transplantation. METHODS Ten patients with an intra- and post-operative vasopressor-dependent systemic vasodilation were studied early after liver transplantation during sedation and mechanical ventilation. To achieve target MAP levels of 60, 75 and 90 mm Hg, the norepinephrine infusion rate was randomly and sequentially titrated. At each target MAP, data on cardiac index (CI), RBF and GFR were obtained by transpulmonary thermodilution (PiCCO), the renal vein thermodilution technique and renal extraction of chromium ethylenediaminetetraaceticacid (51 Cr-EDTA), respectively. Renal oxygen consumption (RVO2 ) and extraction (RO2 Ex) were calculated according to standard formulas. RESULTS At a target MAP of 75 mm Hg, CI (13%), RBF (18%), RDO2 (24%), GFR (31%) and RVO2 (20%) were higher while RO2 Ex was unchanged compared to a target MAP of 60 mm Hg. Increasing MAP from 75 up to 90 mm Hg increased RVR by 38% but had no further effects on CI, RBF, RDO2 or GFR. CONCLUSIONS In patients undergoing liver transplantation, RBF and GFR are pressure-dependent at MAP levels below 75 mm Hg. Our results suggest that MAP should probably be targeted to approximately 75 mm Hg for optimal perioperative renal filtration, perfusion and oxygenation in patients undergoing liver transplantation.
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Noradrenaline up-regulates volume-regulated chloride current by PKA-independent cAMP/exchange protein activated by cAMP pathway in human atrial myocytes.
Xiao, GS, Zhang, YH, Wang, Y, Sun, HY, Baumgarten, CM, Li, GR
British journal of pharmacology. 2018;(16):3422-3432
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Abstract
BACKGROUND AND PURPOSE Adrenergic regulation of cell volume-regulated chloride current (ICl.vol ) is species-dependent. The present study investigates the mechanism underlying adrenergic regulation of ICl.vol in human atrial myocytes. EXPERIMENTAL APPROACH Conventional whole-cell patch voltage-clamp techniques were used to record membrane current in human atrial myocytes. ICl.vol was evoked by hyposmotic bath solution (0.6 times isosmotic, 0.6 T). KEY RESULTS ICl.vol was augmented by noradrenaline (1 μM) during cell swelling in 0.6 T but not under isosmotic (1 T) conditions. Up-regulation of ICl.vol in 0.6 T was blocked by the β-adrenoceptor antagonist propranolol (2 μM), but not by the α1 -adrenoceptor antagonist prazosin (2 μM). This β-adrenergic response involved cAMP but was independent of PKA; the protein kinase inhibitor H-89 (2 μM) or PKI (10 μM in pipette solution) failed to prevent ICl.vol up-regulation by noradrenaline. Moreover, the PI3K/PKB inhibitor LY294002 (50 μM) and the PKG inhibitor KT5823 (10 μM) did not affect noradrenaline-induced increases in ICl.vol . Interestingly, the exchange protein directly activated by cAMP (Epac) agonist 8-pCPT-2'-O-Me-cAMP (50 μM) also up-regulated ICl.vol , and the noradrenaline-induced increase of ICl.vol in 0.6 T was reversed or prevented by the Epac inhibitor ESI-09 (10 μM). CONCLUSION AND IMPLICATIONS These data show that ICl.vol evoked by cell swelling of human atrial myocytes is up-regulated by noradrenaline via a PKA-independent cAMP/Epac pathway in human atrial myocytes. cAMP/Epac-induced ICl.vol is expected to shorten action potential duration during human atrial myocytes swelling and may be involved in abnormal cardiac electrical activity during cardiac pathologies that evoke β-adrenoceptor signalling.
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Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties.
Okkerse, P, Hay, JL, Sitsen, E, Dahan, A, Klaassen, E, Houghton, W, Groeneveld, GJ
British journal of clinical pharmacology. 2017;(4):751-763
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Abstract
AIM: Xen2174 is a synthetic 13-amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects. METHODS This was a randomized, blinded, placebo-controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks). RESULTS Twenty-five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration-time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post-lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg-placebo (95% confidence interval), 22.2% (-5.0%, 57.1%); P = 0.1131]. CONCLUSIONS At the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed.
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Stress hormone epinephrine (adrenaline) and norepinephrine (noradrenaline) effects on the anaerobic bacteria.
Boyanova, L
Anaerobe. 2017;:13-19
Abstract
Microbial endocrinology is a relatively new research area that already encompasses the anaerobes. Stress hormones, epinephrine and norepinephrine, can affect the growth of anaerobic bacteria such as Fusobacterium nucleatum, Prevotella spp., Porhyromonas spp., Tanerella forsythia and Propionibacterium acnes and can increase virulence gene expression, iron acquisition and many virulence factors of some anaerobic species such as Clostridium perfringens, Porphyromonas gingivalis and Brachyspira pilosicoli. Epinephrine and norepinephrine effects can lead to a growth increase or decrease, or no effect on the growth of the anaerobes. The effects are species-specific and perhaps strain-specific. Discrepancies in the results of some studies can be due to the different methods and media used, catecholamine concentrations, measurement techniques and the low number of strains tested. Biological effects of the stress hormones on the anaerobes may range from halitosis and a worsening of periodontal diseases to tissue damages and atherosclerotic plaque ruptures. Optimizations of the research methods and a detailed assessment of the catecholamine effects in conditions mimicking those in affected organs and tissues, as well as the effects on the quorum sensing and virulence of the anaerobes and the full spectrum of biological consequences of the effects are interesting topics for further evaluation.