Peak Norepinephrine Research Articles

Voltammetry in the spleen assesses real-time immunomodulatory norepinephrine release elicited by autonomic neurostimulation

BackgroundThe noradrenergic innervation of the spleen is implicated in the autonomic control of inflammation and has been the target of neurostimulation therapies for inflammatory diseases. However, there is no real-time marker of its successful activation, which hinders the development of anti-inflammatory neurostimulation therapies and mechanistic studies in anti-inflammatory neural circuits.MethodsIn mice, we performed fast-scan cyclic voltammetry (FSCV) in the spleen during intravenous injections of norepinephrine (NE), and during stimulation of the vagus, splanchnic, or splenic nerves. We defined the stimulus-elicited charge generated at the oxidation potential for NE (~ 0.88 V) as the “NE voltammetry signal” and quantified the dependence of the signal on NE dose and intensity of neurostimulation. We correlated the NE voltammetry signal with the anti-inflammatory effect of splenic nerve stimulation (SpNS) in a model of lipopolysaccharide- (LPS) induced endotoxemia, quantified as suppression of TNF release.ResultsThe NE voltammetry signal is proportional to the estimated peak NE blood concentration, with 0.1 μg/mL detection threshold. In response to SpNS, the signal increases within seconds, returns to baseline minutes later, and is blocked by interventions that deplete NE or inhibit NE release. The signal is elicited by efferent, but not afferent, electrical or optogenetic vagus nerve stimulation, and by splanchnic nerve stimulation. The magnitude of the signal during SpNS is inversely correlated with subsequent TNF suppression in endotoxemia and explains 40% of the variance in TNF measurements.ConclusionsFSCV in the spleen provides a marker for real-time monitoring of anti-inflammatory activation of the splenic innervation during autonomic stimulation.

Outcomes Associated With Norepinephrine Use Among Cardiac Intensive Care Unit Patients with Severe Shock.

Recent data suggests improved outcomes among cardiac intensive care unit (CICU) patients treated with norepinephrine, especially patients with severe shock. We aimed to describe the association between norepinephrine and mortality in CICU patients with severe shock, defined as those requiring high-dose vasopressors (HDV). We retrospectively evaluated Mayo Clinic CICU patients treated with vasopressors from 2007 to 2015. HDV was defined as a peak Cumulative Vasopressor Index of four for any vasopressor. Peak norepinephrine equivalent (NEE) dose was used to compare vasopressor doses. Multivariable logistic regression was used to determine predictors of hospital mortality. We included 2,090 patients with a median age of 69 years (IQR 59-78), including 35% females; 44% of patients received HDV. Hospital mortality was higher among patients receiving HDV (42% vs. 16%, unadjusted OR 3.87, 95% CI 3.16-4.75, P < 0.01). On multivariable analysis in HDV patients, hospital mortality increased with rising peak NEE (adjusted OR 1.02 per 0.01 mcg/kg/min, 95% CI 1.01-1.02, P < 0.01) and the use of NE was associated with lower hospital mortality (adjusted OR 0.46, 95% CI 0.31-0.72, P < 0.01). After adjustment for illness severity, peak NEE and norepinephrine use were not associated with mortality among patients who did not require HDV. Mortality is high among CICU patients requiring HDV, and rises with increasing vasopressor requirements. Use of NE was associated with lower mortality among patients requiring HDV, but not among those without HDV, implying that patients with more severe shock may benefit from preferential use of NE.

Selected Articles from This Issue

Malignant pleural mesothelioma (MPM) is an incurable cancer associated with exposure to asbestos, and there remains a critical need for effective front-line therapeutics. Inhibition of heatshock protein 90 (Hsp90) has shown promise in preclinical studies. Fennell and colleagues conducted a dose-escalation study of pemetrexed and cisplatin/carboplatin plus ganetespib, an Hsp90 inhibitor, in patients with chemotherapy-naiïve MPM. At the maximum-tolerated dose, 56% showed a partial response, while 83% showed disease control; median progression-free survival was 6.3 months. Patients with tumors harboring epithelioid histology and global loss of heterozygosity benefitted most from this combination. These results support the further development of combination therapies including ganetespib for patients with MPM.The prognosis of advanced gastric cancer remains dismal, with most patients with advanced disease surviving less than one year. In a multicenter phase II study, Shah and colleagues assessed cabazitaxel, a next generation taxoid, in patients with metastatic gastric cancer. Modest antitumor activity was observed in both taxane-naï;ve and taxane-pretreated patients as 2nd- and 3rd-line therapy. Genomic analyses associated elevated HER2 levels and an M2 tumor-associated macrophage signature with improved survival in patients with metastatic gastric cancer treated with cabazitaxel. Additional study is needed to further elucidate these signatures as prognostic markers for gastric cancer therapy.Multiple factors present prior to chimeric antigen receptor T (CAR T) cell infusion influence the development of immune-mediated toxicities. Faramand and colleagues assessed risk factors for severe toxicity or treatment related death in a cohort of 75 patients with large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel), a standard of care CD19-targeted CAR T therapy. An association was identified between a pro-inflammatory tumor microenvironment—specifically, elevated interleukin 6 levels—and severe cytokine release syndrome (CRS) and neurotoxicity. Furthermore, elevated peak noradrenaline levels were observed in patients developing severe CRS. Analysis of pretreatment patient tumor biopsies revealed an association of myeloid markers with higher toxicity as well. The role of myeloid cells and the tumor microenvironment on mediating toxicities is an evolving concep. and warrants further investigation in a clinical trial.Recent advances in the subtyping of pancreatic adenocarcinoma (PDAC) have revealed two major subtypes of the disease: basal and classical. In an analysis of the COMPASS trial, O'Kane and colleagues assessed the contribution of subtype to response to modified FOLFIRINOX (mFFX) in patients with PDAC. Patients with basal-like tumors showed resistance to mFFX and a shorter median overall survival when compared with patients with classical PDAC. GATA6 and Keratin 5 expression correlated with classifier status: low GATA6 expression and high Keratin 5 expression correlated with the basal subtype. Further analysis of these markers is necessary to assess their utility as surrogate markers for transcriptional subtyping.

395-P: N-hydroxyethyl-1-deoxynojirimycin (Miglitol) Restores the Sympathoadrenal Response to Hypoglycemia following Antecedent Hypoglycemia in Diabetic Rats

Antecedent hypoglycemia leads to a reduction in the sympathoadrenal response during subsequent hypoglycemia, i.e., HAAF. We’ve shown previously that this can be corrected in nondiabetic rats by portal vein infusion of N-hydroxyethyl-1-deoxynojirimycin (NEOH-DNJ; miglitol). In the current study we examined the efficacy of portal vein NEOH-DNJ infusion in restoring the sympathoadrenal response for diabetic animals. Diabetes was induced in rats via streptozotocin (STZ) injection (65mg/kg) 4 weeks prior to experiments. Conscious, unrestrained STZ-diabetic rats underwent hyperinsulinemic-hypoglycemic clamps on two consecutive days with a glycemic nadir of 2.6 ± 0.04 mM. On Day 2 animals received portal vein miglitol infusions (1.45 μmol/kg/min) either upstream, (PORups) or liver adjacent (PORadj), while hypoglycemic controls (HYPO) received normal saline infusion. Serial plasma samples were assayed for glucose, insulin, epinephrine (EPI) and norepinephrine (NE). On Day1 peak epinephrine (22.7 ± 2.1 nM) and norepinephrine (2.92 ± 0.3 nM) values were not significantly different between HYPO, PORups and PORadj (P&amp;gt;0.38). On Day 2, EPI values for untreated HYPO controls were suppressed by 85% relative to Day 1 (P &amp;lt; 0.0001). In contrast, EPI responses for miglitol infused groups, PORups (21.3 ± 2.2 nM) and PORadj (16.1 ± 2.01 nM) were not significantly different from Day 1 values (P = 0.75 and 0.50, respectively). NE demonstrated similar responses with HYPO suppressed by 63% on Day 2 (P&amp;lt;0.05), while miglitol treated groups, PORups and PORadj, demonstrated Day 2 NE values not significantly different from Day 1 (P&amp;gt;0.85). Conclusion: The impaired sympathoadrenal response following antecedent hypoglycemia is restored in STZ-diabetic rats by miglitol (NEOH-DNJ) treatment during subsequent hypoglycemia. As with nondiabetic rats, STZ-diabetic animals demonstrated no differences between portal miglitol infusion sites. Disclosure C. Donovan: None. A.J. Jokiaho: None. Funding JDRF (3-SRA-2017-486-S-B)

Influence of Obesity on Vascular Dysfunction Following Hemorrhagic Shock

Obesity is associated with higher rates for complications after traumatic hemorrhage, including higher incidence of multiple organ failure, thrombosis, and mortality. These adverse events are associated with prolonged tissue hypoperfusion, hypercoagulability, and edema that reflect profound vascular damage. However, the combined impact of obesity and traumatic hemorrhage on vascular function is not well understood. Therefore, we sought to determine the impact of diet‐induced obesity on vasoconstrictor and vasodilator properties of arteries before and after hemorrhagic shock.Male Sprague‐Dawley rats were fed a control (CON; 13.5% kcal fat, n=10), moderate fat (MF, 33% kcal fat n=9) or high fat (HF, 60% kcal fat, n=10) diet for 6–8 weeks. Hemorrhagic shock was induced by laceration of a mesentery artery and a Grade V splenic injury under anesthesia, and a period of hypotension (mean arterial pressure = 30–40 mm Hg) was maintained for 30 minutes. We assessed vasoconstrictor and vasodilator properties in isolated mesenteric arteries harvested before and after hemorrhagic shock. Before hemorrhage, peak norepinephrine (NE) vasoconstriction was higher in CON rats (78±4%) versus HF (62±5%, p=0.01), while MF rats exhibited a peak NE vasoconstriction not different from either groups (71±3%, p&gt;0.05 vs CON and HF). Baseline endothelium‐dependent dilation, assessed as the maximal response to acetylcholine, was not different between groups (CON: 97±1%, MF: 88±4%, HF: 92±3%, p=0.08). Hemorrhage lowered the peak NE vasoconstriction (post: 61±8%, p=0.05) and endothelium‐dependent dilation in CON rats (post: 90±2%, p&lt;0.001), but had no effect on NE vasoconstriction and endothelium‐dependent dilation in MF and HF rats (p&gt;0.05 vs pre‐hemorrhage). Endothelium‐independent dilation, assessed as the response to sodium nitroprusside, was similar pre‐ and post‐hemorrhage in all groups (p&gt;0.05).In conclusion, we find traumatic hemorrhage induces vascular dysfunction characterized by a reduced vasoconstrictor response and impaired endothelial function, but only in rats fed a normal chow diet. While obesity results in vascular dysfunction at baseline, it does not contribute to a further worsening of function after traumatic hemorrhage.Support or Funding InformationFunded by a UO‐OHSU Collaborative Seed Grant

Association Between Neurohormone Levels and Exercise Testing Measures in Patients with Mechanical Circulatory Supports.

Continuous-flow left ventricular assist device (CF-LVAD) recipients exhibit impaired exercise capacity. Long-term continuous blood flow also elevates norepinephrine (NE) and aldosterone (Aldo) levels. However, the relationship between exercise capacity and neurohormonal activation has not been elucidated. Our study objective was to assess the association between cardiopulmonary exercise testing (CPT) measures and neurohormonal levels in CF-LVAD recipients. Symptom-limited CPT on a treadmill, using the modified Bruce protocol was performed in 15 CF-LVAD recipients. Norepinephrine and Aldo levels were measured, and the association between their levels and CPT measures were assessed. Peak VO2 (13.6 ml/kg/min) and percent age, sex predicted VO2 max (49.4%), and oxygen pulse (O2 pulse) (9.0 ± 4.0 ml/beat) were low, whereas minute ventilation/carbon dioxide output (VE/VCO2) slope (35) was elevated. In addition, VO2 at anaerobic threshold (VO2 AT), and O2 pulse values negatively correlated with NE levels. Norepinephrine levels positively correlated with chronotropic responses and heart rate (HR) recovery. Aldo levels in CF-LVAD recipients were not related to any CPT measures. Continuous-flow left ventricular assist device recipients exhibited impaired exercise capacity and chronotropic incompetence (CI). Despite the association of NE levels with chronotropic responses at peak exercise, neither NE levels nor chronotropic responses predicted peak VO2. This suggests that CI may not be the primary factor responsible for the low peak VO2. O2 pulse, which is a combined measure for stroke volume and peripheral oxygen extraction during exercise, was an independent predictor of peak VO2. Future studies should examine the contribution of peripheral factors to exercise capacity limitations.

Esmolol infusion in patients with septic shock and tachycardia: a prospective, single-arm, feasibility study

BackgroundHigh adrenergic tone appears to be associated with mortality in septic shock, while adrenergic antagonism may improve survival. In preparation for a randomized trial, we conducted a prospective, single-arm pilot study of esmolol infusion for patients with septic shock and tachycardia that persists after adequate volume expansion.MethodsFrom April 2016 to March 2017, we enrolled patients admitted to an intensive care unit with sepsis who were receiving vasopressor infusion and were tachycardic despite adequate volume expansion. All patients received a continuous intravenous infusion of esmolol, targeted to heart rate 80–90/min, while receiving vasopressors. The feasibility outcomes were proportion of eligible patients consented, compliance with pre-infusion safety check, and compliance with the titration protocol. The primary clinical outcome was organ-failure-free days (OFFD) at 28 days.ResultsWe enrolled 7 of 10 eligible patients. Mean age was 46 (± 19) years, and mean admission APACHE II was 28 (± 8). Median norepinephrine infusion rate at the initiation of esmolol infusion was 0.20 (0.14–0.23) μg/kg/min. Compliance with the safety check was 100%; compliance with components of the titration protocol was 98–100%. OFFD were 26 (24.5–26); all patients survived to day 90. Median peak esmolol infusion was 50 (25–50) μg/kg/min. Median peak norepinephrine infusion rate during esmolol infusion was 0.46 (0.13–0.50) μg/kg/min. Four patients achieved target heart rate. Protocol-defined stop events, suggesting possible intolerance to a given infusion rate, occurred in three patients, all of whom were receiving at least 50 μg/kg/min of esmolol.ConclusionsIn a pilot, single-arm study, we report the first published experience with esmolol infusion in tachycardic patients with septic shock in the United States. These findings support a phase 2 trial of esmolol infusion for septic shock. Lower infusion rates of esmolol infusion may be better tolerated and more feasible than higher infusion rates for such a trial.Trial registrationThis study was retrospectively registered at ClinicalTrials.gov (NCT02841241) on 19 July 2016.

A Sympathetically Mediated α1‐Adrenoceptor Dependent Pathway Promotes Renal Sodium Chloride Cotransporter Activity in Age‐Related Hypertension

AimHypertension is positively correlated with age and sympathetic tone in human subjects. These studies tested the hypothesis that sodium chloride cotransporter (NCC)‐mediated sodium retention and sympathoexcitation contribute to age‐related hypertension.MethodsThree‐month, 8‐month, and 16‐month old male Sprague‐Dawley (SD) rats underwent one of three studies. In the first study, MAP, HR, NCC activity (peak natriuresis to IV hydrochlorothiazide, HCTZ, 2 mg/kg), and measures of sympathetic tone [peak depressor response to IV hexamethonium (30 mg/kg), and plasma and renal norepinephrine (NE) levels] were assessed. In the second study, renal histology was evaluated and total protein expression of the NCC, with‐no‐lysine 1 (WNK1), and STE‐20 Alanine/Proline kinase (SPAK), and phosphorylated SPAK/oxidative stress response 1 (OxSR1) normalized to β‐actin was assessed in renal cortical tissue. In the third study, rats underwent chronic antagonism of the NCC (s.c. HCTZ, 4 mg/kg/d, 14d) or α1‐adrenoceptors (s.c. terazosin, 10 mg/kg/d, 14d) and MAP, HR, and NCC activity were assessed (n=4–5/group).ResultsBasal MAP and NCC activity increased with age (MAP [mmHg]; 3‐month 124±2 vs 8‐month 140±1 vs 16‐month 149±3, P&lt;0.05: peak ΔUNaV to HCTZ [μeq/min]; 3‐month 9±1 vs 8‐month 18±2 vs 16‐month 15±5, P&lt;0.05). Measures of sympathetic activity, including global and renal NE levels and peak depressor response to hexamethonium, also increased with age (plasma NE [nmol/L]; 3‐month 44±4 vs 8‐month 55±3, P&lt;0.05: renal NE [pg/mg]; 3‐month 612±36 vs 8‐month 835±48 vs 16‐month 974±39, P&lt;0.05: peak depressor response to hexamethonium [mmHg]; 3‐month −33±4 vs 8‐month −64±5 vs 15‐month −60±3, P&lt;0.05).Renal cortical expression of total WNK1 and phosphorylated SPAK/OxSR1 increased with age (WNK1 [ODU/mm2]; 3‐month 0.49±0.07 vs 8‐month 0.62±0.05 vs 16‐month 0.78±0.08, P&lt;0.05: pSPAK/OxSR1 [ODU/mm2]; 3‐month 0.81±0.1 vs 8‐month 0.95±0.14 vs 16‐month 1.37±0.17, p&lt;0.05). Total NCC, SPAK, and OxSR1 expression did not change with age. No gross changes in renal histology were observed in aging rats.Chronic α1‐adrenoceptor antagonism abolished the age‐related increase in NCC activity and attenuated age‐related hypertension (peak ΔUNaV to HCTZ [μeq/min]; 16‐month 15±5 vs. s.c. terazosin 10±3, P&lt;0.05: MAP [mmHg]; 16‐month 149±3 vs s.c. terazosin 134±4, P&lt;0.05). Chronic NCC antagonism attenuated age‐related hypertension (MAP [mmHg] 16‐month 149±3 vs s.c. HCTZ 136±5, P&lt;0.05).ConclusionAge‐related hypertension is accompanied by global and renal sympathoexcitation and increased renal NCC activity. We speculate that in aged animals, elevated sympathetic tone increases NE‐driven renal NCC activity via an α1‐adrenoceptor‐WNK1‐SPAK/OxSR1 dependent pathway, promoting NCC‐mediated sodium reabsorption and the development of age‐related hypertension. Our data suggest that therapies targeting renal sympathetic outflow and α1‐adrenoceptors may be particularly well suited to the elderly hypertensive patient population.Support or Funding InformationThis work was supported by NIH grants R01HL107330 and K02HL112718 and AHA grants 16MM32090001 and AHA17GRNT3367002 to RDW and NIH grant F31DK116501 to AAF.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Persistent injury-associated anemia and aging: Novel insights.

Hypercatecholaminemia and bone marrow dysfunction have been implicated in the pathophysiology of persistent injury-associated anemia. The elderly may be more vulnerable to bone marrow dysfunction due to high basal and peak catecholamine levels and impaired hematopoietic progenitor growth. We hypothesized that aging would adversely affect persistent injury-associated anemia. Male Sprague-Dawley rats aged 8 to 9 weeks and F344-BN rats aged 25 months were randomized to naive controls, lung contusion plus hemorrhagic shock (LCHS), and LCHS plus daily chronic restraint stress (LCHS/CS). Urine norepinephrine was measured on Days 1 and 7. Mobilization of hematopoietic progenitor cells (HPCs), bone marrow colony-forming units-erythroid growth, and peripheral blood hemoglobin, mean corpuscular volume (MCV), and red cell distribution width (RDW) were assessed on Day 7 (*p < 0.05 young vs. aged counterpart by one-way analysis of variance). Aged rats had higher norepinephrine levels at naive baseline (97* vs. 27 ng/mL) and 7 days following LCHS/CS when compared with young (359* vs. 127 ng/mL). Following LCHS/CS, HPC mobilization was greater among young rats when compared with aged (5.4 vs. 2.5%). Colony-forming units-erythroid growth was lower among aged animals for each group (naive: 47* vs. 65; LCHS: 40* vs. 50; LCHS/CS: 38* vs. 44 cells/plate). Aged naive rats had higher initial hemoglobin (15.2* vs. 14.3 g/dL) but lower MCV (48* vs. 59 fL/cell) and larger RDW at baseline and greater differences 7 days after LCHS/CS (MCV: 46* vs. 60 fL/cell; RDW: 17.4* vs. 16.3%). Compared with young rats, aged rats had less HPC mobilization despite elevated basal and peak norepinephrine. Aged rats were disproportionately affected by impaired hematopoietic progenitor growth and an iron-restricted red blood cell phenotype at baseline, which persisted 7 days after injury. Further research is needed to assess how the clinical approach to persistent injury-associated anemia should differ for elderly trauma patients.

New insights into the mechanisms involved in B-type natriuretic peptide elevation and its prognostic value in septic patients.

IntroductionElevated plasma B-type natriuretic peptide (BNP) levels in patients with critical sepsis (severe sepsis and septic shock) may indicate septic cardiomyopathy. However, multiple heterogeneous conditions may also be involved in increased BNP level. In addition, the prognostic value of BNP in sepsis remains debatable. In this study, we sought to discover potential independent determinants of BNP elevation in critical sepsis. The prognostic value of BNP was also evaluated.MethodsIn this observational study, we enrolled mechanically ventilated, critically septic patients requiring hemodynamic monitoring through a pulmonary artery catheter. All clinical, laboratory and survival data were prospectively collected. Plasma BNP concentrations were measured daily for five consecutive days. Septic cardiomyopathy was assessed on day 1 on the basis of left and right ventricular ejection fractions (EF) derived from echocardiography and thermodilution, respectively. Mortality was recorded at day 28.ResultsA total of 42 patients with severe sepsis (N = 12) and septic shock (N = 30) were ultimately enrolled. Daily BNP levels were significantly elevated in septic shock patients compared with those with severe sepsis (P ≤0.002). Critical illness severity (assessed by Acute Physiology and Chronic Health Evaluation II and maximum Sequential Organ Failure Assessment scores), and peak noradrenaline dose on day 1 were independent determinants of BNP elevation (P <0.05). Biventricular EFs were inversely correlated with longitudinal BNP measurements (P <0.05), but not independently. Pulmonary capillary wedge pressures (PCWP) and volume expansion showed no correlation with BNP. In septic shock, increased central venous pressure (CVP) and CVP/PCWP ratio were independently associated with early BNP values (P <0.05).Twenty-eight-day mortality was 47.6% (20 of 42 patients). Daily BNP values poorly predicted outcome; BNP on day 1 > 800 pg/ml (the best cutoff point) fairly predicted mortality, with a sensitivity%, specificity% and area under the curve values of 65, 64 and 0.70, respectively (95% confidence interval = 0.54 to 0.86; P = 0.03). Plasma BNP levels declined faster in survivors than in nonsurvivors in both critical sepsis and septic shock (P ≤0.002). In septic shock, a BNP/CVP ratio >126 pg/mmHg/ml on day 2 and inability to reduce BNP <500 pg/ml implied increased mortality (P ≤0.036).ConclusionsThe severity of critical illness, rather than septic cardiomyopathy, is probably the major determinant of BNP elevation in patients with critical sepsis. Daily BNP values are of limited prognostic value in predicting 28-day mortality; however, fast BNP decline over time and a decrease in BNP <500 pg/ml may imply a favorable outcome.

Exercise induced hyperglycaemia in the absence of diabetes

Exercise induced hyperglycaemia in the absence of diabetes

Brain Death Effects on Catecholamine Levels and Subsequent Cardiac Damage Assessed in Organ Donors

Brain death (BD) causes hemodynamic and neuroendocrine alterations including a catecholamine surge, which in turn causes histologic lesions in cardiac muscle such as contraction bands, focal mononuclear cell infiltrates and cardiomyocyte necrosis. These changes are likely to compromise heart function and could therefore also affect the graft response after heart transplantation. This study was designed to examine the catecholamine surge, the catecholamine release pattern and the histologic lesions traditionally described as characteristic of BD in hearts procured from BD donors. After BD diagnosis, specimens were taken from the left ventricle (n = 50) for histologic examination. Arterial blood samples were collected from 40 of the donors at different time-points (1 hour before BD; on BD diagnosis; and 1, 2, 3 and 4 hours after BD) to determine catecholamine levels by high-performance liquid chromatography (HPLC). The three hormones examined showed above-normal levels (epinephrine 2.36-fold, norepinephrine 8.56-fold, dopamine 54.76-fold). Release patterns included epinephrine and dopamine peaks at the time of BD and a norepinephrine peak 1 hour later. Fifty percent of the BD donors showed contraction bands and 62% displayed cardiomyocyte necrosis, which was associated with focal mononuclear cell infiltrates in 18% of cases. In 40% of donors, colocalized apoptotic and necrotic damage was observed. Differing extents of BD-associated cardiac lesions were observed in the donors, and >50% also showed apoptotic damage. The expected catecholamine peak at the time of BD was only detected for epinephrine and dopamine. Hormone increases were below those described in the literature, except for dopamine.

Norepinephrine and cardiovascular responses to maximal exercise in Parkinson's disease on and off medication

The aim of this experiment is to understand how Parkinson's disease (PD) medication affects the autonomic responses of individuals during an acute exercise stress test. Fourteen people with PD and fifteen healthy individuals age-matched between 50 and 80 years performed a modified Bruce protocol. Subjects with PD performed the test once off medication (PD-off) and then 1 week later on medication (PD-on). Heart rate (HR), blood pressure (BP), VO(2), and norepinephrine (NE) levels were taken at rest and at peak exercise. At peak exercise HR, BP, and NE values for the PD-on and PD-off group were all significantly lower than healthy controls, regardless of whether subjects were on their medication. Autonomic abnormalities during exercise in this population appear to be disease manifested and not impacted by medications used to treat PD. We can assume, both on and off medication, this population will show markedly lower BP, HR, and NE responses.

Effects Of A Dual Challenge On Stress Hormones, Th1/th2 Cytokines, And Lymphocyte Responses In Firefighters

Absent from the literature is an examination of the effects of a dual mental and physical challenge on stress hormones cortisol (CORT), epinephrine (EPI), norepinephrine (NE), Th1 and Th2 cytokines (IL-2, IL-6), and lymphocytes (CD8, CD56) in firefighters. PURPOSE: The purpose of this study was to examine the changes in CORT, EPI, NE, IL-2, IL-6, CD8, and CD56 in firefighters exposed to a decision-making challenge (firefighting strategies and tactics drill) while participating in moderate intensity exercise. Furthermore, relationships among these variables were examined. METHODS: Nine professional firefighters (VO2max = 36.94 ± 5.60 ml/kg/min) were asked to participate in two exercise conditions on a cycle ergometer: 1) 37 min at 60% VO2max along with 20 min of mental stress (firefighting strategies and tactics decision-making challenge (FSC)), and 2) 37 min at 60% VO2max without FSC. Stress hormones and cytokines were obtained at 0 min (baseline), after 37 minutes of exercise, and at 30 and 60 min post-exercise. Lymphocytes were analyzed at 30 min and 37 min during exercise and at 60 min post-exercise. RESULTS: A significant condition by time interaction was revealed in EPI, NE, and IL-2 In addition, significant main effects for time were observed in CORT and CD56, whereas IL-6 and CD8 demonstrated no significant changes. EPI area under the curve (AUC) was correlated with NE AUC, CORT AUC, and peak CD56 (r = 0.72, r = 0.74, and r = 0.66, respectively). NE AUC was correlated with CORT AUC and peak IL-2 (r = 0.64 and r = 0.51, respectively). CORT AUC was correlated with peak CD56 (r = 0.65). IL-6 and CD8 were not related to any of the variables assessed. CONCLUSION: Firefighters participating in a firefighting simulation task (dual challenge) responded with elevations in stress hormones that are related to elevations in IL-2 (Th1) and not related to IL-6 (Th2). These results suggest that firefighting can activate the immune system in support of a response to a possible antigen invasion. However, it is likely that if these stress hormones remained elevated or increased further, a shift from Th1 to Th2 could occur, which may suppress immune function.

Differential Effects of Carvedilol and Metoprolol Succinate on Plasma Norepinephrine Release and Peak Exercise Heart Rate in Subjects With Chronic Heart Failure

Dosing equivalency of carvedilol and metoprolol remains a debate. Degree of beta 1-blockade is best assessed by blunting of the exercise-induced heart rate. Accordingly, the authors have investigated dosing equivalency by examining baseline and peak exercise heart rates and norepinephrine levels in subjects with chronic heart failure treated with carvedilol or metoprolol. Thirty-seven subjects treated with carvedilol (32.9 +/- 3.5 mg; n = 23) or metoprolol succinate (XL) (96.4 +/- 15.9 mg; n = 14) referred for cardiopulmonary exercise testing were studied prospectively. Carvedilol versus metoprolol XL subjects did not differ with respect to baseline heart rate (73 +/- 2 vs 70 +/- 3 bpm), or baseline plasma norepinephrine levels (597.5 +/- 78.3 vs 602.1 +/- 69.6 pg/mL), P = NS. However, despite similar peak exercise norepinephrine levels (2735.8 +/- 320.1 vs 2403.1 +/- 371.6 pg/mL), heart rate at peak exercise was higher in subjects receiving carvedilol (135 +/- 4 bpm) than those receiving metoprolol XL (117 +/- 6 bpm), P = 0.02. Similar norepinephrine release and more complete beta 1-blockade is observed in well-matched subjects with chronic heart failure treated with a mean daily dose of metoprolol XL 96.4 mg compared with carvedilol 32.9 mg.

Temperature‐dependent differences in sympathetic neuroeffector transmission in mesenteric arteries and veins in hypertension

Norepinephrine (NE) is released from sympathetic nerves supplying arteries and veins. We studied temperature‐related (28–37 ºC) differences in NE release and clearance using amperometry to measure NE in vitro. Tissues from sham and DOCA‐salt hypertensive rats were studied. Peak NE currents in sham veins declined more with temperature compared to arteries. Peak currents in DOCA‐salt arteries also showed greater temperature sensitivity than those in sham arteries. Currents in sham veins and DOCA‐salt arteries increased faster, decayed more slowly and were more temperature sensitive than those in sham arteries. Idazoxan (blocks α2 adrenergic receptors, α2ARs) and cocaine (blocks the NE transporter, NET) accelerated current rise time in sham arteries only. NE current decay was accelerated by idazoxan in veins but not arteries at 37 ºC and in arteries but not veins at 28 ºC, with a smaller increase in DOCA‐salt arteries at 28 ºC than sham arteries. We conclude that control of NE release from peri‐arterial nerves is more complex and therefore more temperature‐sensitive than in peri‐venous nerves. DOCA‐salt hypertension impairs NE release and clearance in arteries but not veins. α2ARs functional as autoreceptors and possibly as a “clearance receptor” holding NE in the neuroeffector junction. Clearance of NE in sham arteries is NET‐dependent and in sham veins and DOCA‐salt arteries is α2 NE clearance receptor dependent.

Intraabdominal Hypertension in Patients with Septic Shock

Intraabdominal hypertension (IAH) develops frequently in patients with septic shock. Even a moderate increase in intraabdominal pressure (IAP) in this setting could be associated with high lactate levels. The authors conducted a prospective, observational, nonrandomized control trial in the surgical intensive care unit of an academic tertiary center. Twenty-seven patients with septic shock (septic shock group), and 19 patients undergoing abdominal surgery with more than two risk factors for IAH (postoperative control group) were admitted consecutively to the intensive care unit. IAP was measured every 6 hours during the first 48 hours. IAH was diagnosed with two consecutive measurements greater than 20 mm Hg. The main outcome measures were prevalence of IAH in septic shock and control groups; and comparative lactate levels, norepinephrine requirements and organ dysfunctions in patients with and without IAH in both groups. Fifty-one per cent of patients with septic shock and 31 per cent of control patients developed IAH. Patients with septic shock with and without IAH were comparable in peak norepinephrine dose, sequential organ failure assessment score, and mortality. However, peak lactate levels were significantly higher in patients with septic shock and IAH compared with those without IAH (3.5 mmol/L versus 1.9 mmol/L, P < 0.04). There was a significant positive temporal correlation between IAP and lactate levels in patients with septic shock with IAH. Peak levels of both occurred early and decreased progressively over time. Control patients with and without IAH exhibited comparable peak lactate levels. Intraabdominal hypertension is very common in septic shock and appears to be related to high lactate levels, which diminish as IAP decreases. Future studies should address the usefulness of IAP monitoring in patients with septic shock.

Effects of fish oil on the neuro-endocrine responses to an endotoxin challenge in healthy volunteers

Fish oil (FO) has been shown to modulate the acute and chronic inflammatory responses. Endotoxin (LPS) has been shown to mimic several aspects of sepsis. The study aimed at testing the effects of oral FO supplements in healthy subjects submitted to intravenous LPS on systemic and endocrine response. Fifteen healthy men (aged 26.0+/-3.1 years, BMI 23.8+/-1.9 kg/m2), were enrolled. Subjects were randomised to 3-4 weeks of oral FO supplementation (7.2 g/day, providing 1.1 g/day of 20:5 (n-3) and 0.7 g/day of 22:6 (n-3) fatty acids) or no supplementation and then submitted to endotoxin challenge: 2 ng/kg of LPS. All subjects were studied twice (placebo and LPS). vital signs, energy expenditure (EE), glucose and lipid metabolism ((2)H2-glucose), plasma cytokines and stress hormones for 6 h after LPS or placebo. LPS caused cytokine release, fever, increases in heart rate, resting EE and substrate oxidation, plasma glucagon and glucose concentrations; the neuro-endocrine response was characterised by increased plasma stress hormones. FO significantly blunted fever, ACTH and cortisol plasma levels (no effect on cytokine release). FO blunted the peak norepinephrine after LPS. FO supplements blunted the endocrine stress response and the increase in body temperature, but had no impact on cytokine production after LPS. These findings conflict with the postulated anti-inflammatory effects of FO on arachidonic acid metabolism and cytokine release. These results suggest that FO may exert beneficial effects in sepsis though non-inflammatory which require further investigations.

Medullary noradrenergic neurons release norepinephrine in the medial amygdala in females in response to mating stimulation sufficient for pseudopregnancy

In the female rat, stimuli from the uterine cervix and vagina are carried to the brain areas involved in the mating-induced pseudopregnancy (PSP) response via the ventral noradrenergic bundle. Noradrenergic neurons projecting through this tract synapse in many forebrain areas including the amygdala, and neurons in the posterodorsal medial amygdala (MePD) are activated following mating. The goal of this experiment was to investigate whether norepinephrine (NE) is released into the MePD after mating using microdialysis and to determine the origin of this release. Ovariectomized estrogen- and progesterone-treated rats were implanted unilaterally with guide cannulae aimed at the MePD. Females were placed with males until they received 15 intromissions (15I), 5 intromissions (5I) or 15 mounts-without-intromission (MO). Dialysate samples collected every 20 min for 2 h before to 3 h after mating were analyzed for NE using HPLC with electrochemical detection. A significant increase in mean NE release in the MePD was seen at 80 min after mating onset in females receiving 15I, and no increase was seen in animals receiving 5I or MO. The time of peak NE release varied in 15I animals from 60 to 160 min after mating. Mean baseline levels of NE did not differ between groups. The retrograde tracer FluoroGold (FG), administered through the probe after cessation of dialysis sampling, was observed within identified noradrenergic cells primarily within the A1 and A2 cell groups. Infusion of anti-dopamine-β-hydroxylase-saporin (DBH-SAP) into the MePD lesioned noradrenergic neurons located in the A1 and A2 cell groups. Because high levels of NE release occurred in the MePD only after the females received a number of intromissions sufficient to induce PSP, these results suggest that NE release within the MePD may be important for the establishment of PSP.

Lack of Plasma Norepinephrine Cyclicity, Increased Estradiol during the Follicular Phase, and of Progesterone and Gonadotrophins at Ovulation in Women with Premenstrual Syndrome

In healthy women, plasma norepinephrine (NE) has a cycle with the highest levels occurring at ovulation and early luteal phase. We examined plasma NE cyclicity in premenstrual syndrome (PMS) patients as compared to controls, its relation to estradiol (E₂), progesterone (P), luteinizing hormone and follicle-stimulating hormone, and the correlation of these parameters with the PMS symptoms. Lack of NE cyclicity was observed in PMS patients. In controls, peak NE levels occurred at ovulation and early luteal phase. In PMS, serum E₂ was higher during the follicular phase, while P and gonadotrophins were higher especially at ovulation and the luteal phase. In the late luteal phase, E₂ levels were lower in PMS patients than in controls. A negative correlation was observed between the area under the curve for E₂ in the luteal phase and PMS somatic and mental scores. Plasma NE showed a negative correlation with abrupt mood swings, impatience, nervousness, tiredness, weakness, apathy, and headache. These data suggest that lack of NE cyclicity characterizes PMS, some symptoms being related to low E₂ levels during the late luteal phase and decreased noradrenergic activity at ovulation and the luteal phase.