We have assessed the potential for myocardial ischaemia during laparoscopic cholecystectomy in 16 otherwise healthy patients. Continuous ambulatory ECG monitoring was commenced 12 h before operation and continued for 24 h after operation. The neuroendocrine stress response was assessed by measuring plasma concentrations of adrenaline and noradrenaline, human growth hormone, cortisol, renin and aldosterone, and prolactin, at specified times during surgery. Acute ST segment changes in the ECG occurred in only two patients. These episodes were independent of creation of pneumoperitoneum and changes in position. Acute intraoperative increases in MAP were noted during insufflation of carbon dioxide and reverse Trendelenburg positioning (P < 0.05). A four-fold increase in plasma concentrations of renin and aldosterone was noted after pneumoperitoneum and reverse Trendelenburg positioning (P>> 0.05). There was a linear correlation between changes in plasma renin and aldosterone concentrations and MAP (r = 0.97 and r = 0.85, respectively). Prolactin concentrations increased four-fold after induction of anaesthesia. Cortisol, HGH, adrenaline and noradrenaline concentrations increased after deflation of the pneumoperitoneum. The time profile-concentration changes of increased MAP and renin-aldosterone suggests a cause-effect relationship. Increased intra-abdominal pressure and reverse Trendelenburg positioning may reduce cardiac output and renal blood flow. The early increase in prolactin concentration was probably secondary to the effect of the opioid fentanyl.

BACKGROUND

Endoscopic polypectomy is a standard method of treatment of gastrointestinal polyps, but is associated with substantial risk of complications. The most common is hemorrhage, the rate of which varied between 0.3%, and 6%. Various prophylactic techniques have been used to reduce this incidence. The aim of this study was to establish whether the prophylactic injection of adrenaline-saline solution reduces the risk of postpolypectomy bleeding in colonoscopic polypectomy.

METHODS

Between May 2000 and June 2002, patients with colorectal polyps of size>> or =1 cm were randomized to receive submucosal epinephrine injection (group A) or no injection (group B). The polypectomies were carried out using the conventional method. In group A, epinephrine (1/10,000) was injected into the stalk or base of the polyp. The patients were observed for complications.

RESULTS

A total of 69 patients with 100 polyps were enrolled in this study: n = 50 in group A, and n = 50 in group B, according to randomization. There were a total of nine episodes of postpolypectomy hemorrhage, one in the epinephrine group and eight in the control group (1/50 vs 8/50, p < 0.05). The bleeding correlated with the size of the polyps and the diameter of the stalks.

CONCLUSIONS

Epinephrine injection prior to colonoscopic polypectomy is effective in preventing bleeding.

The effects of conditioned fear on gross activity, heart rate, PQ interval, noradrenaline and adrenaline were studied in freely moving rats. Subcutaneous (s.c.) injections of atropine methyl nitrate (0.5 mg/kg) during rest resulted in a significant shortening of the PQ interval, indicating that the PQ interval can be used as a measure of vagal activity. Conditioned fear was induced by 10-min forced exposure to a cage in which the rat had previously experienced footshocks (5 x 0.5 mA x 3 s). In non-shocked controls, an increase in gross activity was found and a pronounced tachycardia, without changes in PQ interval. Conditioned fear rats showed immobility behaviour, associated with a less pronounced tachycardia and an increase in PQ interval. Noradrenaline was similarly increased in both groups, whereas adrenaline was increased in conditioned fear rats only. To further evaluate the role of the vagus, rats were exposed to conditioned fear after pre-treatment with atropine methyl nitrate (0.5 mg/kg, s.c.). Again, immobility was observed with a concomitant tachycardia, but without an increase in PQ interval. These results indicate that the autonomic nervous system is differentially involved in heart rate regulation in conditioned fear rats and in non-shocked controls: in non-shocked controls a predominant sympathetic nervous system activation results in an increase in heart rate, whereas in conditioned fear rats the tachycardiac response is attenuated by a simultaneous activation of sympathetic nervous system and parasympathetic nervous system.

Psychostimulants, such as cocaine and amphetamines, act primarily through the monoamine neurotransmitters dopamine (DA), norepinephrine, and serotonin. Although stimulant addiction research has largely focused on DA, medication development efforts targeting the dopaminergic system have thus far been unsuccessful, leading to alternative strategies aimed at abating stimulant abuse. Noradrenergic compounds have shown promise in altering the behavioral effects of stimulants in rodents, nonhuman primates, and humans. In this review, we discuss the contribution of each adrenergic receptor (AR) subtype (α1, α2, and β) to five stimulant-induced behaviors relevant to addiction: locomotor activity, conditioned place preference, anxiety, discrimination, and self-administration. AR manipulation has diverse effects on these behaviors; each subtype profoundly influences outcomes in some paradigms but is inconsequential in others. The functional neuroanatomy and intracellular signaling mechanisms underlying the impact of AR activation/blockade on these behaviors remain largely unknown, presenting a new frontier for research on psychostimulant-AR interactions.

The most important causative factor for anaphylaxis in mastocytosis are insect stings. The purpose of this review is to analyse the available data concerning prevalence, diagnosis, safety and effectiveness of venom immunotherapy (VIT) in mastocytosis patients. If data were unclear, authors were contacted personally for further information. Quality of evidence (A: high, B: moderate, C: low and D: very low) and strength of recommendation (strong 1 and weak 2) concerning VIT in mastocytosis patients are assessed according to the Grading of Recommendations Assessment, Development and Evaluation and are marked in square brackets. Results of VIT were described in 117 patients to date. The mean rate of side-effects during treatment in studies published so far is 23.9% (7.6% requiring adrenaline) with an overall protection rate of 72%. Based on the review we conclude that (1) mastocytosis patients have a high risk of severe sting reactions in particular to yellow jacket, (2) VIT could be suggested [2] in mastocytosis, (3) probably should be done life long [2], (4) VIT in mastocytosis is accompanied by a higher frequency of side-effects, so (5) special precautions should be taken into account notably during the built up phase of the therapy [2], (6) VIT is able to reduce systemic reactions, but to a lesser extent compared to the general insect venom allergic population [2], so (7) patients should be warned that the efficacy of VIT might be less than optimal and they should continue carrying two adrenaline auto injectors [2].

Skin sparing mastectomy (SSM) followed by immediate breast reconstruction (IBR) is not only oncologically safe but provides also significant benefits both cosmetically and functionally. The superiority of this technique can only be fully established, however, by developing a framework for minimising complications. The present study seeks to elucidate the key factors affecting outcome.

METHODS

Data for all skin sparing mastectomies with immediate autologous and implant based reconstructions, performed in a three year period (2006-2008) was retrospectively collated. Complications were classified into major and minor. Patients were excluded who had flap loss due to vascular complications.

RESULTS

The total number analysed was 151. 17.2% had major complications, 23% had minor and 61% had no complications. The Wise and the "tennis" incision had significantly higher rates of wound dehiscence when compared with the periareolar incision (p = 0.025, p = 0.098). There was no significant difference between diathermy or blade dissection techniques, or the use of subcutaneous adrenaline infiltration. Increasing BMI was associated with increased skin flap necrosis and wound dehiscence, and an excised breast mass of greater than 750 g and a sternal notch to nipple length of greater than 26 cm are associated as well with increased flap-related complications (p = 0.0002, p = 0.0049).

CONCLUSIONS

Factors such as Wise pattern and tennis racquet incision, BMI and breast mass and sternal notch to nipple length adversely affect skin sparing mastectomy flap morbidity. These factors should be factored in to patient selection and operative planning especially for obese and large breasted women undergoing skin sparing mastectomy with immediate breast reconstruction.

Adrenal phaechromocytomas and extra-adrenal sympathetic paragangliomas (PPGLs) are rare neuroendocrine tumours, characterised by production of the catecholamines: noradrenaline, adrenaline and dopamine. Tumoural secretion of catecholamines determines their clinical presentation which is highly variable among patients. Up to 10-15% of patients present entirely asymptomatic and in 5% of all adrenal incidentalomas a PPGL is found. Therefore, prompt diagnosis of PPGL remains a challenge for every clinician. Early consideration of the presence of a PPGL is of utmost importance, because missing the diagnosis can be devastating due to potential lethal cardiovascular complications of disease. First step in diagnosis is proper biochemical analysis to confirm or refute the presence of excess production of catecholamines or their metabolites. Biochemical testing is not only indicated in symptomatic patients but also in asymptomatic patients with adrenal incidentalomas or identified genetic predispositions. Measurements of metanephrines in plasma or urine offer the best diagnostic performance and are the tests of first choice. Paying attention to sampling conditions, patient preparation and use of interfering medications is important, as these factors can largely influence test results. When initial test results are inconclusive, additional tests can be performed, such as the clonidine suppression test. Test results can also be used for estimation of tumour size or prediction of tumour location and underlying genotype. Furthermore, tumoural production of 3-methoxytyramine is associated with presence of an underlying SDHB mutation and may be a biomarker of malignancy.

Schizophrenia is a debilitating mental illness which involves three groups of symptoms, i.e., positive, negative and cognitive, and has major public health implications. According to various sources, it affects up to 1% of the population. The pathomechanism of schizophrenia is not fully understood and current antipsychotics are characterized by severe limitations. Firstly, these treatments are efficient for about half of patients only. Secondly, they ameliorate mainly positive symptoms (e.g., hallucinations and thought disorders which are the core of the disease) but negative (e.g., flat affect and social withdrawal) and cognitive (e.g., learning and attention disorders) symptoms remain untreated. Thirdly, they involve severe neurological and metabolic side effects and may lead to sexual dysfunction or agranulocytosis (clozapine). It is generally agreed that the interactions of antipsychotics with various neurotransmitter receptors are responsible for their effects to treat schizophrenia symptoms. In particular, several G protein-coupled receptors (GPCRs), mainly dopamine, serotonin and adrenaline receptors, are traditional molecular targets for antipsychotics. Comprehensive research on GPCRs resulted in the exploration of novel important signaling mechanisms of GPCRs which are crucial for drug discovery: intentionally non-selective multi-target compounds, allosteric modulators, functionally selective compounds and receptor oligomerization. In this review, we cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling.

Adrenaline, which is secreted from the adrenal medulla during stress, is considered to be involved in the control of inflammation and immune responses. Therefore, we studied the effects of adrenaline on the plasma levels of one of the major pro-inflammatory cytokines, interleukin-6 (IL-6). Here we describe that in rats, SC administration of adrenaline induces a dose-dependent increase in plasma IL-6 concentrations, reaching its maximum after 2 h. In addition, intravenous (IV) infusion of adrenaline in a dose resulting in circulating adrenaline concentrations similar to those observed during stress, enhanced heart rate and increased plasma IL-6 concentrations. The increase in plasma IL-6 in response to adrenaline given by subcutaneous (SC) route and by IV infusion could be blocked by the beta-adrenergic receptor antagonist l-propranolol but not by d-propranolol. Based on these data we conclude that under physiological conditions circulating adrenaline may be involved in the control of IL-6 production, and thereby may modulate inflammatory responses.

In fish, the catecholamine hormones adrenaline and noradrenaline are released into the circulation, from chromaffin cells, during numerous 'stressful' situations. The physiological and biochemical actions of these hormones (the efferent adrenergic response) have been the focus of numerous investigations over the past several decades. However, until recently, few studies have examined aspects involved in controlling/modulating catecholamine storage and release in fish. This review provides a detailed account of the afferent limb of the adrenergic response in fish, from the biosynthesis of catecholamines to the exocytotic release of these hormones from the chromaffin cells. The emphasis is on three particular topics: (1) catecholamine biosynthesis and storage within the chromaffin cells including the different types of chromaffin cells and their varying arrangement amongst species; (2) situations eliciting the secretion of catecholamines (e.g. hypoxia, hypercapnia, chasing); (3) cholinergic and non-cholinergic (i.e. serotonin, adrenocorticotropic hormone, angiotensin, adenosine) control of catecholamine secretion. As such, this review will demonstrate that the control of catecholamine storage and release in fish chromaffin cells is a complex processes involving regulation via numerous hormones, neurotransmitters and second messenger systems.

BACKGROUND

Excessive sympathoadrenal activation in critical illness contributes directly to organ damage, and high concentrations of catecholamines damage the vascular endothelium. This study investigated associations between potential drivers of sympathoadrenal activation, circulating catecholamines and biomarkers of endothelial damage and outcome in ST segment elevation myocardial infarction (STEMI)-patients, hypothesizing that the catecholamine surge would reflect shock degree and correlate with biomarkers of endothelial damage.

METHODS

This was a prospective study of 678 consecutive STEMI-patients admitted to a single high-volume invasive heart centre for primary percutaneous coronary intervention (pPCI) from September 2006 to July 2008. Blood samples were drawn immediately before pPCI. Plasma adrenaline, noradrenaline, syndecan-1 and thrombomodulin were measured retrospectively with complete data in 571 patients (84%). Median follow-up time was 28 (IQR 23 to 34) months. Follow-up was 99.7% complete. Outcomes were all-cause and cardiovascular mortality, re-myocardial infarction and admission due to heart failure.

RESULTS

Circulating noradrenaline and adrenaline correlated weakly but independently with syndecan-1 (rho = 0.15 and rho = 0.13, both P <0.01) and thrombomodulin (rho = 0.11 and rho = 0.17, both P <0.01), biomarkers of glycocalyx and endothelial cell damage, respectively. Considering biomarkers, patients with shock pre-pPCI had higher adrenaline and syndecan-1 and patients admitted to ICU post-pPCI had higher syndecan-1 (all P <0.05), and in the patients with shock (n = 51) catecholamines correlated strongly with thrombomodulin and syndecan-1 (rho = 0.31 to 0.42, all P <0.05). During follow-up, 78 (14%) patients died (37 cardiovascular deaths) and 65 (11%) were admitted with heart failure. By multivariate Cox proportional hazards analyses, one quartile higher plasma adrenaline was weakly but independently associated with both 30-day and long term mortality and heart failure (30-day all-cause mortality hazard ratio (95% CI) 1.39 (1.01 to 1.92), P = 0.046; 30-day heart failure 1.65 (1.17 to 2.34), P = 0.005; and long-term cardiovascular mortality 1.49 (1.08 to 2.04), P = 0.014). Furthermore, one quartile higher syndecan-1 was also weakly but independently associated with long-term all cause mortality (1.26 (1.02 to 1.57), P = 0.034).

CONCLUSIONS

In STEMI patients treated with pPCI, catecholamines correlated weakly with biomarkers of endothelial damage, with the strongest correlations and highest adrenaline and syndecan-1 levels in patients with shock. Furthermore, adrenaline and syndecan-1 were weakly but independently associated with mortality and heart failure. Acute myocardial infarction appears to cause significant endothelial cell and glycocalyx injury and a parallel increase in circulating catecholamines.

OBJECTIVE

To assess whether exercise induced suppression of heart rate variability in the low frequency domain (0.06-0.15 Hz) is related to the increase in circulating catecholamine concentrations.

METHODS

Randomised crossover trial of three exercise tests characterised by different workloads. Pharmacological simulation of exercise-induced changes in vagal and sympathetic activity.

METHODS

Six healthy men with a mean age of 31.2 (SD 3.0) years.

METHODS

Three different workloads of steady state cycling ergometry: control state without cycling, cycling at a target heart rate of 100 beats/min, and cycling at a target heart rate of 150 beats/min. Intravenous infusion of atropine (target heart rate 100 beats/min) followed by the additional infusion of adrenaline and noradrenaline.

METHODS

Fast Fourier analysis of heart rate variability; blood pressure; and venous plasma concentrations of lactate, adrenaline, and noradrenaline.

RESULTS

During the control exercise period there were no changes in the assessed variables compared with the preceding resting period. During exercise at a heart rate of 100 beats/min systolic blood pressure increased and heart rate variability decreased. During exercise at a heart rate of 150 beats/min systolic blood pressure and lactate, adrenaline, and noradrenaline concentrations increased. In addition, low frequency (LF) was lower than during exercise at 100 beats/min, high frequency (HF 0.15-0.80 Hz) resembled that during exercise at 100 beats/min, and diastolic blood pressure was reduced. Infusion of atropine caused no changes in blood pressure or plasma concentrations of lactate, adrenaline, and noradrenaline and decreased heart rate variability. The additional infusion of adrenaline and noradrenaline completely suppressed heart rate variability and increased blood pressure.

CONCLUSIONS

The reduction in LF and HF during exercise at a heart rate of 100 beats/min, which is not characterised by increased plasma catecholamine concentrations, and during atropine infusion suggests that heart rate variability in the supine state is largely influenced by vagal activity. The additional reduction in LF during exercise at 150 beats/min and during catecholamine infusion may reflect a negative feedback of circulating catecholamines on the sympathetic control of heart rate.

Glycogen synthase (GS) catalyses the incorporation of uridine diphosphate-glucose into glycogen in skeletal muscle. In concert with the glucose transport step, GS activity is thought to be rate-limiting in the disposal of glucose as muscle glycogen. Glycogen synthase is regulated by both allosteric factors (primarily glucose 6-phosphate) and covalent modification by reversible phosphorylation and dephosphorylation leading to inactivation and activation of GS, respectively. Exercise activates both stimulatory and inhibitory regulators of GS and it is thought that the resultant activity of GS during exercise depends on the relative strength of opposing signals. However, the mechanisms by which exercise regulates GS activity are not fully understood. Glycogen breakdown, the GM-protein phosphatase 1 complex and possibly cellular relocalization of GS may be considered important factors involved in the stimulation of GS activity during exercise, while adenosine monophosphate-activated protein kinase and plasma adrenaline (via protein kinase A) can be considered as essential for the exercise-induced inhibitory signals to GS.

To study the effects of standardized mental stress (arithmetic and the Stroop color word test) on plasma coagulation and fibrinolysis, blood samples were obtained before, during, and after 20 minutes of mental stress from 10 healthy, non-smoking young males aged 22 to 30 years. Reactions were compared with those observed during physical exercise and infusion of adrenaline. Both von Willebrand factor antigen and factor VIII coagulant activity increased significantly in response to mental stress (95 +/- 28 vs 123 +/- 56%; p less than 0.05 and 125 +/- 54 vs 217 +/- 170%; p less than 0.05, respectively). There was also a significant increase of factor VII coagulant activity (86 +/- 31 vs 108 +/- 51%; p less than 0.05). Furthermore, mental stress caused an activation of the fibrinolytic system with an elevation of tissue plasminogen activator activity and tissue plasminogen activator antigen (0.80 +/- 0.48 vs 1.23 +/- 0.96 IU/ml; p = 0.076 and 4.38 +/- 1.87 vs 5.78 +/- 2.58 IU/ml; p less than 0.01). Fibrinogen concentration increased during stress (1.95 +/- 0.29 vs 2.11 +/- 0.27 g/l; p less than 0.05). Similar but more pronounced responses were observed during exercise and adrenaline infusion. Parallel to the increases in coagulation and fibrinolytic factors there were significant increases in heart rate, and systolic and diastolic blood pressure. It is concluded that mental stress has significant effects on plasma coagulation and fibrinolysis, and that it could thus affect important risk factors for cardiovascular disease.

A problem in assessing animal welfare is that collecting data in itself may be stressful to the animals. Therefore, noninvasive methods for collecting data have to be devised and tested. A first step in investigating saliva cortisol, urinary cortisol, and urinary catecholamine as noninvasive indicators of canine well-being is the validation of these hormonal measures as alternatives for those in plasma. Using a model of insulin (0.2 U/kg)-induced hypoglycemia, we report on stress-induced responses in saliva cortisol, urinary cortisol, and urinary catacholamines relative to cortisol and catecholamine responses in plasma. Hypoglycemia in six dogs induced significant (P < 0.05) increases in plasma cortisol and adrenaline but not noradrenaline. Saliva cortisol responses expressed as net area under the response curve correlated significantly with plasma cortisol responses (r>> 0.92). Saliva cortisol levels measured 7 to 12% of plasma cortisol concentrations. Cortisol/creatinine rations in urine were significantly higher when voided after insulin administeration, compared to when voided after saline treatment. Insulin-induced increments in cortisol/ creatinine ratios were nonsignificant when urine samples were assayed after dichloromethane extraction. Although urinary adrenaline/creatinine (A/C) ratios were significantly correlated with maximum plasma adrenaline values after insulin administration, A/C ratios did not differ significantly between insulin and saline treatment. The present experiment provides strong support for using saliva sampling and urine collection as noninvasive methods to establish stress-induced cortisol responses. For measuring acute plasma adrenaline responses, measuring A/C ratios may not be a valid alternative.

Fat is an extremely important substrate for muscle contraction, both at rest and during exercise. Triglycerides (TGs), stored in adipose tissue and within muscle fibres, are considered to be the main source of the free fatty acids (FFAs) oxidised during exercise. It is still unclear, however, how the use of these substrates is regulated during exercise. The regulation seems to be multifactorial and includes: (i) dietary and nutritional status; (ii) hormonal milieu; (iii) exercise mode, intensity and duration; and (iv) training status. On the other hand, the mechanism for FFA transport from its storage as triglycerides in adipose tissue and muscle to its place of utilisation in heart, skeletal muscle, kidney and liver is more clearly understood. It has been determined that the plasma FFA turnover rate is sufficiently rapid to account for most of the fat metabolised during low intensity exercise (25 to 40% VO2max). However, an exercise intensity of 65% VO2max results in a slight decrease in the amount of plasma FFA uptake by muscle tissue. Other studies have found that during prolonged exercise, muscle TGs become the predominant source of energy obtained from fat. Furthermore, it is widely documented that endurance activities increase the energy utilisation from fat while sparing carbohydrate sources. For example, during exercise on a cycle ergometer, nonplasma FFAs and plasma FFAs contribute 40%, and carbohydrates 60%, of the total calculated amount of energy expenditure before exercise and vice versa after exercise (60% nonplasma and plasma FFAs and 40% carbohydrates). Although it was many years before it was fully demonstrated, fat is now known to be transported in the blood as FFA bound to the protein carrier albumin. The mobilisation of FFA is primarily a function of sympathetic nervous activity directed towards the adipocytes, or the 'fat pad'. This nervous activity can be direct or may be an effect of circulating catecholamines such as adrenaline (epinephrine). This article summarises the role of fat metabolism during exercise.

Adrenaline is a fundamental circulating hormone for bodily responses to internal and external stressors. Chromaffin cells of the adrenal medulla (AM) represent the main neuroendocrine adrenergic component and are believed to differentiate from neural crest cells. We demonstrate that large numbers of chromaffin cells arise from peripheral glial stem cells, termed Schwann cell precursors (SCPs). SCPs migrate along the visceral motor nerve to the vicinity of the forming adrenal gland, where they detach from the nerve and form postsynaptic neuroendocrine chromaffin cells. An intricate molecular logic drives two sequential phases of gene expression, one unique for a distinct transient cellular state and another for cell type specification. Subsequently, these programs down-regulate SCP-gene and up-regulate chromaffin cell-gene networks. The AM forms through limited cell expansion and requires the recruitment of numerous SCPs. Thus, peripheral nerves serve as a stem cell niche for neuroendocrine system development.

BACKGROUND

Continued or recurrent bleeding after endoscopic treatment for bleeding ulcer is a major adverse prognostic factor. Identification of such ulcers may allow for alternate treatments.

OBJECTIVE

To determine factors predicting treatment failure with combined adrenaline injection and heater probe thermocoagulation.

METHODS

Consecutive patients with bleeding peptic ulcers who received endoscopic therapy between January 1995 and March 1998 were studied. Data on clinical presentation, endoscopic findings, and treatment outcomes were collected prospectively. Multiple logistic regression analysis was used to identify independent risk factors for treatment failure.

RESULTS

During the study period, 3386 patients were admitted with bleeding peptic ulcers: 1144 (796 men, 348 women) with a mean age of 62.5 (SD 17.6) years required endoscopic treatment. There were 666 duodenal ulcers (58.2%), 425 gastric ulcers (37.2%), and 53 anastomotic ulcers (4.6%). Initial haemostasis was successful in 1128 patients (98.6%). Among them, 94 (8.2%) rebled in a median time of 48 hours (range 3-480). Overall failure rate was 9.6%. Mortality rate was 5% (57/1144). Multiple logistic regression analysis revealed that hypotension (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.40-3.48), haemoglobin level less that 10 g/dl (OR 1.87, 95% CI 1.18-2.96), fresh blood in the stomach (OR 2.15, 95% CI 1.40-3.31), ulcer with active bleeding (OR 1.65, 95% CI 1.07-2.56), and large ulcers (OR 1.80, 95% CI 1.15-2.83) were independent factors predicting rebleeding.

CONCLUSIONS

Larger ulcers with severe bleeding at presentation predict failure of endoscopic therapy.

Neurons immunocytochemically labeled with the adrenaline-synthesizing enzyme phenylethanolamine N-methyltransferase were mapped in the brain of rat pretreated with colchicine. In medulla, immunoreactive cells in the C1 and C2 groups were distributed in a more complex manner than described previously. C1 neurons were identified in the reticular formation of ventrolateral medulla and were organized into two populations: (1) a cell column extending throughout the ventrolateral medulla, and lying ventral to the ambiguus cell group and either dorsal to the precerebellar lateral reticular nucleus or interposed between its two subdivisions; (2) a rostral cell cluster forming medial to the column at caudal levels and enlarging close to and in parallel with the ventral surface of the rostral ventrolateral medulla. A large proportion of cells and processes of the rostral cell group were oriented medially and ventromedially. processes of C1 neurons were traced dorsally toward the nucleus tractus solitarii, dorsal motor nucleus, and principal tegmental adrenergic bundle, ventrally toward the ventral surface, laterally toward the trigeminal complex, and medially or ventromedially toward the raphe. C2 neurons were located in the dorsomedial medulla and were subdivided into four distinct populations: (1) neurons in the rostral nucleus paragigantocellularis pars dorsalis (NGCd) and medial longitudinal fasciculus (MLF) were contiguous and similar in size and shape, with their long diameters oriented horizontally or diagonally along several axes; (2) neurons of the periventricular gray were located in a cytoarchitecturally undefined area dorsal to the MLF; these cells were ovoid, smaller, and organized more compactly than those in the NGCd-MLF; (3) a cell group in the rostromedial nucleus tractus solitarii (NTS) and dorsal motor nucleus overflowed caudally into the intermediate thirds of both structures; and (4) a parvicellular group in the NTS was compactly organized in the dorsolateral NTS and was best developed at the level of the area postrema. Processes of C2 neurons were generally directed sagitally, medially, and laterally along the ventricular floor and ventrally or medially toward the raphe; other fibers arborized and terminated within the NTS and dorsal motor nucleus. In the medulla, local processes were traced from C1 and C2 neurons directly into respective ventral and dorsal parts of the medullary raphe and surrounding intraparenchymal blood vessels. Fibers from these neurons were also followed, respectively, onto the ventral subpial surface and the floor of the fourth ventricle.(ABSTRACT TRUNCATED AT 400 WORDS)

Pretreatment of lymphocytes (16 hr, 37 degrees C) with adrenaline at final concentrations of 10(-7) to 10(-9) M, followed by removal of the drug, increased natural killer (NK) cell activity vs K562 leukemic cells in a 4-hr 51Cr-release assay. The most efficient concentration of adrenaline was 10(-8) M; mean increase of NK activity over base-line activity for all donors examined was 30%. However, the individual response to adrenaline pretreatment was variable; in some donors, the effect was equal to maximal interferon (IFN) stimulation. Effects of adrenaline pretreatment were consistently reduced to base-line activity by co-incubation with the nonselective beta-adrenoceptor antagonist propranolol at 100-fold higher concentrations. The enhancing effect of adrenaline (10(-8) M) pretreatment was also observed after 1-hr pretreatment; this effect was prevented by simultaneous incubation with propranolol but was not affected by dex-propranolol. Direct addition of adrenaline to lymphocyte/target cell mixtures was inhibitory at 10(-6) M adrenaline concentration. The inhibitory effect of adrenaline in this assay was again completely prevented by propranolol and unaffected by dex-propranolol. The observed stimulatory effect of adrenaline pretreatment could not be ascribed to IFN production. Data presented indicate a dual effect of adrenaline on NK cell activity and suggest both a positive and a negative beta-adrenoceptor-mediated regulation of human NK cells.

The administration in vivo of either adrenaline or glucagon alone resulted in increases of about 2-fold in the amounts of active, non-phosphorylated, pyruvate dehydrogenase in the livers of fed male or female rats, whereas when administered together increases of about 4-fold were obtained. Ca2+-dependent increases in the amount of active enzyme of up to about 5-fold could be achieved in isolated rat liver mitochondria by incubating them with increasing extramitochondrial [Ca2+]; from this, two conditions of Ca loading were chosen which caused increases in active enzyme similar to those with the hormone treatments given above. The increases in enzyme activity owing to these Ca loads persisted through the 're-isolation' of mitochondria and their incubation in Na+-free KCl-based media containing EGTA. Differences from values obtained with unloaded controls could be diminished by adding Na+ ions to cause the egress of Ca2+ from the mitochondria, or enough extramitochondrial Ca2+ to saturate the enzyme in its Ca2+-dependent activation; the effects of Na+ could be blocked by diltiazem, an inhibitor of mitochondrial Na+/Ca2+ exchange. The re-isolated, Ca-preloaded, mitochondria also exhibited enhanced activities of 2-oxoglutarate dehydrogenase when assayed at non-saturating [2-oxoglutarate] by two different methods; effects of Na+, Ca2+ or diltiazem on the persistent activations of this enzyme were similar to those for pyruvate dehydrogenase. Na+ caused a marked depletion, which could be blocked by diltiazem, of the 45Ca content of re-isolated mitochondria which had pre-loaded with Ca, containing 45Ca, to the same degrees as above. The activities of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase in incubated liver mitochondria prepared from rats subjected to the hormone treatments given above were found to behave in a very similar manner to those exhibited in the re-isolated, Ca-preloaded, mitochondria. It is concluded that these hormones each bring about the activations of these rat liver enzymes by causing increases in intramitochondrial [Ca2+], and that their effects, as such, are additive.

OBJECTIVE

Adrenaline inhibits insulin secretion through activation of alpha(2)-adrenoceptors (ARs). These receptors are linked to pertussis toxin-sensitive G proteins. Agonist binding leads to inhibition of adenylyl cyclase, inhibition of Ca(2+) channels and activation of K(+) channels. Recently, three distinct subtypes of alpha(2)-AR were described, alpha(2A)-AR, alpha(2B)-AR and alpha(2C)-AR. At present, it is unknown which of these alpha(2)-AR subtype(s) may regulate insulin secretion. We used mice deficient in alpha(2)-ARs to analyze the coupling and role of individual alpha(2)-AR subtypes in insulin-secreting beta cells.

METHODS

The inhibitory effect of adrenaline on insulin secretion was measured in freshly isolated and cultured wild type (wt) and alpha(2)-AR knockout (KO) mouse islets in order to examine the receptor subtypes which mediate adrenaline-induced inhibition of insulin secretion. Adenylyl cyclase activity was measured in isolated cultured islets. Membrane potential was measured using the amphotericin B permeabilized patch clamp method in isolated and cultured single islet cells.

RESULTS

In wt, alpha(2A)- and alpha(2C)-AR KO mouse islets, adrenaline, 1 microM/L, inhibited secretion by 83, 80 and 100% respectively. In contrast, in alpha(2A/2C)-AR double KO mouse islets, adrenaline had no effect on stimulated secretion indicating that both alpha(2A)-AR and alpha(2C)-AR, but not alpha(2B)-AR, are functionally expressed in mouse islets. Surprisingly, glucose (16.7 mM/L)-induced secretion in the presence of 1 microM/L forskolin was greatly impaired in alpha(2A)-AR KO islets. However, when cAMP levels were increased further by the combination of forskolin (5 microM/L) and 3-isobutyl-1-methylxanthine (100 microM/L), secretion was stimulated 2.7-fold (8.5-fold in wt islets). Adrenaline lowered the concentration of cAMP in wt and alpha(2C)-AR KO mouse islets by 74%. Adrenaline also hyperpolarized wt and alpha(2C)-AR KO beta cells. In contrast, adrenaline did not inhibit adenylyl cyclase in islets of alpha(2A)-AR KO mice, nor did it hyperpolarize alpha(2A)-AR KO beta cells.

CONCLUSIONS

Adrenaline inhibits insulin release through alpha(2A)- and alpha(2C)-ARs via distinct intracellular signaling pathways.

Acute muscular exercise induces an increased neutrophil count concomitant with recruitment of natural killer (NK), B and T cells to the blood as reflected by an elevation in the total lymphocyte count. Meanwhile, following intense exercise of long duration the lymphocyte count declines, non-MHC-restricted cytotoxicity is suppressed, but the neutrophil concentration increases. In relation to eccentric exercise involving muscle damage, the plasma concentrations of interleukin-1, interleukin-6 and the tumor necrosis factor are elevated. In this review we will propose a model based on the possible roles that stress hormones play a mediating the exercise- related immunological changes: adrenaline and to a lesser degree noradrenaline are responsible for the immediate effects of exercise on lymphocyte subpopulations and cytotoxic activities. The increase in catecholamines and growth hormone mediate the acute effects of exercise on neutrophils, whereas cortisol may be responsible for maintaining lymphopenia and neutrocytosis after exercise of long duration. Lastly, the role of beta-endorphin is less clear, but the cytokine response is closely related to muscle damage and stress hormones do not seem to be directly involved in the elevated cytokine level. Other possible mechanisms of exercise-induced immunomodulation may include the so-called glutamine hypothesis, which is based on the fact that skeletal muscle is an important source of glutamine production and that lymphocytes are dependent on glutamine for optimal growth. Furthermore, physiological changes during exercise, e.g. increased body temperature and decreased oxygen saturation may also in theory contribute to the exercise-induced immunological changes.

1. In anaesthetized cats, the efferent discharge recorded from slips of otherwise intact sinus nerves was sparse in eupnoeic conditions but increased markedly during systemic hypoxia or asphyxia or following the injection of cyanide or acetaldehyde into the circulation of the ipsilateral carotid body.2. When the sinus nerve was cut distal to the efferent slip the responses to cyanide or acetaldehyde were abolished. The sparse ;resting' activity which remained was increased following the intravenous injection of adrenaline. Following distal section, the impulse traffic of the efferent slip did increase during systemic hypoxia but the response was much feebler than when the nerve was otherwise intact.3. The impulse activity of most efferent slips, peeled off from the otherwise intact sinus nerve, was abolished when the glossopharyngeal nerve was cut central to its junction with the same sinus nerve, indicating that the activity was probably recorded from genuine efferent units. The discharge of some ;efferent' preparations was still present, however, following such section and showed an increase to local injections of cyanide. This activity was probably recorded from looping or branching chemoreceptor afferents.4. The discharge of efferent slips of the cut aortic nerve was increased following the intravenous injection of adrenaline and during systemic hypoxia. These responses were not present when the vagus nerve was cut central to the nodose ganglion.5. In eupnoea, chemoreceptor afferent activity recorded from slips of the sinus or aortic nerves is much the same whether these nerves be otherwise intact or whether they be cut. During systemic hypoxia, chemoreceptor afferent discharge was less when it was recorded from the otherwise intact nerves than when these nerve trunks were cut.6. The cell bodies of sinus nerve efferent fibres are synaptically excited by chemoreceptor afferents coursing in the same nerve trunk. The increase of efferent impulse activity aroused by this means depresses chemoreceptor afferent discharge.