Numerous synthetic agonists selectively stimulate beta3-adrenoceptors (ARs). The endogenous catecholamines, noradrenaline and adrenaline, however, stimulate all the beta-AR subtypes, and no selective physiological agonist for beta3-ARs has been described so far. The aim of this study was to investigate whether any naturally occurring amine can stimulate selectively beta3-ARs. Since activation of lipolysis is a well-known beta-adrenergic function, the efficacy and potency of various biogenic amines were compared with those of noradrenaline, isoprenaline, and beta3-AR agonists 4-(-{[2-hydroxy-(3-chlorophenyl)ethyl]-amino} propyl)phenoxyacetate (BRL 37,344) and (R,R)-5-(2-{[2-(3-chlorophenyl )-2-hydroxyethyl]-amino} propyl)-1,3-benzo-dioxole-2,2-dicarboxylate (CL 316,243) by testing their lipolytic action in white fat cells. Five mammalian species were studied: rat, hamster and dog, in which selective beta-AR agonists act as full lipolytic agents, and guinea-pigs and humans, in which beta3-AR agonists are less potent activators of lipolysis. Several biogenic amines were inefficient (e.g. dopamine, tyramine and beta-phenylethylamine) while others (synephrine, phenylethanolamine, epinine) were partially active in stimulating lipolysis in all species studied. Their actions were inhibited by all the beta-AR antagonists tested, including those selective for beta1- or beta2-ARs. Octopamine was the only amine fully stimulating lipolysis in rat, hamster and dog fat cells, while inefficient in guinea-pig or human fat cells, like the beta3-AR agonists. In rat white fat cells, beta-AR antagonists inhibited the lipolytic effect of octopamine with a relative order of potency very similar to that observed against CL 316,243. Competitive antagonism of octopamine effect resulted in the following apparent pA2 [-log(IC50), where IC50 is the antagonist concentration eliciting half-maximal inhibition] values: 7.77 (bupranolol), 6.48 [3-(2-ethyl-phenoxy)-1[(1 S)-1,2,3,4-tetrahydronaphth-1-ylaminol]-(2S)2-propanol oxalate, SR 59230A, a beta3-selective antagonist], 6.30[erythro-D,L-1(7-lethylindan-4-yloxy)-3-isopropylamino-+ ++butan-2-ol, ICI 118,551, a beta2-selective antagonist] and 4.71 [(+/-)-[2-(3-carbomyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1- methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]2-propanolmethane sulphonate, CGP 20712A, a beta1-selective antagonist]. Octopamine had other properties in common with beta3-AR agonists: stimulation of oxygen consumption in rat brown fat cells and very low affinity in displacing [3H]CGP 12,177 binding to [beta1- or beta2-ARs in dog and rat adipocyte membranes. In Chinese hamster ovary (CHO) cells expressing human beta3-ARs, octopamine inhibited [125I]ICYP binding with only twofold less affinity than noradrenaline while it exhibited an affinity around 200-fold lower than noradrenaline in CHO cells expressing human beta1- or beta2-ARs. These data suggest that, among the biogenic amines metabolically related to catecholamines, octopamine can be considered as the most selective for beta3-ARs.

Laparoscopy is frequently associated with postoperative shoulder pain that may last several days. We have assessed the analgesic effect of intraperitoneal local anaesthetics during day-case diagnostic laparoscopy. 80 young women were randomly assigned to one of four groups of 20 patients each: group 1, no peritoneal administration; group 2, 80 ml saline injected under direct vision in the right subdiaphragmatic area at the start of the procedure; group 3, 80 ml 0.5% lignocaine with adrenaline (320,000 dilution); group 4, 0.125% bupivacaine with adrenaline (800,000 dilution). Scapular pain was assessed with a visual analogue pain scale, and information about nausea, vomiting, abdominal pain, and analgesic requirements during the first 48 h was sought. Both local anaesthetics were more effective in reducing postoperative shoulder pain than either control or saline. Analgesic requirements were greater in the non-treatment groups than in the local anaesthetic groups. Intraperitoneal local anaesthetic administration during laparoscopy is both a non-invasive and an efficient method of reducing the intensity of scapular pain.

Sympathoadrenergic pathways are crucial to the communication between the nervous system and the immune system. The present review addresses emerging issues in the adrenergic modulation of immune cells, including: the specific pattern of adrenoceptor expression on immune cells and their role and changes upon cell differentiation and activation; the production and utilization of noradrenaline and adrenaline by immune cells themselves; the dysregulation of adrenergic immune mechanisms in disease and their potential as novel therapeutic targets. A wide array of sympathoadrenergic therapeutics is currently used for non-immune indications, and could represent an attractive source of non-conventional immunomodulating agents.

Blood concentrations of pancreatic glucagon, cortisol, noradrenaline, adrenaline, and growth hormone have been measured during the first 41 hours of insulin deprivation in six insulin-dependent diabetics to assess the importance of these hormones in the pathogenesis of diabetic ketoacidosis. Plasma-glucagon showed an early small significant rise and thereafter a slow increase to a plateau during the remaining experimental period. Plasma-cortisol increased only at the end of the insulin-deprivation period, while plasma-catecholamines and serum-growth-hormone concentrations did not change. In the three of the six patients who developed significant ketosis, plasma-glucagon showed a close correlation with blood-ketones and plasma-free-fatty-acids while for the whole group the change in glucagon concentration correlated significantly with the rise in ketone-body concentration. It is suggested that the excess of glucagon in addition to the insulin lack may be an important factor in determining the degree of hyperglycaemia had hyperketonaemia in the early stages of insulin deprivation.

Tramadol is thought to induce analgesia via both opioid and non-opioid pathways, although the precise mechanisms remain to be elucidated. In this study, we investigated the roles of the mu-opioid receptor (MOP) in analgesic and rewarding effects of tramadol by using MOP knockout (KO) mice. Tramadol-induced antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous and homozygous MOP-KO mice when compared with that in wild-type mice. Interestingly, however, tramadol retained its ability to induce significant antinociception in homozygous MOP-KO mice. The tramadol-induced antinociception remaining in homozygous MOP-KO mice was not significantly affected by methysergide, a serotonin receptor antagonist, but was partially blocked by yohimbine, an adrenaline alpha2 receptor antagonist, and both naloxone, a non-selective opioid receptor antagonist, and yohimbine. In addition, antinociceptive effects of an active tramadol metabolite M1 were abolished or remarkably reduced in MOP-KO mice. On the other hand, neither wild-type nor homozygous MOP-KO mice showed significant place preference for tramadol in a conditioned place preference test, although there were slight tendencies toward preference in wild-type mice and avoidance in homozygous MOP-KO mice. These results strongly support the idea suggested in the previous pharmacological studies that MOP and the adrenaline alpha2 receptor mediate most of the analgesic properties of tramadol.

BACKGROUND

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by adrenergically induced ventricular tachycardia (VT) associated with syncope and sudden death.

OBJECTIVE

This study sought to characterize arrhythmias associated with CPVT with respect to provocation by exercise and drugs, electrocardiographic characteristics, and association with long-term outcomes; and to explore the relation between age and clinical presentation.

METHODS

Seventy patients from 16 families were evaluated with exercise and selective adrenaline challenge, and screened for RyR2 mutations. CPVT was diagnosed in probands with symptoms and stress- or adrenaline-provoked VT, or in asymptomatic relatives with provoked VT or RyR2 mutations. Patients were followed up for recurrent syncope, VT, and sudden death.

RESULTS

Twenty-seven patients including 16 probands were identified (median age 35 years, 67% female). Presentation was cardiac arrest in 33% and syncope in 56%, and 11% were asymptomatic. Polymorphic or bidirectional VT was provoked with exercise in 63% and adrenaline in 82%. The initiating beat of VT was late-coupled and wide (coupling interval 418 ± 42 ms; QRSd 131 ± 17 ms), and QRS morphology suggested an outflow tract origin in 59%. During follow-up of 6.2 ± 5.7 years, 2 patients died despite an implantable cardioverter-defibrillator (ICD), 4 patients received ICD therapy for VT, and 5 patients had inappropriate therapy for supraventricular tachycardia. Patients presenting with late-onset CPVT (age>> 21; n = 10) were often female (80%) and less likely to have RyR2 (Ryanodine receptor type 2) mutations (33%), and fatal events were not observed during follow-up (4.1 ± 3.6 years).

CONCLUSIONS

Ventricular arrhythmia in CPVT is often initiated from the outflow tract region. Despite β-blocker therapy and selective ICD implantation, breakthrough arrhythmias occur and may be associated with adverse outcomes.

Time spent walking and relaxing in a forest environment ("forest bathing" or "forest therapy") has well demonstrated anti-stress effects in healthy adults, but benefits for ill or at-risk populations have not been reported. The present study assessed the physiological and psychological effects of forest therapy (relaxation and stress management activity in the forest) on middle-aged males with high-normal blood pressure. Blood pressure and several physiological and psychological indices of stress were measured the day before and approximately 2 h following forest therapy. Both pre- and post-treatment measures were conducted at the same time of day to avoid circadian influences. Systolic and diastolic blood pressure (BP), urinary adrenaline, and serum cortisol were all significantly lower than baseline following forest therapy (p<0.05). Subjects reported feeling significantly more "relaxed" and "natural" according to the Semantic Differential (SD) method. Profile of Mood State (POMS) negative mood subscale scores for "tension-anxiety," "confusion," and "anger-hostility," as well as the Total Mood Disturbance (TMD) score were significantly lower following forest therapy. These results highlight that forest is a promising treatment strategy to reduce blood pressure into the optimal range and possibly prevent progression to clinical hypertension in middle-aged males with high-normal blood pressure.

The catecholamines dopamine (DA), noradrenaline (NA) and adrenaline (A), their aminoacid precursors tyrosine (Tyr), L-3,4-dihydroxyphenylalanine (L-DOPA), two of their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxy phenyl glycol (MHPG), serotonin (5-HT) and its precursor tryptophan (Trp), were measured by high pressure liquid chromatography (HPLC) with electrochemical detection in seven regions (globus pallidus, putamen, nucleus amygdalae, nucleus caudatus, substantia nigra, gyrus cinguli and raphe) of postmortem brains from eight histologically verified cases with Alzheimer's disease (AD) and six histologically normal controls. Concentrations of L-DOPA, DA, DOPAC, NA and 5-HT were significantly reduced, while Tyr and MHPG concentrations were significantly increased in AD versus control patients. The concentrations of Trp and A in AD patients were not significantly different from controls. Furthermore, for most brain regions examined, significant negative correlations between Tyr and DA as well as between NA and MHPG levels were found. These data confirm and extend findings of monoaminergic systems disturbances in AD, emphasize the significance of dopaminergic deficit for AD and suggest that in pharmacotherapy of AD, attempts to restore deficits of the transmitter systems should be directed to the monoaminergic, in particular the dopaminergic system.

OBJECTIVE

LUCAS is a new device for mechanical compression and decompression of the chest during cardiopulmonary resuscitation (CPR). The aim of this study was to compare the efficacy of this new device with standard manual external chest compressions using cerebral cortical blood flow, cerebral oxygen extraction, and end-tidal CO2 for indirect measurement of cardiac output. Drug therapy, with adrenaline (epinephrine) was eliminated in order to evaluate the effects of chest compressions alone.

METHODS

Ventricular fibrillation (VF) was induced in 14 anaesthetized pigs. After 8 min non-intervention interval, the animals were randomized into two groups. One group received external chest compressions using a new mechanical device, LUCAS. The other group received standard manual external chest compressions. The compression rate was 100 min(-1) and mechanical ventilation was resumed with 100% oxygen during CPR in both groups. No adrenaline was given. After 15 min of CPR, external defibrillatory shocks were applied to achieve restoration of spontaneous circulation (ROSC). Cortical cerebral blood flow was measured continuously using Laser-Doppler flowmetry. End-tidal CO2 was measured using mainstream capnography.

RESULTS

During CPR, the cortical cerebral blood flow was significantly higher in the group treated with LUCAS (p = 0.041). There was no difference in oxygen extraction between the groups. End-tidal CO2, an indirect measurement of the achieved cardiac output during CPR, was significantly higher in the group treated with the LUCAS device (p = 0.009). Restoration of spontaneous circulation was achieved in two animals, one from each group.

CONCLUSIONS

Chest compressions with the LUCAS device during experimental cardiopulmonary resuscitation resulted in higher cerebral blood flow and cardiac output than standard manual external chest compressions. These results strongly support prospective randomised studies in patients to evaluate this new device.

The viral transneuronal tracing method was used to identify the CNS cell groups that regulate the parasympathetic and sympathetic outflow systems of the pancreas. Pseudorabies virus (PRV) was injected into the pancreas of vagotomized rats and after 6 days survival, the pattern of transneuronal labeling in the CNS sympathetic regulatory regions was determined. The converse experiment was performed in order to elucidate the central parasympathetic cell groups that regulate the pancreas. Immunohistochemical methods were used to identify putative neuropeptide- and catecholamine-containing CNS neurons involved in these regulatory circuits. The major finding of this study indicates that five brain regions, viz., paraventricular hypothalamic nucleus, perifornical hypothalamic region, A5 catecholamine cell group, rostral ventrolateral medulla, and lateral paragigantocellular reticular nucleus, contain a considerable amount of overlap in cell body labeling. In addition, the ventrolateral part of the periaqueductal gray matter and gigantocellular reticular nucleus, ventral part also showed a similar overlap, but the numbers of neurons found in these areas were considerably lower than the five major regions. These data suggest that these brain regions may provide parallel and possibly redundant, autonomic pathways affecting glucagon and adrenaline release.

BACKGROUND

Peanut allergy is one of the most common forms of food allergy encountered in clinical practice. In most cases, it does not spontaneously resolve; furthermore, it is frequently implicated in acute life-threatening reactions. The current management of peanut allergy centres on meticulous avoidance of peanuts and peanut-containing foods. Allergen-specific oral immunotherapy (OIT) for peanut allergy aims to induce desensitisation and then tolerance to peanut, and has the potential to revolutionise the management of peanut allergy. However, at present there is still considerable uncertainty about the effectiveness and safety of this approach.

OBJECTIVE

To establish the effectiveness and safety of OIT in people with IgE-mediated peanut allergy who develop symptoms after peanut ingestion.

METHODS

We searched in the following databases: AMED, BIOSIS, CAB, CINAHL, The Cochrane Library, EMBASE, Global Health, Google Scholar, IndMed, ISI Web of Science, LILACS, MEDLINE, PakMediNet and TRIP. We also searched registers of on-going and unpublished trials. The date of the most recent search was January 2012.

METHODS

Randomised controlled trials (RCTs), quasi-RCTs or controlled clinical trials involving children or adults with clinical features indicative of IgE-mediated peanut allergy treated with allergen-specific OIT, compared with control group receiving either placebo or no treatment, were eligible for inclusion.

METHODS

Two review authors independently checked and reviewed titles and abstracts of identified studies and assessed risk of bias. The full text of potentially relevant trials was assessed. Data extraction was independently performed by two reviewers with disagreements resolved through discussion.

RESULTS

We found one small RCT, judged to be at low risk of bias, that enrolled 28 children aged 1 to 16 years with evidence of sensitisation to peanut and a clinical history of reaction to peanut within 60 minutes of exposure. The study did not include children who had moderate to severe asthma or who had a history of severe peanut anaphylaxis. Randomisation was in a 2:1 ratio resulting in 19 children being randomised to the intervention arm and nine to the placebo arm. Intervention arm children received OIT with peanut flour and control arm participants received placebo comprising of oat flour. The primary outcome was assessed using a double-blind, placebo controlled oral food challenge (OFC) at approximately one year. No data were available on longer term outcomes beyond the OFC conducted at the end of the study.Because of adverse events, three patients withdrew from the intervention arm before the completion of the study. Therefore, only 16 participants received the full course of peanut OIT, whereas all nine patients receiving placebo completed the trial. The per-protocol analysis found a significant increase in the threshold dose of peanut allergen required to trigger a reaction in those in the intervention arm with all 16 participants able to ingest the maximum cumulative dose of 5000 mg of peanut protein (which the authors equate as being equivalent to approximately 20 peanuts) without developing symptoms, whereas in the placebo group they were able to ingest a median cumulative dose of 280 mg (range: 0 to 1900 mg, P < 0.001) before experiencing symptoms. Per-protocol analyses also demonstrated that peanut OIT resulted in reductions in skin prick test size (P < 0.001), interleukin-5 (P = 0.01), interleukin-13 (P = 0.02) and an increase in peanut-specific immunoglobulin G(4) (IgG(4)) (P < 0.01).Children in the intervention arm experienced more adverse events during treatment than those in the placebo arm. In the initial day escalation phase, nine (47%) of the 19 participants initially enrolled in the OIT arm experienced clinically-relevant adverse events which required treatment with H(1)-antihistamines, two of which required additional treatment with epinephrine (adrenaline).

CONCLUSIONS

The one small RCT we found showed that allergen-specific peanut OIT can result in desensitisation in children, and that this is associated with evidence of underlying immune-modulation. However, this treatment approach was associated with a substantial risk of adverse events, although the majority of these were mild. In view of the risk of adverse events and the lack of evidence of long-term benefits, allergen-specific peanut OIT cannot currently be recommended as a treatment for the management of patients with IgE-mediated peanut allergy. Larger RCTs are needed to investigate the acceptability, long-term effectiveness and cost-effectiveness of safer treatment regimens, particularly in relation to the induction of clinical and immunological tolerance.

Intravenous infusions of phenylephrine, noradrenaline, adrenaline, and isoprenaline were given to healthy human volunteers after five to seven days on phenelzine, tranylcypromine, or imipramine, and cardiovascular responses were compared with those observed under control conditions. With monoamine oxidase inhibitors there was a 2-2(1/2) fold potentiation of the pressor effect of phenylephrine, but no clinically significant potentiation of cardiovascular effects of noradrenaline, adrenaline, or isoprenaline. With imipramine there was potentiation of the pressor effects of phenylephrine (2-3 fold), noradrenaline (4-8 fold), and adrenaline (2-4 fold); there were dysrhythmias during adrenaline infusions, but no noticeable or consistent changes in response to isoprenaline.Noradrenaline and adrenaline in amounts contained in local anaesthetics used in dentistry are not likely to be significantly potentiated in otherwise healthy patients receiving monoamine oxidase inhibitors. Hazardous potentiation of their cardiovascular effects might occur in patients receiving tricyclic antidepressants.Our observations do not indicate that the hazards associated with isoprenaline inhalation by bronchial asthmatics would be increased by coincident therapy with a monoamine oxidase inhibitor or tricyclic antidepressant.

In addition to calcitonin and katacalcin, it is now known that the human calcitonin gene encodes a novel peptide called calcitonin gene related peptide (CGRP). In experimental animals, CGRP produces vasodilatation and complex changes in plasma calcium. We have now assessed its biological activity in man by infusing human CGRP (hCGRP) into six normal volunteers. hCGRP (545 pmol/min) caused the diastolic pressure to fall from 64 +/- 5 to 55 +/- 7 mmHg (P less than 0.05), the heart rate to increase from 61 +/- 7 to 87 +/- 5 beats/min (P less than 0.05) and the skin temperature to increase from 33.7 +/- 0.9 to 34.9 +/- 0.5 degrees C. Plasma noradrenaline increased from 481 +/- 126 to 835 +/- 65 pg/ml (P less than 0.05) and plasma adrenaline from 57 +/- 17 to 82 +/- 12 pg/ml (P less than 0.05). There were no significant changes in the albumin-corrected plasma calcium. hCGRP is thus a potent endogenous vasodilator in man and is in fact more potent than any other known vasodilator. Together with the observations that CGRP circulates in normal subjects at relatively high concentration (approximately 25 pmol/l) and that CGRP is present in perivascular nerves, this study suggests a possible role for CGRP in controlling peripheral vascular tone in man.

The changes in arterial pressure and arterial concentrations of noradrenaline, adrenaline and dopamine were monitored in 16 patients undergoing endotracheal intubation. Significant increases in mean arterial pressure and plasma noradrenaline were noted. The increases in arterial pressure were associated with increases in noradrenaline concentrations. Adrenaline and dopamine concentrations did not change significantly following intubation. The results suggest a predominantly sympathetic response during intubation and the need for prophylaxis in patients at risk.

N-Benzyl-N'N"-dimethylguanidine sulphate (BW 467C60) and its ortho-chloro derivative (BW 392C60) had adrenergic neurone blocking and sympathomimetic effects resembling those of bretylium and guanethidine in cats, dogs and monkeys, but they were more potent in blocking adrenergic mechanisms in the cat. BW 467C60 was more active than its chloro derivative. Each compound inhibited release of noradrenaline during stimulation of the splenic nerve of cats, and increased smooth muscle responses to adrenaline and noradrenaline. Pressor responses to standard doses of tyramine were also increased except when large doses of BW 467C60 or BW 392C60 were given. The adrenergic neurone block by BW 467C60 was inhibited by dopamine, cocaine and amphetamine in situations in which these amines inhibit the effects of bretylium and guanethidine. In contrast to guanethidine, BW 467C60 and BW 392C60 did not lower the pressor amine content of the iris of cats 24 hr after administration of single doses of the compounds. BW 467C60 depressed the slope of curves relating the frequency of stimuli applied to the cervical sympathetic nerves and the resulting contraction of the nictitating membrane, but the effects of the lower rates of stimulation were preferentially inhibited. Large intravenous doses of BW 467C60 and BW 392C60 blocked autonomic cholinergic mechanisms and caused neuromuscular paralysis of voluntary muscle. These effects were brief, in contrast to the adrenergic neurone blockade. Both BW 467C60 and BW 392C60 were well absorbed from the alimentary tract. In contrast to guanethidine, BW 467C60 did not cause diarrhoea in guinea-pigs.

1. Responses to catecholamines (adrenaline, noradrenaline, nordefrine) were enhanced by 17beta-oestradiol, progesterone and desoxycorticosterone in untreated and reserpine pretreated aortic strips. Responses to tyramine, believed mediated via endogenous catecholamines, were enhanced only in untreated strips.2. Responses to sympathomimetic amines lacking the catechol nucleus (phenylephrine, synephrine, methoxamine) were potentiated inconsistently by the steroids and reserpine pretreatment reduced markedly the frequency of potentiated responses.3. Known inhibitors of catechol-O-methyl transferase (tropolone, U-0521, pyrogallol) potentiated responses to catecholamines and abolished the enhancing effects of the steroids-when the steroids were given first, there was no further increase in response to catecholamines on adding inhibitors of catechol-O-methyl transferase.4. Experiments with the oil-immersion technique, to eliminate diffusion of drug from the tissue, indicated that 17beta-oestradiol, progesterone and desoxycorticosterone decreased the rate at which aortic strips inactivated adrenaline by O-methylation.5. It is concluded that 17beta-oestradiol, progesterone and desoxycorticosterone potentiate responses to catecholamines in aortic strips by inhibiting a major mechanism for their inactivation.

1. The output of adrenaline and noradrenaline from the adrenal medulla during asphyxia, stimulation of the splanchnic nerves or the intra-arterial injection of acetylcholine, has been investigated in foetal and new-born calves up to 3 weeks of age.2. Between 180 days' gestation and term ( approximately 281 days) the response of the foetal adrenal gland of the calf to asphyxia appeared to be independent of its nerve supply and the discharge consisted largely of noradrenaline. A similar type of discharge was obtained after the intra-arterial injection of acetylcholine, but stimulation of the splanchnic nerves resulted in only a small discharge of both adrenaline and noradrenaline.3. Rapid changes occurred in the response of the adrenal medulla to all forms of stimulation during the first 24 hr after birth. For the first 4-6 hr the adrenal medulla was hypersensitive; thereafter the response rapidly declined and a variable period of depressed excitability followed. The changes affected the output of noradrenaline rather than that of adrenaline and were more pronounced during asphyxia or after the intraarterial injection of acetylcholine. Within 24 hr of birth the amount of noradrenaline released in response to either form of stimulation was less than 25% of that found immediately after birth.4. During the hypersensitive phase immediately after birth splanchnic nerve activity appeared to potentiate the direct effect of asphyxia on the noradrenaline cells since the maximum output of noradrenaline was attained more rapidly and at a higher P(O2) if the splanchnic nerves were intact.5. The non-nervous direct response of the adrenal medulla to asphyxia decreased rapidly after birth and disappeared within 24 hr. It did not reappear at any age and was a feature of foetal life.6. The recovery of the response to acetylcholine occurred between 3 and 8 days after birth with a return of the high level of noradrenaline secretion; no similar increase in the output of adrenaline occurred at this stage.7. The response to asphyxia was not restored to the level found in the new-born calf until 2-3 weeks after birth. At this time the effect on the adrenal medulla appeared to be mediated almost entirely by the splanchnic nerves.8. The effects of chloralose and pentobarbitone anaesthesia on the changes in the nervous response to asphyxia after birth were compared. Essentially the same pattern of changes was found with both anaesthetics although the absolute level of discharge under chloralose was greater and a considerably larger amount of adrenaline was secreted at 3 weeks of age.9. At certain ages stimulation of the splanchnic nerves enhanced the response of the adrenal medulla to subsequent injections of acetylcholine. The noradrenaline output was only significantly increased by this procedure during the period of depressed excitability whereas the adrenaline discharge was always increased throughout the first 3 weeks of life.10. The changes in adrenaline and noradrenaline content of the adrenal glands during the 3-week period after birth were investigated. The noradrenaline concentration was low immediately after birth during the hypersensitive phase and increased during the period of reduced sensitivity. The output of this amine was thus inversely related to its content in the adrenal gland. A similar relation did not occur with adrenaline, the concentration of which remained relatively constant during the first 3 weeks of life.

OBJECTIVE

alpha2-Adrenoreceptors restrain sympathetic nervous outflows and inhibit release of noradrenaline from sympathetic nerves. In-frame deletion of the alpha2C-adrenoreceptor subtype (alpha2CDel322-325) increases the risk of congestive heart failure. Increased delivery of catecholamines to cardiovascular receptors might explain this increased risk.

METHODS

Twenty-nine healthy African-Americans genotyped for alpha2-adrenoreceptor subtype polymorphisms underwent 3H-noradrenaline and 3H-adrenaline intravenous infusion and arterial blood sampling for measurements of rates of entry of endogenous noradrenaline and adrenaline into arterial plasma (total body spillovers) by the tracer dilution technique. Eleven subjects were homozygotes for the alpha2CDel322-325 polymorphism, nine heterozygotes, and nine non-carriers. Subjects were studied during supine rest and during and after i.v. infusion of the alpha2-adrenoreceptor antagonist, yohimbine.

RESULTS

At rest, homozygotes for the alpha2CDel322-325 polymorphism had higher total body noradrenaline spillover than did heterozygotes (t=2.90, df=18, P=0.023) or non-carriers (t=3.22, df=18, P=0.010). Adrenaline spillover was higher in homozygotes than non-carriers (t=2.61, df=18, P=0.045). Administration of yohimbine produced larger, more sustained increments in noradrenaline spillover, heart rate, and anxiety in homozygotes than in the other groups.

CONCLUSIONS

In healthy people, alpha2CDel322-325 polymorphism is associated with increased sympathetic nervous and adrenomedullary hormonal activities, both during supine rest and during pharmacologically evoked catecholamine release. Polymorphisms of the alpha2C-adrenoreceptor may help explain individual differences in predisposition to a variety of disorders of catecholaminergic function, such as cardiovascular disorders, depression or anxiety disorders.

Arterial hypertension is known to be frequently associated with thyroid dysfunction, with a particularly high prevalence in chronic hypothyroidism. However, to our knowledge no comprehensive study addressed causal mechanisms possibly involved in this association. We here report the physiological relationships between blood pressure and neuro-humoral modifications induced by acute hypothyroidism in normotensive subjects. Twelve normotensive patients with previous total thyroidectomy were studied. Ambulatory 24-h blood pressure monitoring was performed, and free T(3), free T(4), TSH, PRA, aldosterone, cortisol, adrenaline, and noradrenaline were assayed 6 wk after oral L-T(4) withdrawal (phase 1) and 2 months after resumption of treatment (phase 2). During the hypothyroid state (TSH, 68.1 +/- 27.7 microIU/ml; mean +/- SD), daytime arterial systolic levels slightly, but significantly, increased (125.5 +/- 9.7 vs. 120.4 +/- 10.8 mm Hg; P < 0.05), and daytime diastolic levels (84.6 +/- 7.9 vs. 76.4 +/- 6.8 mm Hg; P < 0.001), noradrenaline (2954 +/- 1578 vs. 1574 +/- 962 pmol/liter; P < 0.001), and adrenaline (228.4 +/- 160 vs. 111.3 +/- 46.1 pmol/liter; P < 0.05) also increased. PRA remained unchanged (0.49 +/- 0.37 vs. 0.35 +/- 0.21 ng/ml.h; P = NS), whereas both aldosterone (310.3 +/- 151 vs. 156.9 +/- 67.5 pmol/liter; P < 0.005) and cortisol (409.2 +/- 239 vs. 250.9 +/- 113 pmol/liter; P < 0.02) significantly increased. By using univariate logistic regression daytime arterial diastolic values, noradrenaline and aldosterone were found to be significantly related to the hypothyroid state (P < 0.02, P < 0.036, and P < 0.024, respectively). In conclusion, our data show that thyroid hormones participate in the control of systemic arterial blood pressure homeostasis in normotensive subjects. The observed sympathetic and adrenal activation in hypothyroidism, which is reversible with thyroid hormone treatment, may also contribute to the development of arterial hypertension in human hypothyroidism.

1. Action potentials were recorded from seventy-four single and twenty-nine small multifibre nerve strands efferent to the trachea and lungs of cats and dogs. From the pathway (vagal or sympathetic), spontaneous activity, conduction velocity and responses to various interventions the efferent fibres were classified in the following way.2. Group I, vagal. These had a mean conduction velocity of 9.7 m/sec, and had a respiratory but seldom a cardiac rhythm. Their discharge was inhibited during hypertension caused by injections of adrenaline and during inflation of the lungs, but was increased during tracheal occlusion, stimulation of peripheral chemoreceptors and irritation of the larynx. The fibres are thought to be constrictor to the airways.3. Group II, sympathetic. These had a mean conduction velocity of 0.85 m/sec and usually had inspiratory and cardiac rhythms. Their discharge usually responded qualitatively as that of group I fibres to the various interventions, but with clear quantitative differences. They are divided into three subgroups on the basis of their responses to injections of adrenaline and to asphyxial stimuli.4. Group III, vagal and sympathetic. These had a mean conduction velocity of 9.0 m/sec, very slow discharge rates and often an expiratory and cardiac modulation. They were activated during hypertension due to adrenaline and often by tracheal occlusion, chemoreceptor stimulation, laryngeal irritation and lung inflation. Their motor action is unknown.5. Group IV, vagal and sympathetic. These had conspicuous cardiac rhythms resembling those of vascular baroreceptors, but their discharge could not be correlated with arterial blood pressure. Their mean conduction velocity was 6.6 m/sec. Some were active after combined vagotomy and sympathectomy. Together with some unclassified fibres, those of group IV are thought to be aberrant afferent nerves or collateral afferent branches, and possibly to subserve local reflexes.6. The results are discussed in relation to nervous control of effector tissues in the airways and autonomic nervous control generally.

Adrenaline, nicotinic acid (NA), vasopressin (LVP) and other drugs affecting vascular motility are known to increase plasminogen activator (PA) and factor-VIII plasma levels in man. To evaluate the hypothesis that NA, LVP and adrenaline release PA from the endothelial cells of the vessel wall through their common effect on vascular motility, PA has been characterized by means of a histochemical technique on vein biopsies obtained from human volunteers after infusion of the compounds. Furthermore, the effect of single and repeated administration has been compared in order to investigate whether the pattern of PA and factor-VIII variations in plasma is similar with the three drugs. There was no major difference in the PA content of the veins following the marked and sustained increase of the corresponding plasma activities. A simple explanation is that the intensity and duration of the stimulus may not be sufficient to deplete the large stores of the vessel walls. The magnitude, time course and duration of the plasmatic response after single and repeated infusions was on the whole different and peculiar for each drug. A derivative of LVP which is free of vasoactive actions was more effective than LVP in inducing the responses, which could also be elicited in two anephric subjects. These findings suggest that vasoactivity is unlikely to provide the clue to a common pathway for the fibrinolysis and coagulation response after the compounds, and support the existence of different specific receptors.