Showing papers on "Norepinephrine (medication) published in 2013"
TL;DR: It is reported that renal nerve stimulation after ureteral obstruction is the primary profibrotic signal and that renal denervation prevents both fibrogenesis and the inflammatory cascade and that their suppression may be a therapeutic approach to fibrosis prevention.
Abstract: The signals that drive fibrogenesis after an initiating insult to the kidney are incompletely understood. Here, we report that renal nerve stimulation after ureteral obstruction is the primary profibrotic signal and that renal denervation prevents both fibrogenesis and the inflammatory cascade. Local infusion of neural factors, norepinephrine, and calcitonin gene-related peptide (CGRP) in denervated kidneys mimicked the fibrotic response observed in innervated obstructed kidneys. Norepinephrine and CGRP act through the α2-adrenergic receptor and CGRP receptor, respectively, because blocking these receptors prevented fibrosis, the inflammatory response, and tubular cell death. In tubular epithelial cells, both norepinephrine and CGRP induced apoptosis and the release of profibrotic factors capable of stimulating the differentiation of fibroblasts to myofibroblasts. In conclusion, these data suggest that nerve-derived signaling molecules may drive renal fibrosis and that their suppression may be a therapeutic approach to fibrosis prevention.
103 citations
TL;DR: The findings suggest that the LC-norepinephrine system of females will be particularly affected by conditions resulting in elevated CRF because of differences in receptor trafficking.
Abstract: Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression
94 citations
TL;DR: The utility of the method was demonstrated by selectively labeling and imaging norepinephrine in secretory vesicles such that discrimination between nore Pinephrine- and epinephrine-enriched populations of chromaffin cells was observed.
Abstract: A method for the selective labeling and imaging of catecholamines in live and fixed secretory cells is reported. The method integrates a tailored approach using a novel fluorescence-based turn-on molecular sensor (NeuroSensor 521) that can exploit the high concentration of neurotransmitters and acidic environment within secretory vesicles for the selective recognition of norepinephrine and dopamine. The utility of the method was demonstrated by selectively labeling and imaging norepinephrine in secretory vesicles such that discrimination between norepinephrine- and epinephrine-enriched populations of chromaffin cells was observed. This method was validated in fixed cells by co-staining with an anti-PNMT antibody.
66 citations
TL;DR: Results show that ascorbate promptly enhances norepinephrine synthesis from dopamine by neuronal cells that it does so at physiologic intracellular concentrations in accord with the kinetics of D βH, and that it both protects cells from superoxide and by providing electrons to DβH.
62 citations
TL;DR: The pressor response to norepinephrine was reduced following lipopolysaccharide and increased to baseline levels following &agr;-2 agonists, while dexmedetomidine administered after lipopoly Saccharide caused a large increase in pressor responsiveness above lipopolySaccharide values.
Abstract: Objective:During septic shock, vasopressors are a cornerstone of therapy. In septic shock, very high doses of vasopressors sometimes have to be used due to vascular desensitization, the mechanisms of which are poorly understood. This study assesses whether α-2 agonists increase pressor responsivenes
60 citations
TL;DR: Survivors of septic shock had greater decreases of cytokines, chemokines and growth factors in early septicshock, and the vasopressin-associated decrease of cytokine levels differed according to severity of shock.
Abstract: Rationale: Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus norepinephrine) could change plasma cytokine levels in early septic shock. Objectives: Our hypotheses were that changes in plasma cytokine levels over 24 hours differ between survivors and nonsurvivors, and that there are different effects of vasopressin and norepinephrine on plasma cytokine levels in septic shock. Methods:Westudied394patientsinarandomized,controlledtrialof vasopressin versus norepinephrine in septic shock. We used hierarchical clustering and principal components analysis of the baseline cytokine concentrations to subgroup cytokines; we then compared survivors to nonsurvivors (28 d) and compared vasopressin- versus norepinephrine-induced changes in cytokine levels over 24 hours. Measurements and Main Results: A total of 39 plasma cytokines were measured at baseline and at 24 hours. Hierarchical clustering and principal components analysis grouped cytokines similarly. Survivors (versus nonsurvivors) had greater decreases of overall cytokine levels (P , 0.001). Vasopressin decreased overall 24-hour cytokine concentration compared with norepinephrine (P ¼ 0.037). In less
59 citations
TL;DR: Cardiovascular failure was dampened as attested by a better mean arterial pressure, cardiac index, cardiac power index, and SvO2, despite lower norepinephrine requirements.
Abstract: The objective of this study was to determine the effects of a TREM (triggering receptor expressed on myeloid cells 1)-like transcript 1-derived peptide (LR12) administration during septic shock in pigs. Two hours after induction of a fecal peritonitis, anesthetized and mechanically ventilated adult male minipigs were randomized to receive LR12 (n = 6) or its vehicle alone (normal saline, n = 5). Two animals were operated and instrumented without the induction of peritonitis and served as controls (sham). Resuscitation was achieved using hydroxyethyl starch (up to 20 mL/kg) and norepinephrine infusion (up to 10 μg/kg per minute). Hemodynamic parameters were continuously recorded. Gas exchange, acid-base status, organ function, and plasma cytokines concentrations were evaluated at regular intervals until 24 h after the onset of peritonitis when animals were killed under anesthesia. Peritonitis induced profound hypotension, myocardial dysfunction, lactic acidosis, coagulation abnormalities, and multiple organ failure. These disorders were largely attenuated by LR12. In particular, cardiovascular failure was dampened as attested by a better mean arterial pressure, cardiac index, cardiac power index, and S(v)O(2), despite lower norepinephrine requirements. LR12, a TREM-like transcript 1-derived peptide, exhibits salutary properties during septic shock in adult minipigs.
51 citations
TL;DR: Femoral arterial pressure monitoring may be more appropriate when high-dose NE therapy is administered, and radial artery pressure frequently underestimates central pressure in septic shock patients receiving high- dose NE therapy.
Abstract: OBJECTIVES The accuracy of arterial blood pressure (ABP) monitoring is crucial in treating septic shock patients. Clinically significant differences in central to peripheral ABP could develop into sepsis during vasopressor therapy. The aim of this study was to investigate the difference between radial (peripheral) and femoral (central) ABP in septic shock patients receiving high-dose norepinephrine (NE) therapy. METHODS AND RESULTS This prospective observational study comparing simultaneous intra-arterial measurements of radial and femoral ABP was performed at a university-affiliated, tertiary referral center between October 2008 and March 2009. Patients with septic shock who needed continuous blood pressure monitoring and high-dose NE therapy 0.1 µg/kg per minute or greater to maintain mean arterial pressure (MAP) of 65 mmHg or greater were included. Statistical analysis was conducted using the Bland-Altman method for comparison of repeated measures. In total, 250 sets of systolic, mean, and diastolic femoral and radial ABP were recorded at baseline and after NE titration. Arterial blood pressure readings from the radial artery were underestimated compared with those from the femoral artery. Overall bias (mean difference between simultaneous measurements) between radial and femoral MAP was +4.9 mmHg; however, during high-dose NE therapy, the bias increased to +6.2 mmHg (95% limits of agreement: -6.0 to +18.3 mmHg). Clinically significant radial-femoral MAP differences (MAP ≥5 mmHg) occurred in up to 62.2% of patients with high-dose NE therapy. CONCLUSIONS Radial artery pressure frequently underestimates central pressure in septic shock patients receiving high-dose NE therapy. Femoral arterial pressure monitoring may be more appropriate when high-dose NE therapy is administered.
48 citations
TL;DR: It is suggested that 071031B is a novel, balanced serotonin and norepinephrine reuptake inhibitor, with more potent antidepressant effects and lower hepatotoxicity and neurotoxicity in vitro than duloxetine.
48 citations
TL;DR: In summary, incubation of 3T3 cells with catecholamines results in long-term DNA damage as measured by increased transformed phenotypes and tumor progression, indicating that they are important mediators of stress effects on genomic instability and vulnerability to tumor formation.
Abstract: Epinephrine and norepinephrine are produced during psychological stress and can directly bind to cells to induce DNA damage. These effects may have more long-lasting consequences such as DNA mutations resulting in an increased potential for cellular transformation and/or tumor progression. This study examined the molecular effects of a chronic (24 h) in vitro exposure to these stress hormones on murine 3T3 cells. Long exposures (24 h) in dose-response experiments with norepinephrine or epinephrine induced significant increases in DNA damage in treated cells compared to that of untreated controls as measured by the alkaline comet assay. Pre-treatment with a blocking agent (the β-adrenergic receptor antagonist propranolol) eliminated this increase in damage. In addition, both norepinephrine and epinephrine increased cellular transformation, as assessed by growth in soft agar, and 3T3 cells pre-treated with either norepinephrine or epinephrine induced a more rapid onset of tumors and more aggressive tumor growth in nude mice. In summary, incubation of 3T3 cells with catecholamines results in long-term DNA damage as measured by increased transformed phenotypes and tumor progression, indicating that they are important mediators of stress effects on genomic instability and vulnerability to tumor formation.
46 citations
TL;DR: Elevated level of circulating renalase in dialysis patients is rather related to kidney function and the sympathetic nervous system hyperactivity found in this population and may give a new way for pathophysiological therapy.
Abstract: Background: hRenalase may degrade catecholamines and regulate sympathetic tone and blood pressure (BP). The aim of the study was to assess dopamine (DA), norepinephrine (NE), and renalase in 75 hemodialysis (HD) and 26 peritoneal dialysis (PD) patients and their correlations with heart rate (HR), BP, a type of hypotensive therapy, and residual renal function. Methods: Renalase, DA, NE were studied using commercially available assays. Results: Renalase and NE were higher and DA was lower in dialyzed groups comparing to healthy volunteers. Hemodialysis patients had lower NE and higher renalase level. Norepinephrine was higher in anuric patients in HD group. Renalase correlated with dialysis vintage and inversely with residual diuresis. Dopamine correlated with residual diuresis in the whole study cohort, with HR in PD patients, with renalase in HD patients. Norepinephrine correlated with aortic diameter in PD patients. Norepinephrine was significantly higher in patients with coronary artery disease (CAD) in...
TL;DR: The data demonstrate that norepinephrine release in the vBNST differs from dopaminerelease in the dlBNST and the NAc in that it signals the absence of reward rather than responding to reward predictive cues.
TL;DR: During resuscitated murine septic shock, early ADM binding with HAM1101 improved catecholamine responsiveness, blunted the shock-related impairment of energy metabolism, reduced nitrosative stress, and attenuated systemic inflammatory response, which was ultimately associated with reduced kidney dysfunction and organ injury.
Abstract: Adrenomedullin (ADM) has been referred to as a double-edged sword during septic shock: On one hand, ADM supplementation improved organ perfusion and function, attenuated systemic inflammation, and ultimately reduced tissue apoptosis and mortality. On the other hand, ADM overproduction can cause circulatory collapse and organ failure due to impaired vasoconstrictor response and reduced myocardial contractility. Since most of these data originate from un-resuscitated shock models, we tested the hypothesis whether the newly developed anti-ADM antibody HAM1101 may improve catecholamine responsiveness and thus attenuate organ dysfunction during resuscitated murine, cecal ligation and puncture (CLP)-induced septic shock. Immediately after CLP, mice randomly received vehicle (phosphate-buffered saline, n = 11) or HAM1101 (n = 9; 2 μg·g−1). Fifteen hours after CLP, animals were anesthetized, mechanically ventilated, instrumented, and resuscitated with hydroxyethylstarch and continuous i.v. norepinephrine to achieve normotensive hemodynamics (mean arterial pressure > 50 to 60 mmHg). HAM1101 pretreatment reduced the norepinephrine infusion rates required to achieve hemodynamic targets, increased urine flow, improved creatinine clearance, and lowered neutrophil gelatinase-associated lipocalin blood levels, which coincided with reduced expression of the inducible nitric oxide synthase and formation of peroxynitrite (nitrotyrosine immunostaining) in the kidney and aorta, ultimately resulting in attenuated systemic inflammation and tissue apoptosis. During resuscitated murine septic shock, early ADM binding with HAM1101 improved catecholamine responsiveness, blunted the shock-related impairment of energy metabolism, reduced nitrosative stress, and attenuated systemic inflammatory response, which was ultimately associated with reduced kidney dysfunction and organ injury.
TL;DR: In rats, cardiac uptake of 18F-LMI1195 was significantly inhibited by phenoxybenzamine but not desipramine, suggesting 18F -LMI 1195 is a substrate for the uptake-2 mechanism and is consistent with the rat heart having a dominant level of the mechanism.
Abstract: A novel 18F-labeled tracer, LMI1195 (N-[3-bromo-4-(3-18F-fluoro-propoxy)-benzyl]-guanidine), is being developed for sympathetic nerve imaging; its high specificity for neural uptake-1 mechanism has previously been demonstrated in cell associative studies and in rabbit and nonhuman primate studies assessing heart uptake. The aim of this study was to investigate the mechanisms of 18F-LMI1195 cardiac uptake in the rat, which is known to contain norepinephrine uptake mechanisms beyond uptake-1. Methods: Tracer accumulation in the heart was studied over time after intravenous administration of 18F-LMI1195 in healthy male Wistar rats by quantitative in vivo PET imaging. The uptake mechanism was assessed by pretreatment with the nonselective norepinephrine uptake-1 and norepinephrine uptake-2 inhibitor phenoxybenzamine (50 mg/kg intravenously; n = 4), the selective norepinephrine uptake-1 inhibitor desipramine (2 mg/kg intravenously; n = 4), or saline control (intravenously; n = 4). Results:18F-LMI1195 produced high and sustained heart uptake allowing clear delineation of the left ventricular wall over 60 min after tracer administration. Pretreatment with phenoxybenzamine markedly reduced the 18F-LMI1195 cardiac uptake when compared with controls. In contrast, there was preserved 18F-LMI1195 uptake after desipramine pretreatment. Conclusion: In rats, cardiac uptake of 18F-LMI1195 was significantly inhibited by phenoxybenzamine but not desipramine, suggesting 18F-LMI1195 is a substrate for the uptake-2 mechanism and is consistent with the rat heart having a dominant level of the mechanism.
TL;DR: Catheter-based renal denervation has been shown to reduce renal norepinephrine spillover, muscle sympathetic nerve activity, and cardiac arrest-like symptoms in patients with hypertension.
Abstract: Catheter-based renal denervation (RDN) has evolved recently as a promising minimally invasive treatment for patients with hypertension, based on the concept of an old surgical technique [(1)][1]. RDN has been shown to reduce renal norepinephrine spillover [(2)][2], muscle sympathetic nerve activity
TL;DR: The effects of continuous‐flow HeartMate II LVAD on cardiac sympathetic innervations using [123I]metaiodobenzylguanidine ([ 123I]MIBG) nuclear imaging are examined.
Abstract: Aims
Dilated cardiomyopathy (DCM) patients have abundant levels of norepinephrine secondary to failure of the norepinephrine transporter uptake mechanism. Little is known about the effects of an LV assist device (LVAD) on cardiac sympathetic innervations and norepinephrine transporter dysfunction. This study examines the effects of continuous-flow HeartMate II LVAD on cardiac sympathetic innervations using [123I]metaiodobenzylguanidine ([123I]MIBG) nuclear imaging.
Methods and results
After injecting 431 ± 21 MBq of [123I]MIBG, planar scintigraphy was performed at 15 min and 4 h in 14 consecutive non-diabetic non-ischaemic DCM patients. Scans were executed early post-LVAD implantation (T1) and prior to either device explantation for myocardial recovery or transplant listing (T2). [123I]MIBG measured parameters included early and delayed heart–mediastinum (H/M) ratios and washout rate (W/O). Catecholamine levels were measured using liquid chromatography–mass spectrometry. Following 208.4 ± 85.5 days of LVAD support, both early and delayed H/M ratios increased by 42.1% (P < 0.001) and 54.7% (P < 0.001), respectively. The W/O rate decreased by 46% (P = 0.003). Plasma norepinephrine, epinephrine, and dopamine decreased significantly in correlation with [123I]MIBG parameters. Ten patients had recovered and had their device explanted as they had demonstrated a higher percentage change in delayed H/M ratio, W/O rate, and norepinephrine levels. Linear regression analysis revealed a strong correlation between percentage changes in both norepinephrine and epinephrine and myocardial recovery.
Conclusion
Combination therapy with LVAD and drug resulted in enhancement of [123I]MIBG uptake in DCM patients.
TL;DR: Rescue treatment with high-dose norepinephrine is futile in patients with severe disease and metabolic acidemia, and the cause of shock and treatment with norpinephrine were not predictive of death when high doses of the drug were deemed necessary.
Abstract: Background Critically ill patients with circulatory shock sometimes need rescue treatment with high doses of norepinephrine, a treatment that may be associated with a poor outcome because of excessive vasoconstriction. Objective To evaluate the outcome of treatment and its determinants in patients with circulatory shock who received high doses of norepinephrine in the intensive care unit and to identify indicators of futility for the treatment. Methods A retrospective study was done on 113 consecutive patients with circulatory shock who received 0.9 μg/kg per minute or greater of norepinephrine during at least 1 hour at any time in the intensive care unit. Data were extracted from the electronic patient data management system according to a predefined checklist. Results A total of 39 patients survived for 28 days after admission to the intensive care unit. The variables independently associated with 28-day mortality in multivariable models included low urine flow, high lactate levels, high organ failure score, high prothrombin time, and need for epinephrine cotreatment. The reason, dose, and duration of norepinephrine administration did not have prognostic significance. Scores greater than 40 on the Acute Physiology and Chronic Health Evaluation II, bicarbonate levels less than 9.0 mEq/L, or receipt of an epinephrine dose of 0.25 μg/kg per minute or greater were associated with 100% mortality. Conclusions Although the cause of shock and treatment with norepinephrine were not predictive of death when high doses of the drug were deemed necessary, rescue treatment with high-dose norepinephrine is futile in patients with severe disease and metabolic acidemia.
TL;DR: The results of this retrospective cohort study evaluated adults who received monotherapy with either norepinephrine or vasopressin as initial vasoactive therapy for the management of septic shock, suggesting noninferiority of vasopressed for the achievement of a mean arterial pressure goal in the first 6 hours of shock onset.
Abstract: BACKGROUNDEarly goal-directed therapy is a time-sensitive therapeutic algorithm with a tiered approach to target hypoperfusion and cardiovascular collapse within the first 6 hours of septic shock. The Surviving Sepsis Campaign guidelines recommend norepinephrine or dopamine as the initial vasoactive agent for resuscitation in septic shock, reserving the administration of vasopressin as adjunctive therapy.OBJECTIVETo determine whether vasopressin was noninferior to norepinephrine as the initial vasopressor to achieve a mean arterial pressure (MAP) goal in the first 6 hours of shock onset.METHODSThis retrospective cohort study evaluated adults who received monotherapy with either norepinephrine or vasopressin as initial vasoactive therapy for the management of septic shock. Patients were excluded if the treatment arm was not monotherapy, if they were admitted to a cardiology or cardiothoracic surgery service, or if they lacked a comparator-based 1:1 frequency matching.RESULTSA total of 130 patients were inc...
TL;DR: Evidence is reported supporting the hypothesis of a clinically relevant inverse relationship between measures of plasma cholesterol and vagally-mediated heart rate variability after controlling for sympathetic nervous system activity and suggesting an important role for the vagal control of Plasma cholesterol levels in cardiovascular disease.
TL;DR: It is suggested that early application of small doses of AVP + NE before bleeding control can “buy” time for the definitive treatment of uncontrolled hemorrhagic shock, which may be an effective measure for the early treatment of traumatic hemorrhagicshock.
Abstract: Implementation of fluid resuscitation and blood transfusion are greatly limited in prehospital or evacuation settings after severe trauma or war wounds. With uncontrolled hemorrhagic shock rats, we investigated if arginine vasopressin (AVP) in combination with norepinephrine (NE) is independent (or slightly dependent) of fluid resuscitation and can "buy" time for the subsequently definitive treatment of traumatic hemorrhagic shock in the present study. The results showed that AVP (0.4 U/kg) alone or with NE (3 μg/kg) with one-eighth and one-fourth volumes of total blood volume of lactated Ringer's infusion significantly increased and maintained the mean arterial pressure. Among all groups, 0.4 U/kg of AVP + NE (3 μg/kg) with one-eighth volume of lactated Ringer's infusion had the best effect: it significantly increased and maintained hemodynamics and prolonged the survival time. This early treatment strategy significantly improved the effects of subsequently definitive treatments (after bleeding controlled): it increased the subsequent survival, improved the hemodynamic parameters, improved the cardiac function, and increased the tissue blood flow and oxygen delivery. These results suggested that early application of small doses of AVP (0.4 U/kg) + NE before bleeding control can "buy" time for the definitive treatment of uncontrolled hemorrhagic shock, which may be an effective measure for the early treatment of traumatic hemorrhagic shock.
TL;DR: Denervation of free flap tissue is demonstrable using spectral analysis of laser Doppler blood flow signals, making norepinephrine potentially the most suitable agent following free tissue transfer.
Abstract: Background The use of pressor drugs after microsurgical free tissue transfer remains controversial because of potential vasoconstrictor effects on the free flap. Noninvasive monitoring of free flaps with laser Doppler flowmetry may provide further information regarding the local regulation of blood flow in the flap tissues during pressor infusions. This study evaluated the effects of four commonly used pressor agents. Methods Twenty four patients (25 data sets) undergoing head and neck cancer resection and free flap reconstruction were recruited. Epinephrine, norepinephrine, dopexamine, and dobutamine were infused in a random order at four infusion rates, after surgery, with free flap and control area (deltoid region) laser Doppler skin blood flow monitoring. Frequency analysis of the Doppler waveform was performed utilizing the time period immediately before the first drug infusion for each patient as baseline. Results At baseline there was less power at the 0.002-0.6 Hz frequency in the flap compared with control tissue consistent with surgical denervation. At maximum epinephrine infusion rates, the control of blood flow moved toward (i.e., proportion of power increased in) the lower frequencies, as smooth muscle mediated (myogenic) control began to dominate blood flow, an effect most marked with norepinephrine. Dobutamine and dopexamine had little effect on control of blood flow. Conclusions Denervation of free flap tissue is demonstrable using spectral analysis of laser Doppler blood flow signals. With norepinephrine the control of blood flow shifts toward low frequency vasomotion where blood flow depends mostly on average blood pressure, making it potentially the most suitable agent following free tissue transfer.
TL;DR: Cardiovascular failure in sepsis involves a combination of hypovolemia, decreased vascular tone, myocardial depression and microcirculatory alterations, so concerns exist on potential detrimental effects on renal function of old generation starches.
Abstract: Cardiovascular failure in sepsis involves a combination of hypovolemia, decreased vascular tone, myocardial depression and microcirculatory alterations. Fluids represent the first line therapeutic intervention, with controversy regarding the type of fluid. Recent data indicate that albumin is safe and might even be beneficial in specific subgroups. Starches may be an alternative, although concerns exist on potential detrimental effects on renal function of old generation starches. Trials testing new generation starches are ongoing. When fluids fail to correct hypotension, vasopressor agents are used. Various adrenergic agents increase blood pressure, especially dopamine, noradrenaline and adrenaline, by stimulating alpha-adrenergic receptors. They also variably stimulate beta-adrenergic receptors, increasing cardiac contractility, heart rate, and splanchnic perfusion, but with increased risk of arrhythmias, immunomodulation and increased metabolism. Furthermore, dopamine stimulates dopaminergic receptors, resulting in doubtful effects on splanchnic and renal perfusion, but also in endocrine alterations. Do these pharmacologic differences among the various alpha-adrenergic agents translate into clinical differences? Several randomized trials tested the effects of these agents on outcome. Epinephrine produces more undesired effects than norepinephrine, but no clear cut differences on outcome were observed in underpowered trials. Norepinephrine should be preferred over dopamine, as suggested in one large trial and confirmed in a meta-analysis. Vasopressin may be considered as an alternative or in addition to adrenergic agents. In one large trial, no significant difference in outcome was observed, and the exact role of vasopressin still needs clarification. Finally, various inotropic agents can counteract septic myocardial depression. So far, no study supports their routine use, but these may be justified on an individual basis.
TL;DR: Evidence is provided for an overall inhibitory effect of curcumin on Gelatinase B in NE-induced hypertrophic stress in H9c2 cardiomyocytes which may contribute in the prevention of ECM remodeling.
Abstract: Background
Extracellular matrix (ECM) remodeling facilitates biomechanical signals in response to abnormal physiological conditions. This process is witnessed as one of the major effects of the stress imposed by catecholamines, such as epinephrine and norepinephrine (NE), on cardiac muscle cells. Matrix metalloproteinases (MMPs) are the key proteases involved in degradation of the ECM in heart.
TL;DR: The three-dimensional, collagen-based cell migration assay is investigated and it is found that this conflicting effect of norepinephrine on pancreatic cancer cells is due to an imbalanced activation of the two pathways that usually mediate a pro-migratory effect of cAMP in other tumour cell types.
TL;DR: Survival of patients with prolonged therapy with norepinephrine and epinephrine above the evaluated thresholds is poor, whereas short-term application of high-dose catecholamines is not associated with poor outcome.
Abstract: Volume management and vasopressor support remain the gold standard of critical care for patients with shock. However, prolonged therapy with catecholamines in high doses is associated with a negative patient outcome. The aim of the present study was to analyze the administered levels of catecholamines over time with respect to survival, and to identify a cut-off to allow a prediction of survival. Consecutively, 9,108 adult patients during 22 months were evaluated. This group included 1,543 patients treated with epinephrine and/or norepinephrine with any dose at any time. Time and dosages of the applied drugs, the sequential organ failure assessment and acute and chronic health evalutation II scores on admission and daily, the length of intensive care unit stay, and the outcomes were recorded. The non-survivors received higher doses of norepinephrine and epinephrine than the survivors (p < 0.001). The receiver operator characteristic curve for the area under the curve with non-survival as the classifier revealed a cut-off level of 294.33 μg/kg for norepinephrine with a sensitivity of 74.73 % and a specificity of 70.48 % and a cut-off for epinephrine of 70.36 μg/kg with a sensitivity of 83.87 % and a specificity of 72.79 %. Dose-dependent time curves using these cut-off values were calculated. Survival of patients with prolonged therapy with norepinephrine and epinephrine above the evaluated thresholds is poor, whereas short-term application of high-dose catecholamines is not associated with poor outcome. Therefore, it remains for the individual clinician, patients, and their surrogates to decide whether the use of high doses of vasopressors is appropriate in view of the low probability of survival.
Patent•
24 Jan 2013
TL;DR: In this paper, a method of selectively reducing renal norepinephrine levels in an animal or human was described, which consisted of selecting a nore-pinephrine target level and applying energy to one or more renal nerves in an amount which was sufficient to reduce renal NN levels to the selected target level within about +/- 30%.
Abstract: A method of selectively reducing renal norepinephrine levels in an animal or human, said method comprising selecting a norepinephrine target level and applying energy to one or more renal nerves in an amount which is sufficient to reduce renal norepinephrine levels to said selected target level within about +/- 30%. Devices for selectively reducing renal norepinephrine levels are also described.
TL;DR: Two compounds, 8b and 21a, along with nomifensine, were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands.
Abstract: Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay.
TL;DR: In fasted and non‐fasted rats, atomoxetine‐induced IBAT activation was associated with higher IBAT temperature and lower blood glucose, mediated by inhibition of norepinephrine reuptake transporters in IBAT leading to increased norpinephrine concentration in the synapse.
Abstract: Brown adipose tissue (BAT) plays a significant role in metabolism. In this study, we report the use of atomoxetine (a clinically applicable norepinephrine reuptake inhibitor) for (18)F-FDG PET imaging of BAT and its effects on heat production and blood glucose concentration. Fasted-male Sprague-Dawley rats were administered with intravenous (18)F-FDG. The same rats were treated with atomoxetine (0.1 mg/kg, i.v.) 30 min before (18)F-FDG administration. To confirm the β-adrenergic effects, propranolol (β-adrenergic inhibitor) 5 mg/kg was given intraperitoneally 30 min prior to atomoxetine administration. The effect of atomoxetine on BAT metabolism was assessed in fasted and non-fasted rats and on BAT temperature and blood glucose in fasted rats. In (18)F-FDG PET/CT images, interscapular BAT (IBAT) and other areas of BAT were clearly visualized. When rats were fasted, atomoxetine (0.1 mg/kg) increased the (18)F-FDG uptake of IBAT by factor of 24 within 30 min. Propranolol reduced the average (18)F-FDG uptake of IBAT significantly. Autoradiography of IBAT and white adipose tissue confirmed the data obtained by PET. When rats were not fasted, atomoxetine-induced increase of (18)F-FDG uptake in IBAT was delayed and occurred in 120 min. For comparison, direct stimulation of β(3)-adrenreceptors in non-fasted rats with CL-316, 243 occurred within 30 min. Atomoxetine-induced IBAT activation was associated with higher IBAT temperature and lower blood glucose. This was mediated by inhibition of norepinephrine reuptake transporters in IBAT leading to increased norepinephrine concentration in the synapse. Increased synaptic norepinephrine activates β(3)-adrenreceptors resulting in BAT hypermetabolism that is visible and quantifiable by (18)F-FDG PET/CT.
TL;DR: The findings suggest that 17β-estradiol exerts cardioprotective effects against ischemia/reperfusion-induced cardiac dysfunction, at least in part, by suppressing norepinephrine overflow, and that nitric oxide production via estrogen receptor activation plays a key role in this process.
TL;DR: In swine with pre-existing atherosclerosis, the PPAR-β/δ agonist GW0742 failed to attenuate septic shock-induced circulatory failure and kidney dysfunction, most likely due to reduced receptor expression coinciding with cardiovascular and metabolic co-morbidity.
Abstract: In un-resuscitated rodent models of septic shock, the peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) agonist GW0742 improved visceral organ function. Therefore, we tested the hypothesis whether GW0742 would attenuate kidney injury during long-term, resuscitated, porcine polymicrobial septic shock. Six, 12, and 18 h after the induction of fecal peritonitis by inoculation of autologous feces, anesthetized, mechanically ventilated, and instrumented male pigs with pre-existing atherosclerosis resulting from familial hypercholesteremia and atherogenic diet randomly received either vehicle (dimethyl sulfoxide, n = 12) or GW0742 (n = 10). Resuscitation comprised hydroxyethyl starch and norepinephrine infusion titrated to maintain mean arterial pressure at baseline values. Despite aggressive fluid resuscitation, fecal peritonitis was associated with arterial hypotension requiring norepinephrine infusion, ultimately resulting in progressive lactic acidosis and acute kidney injury. GW0742 did not beneficially affect any parameter of systemic and regional hemodynamics, gas exchange, metabolism, or organ function. The parameters of inflammation, oxidative and nitrosative stress, and organ injury (post-mortem analysis for histomorphology and markers of apoptosis) were not influenced either. Immunohistochemistry of pre-shock kidney biopsies from a previous study in this swine strain showed markedly lower PPAR-β/δ receptor expression than in healthy animals. In swine with pre-existing atherosclerosis, the PPAR-β/δ agonist GW0742 failed to attenuate septic shock-induced circulatory failure and kidney dysfunction, most likely due to reduced receptor expression coinciding with cardiovascular and metabolic co-morbidity.