Action Of Epinephrine Research Articles

Adrenaline auto-injector injuries: Practical considerations in emergency management in a tertiary hand surgery unit.

Adrenaline auto-injectors are the first line treatment for anaphylaxis in the community setting. Both anaphylaxis and auto-injector carriage are increasing in prevalence. Adrenaline auto-injector injuries are common and most often involve the hand or digits. Such injuries carry a risk of ischemic necrosis due to profound vasoconstriction, especially if there is undying vascular pathology such as Raynaud's disease. The effects can be readily reversed with local infiltration of phentolamine. A survey was circulated to 40 clinicians working in the emergency and hand surgery departments of a major urban center. Knowledge of adrenaline duration of action and its reversal (agent, dose and location in the hospital) was assessed. All clinicians working within the two departments were eligible for participation. Only 25% of clinicians surveyed were aware of the duration of action of adrenaline. Half were aware of the correct reversal agent and only 20% knew the correct dose. Only one person was aware of phentolamine's location within the hospital. There is relatively poor clinician knowledge surrounding adrenaline reversal and a lack of easily accessible information available about dosing and drug location within the hospital. Given the time dependent nature of adrenaline auto-injector injuries Emergency Departments should consider stocking phentolamine in an emergency drugs fridge within the department along with a dosing guide. This is likely to greatly reduce time from presentation to treatment and thus the chances of digital ischemia progressing to necrosis.

Suppression of lusitropy as a disease mechanism in cardiomyopathies.

In cardiac muscle the action of adrenaline on β1 receptors of heart muscle cells is essential to adjust cardiac output to the body's needs. Adrenergic activation leads to enhanced contractility (inotropy), faster heart rate (chronotropy) and faster relaxation (lusitropy), mainly through activation of protein kinase A (PKA). Efficient enhancement of heart output under stress requires all of these responses to work together. Lusitropy is essential for shortening the heartbeat when heart rate increases. It therefore follows that, if the lusitropic response is not present, heart function under stress will be compromised. Current literature suggests that lusitropy is primarily achieved due to PKA phosphorylation of troponin I (TnI) and phospholamban (PLB). It has been well documented that PKA-induced phosphorylation of TnI releases Ca2+ from troponin C faster and increases the rate of cardiac muscle relaxation, while phosphorylation of PLB increases SERCA activity, speeding up Ca2+ removal from the cytoplasm. In this review we consider the current scientific evidences for the connection between suppression of lusitropy and cardiac dysfunction in the context of mutations in phospholamban and thin filament proteins that are associated with cardiomyopathies. We will discuss what advances have been made into understanding the physiological mechanism of lusitropy due to TnI and PLB phosphorylation and its suppression by mutations and we will evaluate the evidence whether lack of lusitropy is sufficient to cause cardiomyopathy, and under what circumstances, and consider the range of pathologies associated with loss of lusitropy. Finally, we will discuss whether suppressed lusitropy due to mutations in thin filament proteins can be therapeutically restored.

Epinephrine facilitates the growth of T cell lymphoma by altering cell proliferation, apoptosis, and glucose metabolism

In recent years, studies have reported the role of stress-regulatory hormones, including epinephrine, in regulating the progression of a few cancers. However, the tumor-promoting action of epinephrine is not yet investigated in T cell malignancy, a rare and complicated neoplastic disorder. More so, very little is known regarding the implication of epinephrine in the glucose metabolic rewiring in tumor cells. The present investigation showed that epinephrine enhanced the proliferation of T lymphoma cells through up- and down-regulating the expression of PCNA, cyclin D, and p53, respectively. In addition, epinephrine inhibited apoptosis in T lymphoma cells possibly by increasing the level of BCL2 (an anti-apoptotic protein) and decreasing PARP level (a pro-apoptotic protein). Intriguingly, epinephrine is reported to stimulate glycolysis in T lymphoma cells by increasing the expression of crucial glycolysis regulatory molecules, namely HKII and PKM2, in a HIF-1α-dependent manner. Moreover, augmented production of ROS has been observed in T lymphoma cells, which might be a central player in epinephrine-mediated T cell lymphoma growth. Taken together, our study demonstrates that epinephrine might have a significant role in the progression of T cell lymphoma.

РОЛЬ ПАРАТИРЕОИДНОГО ГОРМОНА В ФУНКЦИОНАЛЬНОЙ АКТИВНОСТИ СЕРДЕЧНО-СОСУДИСТОЙ СИСТЕМЫ

A comprehensive comparative study of the contractile ability of aorta and systemic hemodynamic responses has been performed in animals with impaired calcium-phosphorus metabolism, caused by removing the parathyroid glands and under the influence of parathyroid hormone (PTH). In addition, the analysis of its pharmacological mechanism of action has been performed. The results of aorta contractility in vitro studies in control and parathyreoidectomied rats as well as under the influence of PTH physiological concentrations (10-10 M), L-blocker of Са-channels of myocyte membrane - verapamil (10-5 M) and a phosphodiesterase inhibitor - theophylline (10-4 M) demonstrated the possible regulatory impact of PTH and related disorders to reduce the aorta contractility induced by adrenaline (10-5 M) and its relaxation caused by papaverine (10-4 M). Further, in vivo studies revealed that the increase of heart rate (HR) and the decrease of blood pressure (BP) in rats with impaired calcium-phosphorus metabolism is caused by the parathyroidectomy. Special attention should be paid to the fact that we have observed increased reactivity of aortic myocytes in parathyreoidectomied animals in response to the action of adrenaline and papaverine, as well as a sharp increase in adrenoreactivity of heart and blood vessels, thus the increase in HR and BP in response to the usual doses of adrenaline. The clinical significance of this phenomenon is undeniable. The possibility of a sharp increase of BP in patients with PTH-dependent disturbance of calcium-phosphorus metabolism and the potential of development of severe vascular complications (strokes, heart attacks) in the context of emotional and stress influences should be considered in clinically similar conditions.

ODP614 Two cases of Graves Disease Associated Hypokalemic Periodic Paralysis

Abstract Introduction Periodic paralysis (PP) is a rare neuromuscular disorder due to a defect in ion channels in muscle, characterized by episodes of painless muscle weakness or paralysis, which may be precipitated by heavy exercise or high-carbohydrate meals. Hypokalemic PP (HPP) is most common of the periodic paralyses, however is still very rare, with an estimated prevalence of 1 in 100,000. An acquired form of hypokalemic PP can be seen in thyrotoxicosis of any cause. We present 2 cases of HPP due to thyrotoxicosis. Case 1 27 year old Asian male presented to the ED due to sudden onset of acute weakness/near paralysis in lower extremities, with weakness of bilateral upper extremities. He was found to be hypokalemic with a potassium of 2.0 mmol/L (3.5-5.1). At the same time, he was also found to be hyperthyroid with a suppressed TSH of 0.03 uIU/Ml (0.35-5.5) and a free T4 2.2 ng/mL (0.5-1.3), Total T3 225 ng/Dl (70-204), Free T3 5.9 pg/mL (1.5-4.1). TSI antibodies elevated at 1.39 IU/L (<0.10). He was started on potassium supplements and methimazole. At a 3-month follow-up, patient reported no further episodes of weakness or paralysis. Case 2 23 year old White male presented to ED with severe muscle weakness and was found to have hypokalemia of 2 mmol/L (3.5-5.1). On further labs, TSH was undetectable at less than 0.01 uIU/mL (0.35-4.94), Free T4 2.81 ng/dL (0.61-1.82), Total T3 of 451 ng/dL(48-178), TSI antibodies were positive at 178%(</=122%). Nuclear uptake scan confirmed Graves’ disease with radioactive iodine uptake of 58.1% at 4 hours and 70% at 24 hours with homogenous uptake in the entire gland and no evidence of hot or cold nodules. He was started on methimazole and propranolol for tachycardia and palpitations and potassium supplements. Muscle weakness resolved on treatment methimazole. Discussion and conclusion We present two cases of HPP likely caused by Graves’ disease. Both patients presented with hypokalemia and further workup revealed underlying thyrotoxicosis. The exact mechanism behind HPP due to thyrotoxicosis is not well understood. It is proposed that excess thyroid hormone may predispose to paralytic episodes by increasing the susceptibility to the hypokalemic action of epinephrine or insulin. This condition has been most widely reported in Asian populations, in which the incidence is approximately 2% in contrast to non-asian population with incidence of 0.1 to 0.2%, and is more common in men. Treatment of thyrotoxicosis with restoration and maintenance of euthyroid state ceases attacks. To summarize, few case series report the association of HPP with Graves’ disease. These patients usually present acutely with severe muscle weakness or paralysis. In conclusion, in diagnosis of HPP, possibility of thyrotoxicosis should be considered, especially in the absence of family history of PP. Presentation: No date and time listed

Evaluation of disorders of adaptive mechanisms in heart failure by microwave dielectrometry

Differential diagnosis of stress adaptive mechanisms is one of the areas of modern biomedical engineering and the most complex part of the pre-nosological diagnosis of cardiac pathology. One of the manifestations of disadaptation in heart failure is a violation of the mechanisms of realization of the intracellular chain "signal-function". The concept of imbalance in the functioning of the adenylate cyclase system and β-adrenergic receptors of the erythrocytes membrane and cardiomyocytes is considered in the pathogenesis of the heart.
 The study of the dielectric constant (ε՜) of erythrocytes of patients with heart failure was performed using an instrument-recording complex based on microwave dielectrometry of the γ-dispersion region of free water dielectric permittivity. Testing of the β-adrenergic complex of the erythrocyte membrane by specific stimulators, blockers, and modulators was implemented at a fixed frequency of microwave radiofrequency generation (f = 37,7 GHz). Interpretation of the obtained experimental data was that the process of interaction of bioregulators with the biological system is accompanied by an increase or decrease in the relative amount of free water, which leads to a change in the real part of ε՜ complex dielectric constant. This allowed us to visualize the violation of the signal cell system at the molecular level, which manifested itself in the change of integral hydration by ε՜ parameter. It was shown that the change in the dielectric constant of the erythrocyte suspension at risk (patients with hereditary predisposition to dilated and ischemic cardiomyopathy) was significant relative to the dielectric parameters of erythrocyte samples from healthy donors; there was a tendency to block β-adrenergic receptors, with the combined action of adrenaline, PGE2 and cordanum, with Δε՜ = 0,009 ± 0,008 х 10-12 F/m. It should be noted the formation of preconditions for changes in the functioning of the adenylate cyclase system and the development of heart failure in the group at risk, is accompanied by dilated and ischemic cardiomyopathy.
 The effectiveness of the microwave dielectrometry method for the assessment of violations of adaptation mechanisms through the adenylate cyclase system of the erythrocyte membrane in dilated and ischemic forms of cardiomyopathies is shown. The results of the study are the basis for the introduction of the dielectric constant criterion in the general algorithm of pre-nosological diagnosis of heart failure.

High doses of catecholamines activate glucose transport in human adipocytes independently from adrenoceptor stimulation or vanadium addition.

BACKGROUNDWhen combined with vanadium salts, catecholamines strongly activate glucose uptake in rat and mouse adipocytes.AIMTo test whether catecholamines activate glucose transport in human adipocytes.METHODSThe uptake of 2-deoxyglucose (2-DG) was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery. Pharmacological approaches with amine oxidase inhibitors, adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline (also named epinephrine).RESULTSIn human adipocytes, 45-min incubation with 100 µmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin. This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium. Among various natural amines and adrenergic agonists tested, no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake. The effect of the catecholamines was not impaired by pargyline and semicarbazide, contrarily to that of benzylamine or methylamine, which are recognized substrates of semicarbazide-sensitive amine oxidase. Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone, and only the former was potentiated by vanadate. Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake. CONCLUSIONHigh doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes. At submillimolar doses, vanadium did not enhance this catecholamine activation of glucose transport. Consequently, this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.

GTPγS Assay for Measuring Agonist-Induced Desensitization of Two Human Polymorphic Alpha2B-Adrenoceptor Variants.

α2-Adrenergic receptors (ARs) mediate many cellular actions of epinephrine and norepinephrine, including inhibition of their secretion (sympathetic inhibition) from adrenal chromaffin cells. Like many other G protein-coupled receptors (GPCRs), they undergo agonist-dependent phosphorylation and desensitization by GPCR kinases (GRKs), a phenomenon recently shown to play a major role in the sympathetic overdrive that accompanies and aggravates chronic heart failure. A three-glutamic acid deletion polymorphism in the human α2B-AR subtype gene (Glu301-303) causes impaired agonist-promoted receptor phosphorylation and desensitization, resulting in enhanced signaling to inhibition of cholinergic-induced catecholamine secretion in adrenal chromaffin cells. One of the various pharmacological assays that can be used to quantify and quantitatively compare the degrees of agonist-dependent desensitization, i.e., G protein decoupling, of these two polymorphic α2B-AR variants (or of any two GPCRs for that matter) is the guanosine-5'-O-3-thiotriphosphate (GTPγS) assay that can directly quantify heterotrimeric G protein activation.

Hemin attenuates response of primary rat adipocytes to adrenergic stimulation.

Hemin is an activator of heme oxygenase-1 (HO-1), an enzyme catalyzing heme degradation. Up-regulation of HO-1 is observed in response to various pathological conditions. Moreover, pharmacological activation of HO-1 is associated with numerous beneficial effects in the organism. Hemin was shown to exert, among other, anti-diabetic and anti-obesity properties. These effects are strongly linked with adipose tissue. However, the direct influence of hemin on metabolism of the fat cells have not been explored. The present study aimed to determine the short-term effects of hemin on metabolism of the primary rat adipocytes. We focused on processes directly related to lipid accumulation, such as lipogenesis and lipolysis. For this purpose, the isolated cells were subjected for 2 h to 40 µM hemin, and effects of this compound on insulin-stimulated glucose conversion to lipids, lactate release, lipolysis induced by various stimuli, and also on the antilipolytic action of insulin were determined. It was shown that hemin did not affect insulin-induced lipogenesis and lactate release. However, hemin significantly decreased lipolysis stimulated by epinephrine. The inhibitory effect of hemin on epinephrine-induced lipolysis was not abolished in the presence of SnMP, an inhibitor of HO-1, which suggests hemin action irrespective of this enzyme. Similar inhibitory effects on epinephrine-induced lipolysis were observed in the presence of 3 and 12 mM glucose. Moreover, hemin was shown to reduce epinephrine-induced lipolysis also when glucose was replaced by alanine or by succinate. Apart from changes in epinephrine action, it was found that the lipolytic response of the adipocytes to isoproterenol was also diminished by hemin. However, hemin failed to affect lipolysis stimulated by dibutyryl-cAMP (a direct activator of protein kinase A), forskolin (an activator of adenylate cyclase), and also by DPCPX (an adenosine A1 receptor antagonist). Additionally, epinephrine-induced lipolysis was shown to be decreased by insulin, and this effect was deepened in the presence of hemin. These results indicate that short-term exposure of the adipocytes to hemin does not affect processes related to glucose metabolism, such as lipogenesis and lactate release. However, hemin was found to decrease the lipolytic response to adrenergic stimulation, which is associated with reduced lipid release from adipocytes. Moreover, our results indicate that hemin is also capable of diminishing the exaggerated lipolysis, which occurs in the presence of supraphysiological concentrations of glucose.

No additive effect of acetaminophen when co-ingested with caffeine on cycling performance in well-trained young men.

We investigated the effect of caffeine and acetaminophen on power output during a 6-min performance test, peripheral fatigue, and muscle protein kinase A (PKA) substrate phosphorylation. Fourteen men [age (means ± SD): 26 ± 6 yr; V̇o2max: 63.9 ± 5.0 mL·min-1·kg-1] completed four randomized trials with acetaminophen (1,500 mg), caffeine (5 mg·kg body wt-1), combined caffeine and acetaminophen (caffeine + acetaminophen), or placebo. Mean power output during the 6-min performance test (placebo mean: 312 ± 41 W) was higher with caffeine (+5 W; 95% CI: 1 to 9; P = 0.017) and caffeine + acetaminophen (+6 W; 95% CI: 0 to 12; P = 0.049) than placebo, but not with acetaminophen (+1 W; 95% CI: -4 to 7; P = 0.529). Decline in quadriceps maximal isometric voluntary torque immediately after the performance test was lower (treatment × time; P = 0.035) with acetaminophen (-40 N·m; 95% CI: -53 to -30; P < 0.001) and caffeine + acetaminophen (-44 N·m; 95% CI: -58 to -30; P < 0.001) than placebo (-53 N·m; 95% CI: -71 to -39; P < 0.001) but was similar with caffeine (-54 N·m; 95% CI: -69 to -38; P < 0.001). Muscle phosphocreatine content decreased more during the performance test (treatment × time; P = 0.036) with caffeine + acetaminophen (-55 mmol·kg dry wt-1; 95% CI: -65 to -46; P < 0.001) than placebo (-40 mmol·kg dry wt-1; 95% CI: -52 to -24; P < 0.001). Muscle net lactate accumulation was not different from placebo (+85 mmol·kg dry wt-1; 95% CI: 60 to 110; P < 0.001) for any treatment (treatment × time; P = 0.066), being +75 mmol·kg dry wt-1 (95% CI: 51 to 99; P < 0.001) with caffeine, +76 mmol·kg dry wt-1 (95% CI: 58 to 96; P < 0.001) with acetaminophen, and +103 mmol·kg dry wt-1 (95% CI: 89 to 115; P < 0.001) with caffeine + acetaminophen. Decline in muscle ATP and glycogen content and increase in PKA substrate phosphorylation was not different between treatments (treatment × time; P > 0.1). Thus, acetaminophen provides no additive performance enhancing effect to caffeine during 6-min maximal cycling. In addition, change in PKA activity is likely not a major mechanism of performance improvement with caffeine.NEW & NOTEWORTHY Here, we show that acetaminophen does not provide additive performance improvement to caffeine during a 6-min cycling ergometer performance test, and that acetaminophen does not improve performance on its own. Neither substance affects peripheral fatigue, muscle glycolytic energy production, or phosphorylation of muscle proteins of importance for ion handling. In contrast to previous suggestions, increased epinephrine action on muscle cells does not appear to be a major contributor to the performance enhancement with caffeine.

Diagnostics possibilities of erythrocytes analysis by the method of laser interference microscopy.

The morphofunctional state of erythrocytes significantly changes by the onset and progression of various diseases, as well as in critical conditions, injuries, accompanied by severe tissue damage. This leads to a violation of microcirculation and has an effect on hemorheology in general. In connection with this, there is a need for the development of adequate methods for assessing the functional activity of erythrocytes. The aim of the work was to study the possibilities of laser interference microscopy in the analysis of the functional state of erythrocytes. The results allowed us to quantify the state of the phase height and phase diameter of erythrocytes. Analysis of the surface nanostructure gave a qualitative assessment of the functional activity of cells. The following patterns were revealed: the action of adrenaline causes the appearance of echinocytes with an increase in phase height and decrease phase diameter and the appearance of spicules on the surface of cells. The action of cortisol leads to a decrease in the phase height and the phase diameter with the appearance of numerous loosening of the structure of the cell surface. Moreover, the traditional method of analyzing the distribution of erythrocytes in a population by morphology (discocytes, stomatocytes, and degeneratively altered cell forms) did not reveal statistically significant differences. Thus, the results indicate that the interference microscopy method allows a qualitative assessment of the morphofunctional activity of native cells. This increases the information content of the analysis and leads to the objectification of data on the functional capabilities of erythrocytes.

Intervention of Tyrosine Hydroxylase Expression Alters Joint Inflammation and Th17/Treg Imbalance in Collagen-Induced Arthritis.

Neuroendocrine dysregulation has been associated with rheumatoid arthritis (RA). Tyrosine hydroxylase (TH), a rate-limiting enzyme for synthesis of neuroendocrine hormones such as epinephrine, is also expressed in T lymphocytes and regulates balance between helper T (Th) 17 cells and regulatory T (Treg) cells. Herein, we aimed to show that TH expression in joints alleviates joint inflammation and Th17/Treg imbalance in collagen-induced arthritis (CIA), an animal model of RA, and these effects may be implemented by the mechanism of epinephrine action on α1-adrenoreceptor (α1-AR) in T cells. CIA was prepared by intradermal injection of collagen type II in tail base of DBA1/J mice. On the 33rd day post-immunization, lentiviral vectors encoding TH or TH shRNA were injected into ankle joints of CIA mice. Limb inflammation of the mice was assessed beginning from day 21 until day 69 post-immunization by measurement of limb swelling, erythema and rigidity. Th17 and Treg differentiation and function in ankle joints were assessed on day 69 post-immunization by test of the expression of Th17 transcriptional factor ROR-γt and the levels of proinflammatory cytokines interleukin (IL)-17 and IL-22 as well as the expression of Treg transcriptional factor Foxp3 and the levels of antiinflammatory cytokines transforming growth factor (TGF)-β1 and IL-10. T cells were obtained from the spleen of mice that had been immunized with collagen type II 41 day earlier and treated with epinephrine or α1-AR agonist phenylephrine in vitro. Flow cytometry was used to analyze the percentages of CD25-IL-17+ cells and CD25+Foxp3+ cells in CD4+ T cells. TH gene overexpression in ankle joints of CIA mice reduced limb inflammation and Th17-related transcription factor expression and inflammatory cytokine production but increased Treg-related antiinflammatory cytokine production in the joints. In contrast, TH gene silence in ankle joints of CIA mice enhanced limb inflammation and Th17 cell activity but decreased Treg cell function in the joints. Epinephrine upregulated α1-AR expression in T cells derived from CIA mice. Both epinephrine and phenylephrine reduced CIA-induced Th17 transcription factor expression and inflammatory cytokine production but enhanced Treg antiinflammatory cytokine production in vitro. Upregulating TH expression in joints alleviates joint inflammation and Th17/Treg imbalance in CIA at least partially by enhancing epinephrine action on α1-AR in T cells.

Bisphenol A disturbs metabolism of primary rat adipocytes without affecting adipokine secretion

Bisphenol A (BPA) is an ubiquitous synthetic chemical exerting numerous adverse effects. Results of rodent studies show that BPA negatively affects adipose tissue. However, the short-term influence of this compound addressing adipocyte metabolism and adipokine secretion is unknown. In the present study, isolated rat adipocytes were exposed for 2 h to 1 and 10 nM BPA. Insulin-induced glucose conversion to lipids along with glucose transport was significantly increased in the presence of BPA. However, basal glucose conversion to lipids, glucose oxidation, and formation of lipids from acetate were unchanged in adipocytes incubated with BPA. It was also shown that BPA significantly increases lipolytic response of adipocytes to epinephrine. However, lipolysis stimulated by dibutyryl-cAMP (a direct activator of protein kinase A) and the antilipolytic action of insulin were not affected by BPA. Moreover, BPA did not influence leptin and adiponectin secretion from adipocytes. Our new results show that BPA is capable of disturbing processes related to lipid accumulation in isolated rat adipocytes. This is associated with the potentiation of insulin and epinephrine action. The effects of BPA appear already after short-term exposure to low doses of this compound. However, BPA fails to change adipokine secretion.

Epinephrine and glucose regulation of leptin synthesis and secretion in a teleost fish, the tilapia (Oreochromis mossambicus)

Acute stress is regulated through the sympathetic adrenergic axis where catecholamines mobilize energy stores including carbohydrates as a principal element of the endocrine stress response. Leptin is a cytokine critical for regulating energy expenditure in vertebrates and is stimulated by various stressors in fish such as fasting, hyperosmotic challenge, and hypoxia. However, little is known about the regulatory interactions between leptin and the endocrine stress axis in fishes and other ectothermic vertebrates. We evaluated the actions of epinephrine and glucose in regulating leptin A (LepA) in vivo and in vitro in tilapia. Using hepatocyte incubations and a homologous LepA ELISA, we show that LepA synthesis and secretion decline as ambient glucose levels increase (10–25 mM). By contrast, bolus glucose administration in tilapia increases lepa mRNA levels 14-fold at 6 h, suggesting systemic factors regulated by glucose may counteract the direct inhibitory effects of glucose on hepatic lepa mRNA observed in vitro. Epinephrine stimulated glucose and LepA secretion from hepatocytes in a dose-dependent fashion within 15 min but had little effect on lepa mRNA levels. An in vivo injection of epinephrine into tilapia stimulated a rapid rise in blood glucose which was followed by a 4-fold increase in hepatic lepa mRNA levels at 2.5 and 6 h. Plasma LepA was also elevated by 6 h relative to controls. Recombinant tilapia LepA administration in vivo did not have any significant effect on plasma epinephrine levels. The results of this study demonstrate LepA is negatively regulated by rises in extracellular glucose at the level of the hepatocyte but stimulated by hyperglycemia in vivo. Further, epinephrine increases LepA. This, along with previous work demonstrating a hyperglycemic and glycogenolytic effect of LepA in tilapia, suggests that epinephrine may stimulate leptin secretion to augment and fine tune glucose mobilization and homeostasis as part of the integrated, adaptive stress response.

Adrenaline Facilitates Synaptic Transmission by Synchronizing Release of Acetylcholine Quanta from Motor Nerve Endings.

The long history of studies on the effect of catecholamines on synaptic transmission does not answer the main question about the mechanism of their action on quantal release in the neuromuscular junction. Currently, interest in catecholamines has increased not only because of their widespread use in the clinic for the treatment of cardiovascular and pulmonary diseases but also because of recent data on their possible use for the treatment of certain neurodegenerative diseases, muscle weakness and amyotrophic sclerosis. Nevertheless, the effects and mechanisms of catecholamines on acetylcholine release remain unclear. We investigated the action of noradrenaline and adrenaline on the spontaneous and evoked quantal secretion of acetylcholine in the neuromuscular junction of the rat soleus muscle. Noradrenaline (10μM) did not change the spontaneous acetylcholine quantal release, the number of released quanta after nerve stimulation, or the timing of the quantal secretion. However, adrenaline at the same concentration increased spontaneous secretion by 40%, increased evoked acetylcholine quantal release by 62%, and synchronized secretion. These effects differ from those previously described by us in the synapses of the frog cutaneous pectoris muscle and mouse diaphragm. This indicates specificity in catecholamine action that depends on the functional type of muscle and the need to take the targeted type of muscle into account in clinical practice.

Diverse Effects of Noradrenaline and Adrenaline on the Quantal Secretion of Acetylcholine at the Mouse Neuromuscular Junction

Despite the long history of investigations of adrenergic compounds and their biological effects, specific mechanisms of their action in distinct compartments of the motor unit remain obscure. Recent results have suggested that not only skeletal muscles but also the neuromuscular junctions represent important targets for the action of catecholamines. In this paper, we describe the effects of adrenaline and noradrenaline on the frequency of miniature endplate potentials, the quantal content of the evoked endplate potentials and the kinetics of acetylcholine quantal release in the motor nerve endings of the mouse diaphragm. Noradrenaline and adrenaline decreased the frequency of the spontaneous release of acetylcholine quanta. The effect of noradrenaline was prevented by the β adrenoreceptor blocker propranolol, whereas the action of adrenaline was abolished by the α adrenoreceptor antagonist phentolamine.Noradrenaline did not alter the quantal content of endplate potentials, while adrenaline suppressed the evoked release of acetylcholine. Blocking the α adrenoreceptors prevented the decrease in quantal secretion caused by adrenaline. Quantal release became more asynchronous under noradrenaline, as evidenced by a greater dispersion of real synaptic delays; in contrast, adrenaline synchronized the release process.Our data suggest an involvement of α and β adrenoreceptors in the diverse modulation of the frequency of miniature endplate potentials, the quantal content of the evoked endplate potentials and the kinetics of acetylcholine quantal secretion in the mouse neuromuscular junction. Moreover, the adrenoblockers affected both the evoked and spontaneous quantal release of acetylcholine, suggesting the presence of endogenous catecholamines in the vicinity of cholinergic synapses.

Дія L-глутамінової кислоти та піридоксину на імунологічні й гематологічні показники за дії епінефрин-індукованого стресу в щурів

Відомо, що глутамінова кислота (L-Glu) є найпоширенішою й універсальною амінокислотою в організмі. Майже в кожній клітині L-Glu може бути використана як субстрат для синтезу нуклеотидів, NADPH, антиоксидантів та багатьох інших біосинтетичних шляхів, що беруть участь у підтримці клітинної цілісності. Цитопротекторні й антиоксидантні властивості L-Glu можуть бути надзвичайно важливими в умовах окисного стресу. Пошук речовин, які б сприяли більш швидкій адаптації організму в умовах оксидаційного стресу, є особливо актуальним. Мета роботи – дослідити дію L-Glu як окремо, так і в поєднанні з піридоксином (L-Glu+Pyr) за дії епінефриніндукованого стресу в щурів. У наших дослідженнях для пом’якшення дії оксидаційного стресу ми досліджували вплив вищезгаданих речовин на показники Т- і В-клітинного імунітету, загальну кількість еритроцитів і лейкоцитів та фагоцитарну активність нейтрофілів.У результаті дослідження встановлено, що після застосування епінефрину та додаткового введення L-Glu і L-Glu+Pyr змінюється рецепторний апарат Т-лімфоцитів. Виявлено, що внутрішньоочеревинне введення епінефрину першій дослідній групі тварин, що зазнавала дії стресу, без додаткового застосування L-Glu й L-Glu+Pyr зумовило підвищення індексу співвідношення Т-хелперів до цитотоксичних Т-лімфоцитів, відносний уміст яких був вірогідно вищим (р0,05) відносно контролю. Відзначено зниження кількості загальних Т-лімфоцитів і з нульовою (0) та середньою (6–10) щільністю рецепторів (р&lt;0,05), кількості Т-супресорів (р0,05) у тварин першої дослідної групи, порівняно з контрольною групою тварин. Додаткове введення L-Glu і L-Glu+Pyr впливало на Т-клітинну ланку імунітету, а саме на кількість Т-загальних лімфоцитів за допомогою підвищення захисних сил організму, про що може свідчити відсутність змін, порівняно з контролем.

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

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

Differences in the actions of adrenaline and noradrenaline with regard to glucose intolerance in patients with pheochromocytoma

Glucose intolerance is often observed in patients with pheochromocytoma. However, it remains controversial issue that glucose intolerance on pheochromocytoma is caused by impaired insulin secretion and/or by increased insulin resistance. We aimed to reveal the mechanism of glucose intolerance on pheochromocytoma with regard to the type and amount of catecholamines released. We evaluated 12 individuals diagnosed with pheochromocytoma and who underwent surgery to remove it. We examined glycemic parameters before and after surgery and investigated the association between the change of parameters of insulin secretion (homeostasis model assessment of β-cell function (HOMA-β)), insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR)) and that of urinary levels of metanephrine/normetanephrine before and after surgery. Overall, fasting plasma glucose, glycated hemoglobin (HbA1c), HOMA-β, and HOMA-IR were improved significantly after surgery. Regression analysis showed that the improvement in HOMA-β from before to after surgery was significantly positively associated with an improvement in urinary levels of metanephrine from before to after surgery and showed a significantly negative association with improvement in urinary levels of normetanephrine from before to after surgery. The improvement in HOMA-IR from before to after surgery was significantly positively associated with an improvement in urinary levels of normetanephrine from before to after surgery. Our results showed that pheochromocytoma extirpation improved glycemic parameters. Furthermore, the different effects elicited by excess amounts of adrenaline and noradrenaline on glucose intolerance were demonstrated.

Assessment of adrenaline-induced DNA damage in whole blood cells with the comet assay.

Harmful effects of elevated levels of catecholamines are mediated by various mechanisms, including gene transcription and formation of oxidation products. The aim of this study was to see whether the molecular mechanisms underlying the damaging action of adrenaline on DNA are mediated by reactive oxygen species (ROS). To do that, we exposed human whole blood cells to 10 μmol L-1adrenaline or 50 μmol L-1H2O2(used as positive control) that were separately pre-treated or post-treated with 500 μmol L-1of quercetin, a scavenger of free radicals. Quercetin significantly reduced DNA damage in both pre- and post-treatment protocols, which suggests that adrenaline mainly acts via the production of ROS. This mechanism is also supported by gradual lowering of adrenaline and H2O2-induced DNA damage 15, 30, 45, and 60 min after treatment. Our results clearly show that DNA repair mechanisms are rather effective against ROS-mediated DNA damage induced by adrenaline.