Epinephrine Release Research Articles

Effect of Coagulation Factor Concentrates on Markers of Endothelial Cell Damage in Experimental Hemorrhagic Shock.

Plasma-based resuscitation showed protective effects on the endothelial glycocalyx compared with crystalloid resuscitation. There is paucity of data regarding the effect of coagulation factor concentrates (CFC) on the glycocalyx in hemorrhagic shock (HS). We hypothesized that colloid-based resuscitation supplemented with CFCs offers a therapeutic value to treat endothelial damage following HS. Eighty-four rats were subjected to pressure-controlled (mean arterial pressure (MAP) 30-35 mm Hg) and lab-guided (targeted cutoff: lactate >2.2. mmol/L and base deficit > 5.5 mmol/L) HS. Animals were resuscitated with fresh frozen plasma (FFP), human albumin (HA) or Ringer's lactate (RL) and RL or HA supplemented with fibrinogen concentrate (FC) or prothrombin complex concentrate (PCC). Serum epinephrine and the following markers of endothelial damage were assessed at baseline and at the end-of-observation (120 min after shock was terminated): syndecan-1, heparan sulfate, and soluble vascular endothelial growth factor receptor 1 (sVEGFR 1). Resuscitation with FFP had no effect on sVEGFR1 compared with crystalloid-based resuscitation (FFP: 19.3 ng/mL vs. RL: 15.9 ng/mL; RL+FC: 19.7 ng/mL; RL+PCC: 18.9 ng/mL; n.s.). At the end-of-observation, syndecan-1 was similar among all groups. Interestingly, HA+FC treated animals displayed the highest syndecan-1 concentration (12.07 ng/mL). Resuscitation with FFP restored heparan sulfate back to baseline (baseline: 36 ng/mL vs. end-of-observation: 36 ng/mL). The current study revealed that plasma-based resuscitation normalized circulating heparan sulfate but not syndecan-1. Co-administration of CFC had no further effect on glycocalyx shedding suggesting a lack of its therapeutic potential. VExperimental in vivo study.

Practical Considerations for In Vivo Mouse Studies.

Obesity and type 2 diabetes are serious conditions that have reached pandemic proportions. The underlying physiology is complex with multiorgan interactions involved and, consequently, multiorgan approaches are necessary for researchers to elucidate and find treatments. As such, in vivo models are an invaluable resource for these studies and mice are, for many reasons, by far the most common species used. The use of animals comes with responsibilities to ensure their welfare and well-being: primarily for the sake of the mice themselves, but also to ensure quality of data. Physiological stress responses, such as adrenalin (epinephrine) and corticosterone release among others, have major consequences on metabolism. Additionally, behavioral stress responses are also a source of data variance. This chapter looks at the main in vivo procedures incorporated in mouse obesity/diabetes protocols and considers the practical factors involved that can be considered to minimize animal stress and improve study data quality.

Controlled delay of the expulsive phase of foaling affects sympathoadrenal activity and acid base balance of foals in the immediate postnatal phase

Stress at foaling has been demonstrated to delay birth. In this study, we followed the hypothesis that even a short delay of foaling increases catecholamine and cortisol release in foals, induces acidosis and impairs neonatal adaptation. Foaling was prolonged for 5 min by transferring mares to an unfamiliar environment at rupture of the allantochorion (group delay, n = 6) while control mares (n = 5) were left undisturbed. In their foals, times from birth to first standing and first suckling, heart rate, heart rate variability (HRV) and salivary cortisol concentration were analysed. Blood for analysis of epinephrine, norepinephrine, hematology and blood gases was collected directly and 30 min after birth. Statistical comparisons were made by repeated measures ANOVA. Times to first standing and suckling did not differ between groups. Fetal heart rate remained unchanged during birth and increased within 15 min postnatum (p < 0.001) while HRV decreased during the first hour of life in foals of both groups (p < 0.05). Immediately after birth, actual base excess was lower in foals with delayed birth than in control foals (p < 0.05). Epinephrine concentration immediately after birth was higher in group delay foals and increased from 0 to 30 min after birth in control foals (time p < 0.001, time x group p = 0.001). Cortisol concentration peaked at 1 h after birth in both groups (p < 0.001). Leukocyte and PMN count decreased from 0 to 30 min after birth (p < 0.001). In conclusion, a 5-min delay at foaling affected epinephrine release and acid base balance, but was without further effect on neonatal adaptation.

A COMPARATIVE EVALUATION OF LOCAL ANESTHETIC EFFECT BETWEEN LIGNOCAINE AND LIGNOCAINE ADMINISTERED WITH EPINEPHRINE IN HEALTHY CHILDREN.

Lignocaine, first amino amide–type local anesthetic when combines or co-administered with Epinephrine, an sympathomimetic amine, allows larger doses for numbing, to decrease bleeding, and to make the numbing effect last longer. The present study focuses on measures to prove this activity in patients with abdominal surgery. Liposomal formulations of Lignocaine and Lignocaine plus epinephrine were prepared by thin film evaporation method. The formulation was injected successfully as liposomal infusion. Thus prepared liposomes were found to be fit for drug delivery when evaluated as per physicochemical parameter. The smooth, even surfaced liposomes with PDI of 0.298 (p&lt;0.05) were found to be efficient in delivering drug when tested In-vitro (Lignocaine as single drug 93.78% and from combined dosage 96.29% Lignocaine with 94.62 % of release of Epinephrine). The randomized, controlled trial conducted on population of children undergone abdominal surgery and grouped into three depending upon the type of formulation they received. Three groups of subjects were made, first receiving Lignocaine liposomal infusion only; second with Lignocaine plus Epinephrine liposomal infusion; third group kept control which received saline solution only. The serum Cortisol concentration was found to be least in Group II in compare to Group I. Similarly end point measurements like cool sensation, warm sensation, hot pain, sensory blockade test showed the superiority of combination of Lignocaine with Epinephrine in lowering pain threshold. The result obtained from above study proved that Epinephrine markedly enhances the Local anesthetic activity of Lignocaine.&#x0D; KEYWORDS: Child Anesthesia, Epinephrine, Lignocaine, Liposomal Infusion, Local anesthetic.

Comparison of hemodynamic changes between intrathecal dexzmedetomidine 5µg and Fentanyl 25µg as adjuvants to 12.5mg of 0.5% hyperbaric bupivacaine for spinal anesthesia

The application of a single high dose of Dexmedetomidine reduced norepinephrine release by as much as 92% in young healthy volunteers. The release of epinephrine is also reduced by the same amount [51]. The baroreceptor reflex is well preserved in patients who received Dexmedetomidine, and the reflex heart rate response to a pressor stimulus is augmented. These results illustrate that cardiovascular response is evoked mainly by decrease in central sympathetic outflow. After clinical approval of Institutional Ethical Committee Clearance and informed written consent of 90 patients of ASA physical class I and II who were posted for elective Total Abdominal Hysterectomy (TAH). The study population was randomly selected based on the closed sealed opaque envelope technique. The mean duration of surgery in Group-B was 61.00±13.60min, Group-D was 66.33±12.79min and Group-F was 67.33±10.72min. There was no statistically significant difference in the mean duration of surgery among three groups (P>0.05). Statistically there was no significant difference in DBP (mm of Hg) measured at various intervals throughout the surgery among the groups (P>0.05).

Effect of adrenalectomy on pulmonary edema resolution.

The capacity of the lung to clear edema fluid has been shown to be one of the factors that can influence the prognosis of cardiogenic and noncardiogenic pulmonary edema. Active Na+ transport across the alveolar epithelium is the main driving force involved in this physiological process. Since endogenous catecholamines are known to activate the sodium-dependent mechanism of alveolar edema clearance, the objective of the present study was to explore if adrenalectomy, which prevents the release of endogenous catecholamines and other hormones, such as corticosterone, into circulation, would affect edema resolution in a model of lung injury induced by thiourea. A high-permeability pulmonary edema was induced in adult male Sprague-Dawley rats using a thiourea-induced pulmonary edema model. To determine if the release of adrenalin and corticosterone is essential for resolution of the thiourea-induced edema, we measured 1) the release of adrenalin and corticosterone in urine and 2) edema resolution in control animals and adrenalectomized animals. The administration of thiourea significantly increased the wet-to-dry ratio after four and eight hours. After 12 and 24 hours, the wet-to-dry ratio gradually returned to baseline. Although thiourea-induced pulmonary edema was associated with a significant increase in urine adrenalin and corticosterone, the absence of adrenalin and corticosterone response in adrenalectomized animals did not prevent the resolution of the edema. These experiments demonstrated that resolution of thioureainduced pulmonary edema can occur in the absence of hormonal secretion by the adrenal glands.

Impact of Cardiovascular Neurohormones on Onset of Vasovagal Syncope Induced by Head-up Tilt.

BackgroundVasovagal reflex is the most common form of syncope, but the pathophysiological mechanisms that initiate the reflex are not well understood. We aimed to study supine and early orthostatic levels of the neurohormones involved in control of circulatory homeostasis in relation to the onset of tilt‐induced vasovagal syncope (VVS).Methods and ResultsA total of 827 patients who were investigated for unexplained syncope with head‐up tilt test (HUT) and optional nitroglycerin provocation (Italian protocol) had blood samples collected while supine and after 3‐minutes of HUT. Of these, 173 (20.9%) patients developed VVS during drug‐free HUT, 161 of whom (males 44.7%; age 45±21 years) had complete data. We analyzed levels of epinephrine, norepinephrine, C‐terminal pro–arginine vasopressin, C‐terminal endothelin‐1, and midregional fragments of pro–atrial natriuretic peptide and pro‐adrenomedullin in relation to time from tilt‐up to onset of VVS. We applied a linear regression model adjusted for age and sex. The mean time to syncope was 11±7 minutes. Older age (β=0.13; SE=0.03, P<0.001), higher supine systolic blood pressure (β=0.06; SE=0.03, P=0.02), and higher supine midregional fragment of pro‐adrenomedullin predicted longer time to syncope (β=2.31; SE=0.77, P=0.003), whereas supine levels of other neurohormones were not associated with time to syncope. Among 151 patients who developed VVS later than 3 minutes of HUT, increase in epinephrine (β=−3.24; SE=0.78, P<0.001) and C‐terminal pro–arginine vasopressin (β=−2.07; SE=0.61, P=0.001) at 3 minutes of HUT were related to shorter time to syncope.ConclusionsOlder age, higher blood pressure, and higher level of pro‐adrenomedullin are associated with later onset of VVS during tilt testing, whereas greater increase of tilt‐induced epinephrine and vasopressin release correlate with shorter time to syncope.

Augmented \u03b22-adrenergic signaling dampens the neuroinflammatory response following ischemic stroke and increases stroke size

BackgroundIschemic stroke provokes a neuroinflammatory response and simultaneously promotes release of epinephrine and norepinephrine by the sympathetic nervous system. This increased sympathetic outflow can act on β2-adrenergic receptors expressed by immune cells such as brain-resident microglia and monocyte-derived macrophages (MDMs), but the effect on post-stroke neuroinflammation is unknown. Thus, we investigated how changes in β2-adrenergic signaling after stroke onset influence the microglia/MDM stroke response, and the specific importance of microglia/MDM β2-adrenergic receptors to post-stroke neuroinflammation.MethodsTo investigate the effects of β2-adrenergic receptor manipulation on post-stroke neuroinflammation, we administered the β2-adrenergic receptor agonist clenbuterol to mice 3 h after the onset of photothrombotic stroke. We immunostained to quantify microglia/MDM numbers and proliferation and to assess morphology and activation 3 days later. We assessed stroke outcomes by measuring infarct volume and functional motor recovery and analyzed gene expression levels of neuroinflammatory molecules. Finally, we evaluated changes in cytokine expression and microglia/MDM response in brains of mice with selective knockout of the β2-adrenergic receptor from microglia and monocyte-lineage cells.ResultsWe report that clenbuterol treatment after stroke onset causes enlarged microglia/MDMs and impairs their proliferation, resulting in reduced numbers of these cells in the peri-infarct cortex by 1.7-fold at 3 days after stroke. These changes in microglia/MDMs were associated with increased infarct volume in clenbuterol-treated animals. In mice that had the β2-adrenergic receptor specifically knocked out of microglia/MDMs, there was no change in morphology or numbers of these cells after stroke. However, knockdown of β2-adrenergic receptors in microglia and MDMs resulted in increased expression of TNFα and IL-10 in peri-infarct tissue, while stimulation of β2-adrenergic receptors with clenbuterol had the opposite effect, suppressing TNFα and IL-10 expression.ConclusionsWe identified β2-adrenergic receptor signaling as an important regulator of the neuroimmune response after ischemic stroke. Increased β2-adrenergic signaling after stroke onset generally suppressed the microglia/MDM response, reducing upregulation of both pro- and anti-inflammatory cytokines, and increasing stroke size. In contrast, diminished β2-adrenergic signaling in microglia/MDMs augmented both pro- and anti-inflammatory cytokine expression after stroke. The β2-adrenergic receptor may therefore present a therapeutic target for improving the post-stroke neuroinflammatory and repair process.

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia.

The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed “hypoglycemia-associated autonomic failure” (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250–300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia (n = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, P < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia (n = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, P < 0.05). Activation of medullary C1 (n = 4; 50 ± 5% vs. control 3 ± 1%, P < 0.05) and C3 (n = 4; 45 ± 5% vs. control 4 ± 1%, P < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 (n = 4; 12 ± 3%, P < 0.05) and C3 (n = 4; 19 ± 5%, P < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia.

Hypoglycemic thalamic activation in type 1 diabetes is associated with preserved symptoms despite reduced epinephrine

Brain responses to low plasma glucose may be key to understanding the behaviors that prevent severe hypoglycemia in type 1 diabetes. This study investigated the impact of long duration, hypoglycemia aware type 1 diabetes on cerebral blood flow responses to hypoglycemia. Three-dimensional pseudo-continuous arterial spin labeling magnetic resonance imaging was performed in 15 individuals with type 1 diabetes and 15 non-diabetic controls during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global cerebral blood flow and regional cerebral blood flow responses to hypoglycemia were measured. Epinephrine release during hypoglycemia was attenuated in type 1 diabetes, but symptom score rose comparably in both groups. A rise in global cerebral blood flow did not differ between groups. Regional cerebral blood flow increased in the thalamus and fell in the hippocampus and temporal cortex in both groups. Type 1 diabetes demonstrated lesser anterior cingulate cortex activation; however, this difference did not survive correction for multiple comparisons. Thalamic cerebral blood flow change correlated with autonomic symptoms, and anterior cingulate cortex cerebral blood flow change correlated with epinephrine response across groups. The thalamus may thus be involved in symptom responses to hypoglycemia, independent of epinephrine action, while anterior cingulate cortex activation may be linked to counterregulation. Activation of these regions may have a role in hypoglycemia awareness and avoidance of problematic hypoglycemia.

318 Chronic stress exposure leads to skin exhaustion through continuous epinephrine release

318 Chronic stress exposure leads to skin exhaustion through continuous epinephrine release

Immediate effect of yogic postures on autonomic neural responses

Aim: The aim of this study is to identify the autonomic responses after immediate yogasana practices. Materials and Methods: Ten male (n = 10) yoga practitioners having more than 8 years of experience in yogasana practice were selected as subjects. Before and after immediate practices of six specific yoga postures were assessed on three different consecutive days for 15 min, 22.5 min, and 30 min. Heart rate variability (HRV) low frequency, HRV high frequency (HF), HRV amplitude, galvanic skin resistance (GSR), and blood volume pulse were assessed under the condition of autonomic neural activity and measured using NeXus-10 device. Results: Findings of the data generalized increasing of GSR (47.93% and 14.40%) and HF HRV (7.74% and 6.69%) and decreasing of low-frequency HRV (5.43% and 5%) immediately after 15 min and 22.5 min practice of yogasana, which indicates parasympathetic (vagal) activation. However, in the case of 30-min yoga practice, it decreased the GSR (11.03%) and HF HRV (2.59%), increased low-frequency HRV (2.23%) which, in turn, indicates the sympathetic activation. Discussion: The possible mechanism of vagal activation is an increase of baroreceptor sensitivity, tissue oxygenation, nervous system metabolism, and activation of vasodilation. It may be attributed to the activation of the head ganglion of the autonomic nervous system and inhibition of the posterior hypothalamic area. The sympathetic activation depends on the release of epinephrine and norepinephrine hormones, activation of vasomotor center, central neural integration, and peripheral inhibitory/excitatory reflex mechanisms. Conclusions: Immediate yogasana practices may enhance the parasympathetic (vagal) dominance, which increases autonomic flexibility and associates with a calm mental state.

Ivabradine reduces baseline and stress-induced increase of heart rate and blood pressure and modulates neuroendocrine stress response in rats depending on stressor intensity.

Ivabradine, a selective inhibitor of the sinoatrial pacemaker, is used in clinical practice to reduce heart rate. However, its potential effect on the neuroendocrine stress response has not been investigated. Therefore, we determined the effect of administering ivabradine to rats on cardiovascular parameters and plasma levels of epinephrine, norepinephrine, and corticosterone. Ivabradine was administered intraperitoneally 30 min before exposing animals to either handling, restraint, or immobilization stress. Heart rate and blood pressure were monitored telemetrically. Blood samples were collected before, during, and after stressor exposure to determine the extent of the neuroendocrine stress response as reflected by plasma epinephrine, norepinephrine, and corticosterone levels. In animals pretreated with ivabradine, significantly lower values of heart rate and blood pressure were found during both the baseline period and during exposure to stressors, as well as during the rest period following stressor exposure. Ivabradine also significantly reduced handling-induced epinephrine and norepinephrine release into the bloodstream. However, ivabradine significantly potentiated restraint- and immobilization-induced increases of plasma epinephrine levels, whereas stress-induced changes in plasma norepinephrine and corticosterone levels were ambiguous. Our data shows that ivabradine significantly reduces blood pressure in rats during both baseline and stressful conditions, and also affects the neuroendocrine stress response. These findings show that viscerosensory signaling from the cardiovascular system may significantly modulate the neuroendocrine stress response.

Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice

ObjectiveLife-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation. MethodsTo test the hypothesis, we induced hypoglycemia or glucopenia in separate cohorts of mice deficient in either POMC or MC4R in the arcuate nucleus (ARC) or the paraventricular nucleus of the hypothalamus (PVH), respectively, and measured their circulating counterregulatory hormones. In addition, we performed a hyperinsulinemic-hypoglycemic clamp study to further validate the function of MC4R in hypoglycemia counterregulation. We also measured Pomc and Mc4r mRNA levels in the ARC and PVH, respectively, in the streptozotocin-induced type 1 diabetes mouse model and non-obese diabetic (NOD) mice to delineate molecular mechanisms by which diabetes deteriorates the defense systems against hypoglycemia. Finally, we treated diabetic mice with the MC4R agonist MTII, administered stereotaxically into the PVH, to determine its potential for restoring the counterregulatory response to hypoglycemia in diabetes. ResultsStimulation of epinephrine and glucagon release in response to hypoglycemia or glucopenia was diminished in both POMC- and MC4R-deficient mice, relative to their littermate controls. Similarly, the counterregulatory response was impaired in association with decreased hypothalamic Pomc and Mc4r expression in the diabetic mice, a phenotype that was not reversed by insulin treatment which normalized glycemia. In contrast, infusion of an MC4R agonist in the PVH restored the counterregulatory response in diabetic mice. ConclusionIn conclusion, hypothalamic Pomc as well as Mc4r, both of which are reduced in type 1 diabetic mice, are required for normal counterregulatory responses to hypoglycemia. Therefore, enhancing MC4R function may improve hypoglycemia counterregulation in diabetes.

Abstract 16720: Exercise-Stimulated Catecholamine Release Enhances Resolution of Acute Inflammation

The mechanisms by which regular exercise prevents the development and progression of chronic inflammatory diseases are largely unknown. We find that exercise (Exe) enhances resolution of acute inflammation by promoting macrophage (MФ) phagocytosis and by augmenting resolvin D1 (RvD1) levels. When compared with sedentary controls (Sed), mice adapted to a 4-week treadmill exercise regimen displayed 1.48-fold higher MФ phagocytotic activity, enhanced RvD1 levels (Sed 28.08±1.5 vs Exe 48.01±8.6 pg/mL, n=6), and earlier neutrophilic clearance (ΔR i ~7 h) during peritonitis. Peritonitis cell extracts from exercise-adapted mice showed elevated expression of Alox15 (48 h: Sed 0.97±0.15 vs Exe 1.5±0.16 relative expression, n=8-9), Alox5 (48 h: Sed 0.77±0.15 vs Exe 1.7±0.27 relative expression, n=4-5), and RvD1 levels (48 h: 29.0±2.1 vs 52.6±8.9 pg/mL, n=5). Because exercise stimulates epinephrine (Epi) release, which has immunomodulatory effects, we questioned if Epi exerts pro-resolving actions on macrophages. Epi-treated macrophages displayed higher 15-lipoxygenase 1 expression and RvD1 levels, which were prevented by incubation with the α1 adrenergic receptor (AR-α1) blocker, Prazosin (Praz). During zymosan-induced peritonitis, Praz abrogated exercise-enhanced neutrophilic clearance (48 h: Exe+Veh 2.07±0.41 vs Exe+Praz 5.2±1.04 x10 6 PMN, n=5), MФ phagocytosis (Exe+Veh 33463.0±2174.0 vs Exe+Praz 8303.0±2748.0 MFI, n=5-7), and RvD1 biosynthesis (Exe+Veh 211.0±55.4 vs Exe+Praz 81.79±11.8 pg/mL, n=6). These results suggest that exercise-stimulated Epi release enhances resolution of acute inflammation in an AR-α1 dependent manner. These findings provide new mechanistic insights into the pro-resolving effects of exercise and may lead to the identification of novel pathways to stimulate resolution biology.

AN INDEX CASE OF A RARE FORM OF INDUCIBLE URTICARIA SUCCESSFULLY TREATED WITH OMALIZUMAB

Introduction Inducible urticarias such as cholinergic or adrenergic urticaria (AU) can be challenging to control. Herein, we report an index case of AU successfully treated with omalizumab. Case Description A 17-year-old female with a history of Ehlers-Danlos syndrome, postural orthostatic tachycardia syndrome, and mast cell activation syndrome presented with diffuse pruritic evanescent welts with erythematous centers surrounded by white halos (Image 1) unresponsive to several therapies including a combination of high dose H1-antihistamines, H2-antihistamine, and leukotriene receptor antagonist in addition to a low dose beta-blocker. Due to the severity and frequency of the hives, omalizumab 300mg subcutaneous injections were initiated every 4 weeks resulting in complete resolution shortly after the first injection. She continues to maintain good control months later with no reported breakthrough episodes. Discussion AU is a rare form of urticaria first described in 1985, distinct from cholinergic urticaria. Although the exact mechanism of AU is unknown, it is believed to be provoked by a stress-induced concomitant release of epinephrine and norepinephrine. Diagnosis can be made by intracutaneous injection of adrenaline or noradrenaline, which produces the characteristic eruption. In this case the patient's diagnosis was based on clinical history and classic presentation of red papules surrounded by white halos. Although AU typically responds to trigger avoidance, H1-antihistamines and beta-blockers, when these treatments fail, additional therapeutic alternatives are limited. This is the first case demonstrating that AU can be successfully treated with omalizumab which should be considered as a treatment option if first line agents prove ineffective.

Quantification of a Glucocorticoid Profile in Non-pooled Samples Is Pivotal in Stress Research Across Vertebrates.

Vertebrates are faced continuously with a variety of potential stressful stimuli and react by a highly conserved endocrine stress response. An immediate catecholamine mediated response increases plasma glucose levels in order to prepare the organism for the “fight or flight” reaction. In addition, in a matter of minutes after this (nor)adrenaline release, glucocorticoids, in particular cortisol or corticosterone depending on the species, are released through activation of the hypothalamic-pituitary-interrenal (HPI) axis in fish or hypothalamic-pituitary-adrenal (HPA) axis in other vertebrates. These plasma glucocorticoids are well documented and widely used as biomarker for stress across vertebrates. In order to study the role of glucocorticoids in acute and chronic stress and gain in-depth insight in the stress axis (re)activity across vertebrates, it is pivotal to pin-point the involved molecules, to understand the mechanisms of how the latter are synthesized, regulated and excreted, and to grasp their actions on a plethora of biological processes. Furthermore, in-depth knowledge on the characteristics of the tissues as well as on the analytical methodologies available for glucocorticoid quantification is needed. This manuscript is to be situated in the multi-disciplinary research topic of glucocorticoid action across vertebrates which is linked to a wide range of research domains including but not limited to biochemistry, ecology, endocrinology, ethology, histology, immunology, morphology, physiology, and toxicology, and provides a solid base for all interested in stress, in particular glucocorticoid, related research. In this framework, internationally validated confirmation methods for quantification of a glucocorticoid profile comprising: (i) the dominant hormone; (ii) its direct precursors; (iii) its endogenously present phase I metabolites; and (iv) the most abundant more polar excreted exogenous phase I metabolites in non-pooled samples are pivotal.

Activation of µ-opioid receptors in the rostral ventrolateral medulla blocks the sympathetic counterregulatory response to glucoprivation.

Activation of neurons in the rostral ventrolateral medulla (RVLM) following glucoprivation initiates sympathoadrenal activation, adrenaline release, and increased glucose production. Here, we aimed to determine the role of RVLM µ-opioid receptors in the counterregulatory response to systemic glucoprivation. Experiments were performed in pentobarbital sodium anesthetized male Sprague-Dawley rats ( n = 30). Bilateral activation of RVLM µ-opioid receptors with [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) (8 mM, 50 nl) depressed adrenal sympathetic nerve activity for ~60 min ( n = 6; Δ49.9 ± 5.8%, P < 0.05). The counterregulatory response to glucoprivation (measured by adrenal sympathetic efferent nerve activity) induced by 2-deoxyglucose (2-DG) ( n = 6; Δ63.6 ± 16.5%, P < 0.05) was completely blocked 60 min after DAMGO microinjections ( n = 6; Δ10.2 ± 3.5%, P < 0.05). Furthermore, DAMGO pretreatment attenuated the increase in blood glucose levels after 2-DG infusion ( n = 6; 6.1 ± 0.7mmol/l vs. baseline 5.2 ± 0.3mmol/l, P > 0.05) compared with 2-DG alone ( n = 6; 7.6 ± 0.4mmol/l vs. baseline 6.0 ± 0.4mmol/l, P < 0.05). Thus, activation of RVLM µ-opioid receptors attenuated the neural efferent response to glucoprivation and reduced glucose production.

Catecholamine-Induced Cardiomyopathy in Pheochromocytoma: How to Manage a Rare Complication in a Rare Disease?

Pheochromocytomas and paragangliomas (PHEOs) are rare neuroendocrine tumors. Clinical manifestations include different cardiovascular signs and symptoms, which are related to excessive secretion of catecholamines. Catecholamine-induced cardiomyopathy in PHEO (CICMPP) is a rare but dreaded complication of PHEO. Once patient is diagnosed with this condition, the prognosis is worse and a surgical risk is much higher than expected. This article focuses on how catecholamines affect the heart and the pathophysiologic mechanism of CICMPP. The cardiovascular responses to catecholamine depend mostly on which catecholamine is released as well as the amount of catecholamine that is released. The acute release of norepinephrine and epinephrine from PHEO increases heart rate, systemic vascular resistance, myocardial contractility, and reduces venous compliance. The excessive adrenergic stimulation by catecholamine results in severe vasoconstriction and coronary vasospasm, myocardial ischemia, and subsequently damage, and necrosis. Chronically elevated catecholamine levels lead to significant desensitization of cardiac β-adrenoceptors. The increased levels of the enzyme β-adrenoceptors kinase (βARK) in the heart seems to mediate these biochemical and physiological changes that are consistently correlated with attenuated responsiveness to catecholamine stimulation. Through these mechanisms different types of cardiomyopathy (CMP) can be formed. This review discusses extensively the 3 types of cardiomyopathies that can be present in a PHEO patient. It also provides the clinical presentation and diagnostic and therapeutic algorithm in managing patients with CICMPP.

Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes

ObjectiveAppropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic β-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses. MethodsHyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase. ResultsGCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated β-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in β-cells. For epinephrine, we found increased responses in GCK-MODY patients, in β-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release. ConclusionsOur data suggest that glucokinase in brain and other non β-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose.