A disturbed metabolism of catecholamines and other neurotransmitters appears to play a major role in the pathogenesis of neurospychiatric symptoms, such as changes in mood and depression. This symptomatology is common in patients with chronic inflammatory disorders such as infections, autoimmune diseases, or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic system but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-γ stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is a co-factor for several aromatic amino acid mono-oxygenases and is rate-limiting for the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). Interferon-γ triggers the high output of reactive oxygen species in macrophages, which can destroy the oxidation-labile BH4. Recent data suggests that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients.

The present approach to the diagnosis, management and follow-up of anaphylaxis during anaesthesia varies in the Scandinavian countries. The main purpose of these Scandinavian Clinical Practice Guidelines is to increase the awareness about anaphylaxis during anaesthesia amongst anaesthesiologists. It is hoped that increased focus on the subject will lead to prompt diagnosis, rapid and correct treatment, and standardised management of patients with anaphylactic reactions during anaesthesia across Scandinavia. The recommendations are based on the best available evidence in the literature, which, owing to the rare and unforeseeable nature of anaphylaxis, mainly includes case series and expert opinion (grade of evidence IV and V). These guidelines include an overview of the epidemiology of anaphylactic reactions during anaesthesia. A treatment algorithm is suggested, with emphasis on the incremental titration of adrenaline (epinephrine) and fluid therapy as first-line treatment. Recommendations for primary and secondary follow-up are given, bearing in mind that there are variations in geography and resources in the different countries. A list of National Centres from which anaesthesiologists can seek advice concerning follow-up procedures is provided. In addition, an algorithm is included with advice on how to manage patients with previous suspected anaphylaxis during anaesthesia. Lastly, Appendix 2 provides an overview of the incidence, mechanisms and possibilities for follow-up for some common drug groups.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of the catecholamines dopamine, noradrenaline, and adrenaline. In response to short term stimuli TH activity is primarily controlled by phosphorylation of serine 40. We have previously shown that phosphorylation of serine 19 in TH can indirectly activate TH via a hierarchical mechanism by increasing the rate of phosphorylation of serine 40. Here we show that phosphorylation of serine 31 in rat TH increases the rate of serine 40 phosphorylation 9-fold in vitro. Phosphorylation of serine 31 in intact bovine chromaffin cells potentiated the forskolin-induced increase in serine 40 phosphorylation and TH activity more than 2-fold. Humans are unique in that they contain four TH isoforms but to date no significant differences have been shown in the regulation of these isoforms. Phosphorylation of the human TH isoform 1 at serine 31 by extracellular signal-regulated protein kinase (ERK) also produced a 9-fold increase in the rate of phosphorylation of serine 40, whereas little effect was seen in the TH isoforms 3 and 4. ERK did not phosphorylate human TH isoform 2. The effect of serine 19 phosphorylation on serine 40 (44 in TH2) phosphorylation is stronger in TH2 than in TH1. Thus hierarchical phosphorylation provides a mechanism whereby the two major human TH isoforms (1 and 2) can be differentially regulated with only isoform 1 responding to the ERK pathway, whereas isoform 2 is more sensitive to calcium-mediated events.

OBJECTIVE

Cardiac arrest (CA) in humans causes warm renal ischemia-reperfusion injury, similar to animal models of ischemic acute kidney injury (AKI). We aimed to investigate the incidence and risk associations of AKI after CA, with or without post-resuscitation cardiogenic shock (PRCS).

METHODS

We examined the renal outcomes of adult patients admitted to the intensive care unit (ICU), who survived for more than 48 h following successful resuscitation after CA.

RESULTS

Of 105 patients (median age 65 years; 69% male), 58 (55.2%) had PRCS and were on vasoactive drugs beyond 24h; and 9 (8.6%) (all of whom had PRCS) received renal replacement therapy. Only 3 (6.4%) of 47 patients without PRCS had RIFLE-'I'/'F' AKI, compared to 30 (51.7%) of 58 patients with PRCS (p<0.001). Median peak serum creatinine in the non-PRCS group was 102 μmol/L (interquartile range 85-115), compared to 155 μmol/L (interquartile range 112-267) (p<0.001) in the PRCS group. On multivariate analysis, cumulative noradrenaline dose during the first 24h in ICU, PRCS, and pre-CA renin-angiotensin-aldosterone-system blockade were independently associated with RIFLE-'I'/'F' AKI; while higher serum lactate 12h after CA, baseline creatinine, and PRCS were independently associated with greater rise in creatinine from pre-CA levels. Estimated time without spontaneous circulation, total adrenaline dose and initial cardiac rhythm during CA, had no independent associations with renal outcomes.

CONCLUSIONS

In the absence of PRCS, CA in isolation is uncommonly associated with significant AKI. The human kidney may be more resistant to warm ischemia-reperfusion injury than previously thought.

BACKGROUND

Acute bronchiolitis in infants frequently results in hospitalization, but there is no established consensus on inhalation therapy--either the type of medication or the frequency of administration--that may be of value. We aimed to assess the effectiveness of inhaled racemic adrenaline as compared with inhaled saline and the strategy for frequency of inhalation (on demand vs. fixed schedule) in infants hospitalized with acute bronchiolitis.

METHODS

In this eight-center, randomized, double-blind trial with a 2-by-2 factorial design, we compared inhaled racemic adrenaline with inhaled saline and on-demand inhalation with fixed-schedule inhalation (up to every 2 hours) in infants (<12 months of age) with moderate-to-severe acute bronchiolitis. An overall clinical score of 4 or higher (on a scale of 0 to 10, with higher scores indicating more severe illness) was required for study inclusion. Any use of oxygen therapy, nasogastric-tube feeding, or ventilatory support was recorded. The primary outcome was the length of the hospital stay, with analyses conducted according to the intention-to-treat principle.

RESULTS

The mean age of the 404 infants included in the study was 4.2 months, and 59.4% were boys. Length of stay, use of oxygen supplementation, nasogastric-tube feeding, ventilatory support, and relative improvement in the clinical score from baseline (preinhalation) were similar in the infants treated with inhaled racemic adrenaline and those treated with inhaled saline (P>0.1 for all comparisons). On-demand inhalation, as compared with fixed-schedule inhalation, was associated with a significantly shorter estimated mean length of stay--47.6 hours (95% confidence interval [CI], 30.6 to 64.6) versus 61.3 hours (95% CI, 45.4 to 77.2; P=0.01) - as well as less use of oxygen supplementation (in 38.3% of infants vs. 48.7%, P=0.04), less use of ventilatory support (in 4.0% vs. 10.8%, P=0.01), and fewer inhalation treatments (12.0 vs. 17.0, P<0.001).

CONCLUSIONS

In the treatment of acute bronchiolitis in infants, inhaled racemic adrenaline is not more effective than inhaled saline. However, the strategy of inhalation on demand appears to be superior to that of inhalation on a fixed schedule. (Funded by Medicines for Children; ClinicalTrials.gov number, NCT00817466; EudraCT number, 2009-012667-34.).

OBJECTIVE

We studied the incidence and hemodynamic characteristics of near-fainting under orthostatic stress in healthy children and teenagers.

BACKGROUND

Orthostatic stress testing is increasingly used to identify young subjects with unexplained syncope. However, the associated incidence of syncope and hemodynamic responses in normal young subjects are not well known.

METHODS

Eighty-four healthy subjects 6 to 16 years old performed forced breathing, stand-up and 70 degrees tilt-up tests. An intravenous line to sample blood for biochemical assessment of sympathetic function was introduced between the stand-up and tilt-up tests. Finger arterial pressure was measured continuously. Left ventricular stroke volume was computed from the pressure pulsations.

RESULTS

Sixteen of the 84 subjects were excluded because of technical problems. The incidence of a near-fainting response in the remaining 68 subjects was 10% (7 of 68) for the stand-up test and 40% (29 of 68) for the tilt-up test. Baseline parasympathetic and sympathetic activity of nonfainting and near-fainting subjects was not different. Near-fainting was characterized by attenuated systemic vasoconstriction and exaggerated tachycardia that occurred as early as 1 min after return to the upright position. On tilt-up, plasma adrenaline levels increased by a factor of 2, with slightly higher increments in the near-fainting subjects.

CONCLUSIONS

Inadequate vasoconstriction is the common underlying mechanism of near-fainting in young subjects. The remarkably high incidence of near-fainting during the tilt-up test after intravascular instrumentation raises serious doubts about the utility of this procedure in evaluating syncope of unknown origin in young subjects.

The release of pancreatic polypeptide (PP) by gut hormones, acetyl choline and adrenaline was investigated in an isolated perfused pancreas preparation. PP was potently released by 1 nmol/1 caerulein (186 +/- 12%, p is less than 0.001) and gastric inhibitory peptide (GIP) (211 +/- 31%, p is less than 0.005) as well as by 1 mumol/1 acetyl choline (1097 +/- 59%, p is less than 0.001). A significant two-fold release of PP was also evoked by 1 nmol/1 vasoactive intestinal peptide (VIP) (129 +/- 38%, p is less than 0.02 and gastrin (108 +/- 25% p is less than 0.01). Insulin release, induced by high glucose concentration was enhanced by both GIP (210 +/- 38%, p is less than (0.01) and VIP (48 +/- 5%, p is less than 0.001). In addition GIP enhanced the release of glucagon by 179 +/- 18% (p is less 0.001) at 1.4 mmol/1 glucose and by 127 +/- 24% (p is less than 0.005) at 8.3 mmol/1 glucose. Thus no simple inter-relationship appears to exist between the control of the three circulating islet hormones.

1. Two types of spontaneous nervous activities have been recorded from the central cut end of the carotid sinus nerve of the cat.2. One type was composed of nerve potentials that exhibited a respiratory or cardiac rhythm, whose rate of firing was depressed by the pressor response to adrenaline, and that were found to arise from post-ganglionic fibres of the superior cervical ganglion.3. The other type of activity consisted of non-rhythmical nerve potentials whose rate of discharge increased 10-30 sec after the injection of adrenaline. The activity of these fibres also increased when the arterial oxygen tension was lowered or when the arterial carbon dioxide tension was raised.4. It is conceivable that either of these two groups of fibres, rather than the chemoreceptor afferent fibres, could provide the source of the microvesicle-containing nerve endings on the type 1 cells of the carotid body.5. A nerve was also described coursing from the sinus nerve to the hypoglossal nerve; the activity in it was sympathetic in origin.

The effect of various inhibitors on insulin release from pieces of rabbit pancreas incubated in vitro was studied. Insulin release was stimulated by glucose (3mg./ml.), leucine (5mm), tolbutamide (200mug./ml.), ouabain (10mum), a raised extracellular K(+) concentration (60mm) and substitution of the Ca(2+) content of the incubation medium by Ba(2+) (2.5mm). (a) Mannoheptulose (6mg./ml.) inhibited glucose-stimulated insulin release only. (b) Anoxia abolished or inhibited insulin release stimulated by glucose, leucine, tolbutamide and K(+), but had little or no effect on release stimulated by ouabain or Ba(2+). (c) 2,4-Dinitrophenol (0.25mm) abolished or inhibited insulin release stimulated by glucose, ouabain or Ba(2+). (d) Diazoxide (250mug./ml.) abolished or inhibited insulin release stimulated by glucose, leucine, tolbutamide, ouabain or Ba(2+) (0.25 or 1mm). Diazoxide had no effect on insulin release stimulated by Ba(2+) (2.5mm) and potentiated release stimulated by K(+). (e) Adrenaline (1mum) abolished insulin release stimulated by glucose, leucine, tolbutamide, ouabain or Ba(2+). K(+)-stimulated release was inhibited by adrenaline. (f) Tetrodotoxin (1mum) had no effect on insulin release stimulated by glucose, leucine, tolbutamide, ouabain, K(+) or Ba(2+). (g) Nupercaine (1mm) abolished insulin release stimulated by glucose or Ba(2+).

BACKGROUND

Thoracoscopic surgery can be associated with considerable postoperative pain. While the benefits of paravertebral block on pain after thoracotomy have been demonstrated, no investigations on the effects of paravertebral block on pain after thoracoscopy have been conducted. We tested the hypothesis that a single-injection thoracic paravertebral block, performed preoperatively, reduces pain scores after thoracoscopic surgery.

METHODS

Of 45 patients recruited, 40 completed the study. They were randomly allocated to two groups: the paravertebral group received i.v. patient-controlled analgesia (PCA) with morphine plus single-injection thoracic paravertebral block with bupivacaine 0.375% and adrenaline 1:200 000 0.4 ml kg(-1) (n=20). The control group was treated with a back puncture without injection and morphine PCA (n=20).

RESULTS

The main outcomes recorded during 48 h after surgery were pain scores using the visual analogue scale (VAS, 0-100). Secondary outcomes were cumulative morphine consumption and peak expiratory flow rate (PEFR). Half an hour and 24 h after surgery, median (25th-75th percentiles) VAS on coughing in the paravertebral group was 31.0 (20.0-55.0) and 30.5 (17.5-40.0) respectively and in the control group it was 70.0 (30.0-100.0) and 50.0 (25.0-75.0) respectively. The difference between the groups over the whole observation period was statistically significant (P<0.05). Twenty-four and 48 h after surgery, median (25th-75th percentiles) cumulative morphine consumption (mg) was 49.0 (38.3-87.0) and 69.3 (38.8-118.5) respectively in the paravertebral group and 51.2 (36.0-84.1) and 78.1 (38.4-93.1) in the control group (statistically not significant). No differences were found in PEFR or the incidence of any side-effects between groups.

CONCLUSIONS

We conclude that single-shot preoperative paravertebral block improves post-operative pain treatment after thoracoscopic surgery in a clinically significant fashion.

Olfactory perception is influenced by hormones. Here we report that adrenaline can directly affect the signal encoding of olfactory receptor cells. Application of adrenaline suppressed action potentials near threshold and increased their frequency in response to strong stimuli, resulting in a narrower dynamic range. Under voltage-clamp conditions, adrenaline enhanced sodium current and reduced T-type calcium current. Because sodium current is the major component of spike generation and T-type calcium current lowers the threshold in olfactory receptor cells, the effects of adrenaline on these currents are consistent with the results obtained under current-clamp conditions. Both effects involved a common cytoplasmic pathway, cAMP-dependent phosphorylation. We suggest that adrenaline may enhance contrast in olfactory perception by this mechanism.

Short-term (6 hr) withdrawal of chow diet from lactating rats decreases the rate of lipogenesis in mammary gland by 87%. This inhibition is in part explained by a 60% decrease in the extraction of glucose (the major lipogenic precursor) by the mammary tissue. These changes are not accompanied by any significant alteration in the arterial concentrations of glucose, lactate or insulin; the concentration of acetoacetate did increase by about 30%. Removal of food for 6 hr did not alter the activation state of acetyl-CoA carboxylase or the total activity of the enzyme. Glucose utilization by mammary gland acini from short-term starved rats was not depressed although a higher proportion of the glucose appeared as lactate in the medium and consequently less glucose was converted to lipid. Insulin was able to reverse these changes. Glucagon, adrenaline or cAMP did not inhibit glucose utilization or lipogenesis in isolated acini. It is concluded that the inhibition of lipogenesis in mammary gland after short-term withdrawal of food is mainly due to decreased extraction of glucose. The signal for this change does not appear to be an alteration in plasma insulin and it is postulated that there may be an intestinal factor(s) which acts synergistically with insulin.

1 Adrenaline (10 nM) significantly enhanced the stimulation-induced efflux of radioactivity from rat atria previously incubated with [3H]-noradrenaline ([3H]-NA). This effect was abolished by metoprolol (.01 muM). 2 Adrenaline in a higher concentration (1 muM) and NA (1 muM) significantly reduced the stimulation-induced efflux of radioactivity. However, in the presence of phenoxybenzamine (10 muM), adrenaline (1 muM) enhanced the efflux, whereas NA (1 muM) had no effect. 3 In rat isolated atria pre-incubated with adrenaline and then incubated with NA, both catecholamines were taken up and were released by field stimulation. When pre-incubation was with adrenaline and incubation was with [3H]-NA, metoprolol decreased the stimulation-induced efflux of radioactivity. This effect did not occur if the atria were pre-incubated with NA instead of adrenaline, suggesting tht neuronally released adrenaline activates prejunctional beta-adrenoceptors. 4 In conscious rats, intravenously administered adrenaline (6.0 and 0.6 nmol/kg) was taken up and retained in the atria and could be released by field stimulation. The release was calcium-dependent from these rats up to 24 h after administration.

The present paper describes the effects of different general anaesthetics on plasma catecholamine (CA) concentrations taken as biochemical index of peripheral sympathetic activity. In chronically catheterized rats, diethyl ether, ketamine and urethane increased plasma adrenaline (A) and noradrenaline (NA) concentrations, indicating that these drugs stimulate both neurosympathetic and adrenomedullary functions. These effects appear to be centrally mediated, since ganglionic blockade or spinal transection completely counteracted the diethyl ether- and ketamine-induced increases in plasma CA levels. Halothane induced a transient decrease in circulating A and an increase in NA. These results support the concept that general anaesthetics may have different effects on sympathetic function. Arterial blood pressure and heart rate were also measured to look for possible correlations with peripheral sympathetic activity. The enhanced release of peripheral CAs seemed to be the determining factor for increasing blood pressure and heart rate with ketamine only. In the other instances the activation of the peripheral sympathetic system appeared to maintain homeostasis by counterbalancing the various depressive effects of anaesthetics on the cardiovascular system.

In order to study blood pressure variability we have measured blood pressure, heart rate, plasma noradrenaline and adrenaline concentration and plasma renin activity during sleep and during the waking process in 20 subjects with borderline hypertension. The responses to a number of standardized tests were also measured. These were reading, mental arithmetic, change in posture, physical exercise and the response to intravenously injected phenylephrine and noradrenaline. The sensitivity of the baroreflex for heart rate control was also determined from the relationship between heart period (R-R interval) and change in systolic pressure after the injection of phenylephrine. Blood pressure was also recorded continuously for 24 hours. From the lowest levels achieved during sleep, blood pressure rose as the subjects regained consciousness but was not restored to its baseline value until mental activity was also restored by reading. Blood pressure rose further with mental arithmetic. These changes were accompanied by a greater proportional rise in plasma adrenaline than in plasma noradrenaline concentrations. Plasma renin activity changed little. The pressor responses to phenylephrine and noradrenaline were inversely related to baroreceptor sensitivity. The fall in blood pressure with sleep and the rise with mental arithmetic was also inversely related to the sensitivity of the reflex. Systolic pressure recorded throughout the day was inversely related to the R-R interval in each subject. The slope of this relationship and range of R-R interval was greatest in the subjects with the most sensitive baroreflexes.

1. Conscious, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, were used to assess responses to 3 min infusions of the potassium channel opener, BRL 38227 (1 and 10 micrograms kg-1 min-1) or adrenaline (0.05 and 0.5 microgram kg-1 min-1) in the absence and in the presence of NG-nitro-L-arginine methyl ester (L-NAME; 3 mg kg-1 h-1), an inhibitor of nitric oxide biosynthesis. 2. In the absence of L-NAME, the low dose of BRL 38227 caused slight hypotension and tachycardia, accompanied by small increases in mesenteric and hindquarters blood flow only. However, there were increases in renal, mesenteric and hindquarters vascular conductances. L-NAME had no effect on any of these responses. 3. The high dose of BRL 38227 caused substantial hypotension and tachycardia. Renal and hindquarters flows did not change significantly, but there was a marked increase in mesenteric flow. There were only modest increases in renal and hindquarters vascular conductances but a substantial mesenteric vasodilatation. In the presence of L-NAME, there was a slight reduction of the latter but no other changes in the responses to BRL 38227. 4. In the absence of L-NAME, the low dose of adrenaline caused slight hypotension but a marked tachycardia. There were no changes in renal or mesenteric blood flow but a clear-cut increase in hindquarters flow. Renal and mesenteric vascular conductances showed only small rises, in contrast to the substantial hindquarters vasodilatation. In the presence of L-NAME, there was significant attenuation of the tachycardia and of the increases in hindquarters flow and vascular conductance in response to adrenaline.5. The high dose of adrenaline caused marked hypotension and tachycardia. Renal flow did not change, but there was a fall in mesenteric and a marked rise in hindquarters flow. Renal vascular conductance showed a slight increase but mesenteric vascular conductance did not change significantly, whereas there was a substantial hindquarters vasodilatation. In the presence of L-NAME, adrenaline caused an increase in blood pressure but no significant change in heart rate; the renal vasodilatation was abolished, there was a mesenteric vasoconstriction, and the hindquarters vasodilatation was markedly reduced. L-NAME also attenuated the tachycardia induced by adrenaline in animals with no cardiac baroreflexes.6. The present results indicate that L-NAME-sensitive mechanisms are involved in the vasodilator and tachycardic effects of adrenaline. The relative lack of effect of L-NAME on responses to BRL 38227 indicates that the changes in the responses to adrenaline were not non-specific or due to changes in haemodynamic status caused by L-NAME. The results raise the possibility that the 'hypertensinogenic' properties of endogenous adrenaline could be amplified when nitric oxide biosynthesis is impaired.

Increased catecholamines after myocardial infarction may contribute to the development of arrhythmias. We have infused adrenaline intravenously in nine normal volunteers to levels similar to those seen after myocardial infarction. Adrenaline caused an increase in systolic blood pressure, a decrease in diastolic blood pressure, and an increase in heart rate. Adrenaline also produced a decrease in T wave amplitude and an increase in the QTc interval. The serum potassium fell dramatically during the adrenaline infusion from a control value of 4.06 mmol/l to 3.22 mmol/l. Hypokalaemia after myocardial infarction is associated with an increased incidence of ventricular arrhythmias. Thus, circulating adrenaline may increase the frequency of arrhythmias both directly via changes in ventricular repolarisation and indirectly via adrenaline induced hypokalaemia.

1. In conscious rabbits, intravenous morphine (3 mg/kg) caused hypertension, bradycardia, hyperglycaemia and sedation. These changes were accompanied by large increases in plasma adrenaline and smaller increases in plasma noradrenaline. 2. These effects of morphine were prevented by intravenous naloxone, demonstrating their dependence on stimulation of opiate receptors. 3. Pretreatment with the antihistamines cimetidine and chlorpheniramine enhanced the morphine-induced rise in blood pressure, excluding a role for histamine release in the hypertensive action of morphine. 4. The centrally acting alpha 2-adrenergic agonist clonidine prevented the morphine-induced hypertension and rise in plasma catecholamines, suggesting that these effects are exerted via central pathways. Clonidine alone reduced blood pressure and heart rate and produced hyperglycaemia. 5. alpha-Adrenergic blockade with phenoxybenzamine reduced the increase in blood pressure after morphine, although the increase in plasma catecholamines was augmented. 6. Pentobarbitone anaesthesia prevented the morphine-induced cardiovascular changes, the increase in plasma catecholamines and the hyperglycaemia. 7. These findings indicate, that in conscious rabbits, morphine induces hypertension by stimulation of opiate receptors leading to increased sympatho-adrenal activity. The hyperglycaemia appears to be in response to secretion of adrenaline. These effects probably result from a central action of morphine.

OBJECTIVE

a) To investigate the functional consequences of sepsis on the beta-adrenergic signal transduction in human circulating lymphocytes; b) to appreciate sepsis-associated catecholamine and cytokine release.

METHODS

Experimental, comparative study.

METHODS

Research laboratory in a university hospital.

METHODS

Healthy controls (n = 10); critically ill patients who were not septic (n = 7); septic patients with severe sepsis or septic shock (n = 11).

RESULTS

Experiments were carried out using freshly isolated peripheral blood mononuclear cells (PBMC). We measured beta-adrenergic receptor (betaAR) number and affinity, and intracellular cAMP content at baseline and after the pharmacological stimulation of each component of the beta-adrenergic complex: betaAR with isoproterenol, Gs-protein with sodium fluoride (NaF), adenylate cyclase with forskolin. Catecholamine (adrenaline, noradrenaline) and cytokine (TNFalpha, IL-1alpha, IL-1beta, IL-6) serum levels were measured. In both septic and non-septic patients we observed a similar 40 % down-regulation of betaARs compared to controls, and a reduced basal and isoproterenol-stimulated cAMP accumulation (p < 0.05). The cAMP production elicited by NaF or forskolin was lower in septic patients than in the controls (p < 0.01). Forskolin-stimulated cAMP accumulation was significantly lower in septic patients than it was in non-septic ones (p < 0.001). Catecholamine serum concentrations were increased in the two patient groups without any significant difference. Elevated cytokine serum levels were detected in 45% of the septic patients (versus 14% of non-septic patients p < 0.05).

CONCLUSIONS

Patients presenting with severe sepsis or septic shock have extended postreceptor defects of the beta-adrenergic signal transduction. This finding suggests a heterologous desensitization of adenylate cyclase stimulation.

The pre- and postnatal development of the adrenal medulla was examined in the rat by immunohistochemistry and by assay of catecholamines. Immunohistochemistry involved the use of antibodies to noradrenaline (NA), adrenaline (A) and the biosynthesizing enzymes dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). Adrenal glands were obtained from animals from the 16th day of gestation to the 7th postnatal day at daily intervals, and at the 14th postnatal day, and from adult rats. Tissues were fixed in ice-cold, 4% paraformaldehyde, buffered at pH 7.3. Cryostat sections (7 microns) were stained with the indirect immunofluorescence technique. Adrenals from the same developmental stages were assayed for the presence of DA (dopamine), NA and A by ion-pair reversed-phase liquid chromatography with electrochemical detection. In adult adrenals the majority of the medullary cells (approximately 80%) were highly immunoreactive to A and moderately immunoreactive to NA. They also showed immunoreactivity to both DBH and PNMT, i.e., they are synthesizing and storing A. The remaining cell clusters were only stained by antibodies to DBH and NA (NA-synthesizing and -storing cells). These findings correlate well with the relative concentrations of A and NA as determined by assay. Three developmental phases could be distinguished. In the first phase, the 16th and 17th prenatal day, medullary cells were only immunoreactive to DBH and NA, and only very small amounts of A as compared to NA were found. During the second period, from the 18th prenatal day to 2 or 3 days after birth, all medullary cells were immunoreactive to DBH, NA, PNMT and A, and during this phase the adrenaline concentration increased daily and became the predominant amine on the 20th day of gestation. Adrenaline represented 75% of total catecholamine on the 1st to 3rd day after birth. The third phase started at the 2nd or 3rd postnatal day and was characterized by the presence of an increasing number of medullary cells solely immunoreactive to DBH and NA, hence synthesizing and storing NA. The remaining cells were immunoreactive to DBH, NA, PNMT and A. Postnatally, the relative concentration of A continued to rise reaching 79% by the 4th postnatal day. These results indicate that initially the adrenal medullary cells are synthesizing and storing almost exclusively NA.(ABSTRACT TRUNCATED AT 400 WORDS)

The posterior hypothalamus of anaesthetized cats was superfused with a push-pull cannula and the release of the endogenous catecholamines noradrenaline, adrenaline and dopamine was determined in the superfusate. The rate of release of the three catecholamines followed an ultradian rhythm, the time interval between two adjacent phases of high rate of release being about 70 min. Pretreatment of the animals with reserpine decreased the levels of catecholamines in the hypothalamus and rest of the brain and reduced their rate of release into the superfusate. Hypothalamic superfusion with superfusing fluid of high concentration of potassium and low concentration of sodium enhanced the rate of release of noradrenaline and adrenaline; this effect was abolished when the hypothalamus was superfused with calcium-free solution. Electrical stimulation of the locus coeruleus ipsilateral to the superfused hypothalamus increased the release of noradrenaline and adrenaline, stimulation of the contralateral locus coeruleus enhanced the release of noradrenaline, adrenaline and dopamine. In both cases, the rate of release of adrenaline was enhanced to a lesser extent than the rate of release of noradrenaline. The release of noradrenaline and adrenaline was increased to a higher extent on stimulation of the ipsilateral locus coeruleus than on stimulation of the contralateral one.

1. Summit metabolism of lambs declined steadily from about 3.5 l. O(2)/kg.hr during the first day of life, to about 2.0 l. O(2)/kg.hr at 2 months of age.2. The contributions of shivering and non-shivering thermogenesis to these changes were estimated by three independent methods; non-shivering thermogenesis was stimulated by catecholamines in a thermoneutral environment, shivering was suppressed by curariform drugs during summit metabolism, and an attempt was made to suppress non-shivering thermogenesis during summit metabolism by use of the sympatholytic drugs phentolamine and propranolol. Drugs were given by intravenous infusion during measurement of oxygen consumption in a closed circuit respiration chamber.3. ;Resting' metabolic rate of lambs during the first day of life was increased two to three-fold, from 1 l. O(2)/kg.hr, by either adrenaline or noradrenaline infused at 1-10 mug/kg.min. The increase declined with increasing age of lamb and was virtually absent by 3 weeks. The response to catecholamines appeared maximal at the dose levels used.4. Muscular paralysis induced by suxamethonium or gallamine reduced summit metabolism by about 2 l. O(2)/kg.hr in all lambs examined within the first 2 months of life. The residual metabolic rate, and the metabolic response to catecholamines under thermoneutral conditions, declined with age in the same manner, and their magnitudes were similar.5. Summit metabolism in lambs aged up to 2 months was depressed to varying degrees by the sympathetic inhibitors phentolamine, propranolol and hexamethonium. The depression with propranolol was greater, and the decline with age clearer, than with phentolamine. Hexamethonium and phentolamine depressed blood pressure, propranolol decreased heart rate and phentolamine and propranolol each suppressed shivering in some experiments.6. In 1 day-old lambs estimates of non-shivering thermogenesis, by the various methods, ranged from 0.8 to 1.4 l. O(2)/kg.hr (mean 1.1 l. or 31% of summit metabolism), and the estimates of shivering ranged from 1.3 to 1.9 l. O(2)/kg.hr (mean 1.6 l. or 46% of summit metabolism). However, in lambs 1-month old, estimates of non-shivering thermogenesis from sympathetic inhibition (0.6 and 0.8 l. O(2)/kg.hr) were considerably higher than estimates from muscular paralysis or stimulation by catecholamines (0.2 and 0.1 l. O(2)/kg.hr). It is suggested that the depression of summit metabolism by the sympathetic inhibitors is not solely due to specific inhibition of non-shivering thermogenesis, at least in the older lambs.7. The possession of a non-shivering thermogenic mechanism in addition to shivering is of clear survival value to new-born lambs.