Showing papers on "Epinephrine published in 2006"

Stress hormone-mediated invasion of ovarian cancer cells.

Abstract: Purpose: There is growing evidence that stress and other behavioral factors may affect cancer progression and patient survival. The underlying mechanisms for this association are poorly understood. The purpose of this study is to determine the effects of stress-associated hormones norepinephrine, epinephrine, and cortisol on the invasive potential of ovarian cancer cells. Experimental Design: The ovarian cancer cells EG, SKOV3, and 222 were exposed to increasing levels of either norepinephrine, epinephrine, or cortisol, and the in vitro invasive potential was determined using the membrane invasion culture system. Additionally, the effects of these stress hormones on matrix metalloproteinase-2 (MMP-2) and MMP-9 were determined by ELISA. The effects of the β-adrenergic agonist isoproterenol on in vivo tumor growth were determined using nude mice. Results: Stress levels of norepinephrine increased the in vitro invasiveness of ovarian cancer cells by 89% to 198%. Epinephrine also induced significant increases in invasion in all three cell lines ranging from 64% to 76%. Cortisol did not significantly affect invasiveness of the EG and 222 cell lines but increased invasion in the SKOV3 cell line ( P = 0.01). We have previously shown that ovarian cancer cells express β-adrenergic receptors. The β-adrenergic antagonist propanolol (1 μmol/L) completely blocked the norepinephrine-induced increase in invasiveness. Norepinephrine also increased tumor cell expression of MMP-2 ( P = 0.02 for both SKOV3 and EG cells) and MMP-9 ( P = 0.01 and 0.04, respectively), and pharmacologic blockade of MMPs abrogated the effects of norepinephrine on tumor cell invasive potential. Isoproterenol treatment resulted in a significant increase in tumor volume and infiltration in the SKOV3ip1 in vivo model, which was blocked by propranolol. Conclusions: These findings provide direct experimental evidence that stress hormones can enhance the invasive potential of ovarian cancer cells. These effects are most likely mediated by stimulation of MMPs.

Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest.

Abstract: Vasopressin administration has been suggested during cardiopulmonary resuscitation, and a previous clinical trial has suggested that vasopressin is most effective when administered with epinephrine. Adult subjects (n = 325) who received ≥1 dose of intravenous epinephrine during cardiopulmonary resuscitation for nontraumatic, out-of-hospital cardiac arrest were randomly assigned to receive 40 IU of vasopressin (n = 167) or placebo (n = 158) as soon as possible after the first dose of epinephrine. The rate of return of pulses was similar between the vasopressin and placebo groups (31% vs 30%), as was the presence of pulses at the emergency department (19% vs 23%). No subgroup appeared to be differentially affected, and no effect of vasopressin was evident after adjustment for other clinical variables. Additional open-label vasopressin was administered by a physician after the study drug for 19 subjects in the placebo group and 27 subjects in the vasopressin group. Results were similar if these subjects were excluded or were assigned to an actual drug received. Survival duration for subjects admitted to the hospital did not differ between groups. In conclusion, vasopressin administered with epinephrine does not increase the rate of return of spontaneous circulation.

Sublingual epinephrine tablets versus intramuscular injection of epinephrine: Dose equivalence for potential treatment of anaphylaxis

Abstract: Background Epinephrine autoinjectors are underused in the emergency treatment of anaphylaxis in the community, perhaps in part because of fear of needles. Objectives To determine the sublingual epinephrine dose from a novel fast-disintegrating tablet required to achieve epinephrine plasma concentrations (EPPCs) similar to those obtained after epinephrine 0.3 mg intramuscular injection. Methods In a prospective 5-way crossover study, sublingual tablets containing epinephrine 0, 10, 20, and 40 mg, and epinephrine 0.3 mg intramuscular in the thigh (EpiPen) were compared in a validated rabbit model. Blood samples were collected before dosing and 5, 10, 15, 20, 30, 40, 60, 90, 120, 150, and 180 minutes afterward. EPPCs were measured by using high-performance liquid chromatography–electrochemical detection. Pharmacokinetic parameters were calculated by using WinNonlin. Results The area under the curve (AUC), maximum concentration (C max ), and time at which C max was achieved (T max ) did not differ significantly ( P > .05) after epinephrine 40 mg (AUC = 1861 ± 537 ng/mL/min, C max = 31.0 ± 13.1 ng/mL, and T max = 9 ± 2 minutes) and epinephrine 0.3 mg intramuscular (AUC = 2431 ± 386 ng/mL/min, C max = 50.3 ± 17.1 ng/mL, and T max = 21 ± 5 minutes). The AUC after tablets containing epinephrine 0 mg (AUC = 472 ± 126 ng/mL/min), epinephrine 10 mg (AUC = 335 ± 152 ng/mL/min), and epinephrine 20 mg (AUC = 801 ± 160 ng/mL/min) did not differ significantly from each other, but were significantly lower ( P Conclusion Sublingual administration of epinephrine 40 mg from this tablet formulation resulted in EPPCs similar to those obtained after epinephrine 0.3 mg intramuscular injection in the thigh. Clinical implications For treatment of anaphylaxis in the community, self-injectable epinephrine is underused. This novel, fast-disintegrating epinephrine tablet formulation for sublingual administration is a feasible alternative that warrants further development.

Vasoactive amines in acute inflammation

Abstract: The pioneer researches of Dale, Lewis, and their colleagues established beyond doubt that histamine could reproduce the acute vascular changes of injury, as seen in such manifestations as the triple response, involving vasodilatation and increased vascular permeability. Also well known is the widespread distribution of histamine in the body and the ease with which it is released from its bound form (see Ciba Foundation Symposium on Histamine, 1955). Evidence has accumulated also of the release of histamine from the tissues by a wide variety of injurious stimuli, including thermal, chemical, and anaphylactic damage. In addition, the introduction of antihistamine drugs to clinical practice provided further evidence for the importance of histamine, since these drugs were found to suppress the vascular changes of allergic reactions, such as urticaria and hay fever. In spite of the partia1 clinical success of antihistamine drugs in combating certain types of hyperergic damage, attempts to demonstrate a role for histamine in experimentally induced inflammation proved disappointing in that antihistamine drugs usually failed to influence the course of events. Spector and Willoughby ( 1 9 5 9 ~ ) ~ however, gave small doses of mepyramine (Neo-AnterganB) to rats and found that this treatment delayed the onset of increased vascular permeability after chemical injury by one to two hours. They were able to show that these doses of antihistamine drugs were small enough to inhibit only histamine. A similar delay was achieved by depleting the rats of their bodily stores of histamine by repeated injections of the histamine liberator, Compound 48/80. Previous work (Spector, 1956) had demonstrated the presence of histamine in turpentine-induced inflammatory exudates in the first 30 minutes after the chemioal injury, but not at later times. These results suggest that endogenous histamine is responsible for the initiation of vascular changes after injury, but that other mechanisms are then required to maintain the vascular changes. Since the results in turpentine-induced pleurisy were obtained, similar findings have been reported in thermal injury in rats íSpector & Willoughby, 19596) and in other species (Wilhelm & Mason, 1960). In ali cases, the administration of small doses of antihistamine drugs affected the earlier, but not the later, phases of increased vascular permeability. For technical reasons, the role of histamine in bacterial-induced injury has proved difficult to elucidate. Sheldon and Bauer ( 1960), however, have shown that after the induction of inflammation by local injection of microorganisms in rats, the vascular changes were greatly delayed if the animals were previously depleted of bodily histamine by repeated injections of histamine releasers. On the other hand, Smith and Miles (1960), studying experimental bacterial peritonitis in the rat, faiied to observe significant release of histamine into the peritoneal fluid. They also reported a failure of antihistamine drugs to modify the inflammatory response in this condition. It may be, therefore, that release of histamine is of little importance ín, at least, some types of bacterial infection. A different type of injury

The effect of nicotine and smoking on the secretion of epinephrine.

Abstract: As early as 1912 Dale and Laidlaw' found that the pressor response of the cat to nicotine was due a t least partially to the liberation of epinephrine by the adrenal glands. Van Slyke and Larson2 have shown that the pressor response to nicotine in dogs is greatly reduced following adrenalectomy. They indicate that release of epinephrine from the adrenal medulla is an important factor in this pressor response to epinephrine. More recently, with the development of fluorimetric and bioassay methods for the quantitative estimation of epinephrine and norepinephrine, the liberation of these substances into the adrenal vein blood has been observed following the administration of nicotine. De Schaepdryver3 has shown that the administration of 0.1 mg./kg. nicotine increased the norepinephrine secretion of the adrenal gland of dogs from a control output of 7 ng.t/kg./min. to 555 ng./kg./min. The epinephrine output was increased from 12 to 1327 ng./kg./min. The epinephrine represented 63 per cent of the total catechols before nicotine and 71 per cent following administration of the compound. Other investigator^^^^ have observed comparable increases in the release of epinephrine from the adrenal glands of dogs following the intravenous administration of nicotine, epinephrine accounting for 80 to 90 per cent of the catecholamines of the adrenal vein blood.

α2-Adrenoceptor subtypes involved in the regulation of catecholamine release from the adrenal medulla of mice

Abstract: Background and purpose: This study was carried out to elucidate which α2-adrenoceptor subtypes mediated the inhibition of noradrenaline and adrenaline release from the adrenal medulla of mice. Experimental approach: Isolated adrenal medullae from wild-type and α2A, α2B and α2C-adrenoceptor knockout (KO) mice were placed in superfusion chambers. Catecholamine overflow was evoked by 1,1-dimethyl-4-phenylpiperazinium (500 μM) in absence or in presence of the α2-adrenoceptor agonist medetomidine. The effect of medetomidine was tested in presence of the α-adrenoceptor antagonists rauwolscine, WB 4101, spiroxatrine, phentolamine and prazosin. Key results: In wild-type mice, medetomidine reduced noradrenaline and adrenaline overflow in a concentration-dependent manner (EC50 in nM: 1.54 and 1.92; Emax in % of inhibition: 91 and 94, for noradrenaline and adrenaline, respectively). The pKD values of the antagonists for noradrenaline overflow did not correlate with pKD values at α2A, α2B, or α2C binding sites. The pKD values of the antagonists for adrenaline overflow correlated positively with pKD values at α2C binding sites (opossum kidney cells). The effect of medetomidine (100 nM) on noradrenaline overflow was significantly reduced in all three α2KO mice (57, 54, 44 % inhibition, for α2A, α2B, and α2C, respectively), whereas the effect of medetomidine on adrenaline overflow was greatly reduced in α2CKO mice (14 % inhibition). Conclusions and implications: In the adrenal medulla of mice, all three α2-adrenoceptor subtypes (α2A, α2B, and α2C) play an equal role in the inhibition of noradrenaline overflow, whereas the α2C-adrenoceptor is the predominant α2-adrenoceptor subtype involved in the inhibitory mechanism controlling adrenaline overflow. British Journal of Pharmacology (2006) 149, 1049–1058. doi:10.1038/sj.bjp.0706950 Published online 30 October 2006

Epinephrine biosynthesis: hormonal and neural control during stress.

Abstract: 1. Stress contributes to the pathophysiology of many diseases, including psychiatric disorders, immune dysfunction, nicotine addiction and cardiovascular illness. Epinephrine and the glucocorticoids, cortisol and corticosterone, are major stress hormones. 2. Release of epinephrine from the adrenal medulla and glucocorticoids from the adrenal cortex initiate the biological responses permitting the organism to cope with adverse psychological, physiological and environmental stressors. Following its massive release during stress, epinephrine must be restored to replenish cellular pools and sustain release to maintain the heightened awareness and sequelae of responses to re-establish homeostasis and ensure survival. 3. Epinephrine is regulated in part through its biosynthesis catalyzed by the final enzyme in the catecholamine pathway, phenylethanolamine N-methyltransferase (E.C. 2.1.1.28, PNMT). PNMT expression, in turn, is controlled through hormonal and neural stimuli, which exert their effects on gene transcription through protein stability. 4. The pioneering work of Julius Axelrod forged the path to our present understanding of how the stress hormone and neurotransmitter epinephrine, is regulated, in particular via its biosynthesis by PNMT.

Sympathomimetic Infusion and Cardiac Repolarization: The Normative Effects of Epinephrine and Isoproterenol in Healthy Subjects

Abstract: Introduction: Catecholamines are known to affect cardiac repolarization, and provocation with either isoproterenol or epinephrine has been proposed as a tool for uncovering latent repolarization abnormalities. This study systematically compares the effects of isoproterenol and epinephrine infusions on QT interval (QT), T waves and U waves in normal subjects. Methods and Results: Twenty-four normal subjects (29 ± 8 years) were evaluated during graded infusions of up to 0.30 μg/kg/minute epinephrine and 5.0 μg/minute isoproterenol. Heart rates at peak doses were 81 ± 13 bpm at 0.28 ± 0.04 μg/kg/minute epinephrine and 104 ± 5 bpm at 2.4 μg/minute isoproterenol. The longest absolute QT increase was 4 ± 5 msec above baseline during isoproterenol (P < 0.001) and 12 ± 23 msec during epinephrine (P = 0.07), while the longest corrected QT interval (QTc) increase was 67 ± 28 msec (P < 0.0001) and 79 ± 40 msec (P < 0.0001) above baseline during isoproterenol and epinephrine, respectively (P = 0.12 for difference). There was a 2-fold increase in U-wave amplitude during each intervention (P < 0.001). The specificity of paradoxical QT prolongation (≥30 msec at 0.05 μg/kg/minute or ≥35 msec at 0.10 μg/kg/minute epinephrine) and an increase in QTc ≥600 msec at any dose epinephrine were 100%. However, the specificity of other proposed criteria that utilized QTc measurement (≥30 msec at 0.10 μg/kg/minute or ≥65 msec at any dose) was poor whether all leads or only lead II were assessed. Conclusion: Both epinephrine and isoproterenol are associated with QTc prolongation and amplification of the U wave in normal subjects. The specificity of proposed criteria for epinephrine provocation in diagnosis of the long-QT syndrome is variable; however, paradoxical QT prolongation at low-dose epinephrine or a QTc ≥600 msec is highly specific.

Acute myocardial infarction after administration of low-dose intravenous epinephrine for anaphylaxis

Abstract: This case describes a 29-year-old woman who presented with an acute severe anaphylactic reaction to penicillin. In addition to other medications administered in the emergency department, she received 0.1 mg intravenously of 1:10 000 epinephrine, after which she immediately developed severe chest pain. Her ECG showed ST elevations consistent with an anterior myocardial infarction, and her serum troponin level was elevated. A CT angiogram showed no signs of coronary artery disease or abnormal anatomy. This case is an example of vasospasm-induced myocardial injury and illustrates a potential danger of intravenous epinephrine use. The authors were able to identify only 2 other case reports where therapeutic doses of epinephrine have been reported to cause this phenomenon.

Epinephrine increases mortality after brief asphyxial cardiac arrest in an in vivo rat model.

Abstract: Epinephrine may be detrimental in cardiac arrest. In this laboratory study we sought to characterize the effect of epinephrine and concomitant calcium channel blockade on postresuscitation myocardial performance after brief asphyxial cardiac arrest. Anesthesized rats were disconnected from mechanical ventilation, resulting in cardiac arrest. Resuscitation was attempted after 1 min with mechanical ventilation, oxygen, chest compressions, and IV medication. In experimental series 1 and 2, animals were allocated to 10 or 30 microg/kg epinephrine or 0.9% saline. In series 3, animals received 30 microg/kg of epinephrine and were randomized to 0.1 mg/kg of verapamil or to 0.9% saline. In series 1 and 3, left ventricular function was assessed using transthoracic echocardiography. In series 2, left atrial pressure was measured. Epinephrine was associated with increased mortality (0/8 [0%] in controls, 4/12 [33.3%] in 10 microg/kg animals, and 16/22 [72.8%] in 30 microg/kg animals; P < 0.05), hypertension (P < 0.001), tachycardia (P = 0.004), early transient left atrial hypertension, and dose-related reduction in left ventricular end diastolic diameter (P < 0.05). Verapamil prevented mortality associated with large-dose epinephrine (0% versus 100%) and attenuated early diastolic dysfunction and postresuscitation hypertension (P = 0.001) without systolic dysfunction. Epinephrine appears to be harmful in the setting of brief cardiac arrest after asphyxia.

Deletion of the neuropeptide Y (NPY) Y1 receptor gene reveals a regulatory role of NPY on catecholamine synthesis and secretion

Abstract: The contribution of neuropeptide Y (NPY), deriving from adrenal medulla, to the adrenosympathetic tone is unknown. We found that in response to NPY, primary cultures of mouse adrenal chromaffin cells secreted catecholamine, and that this effect was abolished in cultures from NPY Y1 receptor knockout mice (Y1−/−). Compared with wild-type mice (Y1+/+), the adrenal content and constitutive release of catecholamine were increased in chromaffin cells from Y1−/− mice. In resting animals, catecholamine plasma concentrations were higher in Y1−/− mice. Comparing the adrenal glands of both genotypes, no differences were observed in the area of the medulla, cortex, and X zone. The high turnover of adrenal catecholamine in Y1−/− mice was explained by the enhancement of tyrosine hydroxylase (TH) activity, although no change in the affinity of the enzyme was observed. The molecular interaction between the Y1 receptor and TH was demonstrated by the fact that NPY markedly inhibited the forskolin-induced luciferin activity in Y1 receptor-expressing SK-N-MC cells transfected with a TH promoter sequence. We propose that NPY controls the release and synthesis of catecholamine from the adrenal medulla and consequently contributes to the sympathoadrenal tone.

Gene expression of phenylethanolamine N-methyltransferase in corticotropin-releasing hormone knockout mice during stress exposure.

Abstract: 1. Aims: Epinephrine (EPI) synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28) is primarily localized in the adrenal medulla (AM). We have recently described existence of the PNMT gene expression in cardiac atria and ventricles and in sympathetic ganglia of adult rats and mice. The aim of the present work was to study regulation of the PNMT gene expression in corticotropin-releasing hormone knockout mice (CRH KO) and matched control wild-type mice (WT) under normal and stress conditions. 2. Methods: Levels of the PNMT mRNA were determined by RT-PCR; PNMT immunoprotein and protein of transcription factor EGR-1 by Western Blot. Plasma EPI and corticosterone (CORT) levels were determined by radioenzymatic and RIA methods. Immobilization (IMMO) was used as a stressor. 3. Results: Stress-induced increases in the PNMT mRNA and protein levels observed in WT mice were almost completely absent in CRH KO mouse adrenal medulla, stellate ganglia, and cardiac atria, while ventricular PNMT mRNA elevation was not CRH-dependent. Plasma EPI and CORT levels were markedly reduced in CRH KO compared to WT mice both before and after the stress. Levels of EGR-1, crucial transcription factor for regulation of the PNMT were highly increased in stressed WT and CRH KO mice in cardiac areas, but not in the adrenal medulla. 4. Conclusions: Data show that the CRH deficiency can markedly prevent immobilization-triggered induction of the PNMT mRNA and protein levels in the adrenal medulla and stellate ganglia. Reduced plasma epinephrine and corticosterone levels and adrenal medullary EGR-1 protein levels in CRH knockout versus WT mice during stress indicate that the HPA axis plays a crucial role in regulation of the PNMT gene expression in these organs. Cardiac atrial PNMT gene expression with stress is also dependent on intact HPA axis. However, in cardiac ventricles, especially after the single stress exposure, its expression is not impaired by CRH deficiency. Since cardiac EGR-1 protein levels in CRH KO mice are also not affected by the single stress exposure, we propose existence of different regulation of the PNMT gene expression, especially in the cardiac ventricles. Overall, our findings reveal that the PNMT gene expression is regulated through the HPA in both sympathoadrenal system and the heart and also via EGR-1 in the adrenal medulla, but apparently not in the heart. Regulation of the PNMT gene expression in various compartments of heart includes both corticosterone-dependent and independent mechanisms.

Endocrine regulation of subcutaneous fat metabolism during cold exposure in humans.

Abstract: Increased oxidation of carbohydrates and free fatty acids is a well-known phenomenon during cold stress. Nevertheless, sources of the fuels used have not been fully clarified as yet. Thus, the aim of our study was to evaluate the effect of acute cold exposure on lipid and carbohydrate metabolism in human subcutaneous adipose tissue and to identify the possible regulatory mechanisms involved. Ten volunteers were exposed for 30 min to an ambient temperature of 4 degrees C. Interstitial metabolism was assessed with the aid of the microdialysis technique. Lipolysis intensity was evaluated from changes of glycerol concentration in plasma and in dialysate. Cold exposure induced a significant increase of glycerol concentration both in plasma (by 199 +/- 16%, p < 0.01) and in dialysate (by 308 +/- 58%, p < 0.001). No changes in glucose concentration were found whether in plasma or in the dialysate. Ethanol concentration in dialysate increased (148 +/- 15%, p < 0.01), indicating a slower blood flow in the subcutaneous region. Plasma concentrations of various gluco- and/or lipid-regulatory hormones remained unaffected by the cold exposure, except for norepinephrine, which rose about threefold (309 +/- 41%, p < 0.001). The data indicate an important role for subcutaneous adipose tissue in mobilization of free fatty acids during cold exposure. This process seems to be regulated by the sympathetic nervous system, whereas hormones involved in the regulation of lipid metabolism, such as epinephrine, insulin, cortisol, and growth hormone, may play a less significant role-at least under the conditions studied.

Effects of increasing infusion rates of dopamine, dobutamine, epinephrine, and phenylephrine in healthy anesthetized cats

Abstract: Objective—To determine the cardiopulmonary effects of increasing doses of dopamine, dobutamine, epinephrine, and phenylephrine and measure plasma concentrations of norepinephrine, epinephrine, and dopamine in cats anesthetized with isoflurane. Animals—6 healthy adult cats. Procedures—Each cat was anesthetized with isoflurane (1.5 X minimum alveolar concentration) on 4 occasions. Cardiopulmonary measurements were obtained after a 30-minute stabilization period; 20 minutes after the start of each infusion dose; and 30, 60, and 90 minutes after the infusion was discontinued. Cats received 5 progressively increasing infusions of epinephrine or phenylephrine (0.125, 0.25, 0.5, 1, and 2 μg/kg/min) or dobutamine or dopamine (2.5, 5, 10, 15, and 20 μg/kg/min). The order of treatment was randomly allocated. Results—All 4 treatments increased oxygen delivery. Heart rate (HR) increased during administration of all drugs except phenylephrine, and mean arterial pressure increased during administration of all drugs exc...

Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine

Abstract: The effects of endogenous β-agonists, such as catecholamines, on alveolar fluid clearance have been studied in several animal models (1). Endogenous epinephrine increased alveolar fluid clearance in rats after severe septic or hemorrhagic shock (2) and during neurogenic pulmonary edema in dogs (3). In addition, intravenous epinephrine administration increased alveolar fluid clearance in anesthetized rats (4). Recently, increased plasma catecholamine levels were reported in patients with hydrostatic pulmonary edema (5) and the acute respiratory distress syndrome (6). However, pulmonary edema fluid catecholamine levels were not reported, and it is uncertain whether the catecholamine levels that are present in pulmonary edema fluid can stimulate alveolar fluid clearance in human lungs. This is a key question, since the degree of endogenous stimulation of alveolar fluid clearance by catecholamines in patients with pulmonary edema will determine whether there can be an additional therapeutic effect of exogenous β-agonists. The importance of this issue was raised at a National Heart Lung and Blood Institute conference on pulmonary edema (7). Although β-adrenergic agonists are known to increase alveolar epithelial sodium transport, the precise role that Cl- transport and Cl- channels play in β-adrenoceptor-stimulated alveolar ion and fluid transport is unclear (8, 9). A series of complementary approaches have suggested an important role for the cystic fibrosis transmembrane conductance regulator (CFTR) in β-adrenoceptor-stimulated alveolar fluid clearance and the resolution of pulmonary edema (10). Interestingly, glibenclamide inhibited cyclic adenosine monophosphate (cAMP)-stimulated alveolar fluid clearance transport in human lungs from lung donors. Recently, CFTRinh-172, a selective inhibitor of the CFTR, has been shown to inhibit the function of CFTR in nasal epithelium in mice (11) and in airway glands from pigs and humans (12). However, it is uncertain whether CFTRinh-172 inhibits the effect of catecholamines on alveolar fluid clearance in the human lung. Therefore, the first objective in the present study was to measure catecholamine levels in pulmonary edema fluid and plasma of patients with hydrostatic pulmonary edema or with increased permeability pulmonary edema (acute lung injury). Because the majority of epinephrine and norepinephrine levels in the pulmonary edema fluid were in the range of ~10-9 M, the second objective was to determine whether 10-9 M epinephrine or norepinephrine stimulated alveolar fluid clearance in isolated human lungs. Since 10-9 M epinephrine did not stimulate alveolar fluid clearance, we tested 10-7 M epinephrine, which markedly stimulated alveolar fluid clearance. The final objective was to determine whether 10-7 M epinephrine stimulated alveolar fluid clearance via CFTR Cl- channels.

Histamine evokes greater increases in phosphatidylinositol metabolism and catecholamine secretion in epinephrine-containing than in norepinephrine-containing chromaffin cells.

Abstract: Chromaffin cells have H1 histamine receptors. Histamine, acting at these receptors, increases the metabolism of inositol-containing phospholipids and stimulates catecholamine secretion from Chromaffin cells. We have investigated the effects of histamine and other agents on the accumulation of inositol monophosphate (InsP1) and catecholamine secretion in purified cultures of norepinephrine-containing and epinephrine-containing bovine Chromaffin cells. Histamine-stimulated InsP, accumulation in epinephrine cells was three times greater than that in norepinephrine cells. In contrast, bradykinin caused roughly equivalent increases in InsP1 accumulation in the two Chromaffin cell subtypes. Histamine-stimulated catecholamine secretion was also greater in epinephrine cells than in norepinephrine cells, whereas high K+, bradykinin, phorbol 12, 13-dibutyrate, and angiotensin II all caused greater secretion from norepinephrine cells than from epinephrine cells. The density of H1 receptors in epinephrine cells was approximately three times greater than that in norepinephrine cells. The greater density of H1 receptors on epinephrine cells may account for the greater effects of histamine on InsP1 accumulation and catecholamine secretion in these cells.

Dopexamine and norepinephrine versus epinephrine on gastric perfusion in patients with septic shock: a randomized study [NCT00134212]

Abstract: INTRODUCTION : Microcirculatory blood flow, and notably gut perfusion, is important in the development of multiple organ failure in septic shock. We compared the effects of dopexamine and norepinephrine (noradrenaline) with those of epinephrine (adrenaline) on gastric mucosal blood flow (GMBF) in patients with septic shock. The effects of these drugs on oxidative stress were also assessed. METHODS : This was a prospective randomized study performed in a surgical intensive care unit among adults fulfilling usual criteria for septic shock. Systemic and pulmonary hemodynamics, GMBF (laser-Doppler) and malondialdehyde were assessed just before catecholamine infusion (T0), as soon as mean arterial pressure (MAP) reached 70 to 80 mmHg (T1), and 2 hours (T2) and 6 hours (T3) after T1. Drugs were titrated from 0.2 mug kg-1 min-1 with 0.2 mug kg-1 min-1 increments every 3 minutes for epinephrine and norepinephrine, and from 0.5 mug kg-1 min-1 with 0.5 mug kg-1 min-1 increments every 3 minutes for dopexamine. RESULTS : Twenty-two patients were included (10 receiving epinephrine, 12 receiving dopexamine-norepinephrine). There was no significant difference between groups on MAP at T0, T1, T2, and T3. Heart rate and cardiac output increased significantly more with epinephrine than with dopexamine-norepinephrine, whereas. GMBF increased significantly more with dopexamine-norepinephrine than with epinephrine between T1 and T3 (median values 106, 137, 133, and 165 versus 76, 91, 90, and 125 units of relative flux at T0, T1, T2 and T3, respectively). Malondialdehyde similarly increased in both groups between T1 and T3. CONCLUSION : In septic shock, at doses that induced the same effect on MAP, dopexamine-norepinephrine enhanced GMBF more than epinephrine did. No difference was observed on oxidative stress.

Inhibition of glucose-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 by epinephrine in pancreatic β-cells

Abstract: Glucose sensing is essential for the ability of pancreatic -cells to produce insulin in sufficient quantities to maintain blood glucose within the normal range. Stress causes the release of adrenergic hormones that increase circulating glucose by promoting glucose production and inhibiting insulin release. We have shown that extracellular signal‐ regulated kinases 1 and 2 (ERK1/2) are responsive to glucose in pancreatic -cells and that glucose activates ERK1/2 by mechanisms independent of insulin. Here we show that glucose-induced activation of ERK1/2 is inhibited by epinephrine through the 2-adrenergic receptor. Epinephrine and the selective 2-adrenergic agonist UK14304 reduced insulin secretion and glucose-stimulated ERK1/2 activation in a pertussis toxin‐sensitive manner, implicating the subunit of a Gi family member. 2adrenergic agonists also reduced stimulation of ERK1/2 by glucagon-like peptide 1 and KCl, but not by phorbol ester or nerve growth factor. Our findings suggest that 2adrenergic agonists act via a Gi family member on early steps in ERK1/2 activation, supporting the idea that ERK1/2 are regulated in a manner that reflects insulin demand. Diabetes 55:1066‐1073, 2006

Fast-disintegrating epinephrine tablets for buccal or sublingual administration

Abstract: Described herein are formulations for fast-disintegrating epinephrine tablets which can be prepared for buccal or sublingual administration, wherein the fast-disintegrating epinephrine tablets can produce plasma epinephrine concentrations substantially equivalent to those achieved by traditional injectable dosage forms comprising epinephrine injected either subcutaneously or intramuscularly.

β1-Adrenoceptor blockade mitigates excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog

Abstract: Mitral regurgitation (MR) is associated with increased neuronal release of norepinephrine (NE) and epinephrine (EP) into myocardial interstitial fluid (ISF) that may be necessary in sustaining left...

Influence of sympathetic activity on blood pressure and vascular damage evaluated by means of urinary albumin excretion.

Abstract: To analyze the influence of sympathetic activity on blood pressure (BP) and its effects on urinary albumin excretion (UAE), the authors carried out a cross-sectional study in their local health coverage area. The following variables were monitored in a representative sample of the general population made up of 495 individuals: anthropometric parameters; blood glucose, creatinine, and lipid levels; 24-hour urinary albumin, norepinephrine, and epinephrine excretion; and BP of patients with known hypertension and newly discovered BP ≥140/90 mm Hg, evaluated by ambulatory monitoring. In the multivariate analysis, only gender, systolic BP, and UAE were associated with norepinephrine levels; only gender, systolic BP, and body mass index were associated with epinephrine. After excluding those patients with chronic kidney disease, the multivariate analysis showed a strong association between UAE ≥30 mg/d and elevated norepinephrine and epinephrine levels. The authors concluded that in the subject population there is an association between elevated adrenergic activity and higher UAE, independent of factors such as age and BP.

Estrés y sistema inmune

Abstract: Stress is defined as the relationship between adverse stimuli that seriously threaten homeostasis and the physiological and behavioral responses of the organism to those stimuli. Central nervous system executes control on the stress response by coordinating those systems involved in homeostasis maintenance, namely the autonomic, neuroendocrine and immune systems. Since the first report of the general adaptation syndrome by Hans Selye in 1936, it was described that stress produces thymus and lymph nodes hypotrophy. Later, clinical and experimental studies in humans and on animal models have shown that stress suppresses immune function with concomitant consequences on individual’s health. In young and adult human beings, psychosocial stress has been related to increased susceptibility and longer duration of infectious diseases, such as influenza, herpes virus infection and AIDS, and stress is also capable to prolong wound healing. Also in animal models, stress reduces antibody production, inhibits normal functioning of natural killer cells, cytotoxic lymphocyte T cells and macrophages and can increase the growth rate and metastasis of carcinogenic tumors, such as mammary gland tumor, controlled by natural killer cells. The adverse immunosuppressive stress effects are mediated by the stress hormones glucocorticoids and catecholamines, epinephrine (adrenaline) and norepinephrine (noradrenaline). Glucocorticoids, cortisol in humans, are released by the adrenal gland cortex, whereas the catecholamine epinephrine (adrenaline) is synthesized and released by the adrenal gland medulla; both hormones, cortisol and adrenaline, reach higher concentrations in the blood stream during exposure to stress stimuli. At the same time, noradrenaline is released directly on immune organs and tissues by terminal endings of sympathetic nervous system neurons, which form synaptic-like connections with the immune cells. Adrenalectomy or sympathectomy in animal models prevent the stress response, thus glucocorticoides, adrenaline and noradrenaline blood levels remain unchanged and immunosupression does not develop. In conclusion, stress and its hormones, glucocorticoids and catecholamines, are capable to alter the illness onset and course and also delay healing of wounds, with a consequent significant economical and social impact.

Carvedilol blocks beta2- more than beta1-adrenoceptors in human heart.

Abstract: Objective: To understand the basis of the effectiveness of carvedilol in heart failure by determining its specific properties at human heart β1- and β2-adrenoceptors. Methods: The positive inotropic effects of noradrenaline (in the presence of the β2-selective antagonist ICI118551) and adrenaline (in the presence of the β1-selective antagonist CGP20712), mediated through β1- and β2-adrenoceptors, respectively, were investigated in atrial and ventricular trabeculae. The patch-clamp technique was used to investigate effects of noradrenaline and adrenaline on L-type Ca2+ current in human atrial myocytes. Results: Carvedilol was a 13-fold more potent competitive antagonist of the effects of adrenaline at β2-adrenoceptors (−logKB=10.13 ± 0.08) than of noradrenaline at β1-adrenoceptors (−logKB=9.02 ± 0.07) in human right atrium. Chronic carvedilol treatment of patients with non-terminal heart failure reduced the inotropic sensitivity of atrial trabeculae to noradrenaline and adrenaline 5.6-fold and 91.2-fold, respectively, compared to β1-blocker-treated patients, consistent with persistent preferential blockade of β2-adrenoceptors. In terminal heart failure carvedilol treatment reduced 1.8-fold and 25.1-fold the sensitivity of right ventricular trabeculae to noradrenaline and adrenaline, respectively, but metoprolol treatment did not reduce the sensitivity to the catecholamines. Increases of current ( I Ca,L) produced by noradrenaline and adrenaline were not different in atrial myocytes obtained from non-terminal heart failure patients treated with metoprolol or carvedilol, consistent with dissociation of both β-blockers from the receptors. Conclusions: Carvedilol blocks human cardiac β2-adrenoceptors more than β1-adrenoceptors, thereby conceivably contributing to the beneficial effects in heart failure. The persistent blockade of β-adrenoceptors is attributed to accumulation of carvedilol in cardiac tissue.