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PubMed1984

Characterization of membrane-bound and soluble catechol-O-methyltransferase from human frontal cortex.

Catechol-O-methyltransferase (COMT; E.C. 2.1.1.6) from human frontal cortex occurs in both a soluble and membrane-bound form. Attempts to solubilize the membrane-bound transferase by repeated washing or by extraction into solutions of high ionic strength were unsuccessful. The finding that Triton X-100 was capable of solubilizing membrane-bound COMT suggested that the membrane-bound transferase is an integral membrane protein. The membrane-bound and soluble enzymes did not differ in their requirements for magnesium ions or in their pH-activity profiles; both enzymes showed an optimum near pH 8.0 when assayed in phosphate buffer. In addition, the two enzymes did not differ in the degree of inhibition caused by CaCl2, both enzymes displaying 65% inhibition at 2.5 mM CaCl2. The competitive inhibitors tropolone and nordihydroguaiaretic acid displayed Ki values for the membrane-bound transferase five- to 10-fold lower than those observed for the soluble transferase. Solubilization of membrane-bound COMT in Triton X-100 resulted in an increase in the apparent Km value of the membrane-bound transferase for dopamine. The increase in Km appeared to be due to apparent competitive inhibition by Triton X-100 and reached a limiting value of approximately 80 microM. These results confirm that membrane-bound COMT is an integral membrane protein that may be structurally distinct from soluble COMT.

Catechol O-Methyltransferase↗
PubMed1988

Spontaneous and ouabain-induced efflux of catecholamines and dihydroxyphenylglycol in two canine blood vessels.

The spontaneous efflux of endogenous noradrenaline, dopamine, dihydroxyphenylglycol (DOPEG) from adrenergic nerve endings of 2 canine blood vessels (the mesenteric artery and the saphenous vein) were studied during 8 successive incubation periods of 15 min each. Extraneuronal uptake and O-methylation were minimized by the presence of adequate concentrations of tropolone and hydrocortisone. Both vessels had an efflux characterized by a decline in the 3 catechols, which was most marked for noradrenaline; the mesenteric artery lost larger amounts than the saphenous vein. Ouabain caused a large increase in the efflux of noradrenaline and dopamine and a reduction of DOPEG efflux. Cocaine had only a modest effect, more evident in the case of the mesenteric artery, increasing noradrenaline and reducing DOPEG effluxes. The combination of ouabain and cocaine had no additive effects, and the effects of ouabain were even reduced (on some parameters) by cocaine. Accordingly, the noradrenaline:DOPEG ratio was markedly increased by ouabain, but not by cocaine; cocaine significantly reduced the effects of ouabain. The ratio dopamine:noradrenaline was decreased by cocaine and by ouabain. Comparison of tissue content and efflux allowed us to conclude that apparently no significant de novo synthesis of noradrenaline occurred during the incubation period. We conclude that a fast and early component of spontaneous efflux is due to loss from the neurons and that its greater magnitude in the mesenteric artery may be due to differences in neuronal [Na+] and/or to differences in neuronal membrane adenosine triphosphatase activity. The results also suggest that neuronal reuptake plays only a minor role in the handling of spontaneously released noradrenaline.

Animals↗
PubMed1969

Steroid potentiation of responses to sympathomimetic amines in aortic strips.

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.

Animals↗
PubMed1970

Uptake, metabolism and release of (3H)-adrenaline by human platelets.

1. Measurements were made of the uptake, metabolism and release of [(3)H]-adrenaline by human platelets in citrated plasma or in an artificial medium.2. Radioactive adrenaline was not taken up at 0-2 degrees C. At 37 degrees C there was a slow uptake which continued for at least 5 hours.3. About half of the radioactivity in the platelets was intact adrenaline. The other half was an acidic metabolite from which adrenaline was released by acid hydrolysis.4. The immediate uptake of adrenaline was proportional to its concentration in the plasma up to at least 1 x 10(-5)M. Uptake measured after 1 h also increased linearly with concentration up to about 1 x 10(-4)M but less with higher concentrations. The highest concentration ratio was about 12.5. The concentration of metabolite in the platelets increased with the concentration of added adrenaline only up to about 2 x 10(-4)M.6. The immediate uptake of adrenaline was partially inhibited by phentolamine and dihydroergotamine. Measurement of uptake both immediately and after 1 h showed that the inhibition produced was not increased beyond about 50% by these drugs or by (+/-)-propranolol, chlorpromazine or amitriptyline up to 1 x 10(-4)M.7. Formation of the metabolite was inhibited by pyrogallol, 8-hydroxyquinoline, or tropolone. This inhibition was associated with a corresponding increase in the adrenaline accumulated intact. Formation of the metabolite was not inhibited by monoamine oxidase inhibitors.8. Reserpine caused a small decrease in the uptake of adrenaline radioactivity in 1 h and a great increase in the proportion recovered as metabolite.9. Thrombin caused the release from platelets of intact adrenaline but not of the metabolite.10. Platelets of albino patients with spontaneous haemorrhages accumulated adrenaline radioactivity at the normal rate but this radioactivity was wholly accounted for by metabolite and not released by thrombin.11. After taking up adrenaline, platelets resuspended in artificial medium at 37 degrees C slowly released both adrenaline and its metabolite. At the same time, the intracellular adrenaline was slowly metabolized.12. The Result suggest that human platelets take up adrenaline by two processes, one of which is inhibited by both alpha- and beta-adrenoceptor blocking agents ad well as by phenothiazines; and that in the platelets adrenaline is partly stored in organelles from which, like 5-hydroxytryptamine, it can be specifically released.

Albinism↗
PubMed1971

3,4-dihydroxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetic acid in the mouse striatum: a reflection of intra- and extra-neuronal metabolism of dopamine?

1. The administration of probenecid to mice increased the concentration of 4-hydroxy-3-methoxyphenylacetic acid (HVA) in the striatum, but did not raise the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC).2. After drug treatments which normally increase the concentration of HVA several-fold, inhibition of catechol-O-methyltransferase (COMT) by tropolone greatly reduced the concentration of HVA but resulted in only a small increase in the concentration of DOPAC in the striatum of the mouse.3. These results indicate that HVA and DOPAC do not occur at the same location in the tissue of the striatum and that DOPAC is not normally metabolized to HVA to any great extent in this tissue.4. When mice were treated with reserpine, which is thought to prevent the intraneuronal storage of dopamine, there was an increase in the striatal concentration of DOPAC which preceded an increase in the concentration of HVA. Since non-cholinergic nerve endings of rat brain contain mitochondria and show monoamine oxidase activity, this result suggests that DOPAC is formed intraneuronally.5. It is concluded that the DOPAC in the striatum represents intraneuronal metabolism of dopamine and that only the HVA which is sensitive to the action of probenecid represents entirely extraneuronal metabolism of this amine. Some of the HVA is not sensitive to the action of probenecid. This suggests that part of the metabolism of dopamine involved both locations.6. A group of drugs which are chemically related to amphetamine were tested for their effects on the concentrations of DOPAC and HVA in the striatum. It is suggested that D-amphetamine, 2-aminotetralin and 1,2,3,4-tetrahydroisoquinoline reduced the intraneuronal metabolism of dopamine whereas adamantanamine did not.

Amantadine↗
PubMed1972

Evaluation of mechanisms controlling the release and inactivation of the adrenergic transmitter in the rabbit portal vein and vas deferens.

1. A method is described for the detection and assay of picogramme quantities of noradrenaline. This involves transferring Krebs solution containing noradrenaline to a cascade system where the catecholamine may be bioassayed on superfused preparations of the rabbit aorta and iliac artery.2. Electrical field stimulation of the rabbit vas deferens and portal vein caused the release, into the bathing medium, of a material which was identified by pharmacological and chemical tests as noradrenaline.3. Cocaine (0.3-5 mug/ml) caused a marked increase in noradrenaline output after electrical stimulation of the portal vein and vas deferens. This effect appeared to be maximal at a concentration of 2.4 mug/ml; when the cocaine concentration was increased above 10 mug/ml the noradrenaline output was greatly reduced.4. Phenoxybenzamine (5 mug/ml) caused a 4-8 times greater increase in noradrenaline output than cocaine; however, the increase in output due to phenoxybenzamine was much smaller in tissues pretreated with cocaine.5. Corticosterone (20 mug/ml) increased noradrenaline output by 30-40% in untreated vas deferentia, but caused a 300% increase in output in tissues pretreated with cocaine. Cocaine also caused a much greater increase in output in tissues pretreated with corticosterone than in untreated tissues.6. Treatment with pargyline plus tropolone caused a 100-200% increase in noradrenaline output; this effect was not modified by cocaine, but was abolished when the tissues were pretreated with either phenoxybenzamine or corticosterone.7. When tissues were stimulated for 240 pulses at 1-16 Hz, the output per pulse of noradrenaline increased linearly with the logarithm of the frequency of stimulation. This relationship between frequency and output was seen in both untreated tissues, and in tissues treated with cocaine, phenoxybenzamine, corticosterone or pargyline plus tropolone.8. It is concluded that cocaine enhances output by blocking the neuronal reuptake of noradrenaline, and corticosterone by blocking the extraneuronal uptake and subsequent metabolism of noradrenaline. Phenoxybenzamine acts by blocking both neuronal and extraneuronal uptake mechanisms. There appears to be a dynamic balance in the distribution of noradrenaline between the two uptake mechanisms after the release of the transmission from the nerve endings.9. It is calculated that more than 90% of the noradrenaline released by nerve stimulation (240 pulses at 2-16 Hz) is inactivated by neuronal and extra neuronal uptake mechanisms.10. It is calculated that the fraction of the total noradrenaline store that is released by one pulse at 2 Hz is 6.6 x 10(-5) in the portal vein and 5.6 x 10(-5) in the vas deferens; the corresponding values at 16 Hz were 15.9 x 10(-5) and 16.2 x 10(-5).

Animals↗
PubMed1974

Studies on the metabolism of catecholamines in the central nervous system of the mouse.

1 The distribution of the metabolites of noradrenaline, 1-(3,4-dihydroxyphenyl)ethane-1,2-diol (DOPEG) and 1-(4-hydroxy-3-methoxyphenyl)ethane-1,2-diol (MOPEG), in the brain of the mouse has been investigated.2 The rate of disappearance of the metabolites after inhibition of the enzyme monoamine oxidase has been used to estimate their turnover rates in the mouse hypothalamus. It was concluded that the turnover of DOPEG was much faster than that of MOPEG.3 When mice were treated with reserpine dissolved in 5% ascorbic acid solution there was an increase in the hypothalamic concentration of both MOPEG and DOPEG. However, similar increases in the concentrations of the two metabolites were seen when the animals were treated with 5% ascorbic acid solution alone.4 The administration of tropolone, an inhibitor of the enzyme catechol-O-methyl transferase, resulted in an increase in the concentration of DOPEG.5 Mice, exposed to a temperature of -15 degrees C showed increased hypothalamic concentrations of both DOPEG and MOPEG.6 The rates of formation in the mouse striatum of 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA), acidic metabolites of dopamine, were compared with the turnover rate of dopamine, estimated from the rate at which this catecholamine disappears after treatment with alpha-methyl-p-tyrosine. It was concluded that the estimate of dopamine turnover obtained by this method is likely to be too large because of the compensatory feedback mechanism which is thought to play a role in the metabolism of dopamine in the brain.

Acetylation↗
PubMed1978

The uptake kinetics and metabolism of extraneuronal noradrenaline in guinea-pig trachea as studied with quantitative fluorescence microphotometry.

1 Extraneuronal uptake of noradrenaline and alpha-methylnoradrenaline into single cells of guinea-pig tracheal smooth muscle have been studied by means of quantitative fluorescence microphotometry. 2 Fluorescence brightness due to accumulation of alpha-methylnoradrenaline was dose-dependent and was increased by the catechol-O-methyltransferase inhibitor drugs, tropolone or beta-thujaplicin (200 micrometer) but not by 3,4-dimethoxy-5-hydroxybenzoic acid (200 microgram). 3 Fluorescence brightness due to accumulation of noradrenaline was increased if animals were pretreated with the monoamine oxidase inhibitor drug, nialamide. 4 The study suggests that metabolism of amines by catechol-O-methyltransferase and monoamine oxidase can occur subsequent to extraneuronal uptake is guinea-pig tracheal smooth muscle. 5 The uptake of noradrenaline into tracheal smooth muscle was concentration-dependent, saturable, and had a Km of 156 micrometer.

Animals↗
PubMed1977

Monoamine oxidase and catechol-O-methyl transferase activity in Tetrahymena.

Tetrahymena pyriformis strain HSM was found to have monomine oxidase (MAO) and a catechol-3-methyl transferase-like (COMT) activity. As in mammalian tissues, the MAO activity is predominantly localized in the mitochondrial pellet and COMT in the cytosol. The COMT-like activity was present in amounts comparable to several mouse tissues and was inhibited by tropolone. MAO activity was much lower than in any of the mouse tissues tested, and its activity varied greatly from preparation to preparation. The substrate preference of Tetrahymena MAO was tryptamine greater than serotonin greater than dopamine, and activity increased with increasing pH from pH 6.5 to pH 7.8, as does that of mouse liver MAO. Teh Km of Tetrahymena MAO for tryptamine was approximately 4 micrometer, an order of magnitude lower than that of mouse liver MAO. Sensitivity of inhibition by MAO inhibitors was variable. In some preparations, no inhibition was observed. In others clear inhibition was obtained, harmine and clorgyline being among the most potent inhibitors.

Animals↗
PubMed1983

Lung transit of 111Indium-labelled granulocytes. Relationship to labelling techniques.

The early in vivo distribution of 111Indium-labelled granulocytes, recorded by dynamic imaging using a gamma camara and computer, varied according to the separation and labelling technique. Following i.v. bolus injection, 4 kinetic patterns could be identified: (A) rapid transit through the pulmonary vasculature, (B) delayed transit through the lung with clearance by about 30 min, (C) complete retention by the lung, for up to 10 min, followed by slow release over a period of 1 to 2 h, (D) delayed transit through the lung with a similar time course to (B) but with subsequent heavy liver uptake. Granulocytes labelled with 111In-tropolonate and maintained in plasma throughout the labelling procedure, whether injected as a 'pure' (separated by plasma-enriched density gradient centrifugation) or 'crude' (separated by differential centrifugation) preparation, displayed type A kinetics, thought to most closely represent the normal behaviour of granulocytes. 'Crude' cells labelled in saline with 111In-acetylacetonate displayed type B kinetics. 'Pure' cells isolated on Percoll-saline and labelled in saline with 111In-acetylacetonate displayed type C kinetics, thought to represent granulocyte 'stimulation' and/or damage, or type D kinetics, thought to represent severe damage. The importance is stressed of labelling granulocytes for kinetic studies with a technique that results in minimal alteration of cell behaviour.

Cell Movement↗
PubMed1985

Quantification of the distribution of the marginating granulocyte pool in man.

The kinetics of autologous granulocytes, separated from whole blood and labelled with 111In-tropolonate with continuous maintenance in plasma, have been studied in man, using a gamma camera and computer, with the aim of quantifying the distribution of the marginating granulocyte pool (MGP). We have used 3 approaches: dynamic gamma camera imaging immediately following i.v. injection of labelled cells, comparison of the activity signal from 111In-granulocytes with that from previously injected 111In-labelled red cells and absolute quantification of 111In present in liver, spleen and blood. Deconvolution analysis of the hepatic and peripheral blood time activity curves indicated that hepatic granulocyte transit time was 2.5 +/- SE 0.14 min. By comparison with 111In red cells, hepatic transit time was calculated to be 7.4 +/- SE 0.82 that of red cells, which, assuming an hepatic red cell content of 6% that of the total red cell mass, is equivalent to a transit time of 1.8 min. By comparison with 111In red cells, lung granulocyte transit time as a factor of red cel transit time was 5.4 +/- SE 0.7 at 5 min and 2.5 +/- SE 0.13 at 40 min after granulocyte injection. Using these kinetic data, in combination with previously published values for splenic granulocyte transit time, it was calculated that, 5 min after injection, the MGP accounted for 54% of the total blood granulocyte pool (TBGP), was 90% filled, and was distributed between spleen (19%), liver (26%), lung (33%) and the remainder of the body (22%). At 40 min, the MGP accounted for 60% of the TBGP, had equilibrated with the circulating granulocyte pool (CGP), and was distributed between the spleen, liver, lung and remainder of the body according to the following respective percentages: 35, 25, 10 and 30. The total granulocyte contents of the spleen and liver calculated on the basis of the kinetic data were 21% and 22% respectively and in broad agreement with the values, 34 and 23% respectively, calculated from quantitative scanning. It was concluded that about 70% of the body's MGP was present in the spleen, liver and lung. If the MGP is itself 60% of the TBGP then only about 18% of the TBGP marginates in extra-hepatosplenopulmonary sites.

Cell Adhesion↗
PubMed1999

Location and catalytic characteristics of a multipotent bacterial polyphenol oxidase.

The melanogenic marine bacterium Marinomonas mediterranea contains a multipotent polyphenol oxidase (PPO) able to oxidize substrates characteristic for tyrosinase and laccase. Thus, this enzyme shows tyrosine hydroxylase activity and it catalyzes the oxidation of a wide variety of o-diphenol as well as o-methoxy-activated phenols. The study of its sensitivity to different inhibitors also revealed intermediate features between laccase and tyrosinase. It is similar to tyrosinases in its sensitivity to tropolone, but it resembles laccases in its resistance to cinnamic acid and phenylthiourea, and in its sensitivity to fluoride anion. This enzyme is mostly membrane-bound and can be solubilized either by non-ionic detergent or lipase treatments of the membrane. The expression of this enzymatic activity is growth-phase regulated, reaching a maximum in the stationary phase of bacterial growth, but L-tyrosine, Cu(II) ions, or 2,5-xylidine do not induce it. This enzyme can be separated from a second PPO form by gel permeation chromatography. The second PPO is located in the soluble fraction and shows a sodium dodecyl sulfate (SDS)-activated action on the characteristic substrates for tyrosinase, L-tyrosine, and L-dopa, but it does not show activity towards laccase-specific substrates. The involvement of the multipotent PPO in melanogenesis and its relationship with the SDS-activated form and with the alternative functions proposed for multicopper oxidases in other microorganisms are discussed.

Catalysis↗
PubMed1992

Redistribution of lymphocytes after cortisol administration.

Major surgical procedures awake an endocrine metabolic stress response characterized by increased secretion of cortisol and lymphopenia. The purpose of this study was to clarify to which tissues the lymphocytes are redistributed after cortisol administration. Lymphocytes were isolated from 16 rabbits, labelled with indium-111-tropolone and reinjected into the rabbits. Eight of the rabbits received 25 mg of cortisol intravenously (group I), while eight received isotonic saline (group II). The redistribution of lymphocytes was imaged with a gamma camera and calculated by a connected computer before and two, four, and seven h after cortisol or saline administration. The radioactivity of cells from the spleen and bone marrow decreased to 84% and 56% of the initial values seven h after cortisol administration. The activity of the lymphatic tissues increased to 121% of initial values. It is concluded that during cortisol-induced lymphopenia the lymphocytes are redistributed from peripheral blood, spleen and bone marrow to lymphatic tissue.

Animals↗
PubMed1988

Magnesium and cell proliferation.

Although studies in mammalian cells and yeast suggest that Mg2+ plays an important role in cell growth and hormone response, intracellular roles of Mg2+ are poorly understood. Thus, we are developing methods to study Mg2+ regulation of growth and hormonal response. Preliminary data using cell-permeable Mg2+ indicators based on tropolone suggest the feasibility of the dynamic and selective determination of intracellular free Mg2+ concentration. "Mg2+-deficient" cell lines have also been developed. Murine S49 lymphoma cells in normal 0.8 mM Mg2+ medium double in 17 hours, but die when placed in 0.2 mM Mg2+ medium. Two classes of S49 clones have been isolated which grow in 30 microM Mg2+ with doubling times of 22 and 60 hours. Although total cell Mg2+ is decreased by 50%, the decrease is selective since cytoplasmic Mg2+ is decreased 75% while particulate Mg2+ is unchanged. Hormonal response in the Mg2+ -deficient cells is defective. Cyclic AMP accumulation in response to beta-adrenergic receptor activation is decreased more than 95%. In contrast, the Mg2+ -deficient cells lose only about 50% of their response to PGE1 receptor activation, retain 50% of their beta-receptors, and accumulate cyclic AMP in response to cholera toxin at the wild-type rate. Mg2+ transport also occurs at the wild-type rate, but with a slightly higher affinity and is no longer hormone-sensitive. Ca2+ content is normal or slightly high. T-lymphocytes isolated from rats made Mg2+ -deficient for 8 weeks give similar results, indicating that the Mg2+ -deficient S49 lymphoma cell clones are a good model for Mg2+ -deficiency. The data suggest that lack of Mg2+ causes growth abnormalities and leads to markedly altered receptor-G-protein coupling, but may have less effect on G-protein-adenylate cylase interaction.

Animals↗
PubMed1977

Possible subdivisions among alpha-adrenoreceptors in various isolated tissues.

The ratio (expressed in log10 units) of the equieffective concentrations of (+)- and (-)-noradrenaline has been measured in a variety of isolated tissues in the presence of cocaine (1 x 10(-5) M), tropolone (3 x 10(-5) M) and (+/-)-propranolol (5 x 10(-7) to 5 x 10(-5) M). The values obtained fall into 3 distinct and statistically different groups. Firstly, a high group comprising (mean +/- s.e.) mouse vasdeferens (2-78 +/- 0-04), rabbit duodenum (2-91 +/- 0-07) and ileum (2-86 +/- 0-05). Secondly a middle group comprising rabbit vas deferens (2-54 +/- 0-04), bladder neck muscle (2-56 +/- 0-07) and spleen 2-50 +/- 0-02), guinea-pig vas deferens (2-55 +/- 0-10) and bladder neck muscle (2-48 +/- 0-13) and rat deferens (2-40 +/- 0-08) and thirdlya low group comprising the bladder detrusor muscle from both the rabbit (2-08 +/- 0-08) and the guinea-pig (2-07 +/- 0-04). Under the same conditions measurement of pA2 values for phentolamine and piperoxan against noradrenaline gave the following values in rat vase deferens (8-22 +/- 0-07 and 6-72 +/- 0-03 respectively) and mouse vas deferens (8-31 +/- 0-05 and 6-53 +/- 0-07 respectively). The results are discussed in relation to other findings conderning the nature of the alpha-adrenoreceptor in these tissues. In spite of the absence of any significant difference between the potency of the alpha-adrenoreceptor blocking agents in the two species it is suggested that alpha-adernoreceptors may not belong to a single homogenous population but may vary in their characteristics from tissue to tissue.

Adrenergic alpha-Antagonists↗
PubMed1978

Possible differences in alpha-adrenoceptors in rabbit ileum and spleen.

In isolated tissues from reserpinized rabbits (5 mg kg-1, i.m. 20 h before experiment) and in the presence of cocaine (3 x 10(-5) M), corticosterone (2.8 x 10(-5)M), tropolone (3 x 10(-5) M), propranolol (4 x 10(-5)M) and disodium EDTA (3 X 10(-5)M), the potency ratios (relative to (-)-noradrenaline) of (-)adrenaline, (-)-phenylephrine and (+/-)-methoxamine were (m+/-s.e.) 2.03 +/- 0.13, 0.045 +/- 0.003 and 0.0062 +/- 0.0018 respectively in splenic strips and 1.77 +/- 0.41, 0.093 +/- 0.018 and 0.029 +/- 0.004 respectively in isolated ileum. Although the pA2 values for phentolamine and thymoxamine against (-)-noradrenaline in the two tissues were very similar there was a statistically significant difference when using yohimbine as the alpha-adrenoceptor blocking agent (pA2 = 6.80 +/- 0.30 in spleen; 5.60 +/- 0.12 in ileum). These differences suggest that the alpha-adrenoceptor in the two tissues is not identical. The pA2 value of phentolamine in rabbits ileum was not significantly different whether (-)noradrenaline or (+/-) methoxamine was used as agonist (7.91 +/- 0.07 and 7.97 +/- 0.06 respectively) while that of yohimbine was 5.56 +/- 0.10 using (-)noradrenaline and 6.19 +/- 0.12 using (+/-)methoxamine. In the light of this latter result and, considering the scatter of the experimentally determined values, there may be two alpha-adrenoceptors in rabbit ileum and either or both may not be identical in all respects to the alpha-adrenoceptor found in rabbit spleen.

Animals↗
PubMed1985

In-vitro and in-vivo metabolism of the presynaptic dopamine agonist 3-PPP to a catecholic analogue in rats.

The dopamine agonist 3-PPP and its enantiomers are hydroxylated in-vitro by rat liver microsomes to the catecholamine 3-(3,4-dihydroxyphenyl)-N-n-propylpiperidine (4-OH-3-PPP) with Km and Vmax values of about 1 microM and 2 nmol (mg protein)-1 min-1 respectively. As the catecholamine formed appears to be a good substrate for catechol-O-methyltransferase, in-vivo catecholamine formation in rats from 3-PPP was only detectable after inhibition of COMT by tropolone. The resulting brain levels of 4-OH-3-PPP, as measured by HPLC with electrochemical detection 45 min after administration, were about 350 pmol g-1 after i.p., and about 100 pmol g-1 after s.c. injection of 45 mumol kg-1 3-PPP, with no significant difference between racemic, ( + ) or (-) 3-PPP. It was estimated that these catecholamine levels represent about 1-5% of the 3-PPP levels after i.p., and about 0.2-0.5% after s.c. administration of 3-PPP. The relevance of this metabolic conversion of 3-PPP for its pharmacological profile is discussed.

Animals↗
PubMed1974

Release of endogenous noradrenaline from an isolated elastic artery.

1. The overflow of noradrenaline following field stimulation of vasoconstrictor nerves has been studied in isolated preparations of the guineapig thoracic aorta.2. Stimulation with trains of 3000 pulses at 5 and 25 pulses.s(-1) resulted in mean overflows of 0.15 and 0.17 (ng.g(-1)).pulse(-1) respectively.3. These overflows were not affected by pre-treatment of the aortae with the inhibitor of neuronal amine re-uptake desmethylimipramine (10(-5)M) or with the inhibitors of extraneuronal amine uptake metanephrine (5 x 10(-4)M) or desoxycorticosterone (2.5 x 10(-5)M).4. In contrast, inhibition of monoamine oxidase and catechol-O-methyl transferase with pargyline (1 x 10(-4)M) and tropolone (2.5 x 10(-4)M) caused the mean overflows to be increased to 0.27 and 0.31 (ng.g(-1)).pulse(-1) in response to stimulation at 5 and 25 pulses.s(-1) respectively. Inhibition of either enzyme alone had little effect.5. It is concluded that in the guinea-pig aorta nervously released noradrenaline is inactivated primarily by enzymic metabolism, while neural re-uptake is insignificant. This situation is the reverse of that existing in the uterine artery of the same species.6. Phenoxybenzamine (10(-5)M) also caused pronounced increases in overflow at both high and low frequencies of stimulation. This could be due to an effect of phenoxybenzamine on release of noradrenaline or on some tissue uptake mechanism distinct from the normal neuronal and extraneuronal pathways.7. Calculations based on the overflow at 5 pulses.s(-1) following total enzyme inhibition indicated that a single stimulating pulse liberated 2.1 x 10(-4) of the total transmitter store.

Journal Article↗