Showing papers on "Epinephrine published in 2003"

Dissociation between reactivity of the hypothalamus-pituitary-adrenal axis and the sympathetic-adrenal-medullary system to repeated psychosocial stress.

Abstract: OBJECTIVE This study investigated endocrine and autonomic stress responses after repeated psychosocial stress. A first goal of the study was to investigate whether peripheral catecholamines and cardiovascular parameters would show similar or different habituation patterns after repeated stress. The second aim was to detect possible subgroups with regard to individual habituation patterns in the hypothalamus-pituitary-adrenal (HPA) axis and monitor their respective sympathetic stress responses. METHODS Sixty-five healthy subjects (19-45 years), 38 men and 27 women, were exposed to the Trier Social Stress Test (TSST) three times with a 4-week interval between stress sessions. Adrenocorticotropic hormone (ACTH), plasma cortisol, salivary cortisol, epinephrine, norepinephrine, and heart rates were measures repeatedly before and after each stress exposure. RESULTS All endocrine measures as well as heart rates increased significantly after each of the three stress sessions (F values >16.00, all p values 5.8, p 10.00, p <.01). No such differences between high and low responders could be observed with regard to catecholamine and heart rate responses. CONCLUSIONS From these data we conclude that habituation to psychosocial stress seems to be specific for a given response system. Although HPA responses quickly habituate, the sympathetic nervous system shows rather uniform activation patterns with repeated exposure to psychosocial challenge.

Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best?*

Abstract: ObjectiveTo assess the effects of different doses of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in patients with septic shock.DesignProspective, randomized, open-label study.SettingA 31-bed, medicosurgical intensive care unit of a university hospital.PatientsConvenience

Adrenergic regulation of clock gene expression in mouse liver

Abstract: A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats, whether activation of the sympathetic nervous system entrains clock gene expression in the liver has yet to be understood. To assess sympathetic innervation from the SCN to liver tissue, we investigated whether injection of adrenaline/noradrenaline (epinephrine/norepinephrine) or sympathetic nerve stimulation could induce mPer gene expression in mouse liver. Acute administration of adrenaline or noradrenaline increased mPer1 but not mPer2 expression in the liver of mice in vivo and in hepatic slices in vitro. Electrical stimulation of the sympathetic nerves or adrenaline injection caused an elevation of bioluminescence in the liver area of transgenic mice carrying mPer1 promoter-luciferase. Under a light-dark cycle, destruction of the SCN flattened the daily rhythms of not only mPer1, mPer2, and mBmal1 genes but also noradrenaline content in the liver. Daily injection of adrenaline, administered at a fixed time for 6 days, recovered oscillations of mPer2 and mBmal1 gene expression in the liver of mice with SCN lesion on day 7. Sympathetic nerve denervation by 6-hydroxydopamine flattened the daily rhythm of mPer1 and mPer2 gene expression. Thus, on the basis of the present results, activation of the sympathetic nerves through noradrenaline and/or adrenaline release was a factor controlling the peripheral clock.

Adrenaline in the treatment of anaphylaxis: what is the evidence?

Abstract: Adrenaline (epinephrine) is the recommended first line treatment for patients with anaphylaxis. This review discusses the safety and efficacy of adrenaline in the treatment of anaphylaxis in the light of currently available evidence. A pragmatic approach to use of adrenaline auto-injectors is suggested. Anaphylaxis is the clinical syndrome representing the most severe systemic allergic reactions. Mediator release results in smooth muscle contraction, vasodilation, increased vascular permeability, and activation of vagal pathways, leading to the classic features of anaphylaxis, including urticaria and angioedema, bronchoconstriction and hypotension. Owing to the nature of anaphylaxis there are few controlled clinical trials, and therapeutic recommendations are based on clinical observation and animal models. We look at the current evidence for the use of adrenaline (epinephrine) in anaphylaxis, including its safety and route and timing of administration. We also discuss adrenaline auto-injectors and their role in patients with anaphylaxis. We searched Medline using the key words adrenaline, anaphylaxis, epinephrine, and Epipen, and articles from the authors' personal collection. When necessary we accessed cross references and related articles. Evidence has been graded, where possible (see bmj.com). Only studies with clinical outcomes have been classified (see table on bmj.com); those showing in vitro improvements have not been graded. Anaphylaxis is a severe, life threatening systemic reaction that can affect all ages. The clinical syndrome may involve multiple target organs, including skin, respiratory, gastrointestinal, and cardiovascular systems. The essential underlying mechanism is the presence of biologically active chemical mediators released from mast cells or basophils.1 If this occurs in the context of a classic IgE mediated reaction from previously sensitised mast cells or basophils then anaphylactic reaction is the preferred term. Degranulation of mast cells or basophils may also occur in non-IgE mediated mechanisms, and these reactions are termed anaphylactoid reactions. Clinically it is not possible to distinguish …

Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs.

Abstract: OBJECTIVE Epinephrine is widely used for treatment of life-threatening hypotension, although new vasopressor drugs may merit evaluation. The purpose of this study was to determine the effects of vasopressin vs. epinephrine vs. saline placebo on hemodynamic variables, regional blood flow, and short-term survival in an animal model of uncontrolled hemorrhagic shock and delayed fluid resuscitation. DESIGN Prospective, randomized, laboratory investigation that used a porcine model for measurement of hemodynamic variables and regional abdominal organ blood flow. SETTING University hospital laboratory. SUBJECTS A total of 21 pigs weighing 32 +/- 3 kg. INTERVENTIONS The anesthetized pigs were subjected to a penetrating liver injury, which resulted in a mean +/- sem loss of 40% +/- 5% of estimated whole blood volume within 30 mins and mean arterial pressures of <20 mm Hg. When heart rate declined progressively, pigs randomly received a bolus dose and continuous infusion of either vasopressin (0.4 units/kg and 0.04 units.kg-1.min-1, n = 7), or epinephrine (45 microg/kg and 5 microg.kg(-1).min(-1), n = 7), or an equal volume of saline placebo (n = 7), respectively. At 30 mins after drug administration, all surviving animals were fluid resuscitated while bleeding was surgically controlled. MEASUREMENTS AND MAIN RESULTS Mean +/- sem arterial blood pressure at 2.5 and 10 mins was significantly (p <.001) higher after vasopressin vs. epinephrine vs. saline placebo (82 +/- 14 vs. 23 +/- 4 vs. 11 +/- 3 mm Hg, and 42 +/- 4 vs. 10 +/- 5 vs. 6 +/- 3 mm Hg, respectively). Although portal vein blood flow was temporarily impaired by vasopressin, it was subsequently restored and significantly (p <.01) higher when compared with epinephrine or saline placebo (9 +/- 5 vs. 121 +/- 3 vs. 54 +/- 22 mL/min and 150 +/- 20 vs. 31 +/- 17 vs. 0 +/- 0 mL/min, respectively). Hepatic and renal artery blood flow was significantly higher throughout the study in the vasopressin group; however, no further bleeding was observed. Despite a second bolus dose, all epinephrine- and saline placebo-treated animals died within 15 mins after drug administration. By contrast, seven of seven vasopressin-treated animals survived until fluid replacement, and 60 mins thereafter, without further vasopressor therapy (p <.01). Moreover, blood flow to liver, gut, and kidney returned to normal values in the postshock phase. CONCLUSIONS Vasopressin, but not epinephrine or saline placebo, improved short-term survival in a porcine model of uncontrolled hemorrhagic shock after liver injury when surgical intervention and fluid replacement was delayed.

Differential control of adrenal and sympathetic catecholamine release by alpha(2)-adrenoceptor subtypes

Abstract: In the adrenergic system, release of the neurotransmitter norepinephrine from sympathetic nerves is regulated by presynaptic inhibitory alpha2-adrenoceptors, but it is unknown whether release of epinephrine from the adrenal gland is controlled by a similar short feedback loop. Using gene-targeted mice we demonstrate that two distinct subtypes of alpha2-adrenoceptors control release of catecholamines from sympathetic nerves (alpha 2A) and from the adrenal medulla (alpha 2C). In isolated mouse chromaffin cells, alpha2-receptor activation inhibited the electrically stimulated increase in cell capacitance (a correlate of exocytosis), voltage-activated Ca2+ current, as well as secretion of epinephrine and norepinephrine. The inhibitory effects of alpha2-agonists on cell capacitance, voltage-activated Ca2+ currents, and on catecholamine secretion were completely abolished in chromaffin cells isolated from alpha 2C-receptor-deficient mice. In vivo, deletion of sympathetic or adrenal feedback control led to increased plasma and urine norepinephrine (alpha 2A-knockout) and epinephrine levels (alpha 2C-knockout), respectively. Loss of feedback inhibition was compensated by increased tyrosine hydroxylase activity, as detected by elevated tissue dihydroxyphenylalanine levels. Thus, receptor subtype diversity in the adrenergic system has emerged to selectively control sympathetic and adrenal catecholamine secretion via distinct alpha2-adrenoceptor subtypes. Short-loop feedback inhibition of epinephrine release from the adrenal gland may represent a novel therapeutic target for diseases that arise from enhanced adrenergic stimulation.

On the mechanism by which epinephrine potentiates lidocaine's peripheral nerve block.

Abstract: Background Adding epinephrine to lidocaine solutions for peripheral nerve block potentiates and prolongs the action, but by incompletely understood mechanisms In an effort to discriminate the pharmacokinetic from the pharmacodynamic effects of epinephrine, the authors measured the lidocaine content of peripheral nerve over the course of block produced by 05% lidocaine, with and without epinephrine, and correlated it with the degree of analgesia Methods Percutaneous sciatic nerve blocks were performed in 18 groups of rats (10 in each) with 01 ml of either 05% lidocaine or 05% lidocaine with epinephrine (1:100,000) Over the full course of nerve block, the authors regularly measured analgesia to toe pinch and then rapidly removed nerves to assay intraneural lidocaine content at 2-120 min after injection Results The kinetics of lidocaine's clearance from nerve was composed of a fast-decaying transient superimposed on a very slowly decaying component The effect of epinephrine on the intraneural lidocaine content was to increase the amount of lidocaine in the slow-decaying component by threefold to fourfold, although the total neural content was not altered by epinephrine for the first 10 min after injection Epinephrine prolonged blockade by almost fourfold and enhanced the intensity of peak analgesia, as well as the fraction of rats with complete block, almost throughout the 2-120-min period of behavioral observation Conclusions Adding epinephrine to lidocaine solutions increases the intensity and duration of sciatic nerve block in the rat The early increase in intensity is not matched with an increase in intraneural lidocaine content at these early times, although the prolonged duration of block by epinephrine appears to correspond to an enlarged lidocaine content in nerve at later times, as if a very slowly emptying "effector compartment" received a larger share of the dose The increase in early analgesia without increased lidocaine content may be explained by a pharmacodynamic action of epinephrine that transiently enhances lidocaine's potency, but also by a pharmacokinetic effect that alters the distribution of the same net content of lidocaine within the nerve

Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the rat.

Abstract: Vagal afferent activity modulates mechanical nociceptive threshold and inflammatory mediator-induced hyperalgesia, effects that are mediated by the adrenal medulla. To evaluate the role of epinephrine, the major hormone released from the adrenal medulla, the beta2-adrenergic receptor antagonist ICI 118,551 was chronically administered to vagotomized rats and epinephrine to normal rats. In vagotomized rats, chronic administration of ICI 118,551 markedly attenuated vagotomy-induced enhancement of bradykinin hyperalgesia but had no effect on nociceptive threshold. In normal rats, chronic epinephrine had the opposite effect, enhancing bradykinin hyperalgesia. Like vagotomy-, epinephrine-induced enhancement of hyperalgesia developed slowly, taking 14 days to reach its peak. Vagotomy induced a chronic elevation in plasma concentrations of epinephrine. We suggest that ongoing activity in vagal afferents inhibits the release of epinephrine from the adrenal medulla. Chronically elevated levels of epinephrine, occurring after vagotomy, desensitize peripheral beta2-adrenergic receptors and lead to enhancement of bradykinin hyperalgesia. The ability of prolonged elevated plasma levels of epinephrine to sensitize bradykinin receptors could contribute to chronic generalized pain syndromes.

Urotensin II Acts Centrally to Increase Epinephrine and ACTH Release and Cause Potent Inotropic and Chronotropic Actions

Abstract: Urotensin II is a small peptide whose receptor was recently identified in mammals as the orphan G protein- coupled receptor-14. The reported cardiovascular responses to systemic urotensin II administration are variable, and there is little detailed information on its central cardiovascular actions. We examined the cardiovascular and humoral actions of intracerebroventricular urotensin II (0.02 and 0.2 nmol/kg and vehicle) and intravenous urotensin II (2, 20, and 40 nmol/kg and vehicle) in conscious ewes previously surgically implanted with flow probes and intracerebroventricular guide tubes. Two hours after intracerebroventricular infusion of urotensin II (0.2 nmol/kg over 1 hour; n5), heart rate (5613 beats per minute (bpm)), dF/dt (an index of cardiac contractility; 533 128 L· min 1 ·s 1 ), and cardiac output (3.40.4 L/min) increased significantly compared with vehicle, as did renal, mesenteric, and iliac blood flows and conductances. Plasma epinephrine, adrenocorticotropic hormone, and glucose levels also increased dramatically (753166 pg/mL, 14.33.5 pmol/L, and 7.01.4 mmol/L, respectively). All of these variables remained elevated for up to 4 hours after infusion. In contrast, 1 hour after intravenous urotensin II (40 nmol/kg bolus; n6), a sustained tachycardia (258 bpm) ensued, but cardiac output, cardiac contractility, total peripheral conductance, and plasma glucose levels did not change significantly. In summary, this is the first study to show that urotensin II acts centrally to stimulate sympathoadrenal and pituitary-adrenal pathways, resulting in increased adrenocorticotropic hormone and epinephrine release and potent chronotropic and inotropic actions. In contrast, tachycardia was the only major response to intravenous urotensin II. These findings suggest that urotensin II is a novel stimulator of central pathways that mediate responses to alerting stimuli or stress. (Hypertension. 2003;42:373-379.)

Regulation of Catecholamines by Sustained and Intermittent Hypoxia in Neuroendocrine Cells and Sympathetic Neurons

Abstract: Chronic intermittent hypoxia, a characteristic feature of sleep-disordered breathing, induces hypertension through augmented sympathetic nerve activity and requires the presence of functional carotid body arterial chemore- ceptors. In contrast, chronic sustained hypoxia does not alter blood pressure. We therefore analyzed the biosynthetic pathways of catecholamines in peripheral nervous system structures involved in the pathogenesis of intermittent hypoxia-induced hypertension, namely, carotid bodies, superior cervical ganglia, and adrenal glands. Rats were exposed to either intermittent hypoxia (90 seconds of room air alternating with 90 seconds of 10% O2) or to sustained hypoxia (10% O2) for 1 to 30 days. Dopamine, norepinephrine, epinephrine, dihydroxyphenylacetic acid, and 5-hydroxytyptamine contents were measured by high-performance liquid chromatography. Expression of tyrosine hydroxylase and its phosphorylated forms, dopamine -hydroxylase, phenylethanolamine N-methyltransferase, and GTP cyclohydrolase-1 were determined by Western blot analyses. Both sustained and intermittent hypoxia significantly increased dopamine and norepinephrine content in carotid bodies but not in sympathetic ganglia or adrenal glands. In carotid bodies, both types of hypoxia augmented total levels of tyrosine hydroxylase protein and its phosphorylation on serines 19, 31, 40, as well as levels of GTP cyclohydrolase-1. However, the effects of intermittent hypoxia on catecholaminergic pathways were significantly smaller and delayed than those induced by sustained hypoxia. Thus, attenuated induction of catecholaminergic phenotype by intermittent hypoxia in carotid body may play a role in development of hypertension associated with sleep-disordered breathing. The effects of both types of hypoxia on expression of catecholaminergic enzymes in superior cervical neurons and adrenal glands were transient and small. (Hypertension. 2003;42:1130-1136.)

Sympathoadrenergic mechanisms in reduced hemodynamic stress responses after exercise.

Abstract: BROWNLEY, K. A., A. L. HINDERLITER, S. G. WEST, S. S. GIRDLER, A. SHERWOOD, and K. C. LIGHT. Sympathoadrenergic Mechanisms in Reduced Hemodynamic Stress Responses after Exercise. Med. Sci. Sports Exerc., Vol. 35, No. 6, pp. 978 –986, 2003. Purpose: This study examines the acute effects of moderate aerobic exercise on 1) hemodynamic and sympathetic activity during behavioral stress and 2) -adrenergic receptor responsivity in a biracial sample of 24 sedentary adults. Methods: Before and after exercise, blood pressure (BP), impedance-derived cardiovascular measures, and plasma norepinephrine (NE) and epinephrine (EPI) were assessed during mental arithmetic and active speech tasks, and -adrenergic receptor responsivity was assessed using a standard isoproterenol challenge procedure. Results: After exercise, BP, NE, and EPI responses to stress were reduced (0.0001 P 0.08), preejection period (PEP) was elongated (P 0.0001), and 1- and 2-receptor responsivity (P 0.02) was enhanced. Approximately 65% of the prepost exercise mean arterial pressure response difference could be accounted for by changes in sympathetic factors, with change in NE and PEP being the single best predictors. Conclusions: Reduced BP responses to stress after acute exercise are strongly linked to a decrease in sympathetic drive, as evidenced by reduced NE responses and elongation of the PEP. Coincident with this overall dampening of the hemodynamic response to stress, increases in cardiac and vascular -adrenergic receptor responsivity occur. These findings may have important implications for future translational studies that seek to articulate the mechanisms through which regular aerobic exercise reduces the risks of hypertensive and coronary heart disease. Key Words: BLOOD PRESSURE, STRESS REACTIVITY, SYMPATHETIC NERVOUS SYSTEM, BETA-ADRENERGIC RECEPTOR, CATECHOLAMINE

Use of epinephrine in the treatment of anaphylaxis.

Abstract: Purpose of review This paper is intended to review recent literature that impacts the use of epinephrine in the therapy of anaphylaxis. Recent findings The most important recent finding regarding the administration of epinephrine is that the intramuscular route of administration is the route of choice for the treatment of anaphylaxis, and the lateral aspect of the thigh is the site of choice. In addition, recent research emphasizes the fact that epinephrine is grossly underused in the management of anaphylaxis, which accentuates the need for further education of both physician and patient in this regard. Summary Several major themes have emerged from this review of the recent literature. The finding that the intramuscular route of administration for epinephrine is superior has now been recognized by the guidelines, and because the site of choice has been found to be the lateral aspect of the thigh, the needle used for injection must be long enough to penetrate the vastus lateralis muscle. The reasons for the underutilization of epinephrine in the treatment of anaphylaxis are also discussed. Other important findings include the fact that outdated EpiPens can usually be administered safely, and alternative routes of administration, which may be more acceptable to patients, may be on the horizon as a result of preliminary studies assessing the administration of sublingual epinephrine by wafer. Finally, it is now understood that epinephrine prescription data may be one of our best tools to study the epidemiology and incidence of anaphylactic episodes.

Effects of epinephrine and norepinephrine on hemodynamics, oxidative metabolism, and organ energetics in endotoxemic rats.

Abstract: To determine whether epinephrine increases lactate concentration in sepsis through hypoxia or through a particular thermogenic or metabolic pathway. Prospective, controlled experimental study in rats. Experimental laboratory in a university teaching hospital. Three groups of anesthetized, mechanically ventilated male Wistar rats received an intravenous infusion of 15 mg/kg Escherichia coli O127:B8 endotoxin. Rats were treated after 90 min by epinephrine (n=14), norepinephrine (n=14), or hydroxyethyl starch (n=14). Three groups of six rats served as time-matched control groups and received saline, epinephrine, or norepinephrine from 90 to 180°min. Mean arterial pressure, aortic, renal, mesenteric and femoral blood flow, arterial blood gases, lactate, pyruvate, and nitrate were measured at baseline and 90 and 180 min after endotoxin challenge. At the end of experiments biopsy samples were taken from the liver, heart, muscle, kidney, and small intestine for tissue adenine nucleotide and lactate/pyruvate measurements. Endotoxin induced a decrease in mean arterial pressure and in aortic, mesenteric, and renal blood flow. Plasmatic and tissue lactate increased with a high lactate/pyruvate (L/P) ratio. ATP decreased in liver, kidney, and heart. The ATP/ADP ratio did not change, and phosphocreatinine decreased in all organs. Epinephrine and norepinephrine increased mean arterial pressure to baseline values. Epinephrine increased aortic blood flow while renal blood low decreased with both drugs. Plasmatic lactate increased with a stable L/P ratio with epinephrine and did not change with norepinephrine compared to endotoxin values. Nevertheless epinephrine and norepinephrine when compared to endotoxin values did not change tissue L/P ratios or ATP concentration in muscle, heart, gut, or liver. In kidney both drugs decreased ATP concentration. Our data demonstrate in a rat model of endotoxemia that epinephrine-induced hyperlactatemia is not related to cellular hypoxia.

A practical guide to anaphylaxis.

Abstract: Anaphylaxis is a life-threatening reaction with respiratory, cardiovascular, cutaneous, or gastrointestinal manifestations resulting from exposure to an offending agent, usually a food, insect sting, medication, or physical factor. It causes approximately 1,500 deaths in the United States annually. Occasionally, anaphylaxis can be confused with septic or other forms of shock, asthma, airway foreign body, panic attack, or other entities. Urinary and serum histamine levels and plasma tryptase levels drawn after onset of symptoms may assist in diagnosis. Prompt treatment of anaphylaxis is critical, with subcutaneous or intramuscular epinephrine and intravenous fluids remaining the mainstay of management. Adjunctive measures include airway protection, antihistamines, steroids, and beta agonists. Patients taking beta blockers may require additional measures. Patients should be observed for delayed or protracted anaphylaxis and instructed on how to initiate urgent treatment for future episodes.

Epinephrine-induced pulmonary edema during arthroscopic knee surgery. A case report.

Abstract: In recent reports, use of dilute epinephrine irrigation fluid has been recommended as a safe and effective way to improve visualization in arthroscopic knee and shoulder surgery 1,2. We are not aware of any reports, in the orthopaedic literature, of adverse reactions to epinephrine utilized in this manner. The anesthesiology literature contains a single case report of nearly fatal ventricular tachycardia in a patient undergoing shoulder arthroscopy with use of dilute epinephrine irrigation fluid 3. We present a case of nearly fatal cardiopulmonary collapse during arthroscopy of the knee in which dilute epinephrine irrigation fluid was utilized. The patient was informed that data concerning her case would be submitted for publication. A nineteen-year-old female college athlete underwent arthroscopy for reconstruction of the anterior cruciate ligament and transplantation of a medial meniscal allograft to treat chronic knee pain and instability. The patient had no relevant medical history, did not take any medications, and had a normal preoperative hemoglobin level and hematocrit. She had no family or personal history of cardiac, pulmonary, or endocrine abnormalities and no history of adverse reactions to general anesthesia. She stated that she did not use any over-the-counter supplements or medications. General endotracheal anesthesia with midazolam, sufentanil, and propofol was administered uneventfully in the operating room. Inhalation anesthetics were not utilized, and no other medications were administered prior to induction. A pneumatic tourniquet was not used. After administration of 0.25% bupivacaine with epinephrine (1:100,000) in the subcutaneous tissue, standard anteromedial and anterolateral arthroscopic portals were made. The arthroscopy was performed with utilization of a pressure-controlled pump system set at 40 mm Hg for irrigation with a dilute epinephrine solution, with the concentration of epinephrine calculated to be 0.3 mg/L (1.5 mL of 1:1000 [1 mg/mL] epinephrine mixed into 5 L of saline solution). …

Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2)

Abstract: Ascorbic acid (vitamin C) is a cofactor required in catecholamine synthesis for conversion of dopamine to norepinephrine by dopamine beta-hydroxylase. Mutant mice lacking the plasma membrane ascorbic acid transporter (SVCT2) have severely reduced tissue levels of ascorbic acid and die after birth. We therefore investigated whether these mice might have impaired synthesis of catecholamines. Levels of catecholamines in brain were unaffected by SVCT2 deficiency. In heart, the only evidence for impaired dopamine beta-hydroxylase activity was a twofold increase in tissue dopamine. An influence of the deficiency on tissue catecholamines was most prominent in the adrenals where norepinephrine was decreased by 50% and epinephrine, by 81%. On the ultrastructural level, adrenal chromaffin cells in SVCT2 null mice showed depletion of catecholamine storage vesicles, increased amounts of rough endoplasmic reticulum, signs of apoptosis, and increased glycogen storage. Decreased plasma levels of corticosterone indicated additional effects of the deficiency on adrenal cortical function. These data show that deranged catecholamine system function in SVCT2 null mice is largely restricted to the adrenal medulla and cannot account for the lethality in these animals. The data, however, establish a crucial role for ascorbic acid in adrenal chromaffin cell function.

Diabetes-induced biochemical changes in central and peripheral catecholaminergic systems.

Abstract: A great variety of alterations have been described in the nervous system of diabetic animals. They are named as diabetic neuropathy and affect the brain, spinal cord and peripheral nerves. In diabetic animals, plasma and tissue catecholamine levels have been reported to be increased, decreased or unchanged, and these disparities have been explained by differences in the tissues selected, severity or duration of diabetes. Dopamine, norepinephrine and epinephrine from different tissues were extracted by absorption onto alumina, and measured by high performance liquid chromatography with electrochemical detection. We found that diabetes alters catecholaminergic systems in a highly specific manner. The dopamine content is reduced in the dopaminergic nigrostriatal system only. Norepinephrine is differently altered in several areas of the sympathetic nervous system. It is increased in cardiac ventricles, and decreased in stellate ganglia and the blood serum. However, it is not altered in the central nervous system. Finally, epinephrine is only altered in the adrenal gland where it is increased, and in the serum where it is reduced. Our results suggest that diabetes reduces the activity of the nigrostriatal dopaminergic system. Changes found at the sympathoadrenal level could be explained by reduced norepinephrine and epinephrine synthesis, with increased storage due to a reduced release from synaptic vesicles.

High Spinal Anesthesia for Cardiac SurgeryEffects on β-Adrenergic Receptor Function, Stress Response, and Hemodynamics

Abstract: BackgroundThis double-blind, randomized, controlled trial examined the effect of high-dose intrathecal bupivacaine in combination with general anesthesia on atrial β-adrenergic receptor function, the stress response, and hemodynamics during coronary artery bypass graft surgery.MethodsThirty-eight pa

Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 2): effect of epinephrine.

Abstract: Background The ability of epinephrine to improve the efficacy of epidurally administered drugs is assumed to result from local vasoconstriction and a consequent decrease in drug clearance. However, because drug concentration in the epidural space has never been measured, our understanding of the effect of epinephrine on epidural pharmacokinetics is incomplete. This study was designed to characterize the effect of epinephrine on the epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidurally administered opioids. Methods Morphine plus alfentanil, fentanyl, or sufentanil was administered epidurally with and without epinephrine (1:200,000) to pigs. Opioid concentration was subsequently measured in the epidural space, central venous plasma, and epidural venous plasma, and these data were used to calculate relevant pharmacokinetic parameters. Results The pharmacokinetic effects of epinephrine varied by opioid and by sampling site. For example, in the lumbar epidural space, epinephrine increased the mean residence time of morphine but decreased that of fentanyl and sufentanil. Epinephrine had no effect on the terminal elimination half-life of morphine in the epidural space, but it decreased that of fentanyl and sufentanil. In contrast, in the lumbar intrathecal space, epinephrine had no effect on the pharmacokinetics of alfentanil, fentanyl, or sufentanil, but it increased the area under the concentration-time curve of morphine and decreased its elimination half-life. Conclusions The findings indicate that the effects of epinephrine on the spinal pharmacokinetics of these opioids are complex and often antithetical across compartments and opioids. In addition, the data clearly indicate that the pharmacokinetic effects of epinephrine in spinal "compartments" cannot be predicted from measurements of drug concentration in plasma, as has been assumed for decades.

Role of corticotrophin-releasing hormone in the impairment of counterregulatory responses to hypoglycemia.

Abstract: We have explored the role of individual elements of the hypothalamic pituitary adrenal axis on the pathogenesis of hypoglycemia-associated autonomic failure. Five groups of male Sprague-Dawley rats were used. Control animals had 3 days of sham treatment followed by a hyperinsulinemic/hypoglycemic glucose clamp on day 4. A second group underwent 3 days of antecedent insulin-induced hypoglycemia then a subsequent clamp. Three more groups underwent pretreatment with corticosterone, adrenocorticotrophic hormone (ACTH), or corticotrophin-releasing hormone (CRH) mirroring the glucocorticoid response of the hypoglycemic group. Subsequent counterregulatory responses showed marked differences. CRH- (and insulin-treated) animals showed markedly reduced epinephrine responses (CRH 1,276 ± 404 pg/ml, controls 3,559 ± 563 pg/ml; P P = 0.007 versus controls); corticosterone pretreatment caused a similar but nonsignificant enhancement. The same pattern was seen for norepinephrine. CRH pretreatment also suppressed glucagon responses to hypoglycemia (control 157 ± 21, CRH 68 ± 10 pg/ml; P = 0.004). The addition of a CRH receptor 1 (CRHr1) antagonist to the antecedent CRH reversed the subsequent suppression of epinephrine. These findings suggest that CRH acting via CRHr1 plays an important role in the sympathoadrenal downregulation seen in this rodent model of antecedent hypoglycemia; this action is not mediated via activation of the hypothalamic-pituitary-adrenal axis.

Survival with full neurologic recovery after prolonged cardiopulmonary resuscitation with a combination of vasopressin and epinephrine in pigs.

Abstract: We sought to determine the effects of a combination of vasopressin and epinephrine on neurologic recovery in comparison with epinephrine alone and saline placebo alone in an established porcine model of prolonged cardiopulmonary resuscitation (CPR). After 4 min of cardiac arrest, followed by 3 min o

Interaction of glucagon and epinephrine in the control of hepatic glucose production in the conscious dog

Abstract: Epinephrine increases net hepatic glucose output (NHGO) mainly via increased gluconeogenesis, whereas glucagon increases NHGO mainly via increased glycogenolysis. The aim of the present study was t...