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Publication
Journal: Biochemical Journal
July/19/1981
Abstract
Submitochondrial particles from bovine heart in which NADH dehydrogenase is reduced by either addition of NADH and rotenone or by reversed electron transfer generate 0.9 +/- 0.1 nmol of O2-/min per mg of protein at pH 7.4 and at 30 degrees C. When NADH is used as substrate, rotenone, antimycin and cyanide increase O2- production. In NADH- and antimycin-supplemented submitochondrial particles, rotenone has a biphasic effect: it increases O2- production at the NADH dehydrogenase and it inhibits O2- production at the ubiquinone-cytochrome b site. The generation of O2- by the rotenone, the uncoupler carbonyl cyanide rho-trifluoromethoxyphenylhydrazone and oligomycin at concentrations similar to those required to inhibit energy-dependent succinate-NAD reductase. Cyanide did not affect O2- generation at the NADH dehydrogenase, but inhibited O2- production at the ubiquinone-cytochrome b site. Production of O2- at the NADH dehydrogenase is about 50% of the O2- generation but the ubiquinone-cytochrome b area at pH 7.4. Additivity of the two mitochondrial sites of O2- generation was observed over the pH range from 7.0 to 8.8. AN O2- -dependent autocatalytic process that requires NADH, submitochondrial particles and adrenaline is described.
Publication
Journal: Life Sciences
January/28/1977
Publication
Journal: Nature Reviews Molecular Cell Biology
October/6/2002
Abstract
Since the discovery in 1957 that cyclic AMP acts as a second messenger for the hormone adrenaline, interest in this molecule and its companion, cyclic GMP, has grown. Over a period of nearly 50 years, research into second messengers has provided a framework for understanding transmembrane signal transduction, receptor-effector coupling, protein-kinase cascades and downregulation of drug responsiveness. The breadth and impact of this work is reflected by five different Nobel prizes.
Publication
Journal: Journal of Clinical Pathology
May/14/1969
Abstract
Manual and automated methods for the determination of blood glucose have been devised using an oxidase/peroxidase system, with dl adrenaline, a non-carcinogen, as oxygen acceptor. The manual technique employs a stable single solution protein precipitant and the other reagents used are also stable. The automated methods are operated at 40/hr sample speed and washover between samples, over a very wide concentration range, is negligible.
Authors
Publication
Journal: British journal of pharmacology and chemotherapy
April/30/2002
Abstract
A method has been described for the study of the central effects produced by the intracerebral injection of drugs in the unanaesthetized mouse. The effects observed were in good agreement with those obtained after similar injections in cats, dogs and human beings. After intracerebral injection, drugs of diverse structure produced certain generalized effects: changes in positioning of the tail, stupor, hyperexcitability and tachypnoea. Both acetylcholine and methacholine produced an akinetic seizure and depression, but the latter compound also caused lacrimation and salivation. Atropine produced piloerection, increased sensitivity to sound and touch, clonic convulsions and scratching, whereas hexamethonium caused Parkinsonian-like muscle tremors and peripheral vasodilatation. After adrenaline, hyperexcitability, exophthalmos, stupor and death from pulmonary oedema were observed, but (+)-methylamphetamine produced only piloerection and exaggerated activity in response to sound and touch. Ergotamine caused a decreased sensitivity to sound and touch, micturition, and stupor, while ergometrine caused clonic convulsions, piloerection, defaecation and stupor.
Publication
Journal: Nature
June/18/1991
Abstract
Cyclic AMP acts as a second messenger in the modulation of several ion channels that are typically controlled by a phosphorylation process. In cardiac pacemaker cells, adrenaline and acetylcholine regulate the hyperpolarization-activated current (if), but in opposite ways; this current is involved in the generation and modulation of pacemaker activity. These actions are mediated by cAMP and underlie control of spontaneous rate by neurotransmitters. Whether the cAMP modulation of if is mediated by channel phosphorylation is, however, still unknown. Here we investigate the action of cAMP on if in excised patches of cardiac pacemaker cells and find that cAMP activates if by a mechanism independent of phosphorylation, involving a direct interaction with the channels at their cytoplasmic side. Cyclic AMP activates if by shifting its activation curve to more positive voltages, in agreement with whole-cell results. This is the first evidence of an ion channel whose gating is dually regulated by voltage and direct cAMP binding.
Publication
Journal: Nature
February/10/2011
Abstract
β-adrenergic receptors (βARs) are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins upon binding catecholamine agonist ligands such as adrenaline and noradrenaline. Synthetic ligands have been developed that either activate or inhibit βARs for the treatment of asthma, hypertension or cardiac dysfunction. These ligands are classified as either full agonists, partial agonists or antagonists, depending on whether the cellular response is similar to that of the native ligand, reduced or inhibited, respectively. However, the structural basis for these different ligand efficacies is unknown. Here we present four crystal structures of the thermostabilized turkey (Meleagris gallopavo) β(1)-adrenergic receptor (β(1)AR-m23) bound to the full agonists carmoterol and isoprenaline and the partial agonists salbutamol and dobutamine. In each case, agonist binding induces a 1 Å contraction of the catecholamine-binding pocket relative to the antagonist bound receptor. Full agonists can form hydrogen bonds with two conserved serine residues in transmembrane helix 5 (Ser(5.42) and Ser(5.46)), but partial agonists only interact with Ser(5.42) (superscripts refer to Ballesteros-Weinstein numbering). The structures provide an understanding of the pharmacological differences between different ligand classes, illuminating how GPCRs function and providing a solid foundation for the structure-based design of novel ligands with predictable efficacies.
Publication
Journal: British Medical Journal
May/26/2013
Abstract
OBJECTIVE
To determine the effects of longer term modest salt reduction on blood pressure, hormones, and lipids.
METHODS
Systematic review and meta-analysis.
METHODS
Medline, Embase, Cochrane Hypertension Group Specialised Register, Cochrane Central Register of Controlled Trials, and reference list of relevant articles.
METHODS
Randomised trials with a modest reduction in salt intake and duration of at least four weeks.
METHODS
Data were extracted independently by two reviewers. Random effects meta-analyses, subgroup analyses, and meta-regression were performed.
RESULTS
Thirty four trials (3230 participants) were included. Meta-analysis showed that the mean change in urinary sodium (reduced salt v usual salt) was -75 mmol/24 h (equivalent to a reduction of 4.4 g/day salt), and with this reduction in salt intake, the mean change in blood pressure was -4.18 mm Hg (95% confidence interval -5.18 to -3.18, I(2)=75%) for systolic blood pressure and -2.06 mm Hg (-2.67 to -1.45, I(2)=68%) for diastolic blood pressure. Meta-regression showed that age, ethnic group, blood pressure status (hypertensive or normotensive), and the change in 24 hour urinary sodium were all significantly associated with the fall in systolic blood pressure, explaining 68% of the variance between studies. A 100 mmol reduction in 24 hour urinary sodium (6 g/day salt) was associated with a fall in systolic blood pressure of 5.8 mm Hg (2.5 to 9.2, P=0.001) after adjustment for age, ethnic group, and blood pressure status. For diastolic blood pressure, age, ethnic group, blood pressure status, and the change in 24 hour urinary sodium explained 41% of the variance between studies. Meta-analysis by subgroup showed that in people with hypertension the mean effect was -5.39 mm Hg (-6.62 to -4.15, I(2)=61%) for systolic blood pressure and -2.82 mm Hg (-3.54 to -2.11, I(2)=52%) for diastolic blood pressure. In normotensive people, the figures were -2.42 mm Hg (-3.56 to -1.29, I(2)=66%) and -1.00 mm Hg (-1.85 to -0.15, I(2)=66%), respectively. Further subgroup analysis showed that the decrease in systolic blood pressure was significant in both white and black people and in men and women. Meta-analysis of data on hormones and lipids showed that the mean change was 0.26 ng/mL/h (0.17 to 0.36, I(2)=70%) for plasma renin activity, 73.20 pmol/L (44.92 to 101.48, I(2)=62%) for aldosterone, 187 pmol/L (39 to 336, I(2)=5%) for noradrenaline (norepinephrine), 37 pmol/L (-1 to 74, I(2)=12%) for adrenaline (epinephrine), 0.05 mmol/L (-0.02 to 0.11, I(2)=0%) for total cholesterol, 0.05 mmol/L (-0.01 to 0.12, I(2)=0%) for low density lipoprotein cholesterol, -0.02 mmol/L (-0.06 to 0.01, I(2)=16%) for high density lipoprotein cholesterol, and 0.04 mmol/L (-0.02 to 0.09, I(2)=0%) for triglycerides.
CONCLUSIONS
A modest reduction in salt intake for four or more weeks causes significant and, from a population viewpoint, important falls in blood pressure in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. Salt reduction is associated with a small physiological increase in plasma renin activity, aldosterone, and noradrenaline and no significant change in lipid concentrations. These results support a reduction in population salt intake, which will lower population blood pressure and thereby reduce cardiovascular disease. The observed significant association between the reduction in 24 hour urinary sodium and the fall in systolic blood pressure, indicates that larger reductions in salt intake will lead to larger falls in systolic blood pressure. The current recommendations to reduce salt intake from 9-12 to 5-6 g/day will have a major effect on blood pressure, but a further reduction to 3 g/day will have a greater effect and should become the long term target for population salt intake.
Publication
Journal: Genes and Development
August/31/1995
Abstract
The role of the glucocorticoid receptor (GR) in glucocorticoid physiology and during development was investigated by generation of GR-deficient mice by gene targeting. GR -/- mice die within a few hours after birth because of respiratory failure. The lungs at birth are severely atelectatic, and development is impaired from day 15.5 p.c. Newborn livers have a reduced capacity to activate genes for key gluconeogenic enzymes. Feedback regulation via the hypothalamic-pituitary-adrenal axis is severely impaired resulting in elevated levels of plasma adrenocorticotrophic hormone (15-fold) and plasma corticosterone (2.5-fold). Accordingly, adrenal glands are enlarged because of hypertrophy of the cortex, resulting in increased expression of key cortical steroid biosynthetic enzymes, such as side-chain cleavage enzyme, steroid 11 beta-hydroxylase, and aldosterone synthase. Adrenal glands lack a central medulla and synthesize no adrenaline. They contain no adrenergic chromaffin cells and only scattered noradrenergic chromaffin cells even when analyzed from the earliest stages of medulla development. These results suggest that the adrenal medulla may be formed from two different cell populations: adrenergic-specific cells that require glucocorticoids for proliferation and/or survival, and a smaller noradrenergic population that differentiates normally in the absence of glucocorticoid signaling.
Publication
Journal: Science
October/2/1989
Abstract
Since the classification of beta-adrenergic receptors (beta-ARs) into beta 1 and beta 2 subtypes, additional beta-ARs have been implicated in the control of various metabolic processes by catecholamines. A human gene has been isolated that encodes a third beta-AR, here referred to as the "beta 3-adrenergic receptor." Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate; only 2 of 11 classical beta-AR blockers efficiently inhibited this effect, whereas two others behaved as beta 3-AR agonists. The potency order of beta-AR agonists for the beta 3-AR correlates with their rank order for stimulating various metabolic processes in tissues where atypical adrenergic sites are thought to exist. In particular, novel beta-AR agonists having high thermogenic, antiobesity, and antidiabetic activities in animal models are among the most potent stimulators of the beta 3-AR.
Publication
Journal: Journal of Comparative Neurology
January/1/1976
Abstract
A sensitive immunofluorescence technique was used to describe systematically the distrubution of dopamine-beta-hydroxylase (DBH)-containing cell bodies, non-terminal fiber pathways, and terminal fields in the brain of the male albino rat. DBH is the enzyme that catalyzes the conversion of dopamine to noradrenaline, and as such is useful as an anatomical marker for noradrenaline and possibly adrenaline neurons. The enzyme is not present in dopamine- or indolamine-containing neurons. Ten micron frozen sections (1-in 20 series) were prepared in the frontal, sagittal, and horizontal planes from the olfactory bulb to the upper cervical segments of the spinal cord; adjacent sections in each plane were stained for DBH and for cells (toluidine blue=azure II). An atlas consisting of 40 projection drawings of selected frontal sections illustrates the results of the investigation. DBH perikarya are confined to three groups in the pons and medulla: the well defined locus coeruleus, a more diffuse but continuous subcoeruleus group that arches through the pons and ventral medulla, and a third dorsal medullary group centered in the dorsal motor nucleus of the vagus. A single principal adrenergic fiber system distributes a great many of the axons from these neuron groups to a majority of nuclear areas in the brain. In the pons and medulla two components of the fiber system may be distinguished. A medullary branch may be followed from the posterior aspect of the subcoeruleus group dorsally and then anteriorly through the lateral tegmental field and ventral aspect of the vestibular complex to a position subjacent to the locus coeruleus, where it is joined by a subcoeruleus branch consisting of a large number of fibers coursing among cells along the length of the subcoeruleus group, and by fibers arising from the locus coeruleus. Anterior to the locus coeruleus the principal adrenergic bundle courses as a single fiber tract immediately ventrolateral to the central gray in the mesencephalon and in the zona incerta and substantia innominata in the diencephalon. At the level of the septal area separate bundles reach the cortex dorsally over the genu of the corpus calosum via the medial septal-diagonal band nuclei and the lateral septum and ventrally between the olfactory tubercle and caudate-putamen. In the medulla and pons adrenergic fibers undoubtedly course in both directions. Anterior to the most rostral pontine cell bodies, however, all fibers presumably ascend. Along the course of the bundle distinct branches emerge to innervate circumscribed terminal fields. In addition, certain regions of the brain such as the reticular formation and pontine gray receive diffuse DBH innervation derived from less clearly defined pathways. A small number of areas in the brain contain little or no detectable DBH. These include the caudate-putamen, nucleus accumbens, globus pallidus, olfactory tubercle, subthalamic nucleus, substantia nigra, pretectal area, third, fourth and sixth cranial verve nuclei, and the trapezoid body nucleus.
Publication
Journal: British Journal of Pharmacology
February/16/1969
Abstract
1. Noradrenaline and adrenaline reduce the output of acetylcholine by the guinea-pig ileum longitudinal strip by up to 80%, both in resting conditions and after stimulation. The effect is graded with dose, and is detectable with noradrenaline 2 x 10(-7) g/ml. Adrenaline is approximately 4 times as active as noradrenaline, and its action after being washed out is more persistent.2. If resting output is high, both amines have a proportionately greater effect and their action, as dosage is increased, is to reduce resting output to a basal level, relatively constant from strip to strip, of about 10 ng/g/min.3. With stimulation, the effect of the amine is greater at low frequencies, when the output per volley is high, than at high frequencies. The effect is reduced by increasing the number of shocks delivered. There thus appears to be a basal output per volley, of the order of 1-2 ng/g/volley, which can be reached either by relatively rapid stimulation, by prolonged stimulation, or by treatment with these amines.4. If noradrenaline is applied during continued stimulation at 40/min, the depression of acetylcholine output during its presence is followed by an augmented output when the drug is withdrawn. The magnitude of this "overshoot" increases with the duration of noradrenaline exposure.5. Phenylephrine 4 mug/ml. and amphetamine 20 mug/ml. reduced the acetylcholine output, but isoprenaline 1 mug/ml., dopamine 1 mug/ml. and methoxamine 10 mug/ml. were ineffective.6. Phenoxybenzamine reduced the resting output and increased the stimulation output. Of the two other blocking agents examined, phentolamine had no effect on either resting or stimulation output and ergotamine transiently reduced stimulation output. The effect of phenoxybenzamine was not due to a reaction with either adrenoceptive or muscarinic receptors.7. Phenoxybenzamine, phentolamine and ergotamine abolished the effect of adrenaline and noradrenaline on both resting output and on output in response to stimulation.8. In strips obtained from animals treated with reserpine and guanethidine, a rise in resting acetylcholine output and in stimulation output at low frequencies was found. In these conditions, noradrenaline was still effective.9. Reducing the hydroxytryptamine content of the strips by treatment with p-chloro-(+/-)-phenylalanine did not significantly affect acetylcholine output.10. It is concluded that acetylcholine output by the nervous networks of the longitudinal strip is under the normal control of the sympathetic by a species of presynaptic inhibition mediated by alpha receptors. This implies that for a tissue under dual autonomic control, withdrawal of sympathetic control will lead to a parasympathetic response which is not only unopposed but also itself enhanced.
Publication
Journal: Acta physiologica Scandinavica
June/30/2000
Publication
Journal: Journal of Physiology
February/16/1987
Abstract
Individual cells were isolated from the sino-atrial node area of the rabbit heart using an enzyme medium containing collagenase and elastase. After enzymatic treatment the cells were placed in normal Tyrode solution, where beating resumed in a fraction of them. Isolated cells were studied in the whole cell configuration. Action potentials as well as membrane currents under voltage-clamp conditions were similar to those in multicellular preparations. Pulses to voltages more negative than about -50 mV caused activation of the hyperpolarizing-activated current, if. Investigation of the properties of this current was carried out under conditions that limited the influence of other current systems during voltage clamp. The if current activation range usually extended approximately from -50 to -100 mV, but varied from cell to cell. In several cases, pulsing to the region of -40 mV elicited a sizeable if. Both current activation and deactivation during voltage steps had S-shaped time courses. A high variability was however observed in the sigmoidal behaviour of if kinetics. Plots of the fully-activated current-voltage (I-V) relation in different extracellular Na and K concentrations showed that both ions carry the current if. While changes in the external Na concentration caused the current I-V relation to undergo simple shifts along the voltage axis, changes in extracellular K concentration were also associated with changes in its slope. Again, a large variability was observed in the increase of I-V slope on raising the external K concentration. The current if was strongly depressed by Cs, and the block induced by 5 mM-Cs was markedly voltage dependent. Adrenaline (1-5 microM) and noradrenaline (1 microM) increased the current if around the half-activation voltage range and accelerated its activation at more negative voltages. Often, however, drug application failed to elicit any modification of if. Current run-down was observed in nearly all cells, although at a highly variable rate. It was accelerated by raising the extracellular K concentration but did not show a marked use dependence. Both the if activation curve and the fully activated I-V relation were affected by run-down, the former being shifted to more negative values along the voltage axis and the latter being depressed with no apparent change of the if reversal potential.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication
Journal: Circulation
December/10/1990
Abstract
There is a varying hormonal activation in heart failure. To be able to evaluate this activation and relate it to prognosis, we took blood samples at baseline and after 6 weeks from 239 patients with severe heart failure (all in New York Heart Association class IV) randomized to additional treatment with enalapril or placebo. In this study (CONSENSUS), which has previously been reported, there was a significant reduction in mortality among patients treated with enalapril. The present data show in the placebo group a significant positive relation between mortality and levels of angiotensin II (p less than 0.05), aldosterone (p = 0.003), noradrenaline (p less than 0.001), adrenaline (p = 0.001), and atrial natriuretic factor (p = 0.003). A similar relation was not observed among the patients treated with enalapril. Significant reductions in mortality in the groups of patients treated with enalapril were consistently found among patients with baseline hormone levels above median values. There were significant reductions in hormone levels from baseline to 6 weeks in the group of patients treated with enalapril for all hormones except adrenaline. There were no correlations between these changes in hormone levels. Summarily, there is a pronounced but variable neurohormonal activation in heart failure even in patients with similar clinical findings. This activation is reduced by enalapril therapy. The results suggest that the effect of enalapril on mortality is related to hormonal activation in general and the renin-angiotensin system in particular.
Publication
Journal: Pharmacological Reviews
July/25/2001
Abstract
The total and regional peripheral resistance and capacitance of the vascular system is regulated by the sympathetic nervous system, which influences the vasculature mainly through changes in the release of catecholamines from both the sympathetic nerve terminals and the adrenal medulla. The knowledge of the targets for noradrenaline and adrenaline, the main endogenous catecholamines mediating that influence, has recently been greatly expanded. From two types of adrenoceptors (alpha and beta), we have now nine subtypes (alpha1A, alpha1B, alpha1D, alpha2A/D, alpha2B, alpha2A/D, beta1, beta2, and beta3) and two other candidates (alpha1L and beta4), which may be conformational states of alpha1A and beta1-adrenoceptors, respectively. The vascular endothelium is now known to be more than a pure anatomical entity, which smoothly contacts the blood and forms a passive barrier against plasma lipids. Instead, the endothelium is an important organ possessing at least five different adrenoceptor subtypes (alpha2A/D, alpha2C, beta1, beta2, and beta3), which either directly or through the release of nitric oxide actively participate in the regulation of the vascular tone. The availability of transgenic models has resulted in a stepwise progression toward the identification of the role of each adrenoceptor subtype in the regulation of blood pressure and fine-tuning of blood supply to the different organs: alpha2A/D-adrenoceptors are involved in the central control of blood pressure; alpha1-(primarily) and alpha2B-adrenoceptors (secondarily) contribute to the peripheral regulation of vascular tone; and alpha2A/D- and alpha2C-adrenoceptors modulate transmitter release. The increased knowledge on the involvement of vascular adrenoceptors in many diseases like Raynaud's, scleroderma, several neurological degenerative diseases (familial amyloidotic polyneuropathy, Parkinson disease, multiple-system atrophy), some kinds of hypertension, etc., will contribute to new and better therapeutic approaches.
Publication
Journal: Journal of Clinical Endocrinology and Metabolism
August/7/2003
Abstract
Although IL-6 is a key modulator of immune function, it also plays a role in regulating substrate metabolism. To determine whether IL-6 affects lipid metabolism, 18 healthy men were infused for 3 h with saline (Con; n = 6) or a high dose (High-rhIL6; n = 6) or a low dose (Low-rhIL6; n = 6) of recombinant human IL-6 (rhIL-6). The IL-6 concentration during Con, Low-rhIL6, and High-rhIL6 was at a steady state after 30 min of infusion at approximately 4, 140, and 320 pg/ml, respectively. Either dose of rhIL-6 was associated with a similar increase in fatty acid (FA) concentration and endogenous FA rate of appearance (R(a)) from 90 min after the start of the infusion. The FA concentration and FA R(a) continued to increase until the cessation of rhIL-6 infusion, reaching levels approximately 50% greater than Con values. The elevated levels reached at the end of rhIL-6 infusion persisted at least 3 h postinfusion. Triacylglycerol concentrations were unchanged during rhIL-6 infusion, whereas whole body fat oxidation increased after the second hour of rhIL-6 infusion. Of note, during Low-rhIL6, the induced elevation in FA concentration and FA R(a) occurred in the absence of any change in adrenaline, insulin, or glucagon, and no adverse side effects were observed. In conclusion, the data identify IL-6 as a potent modulator of fat metabolism in humans, increasing fat oxidation and FA reesterification without causing hypertriacylglyceridemia.
Publication
Journal: Nature
May/3/1998
Abstract
Stimulation of beta2-adrenergic receptors on the cell surface by adrenaline or noradrenaline leads to alterations in the metabolism, excitability, differentiation and growth of many cell types. These effects have traditionally been thought to be mediated exclusively by receptor activation of intracellular G proteins. However, certain physiological effects of beta2-adrenergic receptor stimulation, notably the regulation of cellular pH by modulation of Na+/H+ exchanger (NHE) function, do not seem to be entirely dependent on G-protein activation. We report here a direct agonist-promoted association of the beta2-adrenergic receptor with the Na+/H+ exchanger regulatory factor (NHERF), a protein that regulates the activity of the Na+/H+ exchanger type 3 (NHE3). NHERF binds to the beta2-adrenergic receptor by means of a PDZ-domain-mediated interaction with the last few residues of the carboxy-terminal cytoplasmic domain of the receptor. Mutation of the final residue of the beta2-adrenergic receptor from leucine to alanine abolishes the receptor's interaction with NHERF and also markedly alters beta2-adrenergic receptor regulation of NHE3 in cells without altering receptor-mediated activation of adenylyl cyclase. Our findings indicate that agonist-dependent beta2-adrenergic receptor binding of NHERF plays a role in beta2-adrenergic receptor-mediated regulation of Na+/H+ exchange.
Publication
Journal: British journal of pharmacology and chemotherapy
November/30/1996
Abstract
A method is described for the assay of circulating hormones after their injection or release into the circulation. The method is applicable to cats, dogs and rabbits, and consists of bathing or superfusing isolated smooth muscle preparations in a stream of heparinized arterial blood taken from and returned to the animal at a constant rate. The tone of the smooth muscle preparations was affected by small changes in the concentrations of various amines. Thus increases in blood concentrations of catechol amines can be assayed with the rat stomach strip and chick rectum preparations. The proportions of adrenaline and noradrenaline in a mixture can be determined. Circulating histamine can be assayed on the blood-bathed guinea-pig ileum and bradykinin on the rat duodenum preparations. The uses and limitations of the technique are discussed.
Authors
Publication
Journal: Nature
May/16/1995
Abstract
Catecholamines such as noradrenaline and adrenaline have been implicated in numerous physiological processes but, although catecholamine synthesis begins at mid-gestation, previous studies have provided little evidence for any role in early development. Furthermore, there are several case reports of humans with noradrenaline deficiency. To investigate this, we use gene targeting to produce mice lacking dopamine beta-hydroxylase and therefore unable to synthesize noradrenaline or adrenaline. We report here that in heterozygous mothers, most homozygous embryos died in utero, and only about 5% reached adulthood. Survival probably depends on catecholamine transfer across the placenta because, in homozygous mothers, all embryos die in utero. Mortality was due to lack of noradrenaline in utero because it could be prevented by treatment with dihydroxyphenylserine, a precursor that can be converted to noradrenaline in the absence of dopamine beta-hydroxylase. Mutant embryos had a histological phenotype similar to that of embryos deficient in tyrosine hydroxylase, suggesting that death might be due to cardiovascular failure.
Publication
Journal: Journal of Physiology
April/24/1977
Abstract
1. The effect of adrenaline on the Ca-dependent slow inward current, Is, of mammalian cardiac muscle has been investigated by the voltage-clamp method. The mechanism of the increase in the conductance, gs, was analysed on the basis of a kinetic scheme (Hodgkin & Huxley, 1952) applicable to this system. 2. The rate constants alphad and betad, of activation of gs were not influenced by adrenaline, although the limiting conductance, gs, was greatly increased. 3. Reduction of [Ca]o from 1-8 to 0-2 mM decreased the amplitude of inward tail currents when gs was fully activated; however, the relative decrease of the current amplitude was the same with and without adrenaline. The reversal potential, ER, of Is was not changed by the drug. This indicates that the catecholamine has no influence on the selectivity of these conductance channels. 4. An increase in the number of functional conductance channels by adrenaline is discussed as a possible mechanism for the increase in Gs.
Publication
Journal: Nature
August/31/1979
Publication
Journal: Naunyn-Schmiedeberg's Archives of Pharmacology
February/18/1976
Abstract
The rabbit pulmonary artery contains postsynaptic alpha-adrenoceptors which meidate smooth muscle contraction; its noradrenergic nerves contain presynaptic alpha-adrenoceptors which mediate inhibition of the release of the transmitter evoked by nerve impulses. Dose-response curves for the pre- and postsynaptic effects of eight alpha-receptor agonists were determined on superfused strips of the artery in the presence of cocaine, corticosterone and propranolo. 1. According to the concentrations which caused 20% of the maximal contraction (EC20 post), the postsynaptic rank order of potency was: adrenaline greater than noradrenaline greater than oxymetazoline greater than naphazoline greater than phenylephrine greater than tramazoline greater than alpha-methylnoradrenaline greater than methoxamine. The pA2 values of phentolamine againstoxymethazoline, phenylephrine, alpha-methylnoradrenaline and methoxamine were 7.43, 7.48, 7.59 and 7.69, respectively. 2. For the investigation of presynaptic effects, the arteries were preincubated with 3H-noradrenaline. All agonists inhibited the overflow of tritium evoked by transmural sympathetic nerve stimulation. According to the concentrations which reduced the stimulation-induced overflow by 20% (EC20 pre), the rank order of potency was: adrenaline greater than oxymetazoline greater than tramazoline greater than alpha-methylnoradrenaline greater than noradrenaline greater than naphazoline greater than phenylephrine greater than methoxamine. 10(-5) M phentolamine shifted the presynaptic dose-response curves for moradrenaline and oxymethazoline to the right. 3. The ratio EC20 pre/EC20 post was calculated for each agonist as an index of its relative post- and presynaptic potency. According to the ratios, the agonists were arbitrarily classified into three groups. Group 1 (ratio about 30: preferentially postsynaptic agonists) comprised methoxamine and phenylephrine; group 2 (ratio near 1; similar pre- and postsynaptic potencies) comprised noradrenaline, adrenaline and naphazoline; group 3 (ratio below 0.2; preferentially presynaptic agonists) comprised oxymetazoline, alpha-methylnoradrenaline and tramazoline (as well as clonidine). 4. Preferentially presynaptic and preferentially postsynaptic agonists had opposite effects on the basoconstrictor response to nerve stimulation. Methoxamine and phenylephrine either did not change or enhanced, but never reduced, the response. In contrast, oxymetazoline, alpha-methylnoradrenaline and tramazoline at low concentrations selectively inhibited the response to stimulation at low frequency (0.25-2Hz). 5. It is concluded that alpha-adrenoceptor agonists vary widely in their relative pre- and postsynaptic potencies, possibly because of structural differences between pre- and postsynaptic alpha-receptors. Pre- and postsynaptic components contribute to their overll postsynaptic effec in actively transmitting synapses. The preferential activation of presynaptic alpha-receptors results in alpha-adrenergic inhibition of synaptic transmission.
Publication
Journal: Regulatory peptides
August/23/1984
Abstract
Neuropeptide Y (NPY)-immunoreactive nerve fibers were numerous around arteries and few around veins. NPY probably co-exists with noradrenaline in such fibers since chemical or surgical sympathectomy eliminated both NPY and noradrenaline from perivascular nerve fibers and since double staining demonstrated dopamine-beta-hydroxylase, the enzyme that catalyzes the conversion of dopamine to noradrenaline, and NPY in the same perivascular nerve fibers. Studies on isolated blood vessels indicated that NPY is not a particularly potent contractile agent in vitro. NPY greatly enhanced the adrenergically mediate contractile response to electrical stimulation and to application of adrenaline, noradrenaline or histamine, as studied in the isolated rabbit gastro-epiploic and femoral arteries. The potentiating effect of NPY on the response to electrical stimulation is probably not presynaptic since NPY affected neither the spontaneous nor the electrically evoked release of [3H]noradrenaline from perivascular sympathetic nerve fibers.
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