By using indirect immunofluorescence histochemistry combined with the elution-restaining technique, the presence of a neurotensinlike peptide in some catecholamine neurons in the rat brain has been demonstrated. At the level of the medulla oblongata neurotensinlike immunoreactivity was observed in most of the small-sized catecholamine (adrenaline) cell bodies in the dorsolateral part of the nucleus of the solitary tract and in some catecholamine (noradrenaline) cells in the medial part. Neurotensin-positive fibers were found throughout the solitary tract nucleus with increasing concentrations in the rostral direction. Very few neurotensin fibers were seen in the vagal dorsal motor nucleus, which contained a dense network of adrenaline fibers. In the ventral mesencephalon, neurotensinlike immunoreactivity was seen mainly in dopamine cell bodies in the ventral tegmental area, including midline structures, with only single examples of coexistence in the substantia nigra. The dopamine cell bodies of both the A9 and A10 cell groups were surrounded by dense to medium-dense networks of neurotensin fibers. In the hypothalamus numerous dopamine neurons in the arcuate nucleus exhibited neurotensinlike immunoreactivity. Neurotensin-positive nerve terminals, partially overlapping catecholamine (mainly dopamine) fibers, were seen in the external layer of the median eminence. The present results demonstrate coexistence of neurotensinlike immunoreactivity and catecholamines in populations of neurons in some of the central catecholamine cell groups and provide a morphological basis for interactions between the peptide and amines.

In the chronically catheterized fetal lamb, intravenous infusion of adrenaline at 0.5 microgram/min produced slowing of the secretion of lung liquid or its absorption, an effect which increased exponentially with advancing gestation. Between 120 and 130 days, the characteristic response was slowing of secretion, whereas after 130 days it was absorption. Stimulus-response curves, relating secretion or absorption rate to plasma adrenaline concentration, were obtained by infusing adrenaline into the fetus intravenously at rates between 0.1 and 1.0 microgram/min (0.55-5.5 nmol/min). These curves allowed estimation of the minimum concentration of adrenaline required to inhibit secretion [( Ai]) and this was found to decrease from 0.43 ng/ml. (2.35 nM) at 132-4 days' gestation to 0.029 ng/ml. (0.16 nM) at gestations above 140 days. During spontaneous labour there was a slowing of lung liquid secretion in the early stages followed by absorption during the last 50-150 min. The mean concentration of adrenaline in plasma increased from 0.087 ng/ml. (0.48 nM) in early labour to 6.86 ng/ml. (37.5 nM) in the last 50 min and to 7.17 ng/ml. (39.2 nM) in the early post-natal period. Mean noradrenaline levels at the same times were 1.71 ng/ml. (10.1 nM), 12.14 ng/ml. (71.8 nM) and 9.10 ng/ml. (53.9 nM). The relationship between the plasma adrenaline concentration and the rate of absorption during labour was similar to that found when adrenaline was infused at various rates into the non-labouring fetus of comparable gestational age. The upper airway of the fetus was shown to be capable of acting as a one-way valve allowing outflow but not inflow of liquid. Thus withdrawal of liquid at 5-20 ml./hr from the fetal trachea below the larynx caused closure of the upper airway and this result was obtained both when the recurrent laryngeal nerves were intact and when they were divided.

1. Membrane events accompanying adrenaline-stimulated Cl secretion by the isolated rabbit corneal epithelium were investigated with micro-electrodes. 2. Pulses of adrenaline (5 X 10(-10) M final concentration) delivered to either side of the epithelium produced a transient decrease in epithelial resistance occuring at the outer membrane of the squamous cell. This response was reversible and could be blocked completely by total Cl substitution with SO4. 3. Adrenaline generally produced a small transient increase in epithelial potential occuring also at the squamous cell outer membrane. Reversal potentials obtained for the adrenaline response were 45-1 mV for corneal potential and 22-8 mV for outer membrane. 4. Adrenaline always hyperpolarized epithelial potential when the tear side was bathed in Cl-free solution. Reversing the gradient (Cl-free on the stromal side) slowly and consistently changed the response to a depolarization which reached a steady level after 2 hr. 5. The reversal potential of the outer membrane for the adrenaline response was found to be a semilogarithmic function of the tear side Cl concentration over a broad range with a slope of 56 mV/decade. The reversal potential was zero at a tear side Cl concentration of 41-5 mM, which value may be taken to be representative of cell Cl concentration. 6. After abolishing the adrenaline response by perfusing both sides of the tissue with Cl-free solution, reintroduction of Cl to the stromal side led to a recovery of the epithelial potential response in the hyperpolarizing direction. The recovery of the response was inhibited by ouabain (10(-5) M). 7. The results supported the following model for the influence of adrenaline on anion transport in the epithelium: Cl is transported against an electrochemical potential gradient into the cells from the stromal side by an active process linked to Na-k activated ATPase. Normally a slight gradient exists from cells to tears favouring the passive outward diffusion of Cl. This latter process is enhanged by adrenaline, which increases cell cyclic AMP, in turn increasing the passive Cl permeability of the outer cellular membrane.

1. Adipose tissues from rats fed a balanced diet were incubated in the presence of glucose (20mm) with the following additions: insulin, anti-insulin serum, insulin+acetate, insulin+pyruvate, insulin+lactate, insulin+phenazine methosulphate, insulin+oleate+albumin, insulin+adrenaline+albumin, insulin+6-N-2'-O-dibutyryl 3':5'-cyclic AMP+albumin. 2. Measurements were made of the whole tissue concentrations of adenine nucleotides, hexose phosphates, triose phosphates, glycerol 1-phosphate, 3 phosphoglycerate, 6-phosphogluconate, long-chain fatty acyl-CoA, acid-soluble CoA, citrate, isocitrate, malate and 2-oxoglutarate, and of the release into the incubation medium of lactate, pyruvate and glycerol after 1h of incubation. 3. Fluxes of [(14)C]glucose carbon through the major pathways of glucose metabolism were calculated from the yields of (14)C in various products after 2h of incubation. Fluxes of [(14)C]acetate, [(14)C]pyruvate or [(14)C]lactate carbon in the presence of glucose were also determined. 4. Measurements were also made of the whole-tissue concentrations of metabolites in tissues taken directly from Nembutal-anaesthetized rats. 5. Whole tissue mass-action ratios for phosphofructokinase, phosphoglucose isomerase and the combined (aldolasextriose phosphate isomerase) reaction were similar in vivo and in vitro. The reactants of phosphofructokinase appeared to be far from mass-action equilibrium. In vitro, the reactants of hexokinase also appeared to be far from mass-action equilibrium. 6. Correlation of observed changes in glycolytic flux with changes in fructose 6-phosphate concentration suggested that phosphofructokinase may show regulatory behaviour. The enzyme appeared to be activated in the presence of oleate or adrenaline and to be inhibited in the presence of lactate or pyruvate. 7. Evidence is presented that the reactants of lactate dehydrogenase and glycerol 1-phosphate dehydrogenase may be near to mass-action equilibrium in the cytoplasm. 8. No satisfactory correlations could be drawn between the whole-tissue concentrations of long-chain fatty acyl-CoA, citrate and glycerol 1-phosphate and the observed rates of triglyceride and fatty acid synthesis. Under the conditions employed, the concentration of glycerol 1-phosphate appeared to depend mainly on the cytoplasmic [NAD(+)]/[NADH] ratios. 9. Calculated hexose monophosphate pathway flux rates roughly correlated with fatty acid synthesis rates and with whole tissue [6-phosphogluconate]/[glucose 6-phosphate] ratios. The relative rates of production of NADPH for fatty acid synthesis by the hexose monophosphate pathway and by the ;malic enzyme' are discussed. It is suggested that all NADH produced in the cytoplasm may be used in that compartment for reductive synthesis of fatty acids, lactate or glycerol 1-phosphate.

1. Direct observations have been made on the responses of individual vessels of the microcirculation of rat spinotrapezius muscle to stimulation of the sympathetic paravascular nerve fibres and to topically applied catecholamines.2. All arteries and arterioles were constricted by sympathetic stimulation, the maximum response occurring at a stimulus frequency of 8-10 Hz. Primary and secondary arterioles (13-50 mum internal diameter) showed the greatest percentage change in diameter and remained constricted throughout the 1 min stimulation period whilst terminal arterioles (7-13 mum internal diameter) constricted initially but then returned towards their control diameter before the stimulus ceased.3. By contrast the venules and veins showed no response to sympathetic stimulation.4. In accord with these observations, fluorescence histochemical studies revealed a network of noradrenergic nerve fibres on all arterial vessels but showed no innervation of any venous vessels.5. Topically applied noradrenaline or adrenaline (10(-10)-10(-8) g/ml.) dilated the majority of arteries and arterioles while higher concentrations of either agent produced dose-dependent constrictor responses. In addition, many venules dilated in response to adrenaline (10(-9) g/ml.) while others constricted, but concentrations of either noradrenaline or adrenaline greater than 10(-8) g/ml. produced dose-dependent constriction of all venules and veins.6. The behaviour of the more proximal and more distal arterioles during sympathetic stimulation is in accord respectively with the changes in muscle vascular resistance and in capillary surface area recorded in previous studies during sympathetic stimulation.7. The observation that venous vessels are not influenced by sympathetic nerve fibres contrasts with the established view that venous vessels of skeletal muscle are strongly constricted during sympathetic stimulation. However, reappraisal of the evidence used to support this view indicates that such results may have been misinterpreted, while other available evidence supports the proposal that the present findings may be representative of skeletal muscle vasculature in general.

1. Exposure to altitude hypoxia elicits changes in glucose homeostasis with increases in glucose and insulin concentrations within the first few days at altitude. Both increased and unchanged hepatic glucose production (HGP) have previously been reported in response to acute altitude hypoxia. Insulin action on glucose uptake has never been investigated during altitude hypoxia. 2. In eight healthy, sea level resident men (27 +/- 1 years (mean +/- S.E.M); weight, 72 +/- 2 kg; height, 182 +/- 2 cm) hyperinsulinaemic (50 mU min-1 m-2), euglycaemic clamps were carried out at sea level, and subsequently on days 2 and 7 after a rapid passive ascent to an altitude of 4559 m. 3. Acute mountain sickness scores increased in the first days of altitude exposure, with a peak on day 2. Basal HGP did not change with the transition from sea level (2.2 +/- 0.2 mg min-1 kg-1) to altitude (2.0 +/- 0.1 and 2.1 +/- 0.2 mg min-1 kg-1, days 2 and 7, respectively). Insulin-stimulated glucose uptake rate was halved on day two compared with sea level (4.5 +/- 0.6 and 9.8 +/- 1.1 mg min-1 kg-1, respectively; P < 0.05), and was partly restored on day 7 (7.4 +/- 1.4 mg min-1 kg-1; P < 0.05 vs. day two and sea level). Concentrations of glucagon and growth hormone remained unchanged, whereas glucose, C-peptide and cortisol increased on day 2. Noradrenaline concentrations increased during the stay at altitude, while adrenaline concentrations remained unchanged. In response to insulin infusion, catecholamines increased on day 2 (noradrenaline and adrenaline) and day 7 (adrenaline), but not at sea level. 4. In conclusion, insulin action decreases markedly in response to two days of altitude hypoxia, but improves with more prolonged exposure. HGP is always unchanged. The changes in insulin action may in part be explained by the changes in counter-regulatory hormones.

EA have been a major benefit, and a major detriment, to humans since early in recorded history. Their medicinal properties have been used, and continue to be used, to aid in childbirth, with new uses being found in the treatment of neurological and cardiovascular disorders. The surprisingly broad range of pharmaceutical uses for EA stems from their affinities for multiple receptors for three distinct neurotransmitters (serotonin, dopamine, and adrenaline), from the great structural diversity of natural EA, and from the application of chemical techniques that further expand that structural diversity. The dangers posed by EA to humans and their livestock stem from the ubiquity of ergot fungi (Claviceps species) as parasites of cereals, and of related grass endophytes (Epichloë, Neotyphodium, and Balansia species) that may inhabit pasture grasses and produce toxic levels of EA. Further concerns stem from saprophytic EA producers in the genera Aspergillus and Penicillium, especially A. fumigatus, an opportunistic pathogen of humans. Numerous fungal species produce EA with a wide variety of structures and properties. These alkaloids are associated with plants in the families Poaceae, Cyperaceae, and Convolvulaceae, apparently because these plants can have symbiotic fungi that produce EA. Pharmacological activities of EA relate to their specific structures. Known as potent vasoconstrictors, the ergopeptines include a lysergic acid substituent with an amide linkage to a complex cyclol-lactam ring structure generated from three amino acids. Simpler lysergyl amides and clavines are more apt to have oxytonic or psychotropic activities. One of the lysergyl amides is LSD (5), the most potent hallucinogen known. The EA biosynthetic pathway in Claviceps species has been studied extensively for many decades, and recent studies have also employed epichloës and A. fumigatus. The early pathway, shared among these fungi, begins with the action of an aromatic prenyl transferase, DMATrp synthase, which links a dimethylallyl chain to L-tryptophan. When the dmaW gene encoding DMATrp synthase was cloned and sequenced, the predicted product bore no identifiable resemblance to other known prenyl transferases. The dma W genes of Claviceps species are present in clusters of genes, several of which also have demonstrated roles in EA biosynthesis. In many other fungi, dma W homologues are identifiable in otherwise very different gene clusters. The roles of DMA Trp synthase homologues in these other fungi are probably quite variable. One of them is thought to prenylate the phenolic oxygen of L-tyrosine, and another catalyzes the unusual reverse prenylation reaction in the biosynthesis of fumigaclavine C(10), an EA characteristic of A. fumigatus. The second step of the EA pathway is N-methylation of DMATrp (12) to form 13, which is then subjected to a series of oxidation/oxygenation and reduction reactions to generate, in order, chanoclavine-I (16), agroclavine (19), and elymoclavine (6). Shunt reactions generate a wide variety of other clavines. Two epimerizations occur in this pathway: one from 12 to 16, the other from 16 to 19. Further oxidation of 6, catalyzed by the cytochrome-P450 CloA, generates lysergic acid (1). An unusual NRPS complex, lysergyl peptide synthetase (LPS), is responsible for linking 1 to three hydrophobic L-amino acids to generate the ergopeptide lactams. The LPS complex includes two polypeptides, one (LPS 2) possessing a single module for activation of 1, and the other (LPS 1) possessing three modules, each specifying one of the L-amino acids. Variations in LPS 1 sequences are associated with variations in the incorporated amino acids, leading to differences between strain chemotypes, and even multiple ergopeptines within strains. For example, C. purpurea P1 produces two distinct ergopeptines (ergotamine (4) and ergocryptine (Table I)), each of which is believed to be generated by multiple LPS 1 subunits encoded by separate, but related, genes (lpsA1 and lpsA2). The main ecological roles of EA in nature are probably to protect the fungi from consumption by vertebrate and invertebrate animals. The EA produced by plant-symbiotic fungi (such as epichloë endophytes) may protect the fungus by protecting the health and productivity of the host, which may otherwise suffer excessive grazing by animals. The EA, at levels typical of plants bearing these symbionts, can negatively affect the health of large mammals as well herbivorous insects. Some clavines have substantial anti-bacterial properties, which might protect the fungus and, in some cases, their host plants from infection. However, the fact that a large number of epichloë, and even several Claviceps species, produce no detectable EA indicates that the selection for their production is not universal. An unfortunate fact for many livestock producers is that some of the most popular forage grasses tend to possess EA-producing epichloë endophytes. Such endophytes are easily eliminated, but confer such fitness enhancements to their hosts that their presence is often preferred, despite the toxic EA. The future looks promising for continued interest in EA. Research continues into their pharmacological properties, medicinal uses, and structure-function relationships. New clavines and lysergic acid derivatives are identified regularly from new sources, such as marine animals. Also, programs are well underway to modify or replace epichloë endophytes of forage grasses in order to produce new grass cultivars that lack these toxins.

The recently identified transport proteins organic cation transporter 1 (OCT1), OCT2, and extraneuronal monoamine transporter (EMT) accept dopamine, noradrenaline, adrenaline, and 5-hydroxytryptamine as substrates and hence qualify as non-neuronal monoamine transporters. In the present study, selective transport substrates were identified that allow, by analogy to receptor agonists, functional discrimination of these transporters. To contrast efficiency of solute transport, stably transfected 293 cell lines, each expressing a single transporter, were examined side by side in uptake experiments with radiolabeled substrates. Normalized uptake rates indicate that tetraethylammonium, with a rate of about 0.5 relative to 1-methyl-4-phenylpyridinium (MPP+), is a good substrate for OCT1 and OCT2. It was not, however, accepted as substrate by EMT. Choline was transported exclusively by OCT1, with a rate of about 0.5 relative to MPP+. Histamine was a good substrate with a rate of about 0.6 relative to MPP+ for OCT2 and EMT, but was not transported by OCT1. Guanidine was an excellent substrate for OCT2, with a rate as high as that of MPP+. Transport of guanidine by OCT1 was low, and transport by EMT was negligible. With the guanidine derivatives cimetidine and creatinine, a pattern strikingly similar to guanidine was observed. Collectively, these substrates reveal key differences in solute recognition and turnover and thus challenge the concept of "polyspecific" organic cation transporters. In addition, our data, when compared with previous studies, suggest that OCT2 corresponds to the organic cation/H+ antiport mechanism in renal brush-border membrane vesicles, and that EMT corresponds to the guanidine/H+ antiport mechanism in membrane vesicles from placenta and intestine.

Single bovine adrenal medullary cells have been obtained by retrograde perfusion of adrenal medullae with a solution of 0.05% collagenase in Ca++-free Krebs Henseleit buffer. Chromaffin cells were obtained in high yield (5 X 10(6) cells/g medulla), and more than 95% of these were viable as shown by exclusion of trypan blue. The isolated cells were capable of respiring at a linear rate for a minimum of 120 min. Ultrastructural examination revealed that the cells were morphologically intact, and two distinct types of adrenal medullary cells were identified, on the basis of the morphology of their electron-dense vesicles, as (a) adrenaline-containing and (b) noradrenaline-containing cells. Biochemical analysis showed that the cells contained catecholamines and dopamine-beta-hydroxylase (DBH). The cells released catecholamines and DBH in response to acetylcholine (ACh), and this release was accompanied by changes in the vesicular and surface membranes observed at the ultrastructural level. The time-course of ACh-stimulated catecholamine and DBH release, and the dependence of this release on the concentration of ACh and extracellular Ca++ have been investigated. The isolated cells were pharmacologically sensitive to the action of the cholinergic blocking agents, atropine and hexamethonium.

1. The predominant acute effect of E. coli endotoxin in anaesthetized, ventilated cats was pulmonary hypertension resulting from a 8-12 fold increase in pulmonary vascular resistance. This was followed by decreases in left ventricular (LV) and systemic arterial pressures and in LV dP/dt max. Recovery occurred within 2-4 min and was dependent upon increased sympathetic drive; recovery did not occur in cats treated with the beta-adrenoceptor blocking drug alprenolol.2. The pulmonary vasoconstriction was reduced in cats given compound 48/80 and evidence is presented that it results primarily from histamine release.3. Over the 2-3 h period following endotoxin injection, systemic arterial pressure tended to decrease and heart rate and myocardial metabolic heat production to increase. Myocardial blood flow and LV dP/dt remained fairly stable until the terminal stages of shock.4. The predominant delayed effect of E. coli endotoxin in cats were a markedly reduced stroke volume, an increase in peripheral vascular resistance and a severe metabolic acidosis (arterial base excess-20 mEq/litre). Arterial pO(2) and pCO(2) were not significantly affected. It is concluded that myocardial contractility is maintained at this time through the release of catecholamines and that endotoxin itself depresses contractility.5. The effects of adrenaline and noradrenaline infusions on systolic and diastolic blood pressures, heart rate, cardiac output, myocardial blood flow and LV dP/dt max were markedly reduced in the period 2-3 h after endotoxin. In a few animals some recovery of the response to noradrenaline occurred and was associated with a general circulatory improvement and a reduced metabolic acidosis.

Acute sublingual administration of nifedipine 10--20 mg to 13 hypertensive patients caused a rapid decrease in blood pressure (BP) and a concomitant increase in heart rate (HR), plasma noradrenaline (NA) and plasma renin activity (PRA); there was no significant change in plasma adrenaline (A) or aldosterone (ALDO). Basal PRA was the major determinant of the rise in PRA, as a close correlation was present between the basal value and the increase caused by nifedipine (r = 0.92), p less than 0.001). The rise in PRA was also correlated with the plasma concentration of nifedipine after 60 min (r = 0.80, p less than 0.01), but it was not correlated with the decrease in BP, the rise in HR or the increase in NA. Nifedipine 30--60 mg daily for 6 weeks caused a reduction in mean BP from 133 to 113 mmHg (p less than 0.001). Body weight and serum potassium decreased but no consistent change was noted in NA, PRA, ALDO or 24 h-excretion of catecholamines. A significant correlation was present between the change in NA and that in PRA (r = 0.74, p less than 0.01). The alterations in the various parameters in the acute and chronic studies were not correlated. The findings indicate that different regulatory mechanisms are activated during acute and chronic administration of nifedipine. It is suggested that an initial rise in sympathetic activity gradually decreases during prolonged therapy, but it still remains a determinant of PRA.

SK-N-SH and SH-SY5Y human neuroblastoma cells treated by 12-)-tetradecanoyl-phorbol-13-acetate(TPA) express morphological and biochemical changes, which indicate that differentiation towards more mature cells has occurred. The most prominent morphological changes were the development in 40-60% of the cells of cell-surface projections longer than 50 micrometers and cytoplasmic neurosecretory granules demonstrated by electron microscopy. At the biochemical level, TPA induced a two-fold increase in the relative activity of neuron-specific enolase and 30- to 40-fold increase in noradrenaline and adrenaline concentrations. A decrease in proliferation rate of TPA-treated cells was observed. The biological effects of TPA were slightly potentiated by nerve growth factor.

1. The effects of noradrenaline, adrenaline and isoprenaline on neuromuscular transmission in the rat diaphragm and the influence of adrenergic blocking agents on these actions were investigated.2. The resting membrane potential of the muscle fibre was increased by adrenaline (5 x 10(-6)-10(-5) g/ml.) and isoprenaline (5 x 10(-6) g/ml.) up to 3-4 mV, but noradrenaline (5 x 10(-6)-10(-5) g/ml.) had little effect.3. The amplitude and the half-decay time of the end-plate potential (e.p.p.) were increased by noradrenaline (1 x 10(-6) g/ml.), adrenaline (1 x 10(-7)-10(-5) g/ml.) and isoprenaline (1-5 x 10(-6) g/ml.). The potentiation of the amplitude of the e.p.p. was greater with noradrenaline than with adrenaline and isoprenaline.4. Noradrenaline (5 x 10(-6) g/ml.) increased the frequency of miniature end-plate potentials (m.e.p.p.), but not their amplitude. However, isoprenaline (5 x 10(-6) g/ml.) increased the amplitude of m.e.p.p.s without change in frequency. Adrenaline (5 x 10(-6) g/ml.) increased both frequency and amplitude of m.e.p.p.s.5. Adrenaline (5 x 10(-6) g/ml.) and isoprenaline (5 x 10(-6) g/ml.) increased the input resistance of the muscle membrane. The effect was blocked by the beta-blocker, pronethalol (2 x 10(-6) g/ml.), but not by the alpha-blocker, phentolamine (2 x 10(-6) g/ml.). Noradrenaline did not change the input resistance of the muscle fibre.6. Noradrenaline (5 x 10(-6) g/ml.) and adrenaline (5 x 10(-6) g/ml.) augmented the extracellularly recorded end-plate current (e.p.c.), but they had no effect on the half duration, nor on the action current (a.c.) of the nerve terminal, nor on the synaptic delay. Isoprenaline (5 x 10(-6) g/ml.) had no effect on any of these parameters. The actions of noradrenaline and adrenaline on e.p.c. were abolished by phentolamine (2 x 10(-6) g/ml.), but not by pronethalol (2 x 10(-6) g/ml.).7. Adrenaline (5 x 10(-6) g/ml.) and isoprenaline (5 x 10(-6) g/ml.) enhanced the amplitude of the acetylcholine potential elicited by iontophoretic application of acetylcholine. No such effect was produced by noradrenaline (5 x 10(-6) g/ml.).8. It was concluded that noradrenaline acts on the nerve ending increasing the release of transmitter, and that isoprenaline acts on the post-synaptic membrane enhancing the input resistance, while adrenaline has both presynaptic and post-synaptic actions. The effect on the nerve ending is concerned with the alpha-action, whereas that on post-synaptic membrane with beta-action of the catecholamines.

Cigarette smoking has been implicated in colon cancer. Nicotine is a major alkaloid in cigarette smoke. In the present study, we showed that nicotine stimulated HT-29 cell proliferation and adrenaline production in a dose-dependent manner. The stimulatory action of nicotine was reversed by atenolol and ICI 118,551, a beta(1)- and beta(2)-selective antagonist, respectively, suggesting the role of beta-adrenoceptors in mediating the action. Nicotine also significantly upregulated the expression of the catecholamine-synthesizing enzymes [tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DbetaH) and phenylethanolamine N-methyltransferase]. Inhibitor of TH, a rate-limiting enzyme in the catecholamine-biosynthesis pathway, reduced the actions of nicotine on cell proliferation and adrenaline production. Expression of alpha7-nicotinic acetylcholine receptor (alpha7-nAChR) was demonstrated in HT-29 cells. Methyllycaconitine, an alpha7-nAChR antagonist, reversed the stimulatory actions of nicotine on cell proliferation, TH and DbetaH expression as well as adrenaline production. Taken together, through the action on alpha7-nAChR nicotine stimulates HT-29 cell proliferation via the upregulation of the catecholamine-synthesis pathway and ultimately adrenaline production and beta-adrenergic activation. These data reveal the contributory role alpha7-nAChR and beta-adrenoceptors in the tumorigenesis of colon cancer cells and partly elucidate the carcinogenic action of cigarette smoke on colon cancer.

Allergic rhinitis is common worldwide, with significant morbidity and impact on quality of life. In patients who don't respond adequately to anti-allergic drugs. Subcutaneous allergen immunotherapy is effective although requires specialist administration. Sublingual immunotherapy may represent an effective and safer alternative. This Cochrane systematic review is an update of one published in 2003. We searched Cochrane ENT Group Trials Register, Central, PubMed, EMBASE, CINAHL, Web of Science, Biosis Previews, Cambridge Scientific Abstarcts, mRCT and additional sources. We included randomised, double-blind, placebo- controlled trials of sublingual immunotherapy in adults and children. Two authors selected studies and assessed them for quality. Data were put into RevMan 5.0 for a statistical analysis. We used standardised mean difference (SMD), with a random effect model to combine data. Sixty studies were included, with 49 suitable for meta-analysis. We found significant reductions in symptoms (SMD -0.49; 95%CI (-0.64 to -0.34, P < 0.00001)) and medication requirements (SMD -0.32; 95%CI (-0.43 to -0.21, P < 0.00001)) compared with placebo. None of the trials reported severe systemic reactions, anaphylaxis or use of Adrenaline. This updated review reinforces the conclusion of the original 2003 Cochrane Review that sublingual immunotherapy is effective for allergic rhinitis and appears a safe route of administration.

Determinants of plasma glucose concentrations were studied in patients on admission to hospital with confirmed acute myocardial infarction but without previous glucose intolerance as evidenced by raised concentrations of glycosylated haemoglobin (HbAlc). Mortality in hospital increased significantly with increasing plasma concentrations of glucose in patients with both normal (p less than 0.0001, n = 311) and borderline (p less than 0.02, n = 70) concentrations of HbAlc. There was a weak relation between plasma glucose concentrations and infarct size as estimated by peak aspartate transaminase activity in both HbAlc groups (rs = 0.26, n = 101 and rs = 0.41, n = 35 respectively). A correlation was found between adrenaline and plasma glucose concentrations (r = 0.47, n = 27) and cortisol and plasma glucose concentrations (r = 0.75, n = 19), but the relation of plasma noradrenaline and plasma glucose suggested a threshold effect. Concentrations of adrenaline, but not those of noradrenaline or cortisol, correlated with infarct size as measured both by peak aspartate transaminase activity and cumulative release of creatine kinase MB isoenzyme. Multiple regression analysis showed that concentrations of cortisol, adrenaline, and noradrenaline (but not the concentration of HbAlc, infarct size, or age) are the main determinants of plasma glucose concentration measured in non-diabetic patients when admitted to hospital after acute myocardial infarction.

The properties of a new fluorescence histochemical method for arylethylamines based on reaction with a mixture of 4% formaldehyde and 0.5% glutaraldehyde in aqueous solution are described. At room temperature the aldehyde mixture produced a well-localized fluorescence reaction in tissues, which, when examined microscopically in aqueous solution, was sufficiently intense for fine terminal noradrenergic axons to be seen. If the tissue was subsequently dried, the fluorescence intensity increased. At the same time as inducing the fluorophores, the aldehyde mixture fixed the tissue to a standard well suited for electron microscopy. It thus proved possible to locate amine containing cells in the fluorescence microscope and subsequently examine their ultrastructure. In aqueous models, the aldehyde mixture formed fluorescent products with adrenaline, noradrenaline, dopamine, dopa, 5-hydroxytryptamine and 5-hydroxytryptophan, but not with histamine or octopamine. The fluorescence induced in the aldehyde mixture remained stable if the tissue was subsequently transferred to saline or distilled water and when it was dehydrated in ethanol and cleared with xylene, benzene, chloroform or acetone.

Liquid chromatography with electrochemical detection is used for the determination of adrenaline, noradrenaline and dopamine in rat heart tissue, and the method has also been applied to the determination of basic levels of these compounds in blood plasma. The catecholamines are isolated from the biological sample by adsorption onto alumina and are then desorbed by elution with perchloric acid. The stability of the compounds during the different stages in the work-up process has been studied. A greatly simplified procedure for the preparation of alumina is presented. Both ion-pair reversed-phase and ion-exchange liquid chromatography have been used for the separation of the catecholamines. For plasma samples the method has been validated against radioenzymatic assay and the choice of method is discussed.

The highly specific beta-adrenoceptor radioligand, (+/-)-[125I]iodocyanopindolol, has been used to subclassify beta-adrenoceptors in membranes from human right atrial appendage obtained during open heart surgery. Binding of (+/-)-[125I]iodocyanopindolol was saturable (Bmax = 86.4 +/- 7.4 fmol (+/-)-[125I]iodocyanopindolol bound/mg protein, n = 4), of high affinity (KD = 53 +/- 6 pM, n = 4), rapid, reversible, and stereospecific. The relative potencies of isoprenaline, adrenaline, and noradrenaline for inhibition of (+/-)-[125I]iodocyanopindolol binding and activation of adenylate cyclase were 1:10:10, indicating a population composed mainly of beta 1-adrenoceptors. Inhibition of (+/-)-[125I]iodocyanopindolol binding by beta 1- (practolol, metoprolol, betaxolol) and beta 2- (IPS 339, ICI 118,551, zinterol, procaterol) selective drugs, however, resulted in biphasic displacement curves with slope factors (nH, pseudo Hill coefficients) significantly less than 1.0. Nonlinear regression analysis of these curves revealed a beta 1: beta 2 ratio of 80:20 in human right atrial appendage. Nonselective beta-adrenergic drugs (propranolol, isoprenaline, and adrenaline), on the contrary, inhibited binding with monophasic displacement curves and nH = 1.0. Binding of agonists to the beta-adrenoceptors in human right atrial appendage seems to be regulated by guanyl nucleotides. In the absence of GTP, isoprenaline binds to high and low affinity state of the beta-adrenoceptors. GTP (10(-4) M) converts this heterogeneous binding into a homogeneous one of low affinity. It is concluded that, in human right atria, beta 1- and beta 2-adrenoceptors coexist; however, beta 1-adrenoceptors predominate. The physiological function of beta 2-adrenoceptors in human right atrium remains to be elucidated.

1. Renin reacts with renin-activator to form a strong pressor substance which is heat-stable, water- and alcohol-soluble, fluorescent, acid-stable, and alkali-labile. It is a reducing substance and is destroyed by strong oxidizing substances. It forms crystalline salts with oxalic and picric acids. The color reaction for arginine is the only one found to be strongly positive. It is suggested that this substance be called angiotonin. 2. Angiotonin produces a sharp, immediate rise in arterial pressure when injected intravenously. Pithing and dissipation of the anesthetic appear to increase the response. Tachyphylaxis occurs, in contrast to renin, only after many single doses. 3. The responses to adrenaline and angiotonin do not parallel one another. Cocaine, atropine, and stilbestrol do not affect the pressor action of angiotonin. Suprarenalectomy in brief experiments is also without effect. 4. Maximal amounts of angiotonin result when the proportion between renin and activator is roughly 3 to 100. This is not a stoichiometric relationship in the chemical sense. The temperature suitable for good yields is about 38 degrees C., and the time of reaction from 10 to 20 minutes. 5. Renin destroys angiotonin when incubated with it. 6. Angiotonin causes marked contraction of intestinal segments of rabbits without reducing their rhythmic motion. It sensitizes the intestine to further doses of angiotonin and alters the intestine such that renin-activator contracts it. Angiotonin also constricts the vessels of a rabbit's ear perfused with blood or Ringer's solution.