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PubMed1987

Spectroscopic evidence of two melittin molecules bound to Ca2+-calmodulin.

According to Comte et al. (Comte, M., Maulet, Y. and Cox, J.A., (1983), Biochem.J., 209, 269-272), melittin (Mel) gives rise to a one:one complex. We evidence here, by fluorescence anisotropy and gel filtration binding assay (in the presence of 5 mM CaCl2 and 100 mM NaCl) the existence of two complexes: the well-known CaM.Ca4.Mel and a second CaM.Ca4.Mel2 which had not yet been reported. The affinity of Mel for the CaM.Ca4.Mel species is about three orders of magnitude lower than the affinity of Mel for the CaM-Ca4 species.

Animals↗
PubMed1986

[Determination of plasma catecholamines in clinical biology].

The use of sensitive detectors has enabled the development of high performance liquid chromatography (HPLC) for the dosage of plasma catecholamines (adrenalin, A; noradrenalin, NA and dopamine, DA). Separation of the catecholamines may be done with a pair of ions chromatography on grafted silica or with an exchange of ions chromatography. The quantification is carried out, either by electro-chemical detection (HPLC-ECD), or by fluorometry after catecholamines shunting into trihydroxyindoles compounds (THI). The THI method, more sensitive, does not permit the detection of DA. Plasma levels of A or NA of 30 pg/ml (or 150 fmol/ml) may be measured by HPLC-ECD). The validation of this method as compared with a radioenzymatic method (RA-COMT) permits to imagine that the HPLC-ECD method, which has the advantage of being more economical, less complex and faster than the RA-COMT method, represent a useful tool for the exploration of the adrenergic system clinically as well as in research.

Chromatography, High Pressure Liquid↗
PubMed1985

Effects of two venotropic drugs on inactivation and O-methylation of catecholamines in an isolated canine vein.

Clobenoside (1-O-ethyl-3-O-propyl-5,6-di-O-chlorbenzyl-D-glucofuranose, CL) and Venoruton [O-(beta-hydroxyethyl)-rutosides, HR] did not cause supersensitivity to either exogenous or endogenous (stimulation-released) noradrenaline, in strips of the saphenous vein of the dog. Both drugs caused a significant blockade of the inactivation of noradrenaline, in oil immersion experiments. In incubation experiments with 3H-isoprenaline, CL and HR (100 to 900 mumol/l) caused a dose-dependent inhibition of O-methylation; they had additive effects with the COMT inhibitor, U-0521 and their effects were abolished in the presence of hydrocortisone. In incubation experiments with 3H-adrenaline, formation of metanephrine was inhibited, neuronal uptake and oxidative deamination remaining unaffected. After intravenous administration of HR (100 mg/kg), the O-methylating capacity of blood vessels was similarly reduced. It is concluded that CL and HR affected exclusively the extraneuronal O-methylating system (probably both by inhibiting COMT and depressing uptake) and that this effect may contribute to their therapeutic actions.

Animals↗
PubMed1985

External and internal standards in the single-isotope derivative (radioenzymatic) measurement of plasma norepinephrine and epinephrine.

In plasma from normal humans (n = 9, 35 samples) and from patients with diabetes mellitus (n = 12, 24 samples) single-isotope derivative (radioenzymatic) plasma norepinephrine and epinephrine concentrations calculated from external standard curves constructed in a normal plasma pool were identical to those calculated from internal standards added to an aliquot of each plasma sample. In plasma from patients with end-stage renal failure receiving long-term dialysis (n = 34, 109 samples), competitive catechol-O-methyltransferase (COMT) inhibitory activity resulted in a systematic error when external standards in a normal plasma pool were used, as reported previously; values so calculated averaged 21% (+/- 12%, SD) lower than those calculated from internal standards. However, when external standard curves were constructed in plasma from a given patient with renal failure and used to calculate that patient's values, or in a renal failure plasma pool and used to calculate all renal failure values, norepinephrine and epinephrine concentrations were not significantly different from those calculated from internal standards. We conclude: (1) External standard curves constructed in plasma from a given patient with renal failure can be used to measure norepinephrine and epinephrine in plasma from that patient; further, external standards in a renal failure plasma pool can be used for assays in patients with end-stage renal failure receiving long-term dialysis. (2) Major COMT inhibitory activity is not present commonly if samples from patients with renal failure are excluded. Thus, it would appear that external standard curves constructed in normal plasma can be used to measure norepinephrine and epinephrine precisely in samples from persons who do not have renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Catechol O-Methyltransferase↗
PubMed1980

Catecholamine metabolism in pargyline treated rats exposed to stress.

The administration of pargyline to normal rats enhanced the adrenal catecholamines noradrenaline + adrenaline content, tyrosine hydroxylase (TH) and catechol -0-methyl transferase (COMT) activity together with a reduction in monoamine oxidase (MAO) activity. The pargyline pretreated rats exposed to acute stress exhibited a significant increase in adrenal catecholamine content and COMT activity with no change in TH and phenylethanolamine-N-emthyl transferase (PNMT) activity as compared to normal stressed rats. However, adrenal MAO activity was decreased in pargyline pretreated stressed rats. Thus, these observations tend to suggest that pargyline treatment before exposure to stress considerably influence the usual stress response in term of catecholamine metabolism.

Adrenal Glands↗
PubMed1984

Catechol-O-methyltransferase and Parkinson's disease.

OMD inhibits L-DOPA utilization in rat corpus striatum. This effect is probably mediated through competition with L-DOPA for brain uptake mechanism. Such competition may explain the inhibition exerted by OMD on L-DOPA-induced rotation in rats with unilateral destruction of the nigrostriatal pathway. U-0521, a potent COMT inhibitor, was shown, after i.p. injection, to effectively block the accumulation of OMD in the plasma and to enhance L-DOPA metabolism in rat brain. This drug, however, was not active when given orally to rats and to a single patient with Parkinson's disease. It is suggested that the combined use of L-DOPA plus an orally active COMT inhibitor may be useful in future treatment of Parkinson's disease.

Animals↗
PubMed1978

Sensitization to the generalized Shwartzman reaction by catechol-O-methyltransferase inhibitors.

The generalized Shwartzman reaction (GSR) was produced by a single injection of endotoxin in male rats pretreated with catechol-o-methyltransferase (COMT) inhibitors (tropolone, pyrogallol). Such a result was not obtained with inhibitors (pargyline, phenelzine, isocarboxazide) of the monoamine oxidase (MAO). The inhibitors of the COMT were found to enhance the action of endotoxin on the coagulation system such as evidenced by the increased consumptions of Hageman factor, fibrinogen, and platelets. Tropolone-treated rabbits did not require exogenous stimulation of alpha-adrenergic receptor sites by norepinephrine to localize thrombi in the glomerular capillaries when Hageman factor was activated by ellagic acid and fibrinolysis inhibited by epsilon-amino-caproic acid. It is concluded that interference with the degradation of circulating catecholamines results in sensitization to the generalized Shwartzman reaction.

Animals↗
PubMed1981

Structured exploratory data analysis (SEDA) for determining mode of inheritance of quantitative traits. I. Simulation studies on the effect of background distributions.

We examine through simulations the effectiveness of a new methodology to help distinguish among monogenic, multifactorial, and sporadic trait transmission from parents to offspring in nuclear family data sets. The major gene index (MGI), which compares the deviation of the offspring from the midparental value with a function of the individual deviations between parents and offspring, aids in the discrimination of multifactorial from sporadic and monogenic models. In contrast with other methodologies, the ability of the MGI to separate multifactorial, monogenic, and sporadic models improves with increased skewness in the trait distribution. The midparental correlation coefficient serves as a further guide for indicating mode of inheritance. A new class of techniques, the offspring between parents function (OBP), is introduced that provides a more sensitive tool to help in assessing mode of transmission through the analysis of the level, shape, and undulation characteristics of the curves. Four data examples are used to illustrate the methodology: erythrocyte catechol-O-methyltransferase (COMT) activity, height, weight, and triglyceride measurements. Height appears largely multifactorial, and weight appears to be mostly sporadic, while COMT and triglyceride measurements suggest the presence of some major gene influences.

Genetics↗
PubMed1981

Catechol-O-methyl transferase activity in human mononuclear cells.

Catechol-O-methyl transferase (COMT) activity was investigated in human peripheral mononuclear cells and in human lymphoblastoid cells lines. In any case, we have detected enzymatic activity in the membrane fraction of the cells. Km was found to be 4-9 10(-6) M and the enzyme was inhibited by tropolone and the lack of magnesium. The eventual association of COMT with adrenergic receptor-adenylate cyclase system in mononuclear cells is discussed.

Adult↗
PubMedDate not supplied

Metoprine, an inhibitor of histamine N-methyltransferase but not catechol-O-methyltransferase, suppresses feeding in sated and in food deprived rats.

Metoprine is a histamine N-methyltransferase (HMT) inhibitor often used to elevate endogenous histamine (HA) levels when studying the role of brain HA. Since central histaminergic systems may be involved in the regulation of feeding, the effect of metoprine on food intake was studied in sated and in food deprived rats. The treatment caused a dose-dependent decrease in food intake in sated rats. It also suppressed deprivation-induced feeding. To clarify the specificity of the treatment, the effect of metoprine on another methylating enzyme, catechol-O-methyltransferase (COMT), was examined indirectly by examining the ratio of the non-methylated dopamine metabolite, dihydroxyphenylacetic acid (DOPAC) to that of its methylated product homovanillic acid (HVA). The dopamine metabolites did not change in a manner consistent with COMT inhibition, but instead a transient decrease in DOPAC levels was observed. However, the suppression of feeding is considered to be related to the metoprine-induced inhibition of brain HA catabolism and not with the changes in dopaminergic systems. Metoprine had no effect on brain concentration of serotonin (5-HT) or its metabolite 5-hydroxyindoleacetic acid (5-HIAA). The results provide further support for the role of brain HA in the control of feeding behavior.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

[Study on the metabolism of droxidopa in humans].

Supplement of the deficient neurotransmitters is one of the most effective therapies for neurodegenerative disorders. For the treatment of Parkinson's disease, L-DOPA therapy has been applied to replace dopamine, and droxidopa (L-threo-3,4-dihydroxyphenylserine) therapy to supply noradrenaline (NA). Droxidopa, an artificial amino acid, is decarboxylated by aromatic L-amino acid decarboxylase (AADC) into NA. By application for Parkinson's disease, it alleviated neurological symptoms such as freezing phenomenon, which are refractory to L-DOPA. However, as a precursor of a monoamine, droxidopa was found to be not so effective as L-DOPA; and the clinical efficiency of droxidopa is variable among patients. The metabolic pathway of droxidopa in the brain was examined using human materials. The intraventricular fluid of patients treated with droxidopa, and of control was analyzed by high-performance liquid chromatography with multi-eletrochemical detection (Neurochem). In the intraventricular fluid of the patients treated, free NA concentration increased to be 5.67 +/- 3.40 nM from non-detectable level in the control patients. The patients with higher free NA levels clinically responded better to droxidopa. However, free NA levels varied among patients; and the mechanism of the individual variance should be clarified. In the intraventricular fluid, in addition to NA, a large amount of a metabolite of droxidopa by catechol-O-methyltransferase (COMT), 3-O-methoxy-droxidopa (3OMD), was detected, followed by the metabolites by DOPS-aldolase (DOPS-ALD), protocatechualdehyde and protocatechuic acid. It indicates that considerable parts of administered droxidopa are catabolized by COMT and DOPS-ALD, but not by AADC.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗
PubMed1993

Enzymatic stimulation and enzymatic inhibition in Parkinson's disease.

In order to supplement the deficient catecholamine neurotransmitters, dopamine and noradrenaline, in parkinsonian brains, the following strategies have been tried: (1) the precursor amino acids, L-DOPA and L-threo-dihydroxyphenylserine (DOPS), (2) 6R-L-erythro-tetrahydrobiopterin (BPH4) as tyrosine hydroxylase (TH) cofactor and nicotinamide adenine dinucleotide (NADH) as cofactor of dihydropteridine reductase to stimulate TH, (3) brain transplant of TH-containing cells, (4) inhibitors of monoamine oxidase (MAO) and/or catechol O-methyltransferase (COMT) with or without L-DOPA or L-DOPS, and (5) dopamine receptor agonists. Among these strategies, the precursor, L-DOPA, L-DOPS, MAO and COMT inhibitors, and dopamine receptor agonists have proved to be clinically effective. As a new strategy, increase in deficient TH activity has been tried experimentally and clinically either by stimulation of residual TH activity by the cofactors, BPH4 or NADH, or by brain transplant of natural TH-containing cells (fetal substantia nigra) or genetically engineered TH-containing cells.

Antiparkinson Agents↗
PubMed1994

Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats.

Normetanephrine (NMN) and metanephrine (MN), are the O-methylated metabolites of norepinephrine (NE) and epinephrine (E), whereas dihydroxyphenylglycol (DHPG) is the deaminated metabolite of both NE and E. This study compared production of NMN, MN and DHPG during tracer and high-dose infusions of Ne and E in rats, with and without inhibition of catechol-O-methyltransferase (COMT) or the A and B forms of monoamine oxidase (MAO). Animals also received infusions of NMN and MN to compare plasma clearances and spillovers of NMN and MN with and without MAO inhibition. Inhibition of COMT increased plasma DHPG and decreased plasma NMN and MN, whereas inhibition of MAO decreased plasma DHPG and increased plasma NMN and MN. The increase in NMN and MN after MAO inhibition reflected blocked deamination of NMN and MN by MAO-A, but not MAO-B. The A form of MAO was also largely responsible for deamination of NE. Infused E was deaminated to DHPG less efficiently than NE. High doses of infused E were O-methylated more efficiently than NE, whereas tracer doses were O-methylated similarly. After MAO inhibition NE was O-methylated more efficiently than E. Increased plasma NMN after MAO inhibition reflected the combined effects of a decrease in the plasma clearance of NMN and an increase in the spillover of NMN into plasma, whereas the smaller increase in plasma MN was due solely to a decrease in the plasma clearance of MN. Thus, E and MN are not deaminated at extraneuronal sites of O-methylation, whereas NE is both O-methylated and deaminated with proportionally more deaminated than O-methylated as the concentration of NE increases. The above results support the preference of NE over E for neuronal pathways of metabolism, but indicate considerably more complex differences in the metabolism of NE and E by extraneuronal O-methylation and deamination.

Animals↗
PubMedDate not supplied

[Effect of euphylline and halidor on several indices of catecholamine and serotonin metabolism in the brains and blood of rats].

Euphylline and galidore did not alter the concentration of catecholamines and serotonin in brain of intact rats, but exhibited opposite effects on metabolism of biogenic amines, if their precursors were administered into animals. Galidore decreased the activity of catechol-O-methyl transferase (COMT) and 5-hydroxytryptophane decarboxylase. Euphylline did not influence the COMT activity but increased the activity of 5-HT-decarboxylase. Both preparations did not alter the monoaminooxidase activity.

Aminophylline↗
PubMed1997

New options for treatment of Parkinson's disease.

New medications recently developed for treating Parkinson's disease include two inhibitors of catechol-O-methyltransferase (COMT), entacapone and tolcapone, which, by decreasing the elimination of levodopa, extend the duration of its effects. Increased 'on' time and less 'wearing-off' symptomatology can be expected with the use of these COMT inhibitors. Two non-ergot dopaminergic agonists (pramipexole and ropinirole) and a long-acting ergoline (cabergoline) are also being introduced. These dopaminergic agonists, like the ergot derivatives currently available (bromocriptine, lisuride, and pergolide), are useful as adjuncts to levodopa, and are also efficacious as monotherapies.

Antiparkinson Agents↗
PubMedDate not supplied

[Microdialysis study of tolcapone effect during blockage of neuronal dopamine reuptake caused by GBR-12909].

In vivo brain functions analysis was conducted to assess the effect of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor on extracellular levels of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of awake, freely moving eats during GBR 12909-induced blockade of DA uptake. Tolcapone administration (30 mg/kg, i.p.) failed to change the dopamine output but caused a marked and long-lasting decrease in the extracellular level of HVA and increase in that of DOPAC. In contrast, injection of the DA uptake inhibitor GBR 12909 directly into the striatum (5 microM) or i.p. (20 mg/kg) led to increase in the DA level but had no significant effect on the metabolites. Co-administration of tolcapone (30 mg/kg i.p.) and CBR 12909 (20 mg/kg) increased the DA level further, whereas the changes in HVA and DOPAC levels remained approximately the same as after injection of tolcapone alone. Behavioral observation showed GBR 12909-induced hyperactivity and stereotypy to be potentiated by tolcapone. These findings show that in the rat striatum under conditions of normal nerve activity DA uptake completely inhibits the increase in striatal DA neurotransmission induced by tolcapone (30 mg/kg i.p.) through COMT inhibition.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

The actions of ketamine on vascular smooth muscle.

The responses of rabbit aortic strips superfused with noradrenaline, adrenaline and 5-HT were studied alone and in combination with ketamine (50 mug/ml). Ketamine caused a slight depression of the isolated aorta but potentiated responses to adrenaline but not to noradrenaline or 5-hydroxytryptamine. Ketamine did not potentiate aortic strips contracted to a stable level by pyrogallol and adrenaline. Experiments carried out with COMT from homogenates of rat liver showed that, in contrast to pyrogallol (10(-5) M), ketamine (10(-3) M) did not inhibit the enzyme. Other experiments with rabbits given 6-hydroxydopamine showed that aortas of these rabbits responded in a similar manner to controls when treated with ketamine and catecholamines. Results obtained with aortas contracted by adrenaline and noradrenaline with ketamine present, followed by oil immersion, showed that ketamine prolonged greatly the relaxation induced by adrenaline and to a lesser extent the relaxation induced by noradrenaline. The results of these studies indicate that ketamine prevented catecholamines from reaching the intracellular site of COMT. In this respect, ketamine can be termed an inhibitor of uptake site 2. If this hypothesis is valid then the action of ketamine on vascular tissue might explain the cardiovascular effects of the drug in man and experimental animals.

Animals↗
PubMed1976

[Determination of monoamine oxidase and catechol-O-methyltransferase in human blood components: methodical aspects (author's transl)].

Controversal findings are reported with respect to alternations in activity of monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) in psychoses. Initially we determined the interindividual differences of some biochemical properties of the two enzymes in normal control subjects. Platelet rich plasma and lysate of red blood cells, respectively, were used for assay. Enzyme activity was referred to mg of protein or mg hemoglobin and number of platelets, respectively. Substrates used for COMT assay were: 3,4-dihydroxybenzaldehyde and 3,4-dihydroxybenzoic acid; for MAO determination: tyramine, tryptamine and phenylethylamine. Interindividual as well as intraindividual differences in the biochemical characteristics (apparent Km, Vmax, IC50, meta/para ratio of O-methylation in vitro) were remarkably low, the coefficient of variation was in the range of 30%.

Affective Symptoms↗