Showing papers on "Epinephrine published in 2011"

Do Stress Responses Promote Leukemia Progression? An Animal Study Suggesting a Role for Epinephrine and Prostaglandin-E2 through Reduced NK Activity

Abstract: In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E2 or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition.

Anaphylaxis pathogenesis and treatment.

Abstract: To cite this article: Simons FER. Anaphylaxis pathogenesis and treatment. Allergy 2011; 66 (Suppl. 95):31–34. Abstract Anaphylaxis is a serious allergic reaction that is rapid in onset and sometimes leads to death. Understanding mechanisms, triggers, and patient-specific risk factors for severe or fatal anaphylaxis is critically important. Diagnosis of anaphylaxis is currently based on established clinical criteria. Epinephrine (adrenaline) is the first-line medication for anaphylaxis treatment and delay in injecting it contributes to biphasic reactions, hypoxic-ischemic encephalopathy, and fatality. Here, we focus on four important areas of translational research in anaphylaxis: studies of potential new biomarkers to support the clinical diagnosis of anaphylaxis, laboratory tests to distinguish allergen sensitization from clinical risk of anaphylaxis, the primary role of epinephrine (adrenaline) in anaphylaxis treatment, and strengthening the overall evidence base for anaphylaxis treatment.

Effect of the addition of vasopressin or vasopressin plus nitroglycerin to epinephrine on arterial blood pressure during cardiopulmonary resuscitation in humans

Abstract: Background: Infusion of a vasopressor during cardiopulmonary resuscitation (CPR) in humans increases end decompression (diastolic) arterial blood pressure, and consequently increases vital organ perfusion pressure and survival. Several vasoactive drugs have been tested alone or in combination, but their hemodynamic effects have not been investigated clinically in humans. Study Objective: We tested the hypothesis that epinephrine (1 mg) co-administered with vasopressin (40 IU) ± nitroglycerin (300 μg) results in higher diastolic blood pressure than epinephrine alone. Study Design: A prospective, randomized, double-blinded controlled trial in the prehospital setting. The study included 48 patients with witnessed cardiac arrest. Patients received either epinephrine alone (E alone) or epinephrine plus vasopressin (E+V) or epinephrine plus vasopressin plus nitroglycerin (E+V+N). A femoral arterial catheter was inserted for arterial pressure measurement. Outcome Measures: The primary end point was diastolic blood pressure during CPR, 15 min after the first drug administration (T = 15 min). Results: After exclusions, a total of 44 patients were enrolled. Diastolic blood pressures (mm Hg) at T = 15 min were not statistically different between groups (median [interquartile range]: 20 [10], 15 [6], and 15 [13] for E alone, E+V, and E+V+N, respectively. The rate of return of spontaneous circulation was 63% (n = 10) in the epinephrine group, 43% (n = 6) in the epinephrine plus vasopressin group, and 36% (n = 5) in the triple therapy group (NS). Conclusions: Addition of vasopressin or vasopressin plus nitroglycerin to epinephrine did not increase perfusion blood pressure compared to epinephrine alone in humans in cardiac arrest, suggesting the absence of benefit in using these drug combination(s).

Epinephrine improves 24-hour survival in a swine model of prolonged ventricular fibrillation demonstrating that early intraosseous is superior to delayed intravenous administration.

Abstract: Vasopressors administered IV late during resuscitation efforts fail to improve survival. Intraosseous (IO) access can provide a route for earlier administration. We hypothesized that IO epinephrine after 1 minute of cardiopulmonary resuscitation (CPR) (an "optimal" IO scenario) after 10 minutes of untreated ventricular fibrillation (VF) cardiac arrest would improve outcome in comparison with either IV epinephrine after 8 minutes of CPR (a "realistic" IV scenario) or placebo controls with no epinephrine.

Urethane anesthesia and pituitary-adrenal function in the rat.

Abstract: Urethane anaesthesia produced a prolonged hypersecretion of ACTH as shown by plasma and adrenal corticosterone and adrenal ascorbic acid changes. There was also a concurrent depletion of the adrenaline content of the adrenal gland. Adrenal demedullation did not prevent the steroid changes induced by the anaesthetic. Hyperactivity of the pituitary-adrenal axis for 24 hr in the urethane-anaesthetised rats did not prevent further alteration of steroid levels in response to a stress.

Treatment with epinephrine (adrenaline) in suspected anaphylaxis during anesthesia in Denmark.

Abstract: Background: Literature on the use of epinephrine in the treatment of anaphylaxis during anesthesia is very limited. The objective of this study was to investigate how often epinephrine is used in the treatment of suspected anaphylaxis during anesthesia in Denmark and whether timing of treatment is important. Methods: A retrospective study of 270 patients investigated at the Danish Anaesthesia Allergy Centre after referral due to suspected anaphylaxis during anesthesia was performed. Reactions had been graded by severity: C1, mild reactions; C2, moderate reactions; C3, anaphylactic shock with circulatory instability; C4, cardiac arrest. Use of epinephrine, dosage, route of administration, and time between onset of circulatory instability and epinephrine administration were noted. Results: A total of 122 (45.2%) of referred patients had C3 or C4 reactions; of those, 101 (82.8%) received epinephrine. Route of administration was intravenous in 95 (94%) patients. Median time from onset of reported hypotension to treatment with epinephrine was 10 min (range, 1–70 min). Defining epinephrine treatment less than or equal to 10 min after onset of hypotension as early, and more than 10 min as late, infusion was needed in 12 of 60 patients (20%) treated early versus 12 of 35 patients (34%) treated late (odds ratio, 2.09) (95% confidence interval, 0.81–5.35). Conclusion: Anaphylaxis may be difficult to diagnose during anesthesia, and treatment with epinephrine can be delayed as a consequence. Anaphylaxis should be considered and treated in patients with circulatory instability during anesthesia of no apparent cause who do not respond to the usual treatments.

Epinephrine autoinjector availability among children with food allergy.

Abstract: Epinephrine is the treatment of choice for anaphylaxis Delay in administration of epinephrine is a known risk factor for food allergy reaction-related mortality; however, individuals with food allergy may not have epinephrine readily available This study was designed to determine the percent of food-allergic children that have an epinephrine autoinjector readily available and factors associated with epinephrine autoinjector carriage rates Parents completed a questionnaire on food allergy and food allergy preparedness Staff recorded whether an epinephrine autoinjector and medical alert bracelet was immediately available in clinic Parental responses from 63 food-allergic children were included Fifty-nine percent (37/63) had an epinephrine autoinjector present in the clinic, and 79% (50/63) reported receiving training in epinephrine autoinjector use There was no correlation between epinephrine autoinjector presence in the clinic and parental report of having an epinephrine autoinjector available at all times (phi = 021) Epinephrine autoinjector training was associated with increased odds of having an epinephrine autoinjector immediately available (adjusted odds ratio, 874 [169, 4504]) Fewer school aged children (≥5 years old) reportedly had their epinephrine autoinjector with them when eating lunch (25% [8/32] versus 42% [13/31]; p = 0002) or snacks (28% [9/32] versus 37% [13/31]; p = 0005) when compared with those <5 years old Many children do not have their epinephrine autoinjectors readily available despite parental report Epinephrine autoinjector training improved the odds of having an epinephrine autoinjector readily available Continued patient education on the importance of having an epinephrine autoinjector easily accessible, especially when eating, is important

Tetrodotoxin-Bupivacaine-Epinephrine Combinations for Prolonged Local Anesthesia

Abstract: Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX) with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL) solutions, with or without epinephrine 5 µg/mL (1:200,000) in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001) or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001). Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia.

Marked increases in plasma catecholamine concentrations precede hypotension and bradycardia caused by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in conscious rats.

Abstract: Plasma noradrenaline and adrenaline responses to 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a selective putative 5-HT1A receptor agonist, have been studied in conscious, freely moving rats. Intravenously administered 8-OH-DPAT caused dose-related and sustained increases in plasma noradrenaline (2-fold) and adrenaline (11-fold) concentrations. Neither metergoline pretreatment (0.5 mg kg-1 i.v.) nor splanchnicectomy had any effect on the noradrenaline and adrenaline elevation caused by 8-OH-DPAT (250 micrograms kg-1 i.v.). The catecholamine responses peaked early but were still present during nadirs in blood pressure and heart rate. The discrepancy between plasma catecholamine and cardiovascular changes raises further questions about the mechanism of action of 8-OH-DPAT and supports other evidence suggesting a role for vagus stimulation in the cardiovascular effects caused by this drug.

Dose-dependent hemodynamic and metabolic effects of vasoactive medications in normotensive, anesthetized neonatal piglets.

Abstract: The developmentally regulated hemodynamic effects of vasoactive medications have not been well characterized. We used traditional and near-infrared spectroscopy monitoring technologies and investigated the changes in heart rate, blood pressure, common carotid artery (CCA) blood flow (BF), cerebral, renal, intestinal, and muscle regional tissue O2 saturation, and acid-base and electrolyte status in response to escalating doses of vasoactive medications in normotensive anesthetized neonatal piglets. We used regional tissue O2 saturation and CCA BF as surrogates of organ and systemic BF, respectively, and controlled minute ventilation and oxygenation. Low to medium doses of dopamine, epinephrine, dobutamine, and norepinephrine increased blood pressure and systemic and regional BF in a drug-specific manner, whereas milrinone exerted minimal effects. At higher doses, dopamine, epinephrine, and norepinephrine but not dobutamine decreased systemic, renal, intestinal, and muscle BF, while cerebral BF remained unchanged. Epinephrine induced significant increases in muscle BF and serum glucose and lactate concentrations. The findings reveal novel drug- and dose-specific differences in the hemodynamic response to escalating doses of vasoactive medications in the neonatal cardiovascular system and provide information for future clinical studies investigating the use of vasoactive medications for the treatment of neonatal cardiovascular compromise.

Adrenergic Mediation of Hypoglycemia-Associated Autonomic Failure

Abstract: OBJECTIVE We tested the hypothesis that adrenergic activation, cholinergic activation, or both, mediate the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans. RESEARCH DESIGN AND METHODS Seventeen healthy adults were studied on 2 consecutive days on three occasions. Day 1 involved hyperinsulinemic euglycemic (90 mg/dL × 1 h), then hypoglycemic (54 mg/dL × 2 h) clamps, in the morning and afternoon on all three occasions with 1 ) saline infusion, 2 ) adrenergic blockade with the nonselective α-adrenergic and β-adrenergic antagonists phentolamine and propranolol, or 3 ) adrenergic blockade plus cholinergic blockade with the muscarinic cholinergic antagonist atropine in random sequence. Day 2 involved similar morning euglycemic and hypoglycemic clamps, with saline infusion, on all three occasions. RESULTS Compared with the responses to hypoglycemia during saline infusion on day 1, the plasma epinephrine and norepinephrine responses to hypoglycemia were reduced on day 2 (351 ± 13 vs. 214 ± 22 pg/mL for epinephrine and 252 ± 4 vs. 226 ± 7 pg/mL for norepinephrine during the last hour; both P < 0.0001). However, the plasma epinephrine and norepinephrine responses to hypoglycemia were not reduced on day 2 when adrenergic or adrenergic plus cholinergic blockade was produced during hypoglycemia on day 1. CONCLUSIONS Adrenergic blockade prevents the effect of hypoglycemia to reduce the plasma catecholamine responses to subsequent hypoglycemia. Thus, adrenergic activation mediates the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans.

Inverted Takotsubo cardiomyopathy following accidental intravenous administration of epinephrine in a young woman

Abstract: The Takotsubo cardiomyopathy (TTC), also called ‘‘stress cardiomyopathy’’, ‘‘transient apical ballooning’’ or ‘‘broken heart syndrome’’, is a disorder associated with transient left-ventricular dysfunction in absence of substantial coronary artery disease. The clinical presentation is similar to an acute coronary syndrome with acute chest pain and dyspnea accompanied by ECG changes, such as T wave inversions or mild ST segment elevations, minimal elevation of cardiac enzymes, and typical wall-motion abnormalities. Generally, left-ventricular function and ECG changes normalize within several days or weeks. TTC is predominantly seen in postmenopausal women following severe emotional or physical stress. A 39-year-old female had a history of Crohn’s disease, lastly treated with adalimumab and corticosteroids. A few weeks after discontinuing corticosteroid therapy, she complained about fatigue and ostealgia. To exclude secondary adrenal insufficiency, an adrenocorticotropic hormone (ACTH) stimulation test was performed with normal result. Accidentally, 1 mg of epinephrine was injected intravenously thereby. Immediately, the patient developed tachycardia and nausea for several minutes. Not until 60 min later, she suffered from stenocardia and acute dyspnea. Emergency echocardiography showed a severely reduced left-ventricular function, and the patient was transferred to our hospital. On admission, the patient presented with ongoing pulmonary edema and bilateral pleural effusion. She was transferred to intensive care unit and treated with diuretics and continuous positive airway pressure ventilation. Electrocardiogram showed minimal ST elevations in the inferolateral leads and inverted T waves in I and aVL, but the QT interval was normal. The cardiac biomarkers were mildly elevated with a peak Troponin T of 0.39 lg/l, but creatine kinase levels remained in normal range. Transthoracic echocardiography verified a highly reduced leftventricular function (ejection fraction 0.35) and showed midventricular wall-motion abnormalities. Subsequent leftheart catheterization ruled out coronary artery disease and demonstrated severe midventricular akinesis with hypercontractile apical segments (Fig. 1). Magnetic resonance tomography confirmed the pattern of midventricular ballooning and ruled out myocarditis or myocardial necrosis (Fig. 2). Laboratory work-up showed cortisol, folliclestimulating hormone (FSH), luteinizing hormone (LH), and estradiol in normal range. Under treatment with b-blockers, ACE-inhibitors, and diuretics the patient recovered within the following days. After 6 days, the patient was discharged with mild exertional dyspnea and still highly reduced left-ventricular function (EF 0.35). Ten days later, the patient presented free of symptoms, and echocardiography demonstrated a complete recovery of the left-ventricular function. TTC is an increasingly recognized syndrome with transient left-ventricular dysfunction, but the pathophysiology remains unclear. An excessive release of catecholamines seems to play a pivotal role [1]. This is supported by the case above that furthermore demonstrates the early course of TTC with an onset of symptoms 1 h after T. Härle (&) K. Kronberg A. Elsässer Department of Cardiology, Heart Center, Klinikum Oldenburg gGmbH, Rahel-Straus-Str. 10, 26133 Oldenburg, Germany e-mail: t.haerle@gmx.de

Modulation of β-Adrenergic Receptors in the Ventromedial Hypothalamus Influences Counterregulatory Responses to Hypoglycemia

Abstract: OBJECTIVE Norepinephrine is locally released into the ventromedial hypothalamus (VMH), a key brain glucose-sensing region in the response to hypoglycemia. As a result, this neurotransmitter may play a role in modulating counterregulatory responses. This study examines whether norepinephrine acts to promote glucose counterregulation via specific VMH β-adrenergic receptors (BAR). RESEARCH DESIGN AND METHODS Awake male Sprague-Dawley rats received, via implanted guide cannulae, bilateral VMH microinjections of 1 ) artificial extracellular fluid, 2 ) B2AR agonist, or 3 ) B2AR antagonist. Subsequently, a hyperinsulinemic-hypoglycemic clamp study was performed. The same protocol was also used to assess the effect of VMH delivery of a selective B1AR or B3AR antagonist. RESULTS Despite similar insulin and glucose concentrations during the clamp, activation of B2AR in the VMH significantly lowered by 32% ( P < 0.01), whereas VMH B2AR blockade raised by 27% exogenous glucose requirements during hypoglycemia ( P < 0.05) compared with the control study. These changes were associated with alternations in counterregulatory hormone release. Epinephrine responses throughout hypoglycemia were significantly increased by 50% when the B2AR agonist was delivered to the VMH ( P < 0.01) and suppressed by 32% with the B2AR antagonist ( P < 0.05). The glucagon response was also increased by B2AR activation by 63% ( P < 0.01). Neither blockade of VMH B1AR nor B3AR suppressed counterregulatory responses to hypoglycemia. Indeed, the B1AR antagonist increased rather than decreased epinephrine release ( P < 0.05). CONCLUSIONS Local catecholamine release into the VMH enhances counterregulatory responses to hypoglycemia via stimulation of B2AR. These observations suggest that B2AR agonists might have therapeutic benefit in diabetic patients with defective glucose counterregulation.

Simultaneous Parasympathetic and Sympathetic Activation Reveals Altered Autonomic Control of Heart Rate, Vascular Tension, and Epinephrine Release in Anesthetized Hypertensive Rats

Abstract: Sympathetic hyperactivity and parasympathetic insufficiency characterize blood pressure control in genetic hypertension, but is difficult to demonstrate experimentally in anesthetized rats. Here we present a pharmacological approach to activate sympathetic and parasympathetic nerves simultaneously, and identify their contribution. Anaesthetized normotensive (WKY) and spontaneously hypertensive rats (SHR) were injected i.v. with 4-aminopyridine (4-AP), a voltage-sensitive K+ channel inhibitor. Blood pressure was recorded through a femoral artery catheter, cardiac output and heart rate (HR) through an ascending aorta flow probe. Total peripheral vascular resistance (TPVR) was calculated. 4-AP induced an immediate, atropine- and hexamethonium-sensitive bradycardia in WKY, and in strains, a subsequent, sustained tachycardia, and norepinephrine but not epinephrine release. The tachycardia was eliminated by reserpine, nadolol or right vagal nerve stimulation, but not adrenalectomy, scopolamine or hexamethonium. 4-AP-induced, atropine-sensitive bradycardia was observed in reserpinized or nadolol-treated SHR, where atropine also increased the late HR-response. 4-AP increased TPVR, transiently in WKY but sustained in SHR. Yohimbine but not phentolamine prevented TPVR down-regulation in WKY. Reserpine, phentolamine and prazosin eliminated the late vasoconstriction in SHR. Plasma epinephrine overflow increased in nadolol-treated SHR. Conclusions: 4-AP activated parasympathetic ganglion transmission and peripheral, sympathetic nerve norepinephrine release. The sympathetic component dominated the HR-response to 4-AP in SHR. α2-adrenceptor-dependent vasodilatation opposed norepinephrine-induced α1-adrenergic vasoconstriction in WKY, but not in SHR. A βAR-activated, probably vagal afferent mechanism, hampered adrenal epinephrine secretion in SHR. Thus, 4-AP exposed mechanisms, which contribute to hypertension, and may allow identification of the factors responsible.

Role of catecholamine-induced activation of vagal afferent pathways in regulation of sympathoadrenal system activity: negative feedback loop of stress response.

Abstract: Stress-induced activation of the hypothalamic-pituitary-adrenal axis and sympathoadrenal system is precisely regulated by well-documented negative feedback mechanisms. These include direct negative feedback effect of glucocorticoids on brain structures regulating the hypothalamic-pituitary-adrenal axis activity. However, since the blood-brain-barrier is impermeable to circulating catecholamines, the role of circulating epinephrine and norepinephrine in feedback regulation of the sympathoadrenal system activity is unclear. Here we show that vagal innervation of the adrenal medulla combined with the presence of β-adrenergic receptors on vagal sensory neurons, the epinephrine-induced activation of vagal afferents, and increased plasma epinephrine levels following subdiaphragmatic vagotomy indicate that sensory fibers of the vagus nerve participate in the monitoring of plasma and tissue catecholamine concentrations. Furthermore, it shows that signaling transmitted by vagal afferents regulates sympathoadrenal system activity at the level of the brain. Therefore, we propose that vagal sensory fibers, directly activated by epinephrine and norepinephrine, represent the afferent limb of a negative feedback loop that adjusts the activity of the sympathoadrenal system according to actual plasma and tissue catecholamine levels.

Randomized, Blinded Comparison of Epinephrine and Vasopressin for Treatment of Naturally Occurring Cardiopulmonary Arrest in Dogs

Abstract: Background Administration of epinephrine during CPR is recommended for treatment of cardiopulmonary arrest (CPA) in dogs. Administration of epinephrine during CPR might be associated with deleterious adverse effects. Vasopressin has been studied for use in CPR as an alternative. Hypothesis That administration of vasopressin instead of epinephrine with standard CPR techniques will result in improved outcome. Animals Seventy-seven client-owned dogs identified in the ER/ICU with CPA were eligible for inclusion. Methods Randomized, prospective clinical study. Dogs were randomized to receive epinephrine (0.01–0.02mg/kg) or vasopressin (0.5–1 U/kg) in a blinded fashion. Attending veterinarians were asked to adhere to standardized CPR protocol for the 1st 6 minutes of CPR, during which time doses of the study drug were administered at 3-minute intervals. Results A total of 60 dogs completed this study with 31 receiving epinephrine and 29 receiving vasopressin. Overall rate of return of spontaneous circulation (ROSC) was 60% (36/60), 32% (19/60) of dogs survived to 20 minutes, 18% (11/60) survived to 1 hour. No difference was seen in rates of ROSC between the 2 groups (P = .20). Dogs receiving epinephrine were more likely to survive to 1 hour (odds ratio 5.86; 95% CI: 1.19–28.95) than those receiving vasopressin (P = .027). Conclusions and Clinical Importance ROSC was similar in dogs receiving epinephrine or vasopressin. In this study, a survival advantage at 1 hour was seen in those animals receiving epinephrine. No advantage of routine use of vasopressin over epinephrine was detected. Further studies are required to examine subgroups of dogs that might benefit from specific interventions.

Pulmonary vasoconstrictive and bronchoconstrictive responses to anaphylaxis are weakened via β2-adrenoceptor activation by endogenous epinephrine in anesthetized rats.

Abstract: Background: Patients treated with propranolol, a nonselective β-adrenoceptor antagonist, have increased incidence and severity of anaphylaxis We determined whether β 1 - or β 2 -adrenoceptor antagonist modulated pulmonary vasoconstriction and bronchoconstriction in rat anaphylactic hypotension Methods: Anesthetized ovalbumin-sensitized male Sprague-Dawley rats were randomly allocated to the following pretreatment groups (n = 7/group): (1) sensitized control (nonpretreatment), (2) propranolol, (3) the selective β 2 -adrenoceptor antagonist ICI 118,551, (4) the selective β 1 -adrenoceptor antagonist atenolol, and (5) adrenalectomy Shock was induced by an intravenous injection of the antigen Mean arterial pressure, pulmonary arterial pressure, left atrial pressure, central venous pressure, portal venous pressure, airway pressure, and aortic blood flow were continuously measured Results: In either sensitized control or atenolol-pretreated rats, mean arterial pressure and aortic blood flow decreased substantially, whereas pulmonary arterial pressure and airway pressure did not increase soon after antigen injection In contrast, in rats pretreated with either propranolol, ICI 118,551, or adrenalectomy, airway pressure significantly increased by 14 cm H 2 O, and pulmonary arterial pressure by 75 mmHg after antigen injection At 25 min after antigen injection, the plasma concentration of epinephrine increased 14-fold in the sensitized rats except for the adrenalectomy group Portal venous pressure after antigen injection increased by 16 mmHg similarly in all sensitized rats All of the sensitized control group and two of the atenolol group were alive for 60 min after antigen injection, whereas all rats of the propranolol, ICI 118,551, and adrenalectomy groups died within 50 min after antigen injection Conclusions: The pulmonary vasoconstrictive and bronchoconstrictive responses to systemic anaphylaxis were weakened via β 2 -adrenoceptor activation by epinephrine endogenously released from the adrenal gland in the anesthetized Sprague-Dawley rats

Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis

Abstract: Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8 weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin α2C-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca2+/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload.

Transpulmonary Pyruvate kinetics

Abstract: Shuttling of intermediary metabolites, such as pyruvate, contributes to the dynamic energy and biosynthetic needs of tissues. Tracer kinetic studies offer a powerful tool to measure the metabolism of substrates like pyruvate that are simultaneously taken up from and released into the circulation by organs. However, we understood that during each circulatory passage, the entire cardiac output transits the pulmonary circulation. Therefore, we examined the transpulmonary pyruvate kinetics in an anesthetized rat model during an unstimulated (Con), lactate clamp (LC), and epinephrine infusion (Epi) conditions using a primed-continuous infusion of [U-¹³C]pyruvate. Compared with Con and Epi stimulation, LC significantly increased mixed central venous ([v]) and arterial ([a]) pyruvate concentrations (P < 0.05). We hypothesized that the lungs, specifically the pulmonary capillary beds are sites of simultaneous production and removal of pyruvate and contributes significantly to whole body carbohydrate intermediary metabolism. Transpulmonary net pyruvate balances were positive during all three conditions, indicating net pyruvate uptake. Net balance was significantly greater during epinephrine stimulation compared with the unstimulated control (P < 0.05). Tracer-measured pyruvate fractional extraction averaged 42.8 ± 5.8% for all three conditions and was significantly higher during epinephrine stimulation (P < 0.05) than during either Con or LC conditions, that did not differ from each other. Pyruvate total release (tracer measured uptake - net balance) was significantly higher during epinephrine stimulation (400 ± 100 μg/min) vs. Con (30 ± 20 μg/min) (P < 0.05). These data are interpreted to mean that significant pyruvate extraction occurs during circulatory transport across lung parenchyma. The extent of pulmonary parenchymal pyruvate extraction predicts high expression of monocarboxylate (lactate/pyruvate) transporters (MCTs) in the tissue. Western blot analysis of whole lung homogenates detected three isoforms, MCT1, MCT2, and MCT4. We conclude that a major site of circulating pyruvate extraction resides with the lungs and that during times of elevated circulating lactate, pyruvate, or epinephrine stimulation, pyruvate extraction is increased.

Adrenergic Signaling in Human Oral Keratinocytes and Wound Repair

Abstract: Catecholamines are present in saliva, but their influence on oral epithelium is not understood. Because psychological stress increases salivary catecholamines and impairs oral mucosal wound healing, we sought to determine if epithelial adrenergic signaling could link these two findings. We found that cultured human oral keratinocytes (HOK) express the α(2B)- and β(2)-adrenergic receptors (ARs). Exposure of HOK to either epinephrine or the β-AR agonist, isoproterenol, reduced migratory speed and decreased in vitro scratch wound healing. Incubation with the β-AR antagonist timolol reversed the catecholamine-induced effects, indicating that the observed response is mediated by β-AR. Epinephrine treatment decreased phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38; these decreases were also reversed with timolol. Cultured HOK express enzymes of the epinephrine synthetic pathway, and generate epinephrine. These findings demonstrate that stress-induced elevations of salivary catecholamines signal through MAPK pathways, and result in impaired oral keratinocyte migration required for healing.

Stress-induced epinephrine levels compromise murine dermal fibroblast activity through β-adrenoceptors

Abstract: Stress-induced catecholamine impairs the formation of granulation tissue acting directly in fibroblast activity; however, the mechanism by which high levels of catecholamines alter the granulation tissue formation is still unclear. Thus, the aim of this study was to investigate how high levels of epinephrine compromise the activity of murine dermal fibroblasts. Dermal fibroblasts isolated from the skin of neonatal Swiss mice were preincubated with α- or β-adrenoceptor antagonists. Thereafter, cells were exposed to physiologically elevated levels of epinephrine or epinephrine plus α- or β-adrenoceptor antagonists, and fibroblast activity was evaluated. The blockade of β1- and β2-adrenoceptors reversed the increase in fibroblast proliferation, ERK 1/2 phosphorylation, myofibroblastic differentiation and the reduction of collagen deposition induced by epinephrine. In addition, the blockade of β3-adrenoceptors reversed the increase in fibroblast proliferation and nitric oxide synthesis as well as the reduction of fibroblast migration, AKT phosphorylation and active matrix metalloproteinase-2 expression induced by epinephrine. However, the blockade of α1- and α2-adrenoceptors did not alter the effects of epinephrine on the activity of murine dermal fibroblasts. In conclusion, high levels of epinephrine directly compromise the activity of neonatal mouse skin fibroblasts through the activation of β1-, β2- and β3-adrenoceptors, but not through α1- and α2-adrenoceptors.

Anaphylaxis: recognition and management.

Abstract: Anaphylaxis is a severe, life-threatening, systemic allergic reaction that is almost always unanticipated and may lead to death by airway obstruction or vascular collapse. Anaphylaxis occurs as the result of an allergen response, usually immunoglobulin E-mediated, which leads to mast cell and basophil activation and a combination of dermatologic, respiratory, cardiovascular, gastrointestinal, and neurologic symptoms. Dermatologic and respiratory symptoms are most common, occurring in 90 and 70 percent of episodes, respectively. The three most common triggers are food, insect stings, and medications. The diagnosis of anaphylaxis is typically made when symptoms occur within one hour of exposure to a specific antigen. Confirmatory testing using serum histamine and tryptase levels is difficult, because blood samples must be drawn with strict time considerations. Allergen skin testing and in vitro assay for serum immunoglobulin E of specific allergens do not reliably predict who will develop anaphylaxis. Administration of intramuscular epinephrine at the onset of anaphylaxis, before respiratory failure or cardiovascular compromise, is essential. Histamine H(1) receptor antagonists and corticosteroids may be useful adjuncts. All patients at risk of recurrent anaphylaxis should be educated about the appropriate use of prescription epinephrine autoinjectors.

Apical ballooning syndrome following perioperative anaphylaxis is likely related to high doses of epinephrine.

Abstract: Apical ballooning syndrome, a reversible left ventricle dysfunction, has been reported following anaphylaxis and, during this clinical circumstance, is seemingly linked to the use of either low or high doses of epinephrine. We report a severe succinylcholine-induced IgE-mediated anaphylaxis in a 65-year-old woman, in whom the diagnosis of apical ballooning syndrome following anaphylaxis was established. As a thorough description of the clinical features and resuscitative measures could be obtained, we discuss the reasons for apical ballooning syndrome occurrence and highlight the fact that optimal care management of anaphylaxis should include a progressive titration of epinephrine.

The role of the adrenal glands and of α‐ and β‐adrenergic receptors in bronchodilatation of guinea‐pig lungs in vivo

Abstract: Adrenaline, aminophylline, isoprenaline, noradrenaline, papaverine and phenylephrine exerted non-specific bronchodilator effects in guinea-pig lungs in vivo. The descending order of bronchodilator potency was isoprenaline > adrenaline > noradrenaline > phenylephrine. These agents also exerted a bronchoconstrictor effect, the descending order of bronchoconstrictor potency being phenylephrine > noradrenaline > adrenaline > isoprenaline. Bronchodilator activity could be antagonized by either α- or β–adrenergic receptor antagonists. The bronchodilator action of aminophylline, papaverine, phenylephrine and noradrenaline was partly mediated via the adrenal gland.