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PubMed1975

Functional and biochemical aspects of catecholamine metabolism in brain under hypoxia.

Animals exposed to 6% oxygen showed a partial inhibition of the rate of tyrosine hydroxylation and a blockade of the conditioned avoidance response. The behavioral disruption was suggested to result, at least in part, from a dopaminergic disturbance, since the behavior was restored by the administration of DOPA or apomorphine but not by 5-hydroxytryptophan. Biochemical data showed a selective retardation in brain dopamine (DA) disappearance after synthesis inhibition. Methoxytyramine formation was markedly retarded. Analysis of this effect indicated that the decreased DA turnover was related to the release of transmitter rather than to an effect on catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO). In addition, there was evidence for a partial inhibition of MAO activity by hypoxia as well as a decreased activity of dopamine-betahydroxylase. It was concluded that the disruption of behavior was related to decreased dopaminergic receptor activation and that decreased synthesis played at most a contributory role.

5-Hydroxytryptophan↗
PubMed1976

Catecholamines released from cerebral cortex in the cat; decrease during sensory stimulation.

In an attempt to determine the functional role of catecholamine (CA) nerve terminals in cerebral cortex the release of endogenous norepinephrine (NE) and dopamine (DA) into superfusates from visual and somatosensory cortex of the cat have been measured by a sensitive radiometric enzymatic assay based on the methylation of CA by catechol-O-methyltransferase (COMT) in the presence of a [3H]-methyl donor and followed by resolution of 3H derivatives through a series of organic extractions. In the flaxedilized animal maintained under local anaesthesia with artificial respiration the concentration of CA measured in 30-min superfusates was fairly constant in a given experiment under basal conditions without sensory stimulation, but varied widely from one experiment to another. Variations in NE were often independent of those for DA. For visual cortex the average basal release of NE in experiments was 20.09 +/- 3.64 pg/min/sq.cm while the average for DA was 34.01 +/- 7.62 pg/min/sq.cm. In all experiments intermittent visual stimulation (15/sec) produced a significant reduction in release rate averaging about 42% for NE and 64% for DA in visual cortex. The reduction was relatively non-specific since visual or somatic sensory stimulation produced a decrease in release from both visual and somatic sensory cortical areas. Since it has been shown that there is a relatively non-specific increase in acetylcholine (ACh) release from sensory cortex during stimulation, it is proposed that ACh may regulate CA release at presynaptic CA terminals in the cortex as it does in the periphery. A marked increase in CA release observed on perfusing with nicotine or atropine is consistent with this hypothesis.

Acetylcholine↗
PubMed1979

The intracortical distribution of norepinephrine, dopamine and serotonin in the cerebral cortex of the cat.

The intracortical distribution of the biogenic amines (BA), norepinephrine (NE), dopamine (DA) and serotonin (5-HT), was determined for the parietal and occipital cortical areas of the cat. Under microscopic control, slices of each region were dissected out into 4 fractions: (1) an upper gray fraction (G1); (2) a medium gray fraction (G2); (3) a lower gray fraction (G3) and (4) a white-matter fraction (W). The BA were assayed by means of specific and sensitive radioenzymatic techniques; using catechol-O-methyltransferase (COMT) for the catecholamines (CA), and N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) for the 5-HT. In the two cortical regions studied, NE and DA were found to be distributed in an orderly laminar fashion. The highest levels of endogenous CA were measured in the superficial layers (fractions G1 and G2) while the white matter (fraction W) exhibited the lowest content of both NE and DA. DA represented 32--38% of the total CA content of the parietal cortex and 32--41% of the total CA content in the occipital cortex. In the parietal cortex, the distribution of 5-HT was similar in pattern to that of the CA, i.e., a decreasing concentration gradient with the highest endogenous levels in the G1 fraction and the lowest content in the W fraction. In the occipital cortex, the distribution was also found to be laminar for the gray matter but the W fraction showed a higher endogenous content than the lower gray fraction (G3). The release of NE, DA and 5-HT was studied by means of cortical superfusion in an in vivo preparation. The concentrations of BA measured in 30 min interval superfusates was fairly constant in a given experiment under basal conditions but varied widely from experiment to experiment. Variations in the basal overflow of NE were often independent of those found for DA and the basal overflow of 5-HT seemed independent of those of CA. The laminar intracortical distribution of endogenous NE, DA and 5-HT in cerebral cortex demonstrated by microdissection and biochemical assay techniques suggests a definite and structured pattern of aminergic innervation. Furthermore, the fact that these BA are released and a basal overflow can be detected and measured appears compatible with significant roles of NE, DA and 5-HT in synaptic transmission in the cerebral cortex.

Acetylserotonin O-Methyltransferase↗
PubMed1981

Modes of adaptation of peripheral neuroendocrine mechanisms of the sympatho-adrenal system to short-term stress as studied in two inbred rat strains.

Alterations in mechanisms involved in catecholamine (CA) and corticosterone (B) regulation following short periods of stress have been investigated in two inbred rat strains: a strain more reactive to stress, Wistar-Kyoto (WK), and a less reactive strain, Brown-Norway (BN). Measurements after decapitation stress alone and after decapitation following different periods of immobilization stress, indicate that: (a) plasma CA levels immediately after severe stress (i.e. decapitation) are directly related to the behavioral reactivity of the two rat strains to stress but inversely related to adrenal gland size, their content of CA and biosynthetic enzymes, and to plasma levels of MHPG; (b) levels of B in adrenal glands and in plasma after stress are similar in both strains, in spite of different gland sizes; (c) CAT activity in presynaptic sympathetic terminals is directly related to plasma CA after short-term stress; and (d) liver COMT activity is directly related to plasma CA levels after stress, but inversely plasma levels of MHPG. The implications of the findings are discussed further in the text and lead to the conclusion that the BN strain represents a mode of a slower response to stressful stimuli than WK.

Adaptation, Physiological↗
PubMed1979

Antithyroid and antiperoxidase activity of tropolone and 3-hydroxy-4-pyrone.

Tropolone (TR) and 3-hydroxy-4-pyrone were investigated for antithyroid activity following the finding that the 2-hydroxy-oxo pyridine, 3-hydroxy-4(1H)-pyridone (DHP, I), is goitrogenic. Both compounds inhibited the thyroidal uptake of radioiodine in rats and resembled the thioamide drugs in inhibiting the organic binding of iodine by the thyroid gland rather than the trapping of iodide, but were weaker binding inhibitors than 6-methyl-2-thiouracil (MeTU). Both compounds also inhibited the iodination of bovine serum albumin and thyroglobulin, catalyzed by thyroidperoxidase (TPO), lactoperoxidase (LPO), chloroperoxidase (CPO) and horseradish peroxidase (HPO) in vitro. The inhibitory effect of TR but not that of 3-hydroxy-4-pyrone was antagonized by ferrous ions. When fed to mice at levels of intake expected to produce goitre both compounds were toxic and caused severe liver damage. Thyroid enlargement was not observed in any of these feeiding experiments, but the thyroids of mice fed 0.1% TR showed moderate hyperplasia. It was concluded that both compounds are weakly goitrogenic. Hyperactivity was observed in the mice fed TR which may be associated with inhibition of catechol methyl transferase (COMT).

Animals↗
PubMed1981

Validity of liquid chromatography with electrochemical detection for measuring dopamine in human plasma.

We tested the validity of liquid chromatography with electrochemical detection (LCEC) for measuring dopamine levels in human plasma, by adding known amounts of dopamine standard to human plasma, and by comparison with levels obtained using the catechol-O-methyltransferase radioenzymatic (COMT-RE) assay technique. The correlation between the obtained dopamine concentrations and picograms of added standard was 1.00 and the correlation between the two assay techniques across 32 plasma samples was 0.97. These results demonstrate that LCEC validly measures human plasma dopamine.

Catechol O-Methyltransferase↗
PubMed1975

Studies on the temperature-dependent sensitivity of mouse atria to adrenergic drugs.

The sensitivity of mouse atria (chronotropic response) to beta-adrenergic receptor antagonists was examined at 37 and 26 degrees C under various experimental conditions. When isoproterenol was used as agonist, at 37 degrees C, the pA2 value (from pA2 plots) for propranolol was 8.86 and the slope of the regression line was 0.54. At 26 degrees C, the pA2 value for propranolol was 9.2 and the slope was 0.7. In the presence of tropolone, 10-5 M, the values for pA2 and slope of the regression lines were, respectively, 9.0 and 0.90 at 37 degrees C and 9.17 and 0.98 at 26 degrees C. In other words, decreasing antagonism was prevented by low temperature and tropolone. Isoproterenol was potentiated by tropolone and low temperature, but the effects of low temperature were reduced by tropolone. With sotalol as antagonist, there was greated blockade (dose ratios) of the effects of isoproterenol at 26 than at 37 degrees C. When nylidrin, a non-catecholamine, was used as agonist there was no temperature-dependent sensitivity to sotalol. Furthermore, nylidrin was not potentiated by low temperature. The data show that the observed degree of beta-receptor antagonism can be altered by changing the bath temperature and suggest that this effect is related to COMT activity or an influence of agonist disposition in the tissue.

Adrenergic beta-Antagonists↗
PubMed1977

Changes in striatal dopamine metabolism during precipitated morphine withdrawal.

Precipitation of withdrawal in morphine tolerant/dependent rats by either naloxone or the partial agonist ZK 48491 caused a significant increase in the contration of striatal DA, which persisted for at least 1 h. During the same time the probenecid-induced accumulation of HVA and DOPAC was reduced in the striatum in relation to probenecid-treated tolerant/dependent controls. 20 min after precipitation of withdrawal by naloxone, the striatal concentration of 3-methoxytyramine was decreased by about 40%, while the activity of the DA metabolizing enzymes, MAO and COMT, remained unchanged. Naloxone-precipitated withdrawal was, further, found to delay the depletion of striatal DA caused by inhibition of synthesis 90 min after alpha-methyl-p-tyrosine treatment. All these results provide evidence for a decreased release of DA from the striatum during precipitated morphine withdrawal.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Temperature dependence of beta 1-adrenoceptor-mediated responses examined by use of partial agonists.

The inotropic and chronotropic responses of guinea pig atria, and the relaxation responses of guinea pig intestine, trachea, lung, uterus and vas deferens to catecholamines have been examined at bath temperatures of 38 degrees C and 30 degrees C. Hypothermia resulted in a supersensitivity of cardiac tissues with a decrease in isoprenaline EC50 and an increase in the maximum response to the partial agonist, salbutamol. Ileum responses to isoprenaline were potentiated at 30 degrees C but no partial agonist could be found on this tissue. Responses of the lung and vas deferens to partial agonists were not affected by temperature, while uterine responses were inhibited by hypothermia. The trachea was supersensitive to isoprenaline at 30 degrees C, however this was not due to a change in beta-adrenoceptor sensitivity but an inhibition of COMT. Partial agonist responses of trachea were similar at both temperatures. beta-Adrenoceptor supersensitivity was therefore observed only where responses are mediated primarily by beta 1-adrenoceptors and supports the concept that beta 1- but not beta 2-adrenoceptors exhibit hypothermia-induced supersensitivity.

Adrenergic beta-Agonists↗
PubMed1992

Determination of the catechol-O-methyltransferase inhibitor Ro 40-7592 in human plasma by high-performance liquid chromatography with coulometric detection.

A sensitive and specific high-performance liquid chromatographic method has been developed to measure the catechol-O-methyl-transferase (COMT) inhibitor 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592) in human plasma. The compound and the internal standard were extracted from plasma at pH 2 with n-butyl chloride-ethyl acetate (95:5, v/v). The extract was chromatographed on a reversed-phase column (Hypersil ODS, 5 microns) using a mixture of phosphate buffer (0.05 M, pH 2), methanol and tetrahydrofuran (45:55:5, v/v/v) as the mobile phase. Long-retained components were removed from the system by means of a simple column-switching system. Quantification of the catechol-O-methyltransferase inhibitor was performed by means of coulometric detection (0.1 V). The limit of quantification was about 1 ng/ml, using a 1-ml specimen of plasma. The recovery from human plasma was greater than 88%. The mean inter-assay precision was 5.3% in the range 2.5-1000 ng/ml. Linearity of the standard curve was obtained in the concentration range 2.5-500 ng/ml. The catechol-O-methyltransferase inhibitor was stable in human plasma when stored for six months at -20 degrees C and for 24 h at room temperature. The practicability of the new method was demonstrated by the analysis of more than 400 plasma samples from a tolerance study performed in human volunteers.

Benzophenones↗
PubMed1989

Inhibition of rat liver microsomal estrogen 2-hydroxylase by 2-methoxyestrogens.

The inhibition of estrogen 2-hydroxylase by 2-methoxyestrogens was demonstrated in screening assays and has been further investigated under initial velocity conditions. The ability of 2-methoxyestradiol and 2-methoxyestrone to block the conversion of estradiol to 2-hydroxyestradiol by male rat liver microsomal preparations was determined by measuring the release of 3H2O from [2-3H]estradiol. The apparent Kis were found to be 34.86 microM for 2-methoxyestradiol and 18.65 microM for the methoxyestrone, with the apparent Km for the substrate estradiol in these essays of 3.21 microM. Mixed inhibition studies with the methoxyestrogens and 2,4-dibromoestradiol, an effective estrogen 2-hydroxylase inhibitor, in male rat liver microsomes resulted in Dixon plots consisting of a series of parallel lines. Thus, methoxyestrogens and 2,4-dibromoestradiol are mutually exclusive inhibitors, i.e., the binding of one compound to the enzyme interferes with the binding of the other. These results indicate that the compounds are interacting at the same enzymatic site. Finally, a method utilized to measure estrogen 2-hydroxylase activity in vitro is a radioenzymatic assay involving addition of catechol o-methyltransferase (COMT) and radiolabeled S-adenosylmethionine, and the amount of catechol estrogens formed is determined by the amount of radiolabeled methoxyestrogens isolated. The results described here demonstrate inhibition of estrogen 2-hydroxylase by methoxyestrogens; however, under enzymatic conditions of low product formation, the estrogen 2-hydroxylase inhibitory effect of catechol estrogen products from the radioenzymatic assay would be insignificant. Thus, these interactions of methoxyestrogens suggest that the steroid hormonal environment be considered in the examination of estrogen 2-hydroxylase and the catechol estrogen products. off

2-Methoxyestradiol↗
PubMed1983

O-methylation of dopamine-o-sulfates with catechol-0-methyltransferase.

[2H2]-dopamine-3-0-sulfate (DM-3-0-S) and [2H2]-dopamine-4-0-sulfate (DM-4-0-S) were synthesized to investigate the possibility of their being substrates for catechol-0-methyltransferase (COMT). [2H5]-3-0-methyldopamine (3-0-Me-DM) and [2H5]-4-0-methyldopamine (4-0-Me-DM) were also synthesized as internal standards for the determination of enzymatic products by gas chromatography-mass spectrometry (GC-MS). [2H2]-DM-3-0-S or [2H2]-DM-4-0-S was incubated at 37 degrees for 60 min in the presence of S-adenosyl-L-methionine with a crude enzyme preparation obtained from rat liver homogenate. The incubation mixture was treated with 0.5N HCl at 100 degrees C for 1h to hydrolyze the remaining sulfate moiety. The reaction products were extracted with an Amberlite XAD-4, derivatized with pentafluoropropionic anhydride and determined by GC-MS. When [2H2]-DM-3-0-S was used as a substrate, [2H2]-3-0-Me-DM was found to be a major product accompanied by [2H2]-4-0-Me-DM as a minor product. The ratio of [2H2]-3-0-Me-DM to [2H2]-4-0-Me-DM was found to be 26:1, while the ratio was 5.4:1 when [2H2]-dopamine was used as a substrate. When [2H2]-DM-4-0-S served as a substrate, [2H2]-3-0-Me-DM was preferentially produced without detectable formation of [2H2]-4-0-Me-DM.

Animals↗
PubMed1990

Intracellular accumulation of isoproterenol enhances the lactate production in the perfused rat heart.

Effects of intracellular accumulation of isoproterenol (ISO) on lactate production were examined in perfused rat heart. The lactate production during ISO perfusion in rat heart was increased and subsequent addition of an inhibitor of catechol-O-methyl transferase (COMT) further enhanced the production, and the enhanced production was significantly reduced by uptake2 inhibitor. The perfusion with ISO free-medium in the heart with high intracellular accumulation of ISO produced lactate more than that in the low intracellular accumulation. The present experiments demonstrated that the enhanced lactate production is accompanied by intracellular accumulation of ISO in the perfused rat heart, and suggested that the accumulated ISO may activate intracellular beta-adrenoceptors in the rat heart.

Animals↗
PubMed1990

Overflow of endogenous dopamine and 3,4-dihydroxyphenylacetic acid from tissues of the rat brain, elicited by electrical stimulation, depolarization by potassium and activation of carrier-mediated release.

Overflow of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) from slices of striatum and slices containing the nucleus accumbens of the rat, during spontaneous loss and as elicited by electrical stimulation, depolarization by potassium and carrier-mediated release, in conditions of inhibition of COMT was studied. Levels of dopamine and DOPAC in tissues and in the superfusates were quantified by means of high pressure liquid chromatography with electrochemical detection (HPLC-ECD). Inhibition of neuronal uptake by cocaine (10 mumol/l) or GBR 12909 (100 nmol/l) was found to increase only the spontaneous outflow of dopamine. Electrical stimulation of slices of striatum produced an increase in levels of overflow of dopamine, but not of DOPAC. Inhibition of neuronal uptake during electrical stimulation potentiated the release of dopamine and slightly reduced levels of DOPAC in the effluent. Changes in the electrically-stimulated or potassium-evoked release of dopamine, as a result of blockade or activation of prejunctional dopamine receptors, did not affect levels of DOPAC in the effluent. Release of dopamine, induced through a favourable sodium gradient, was not accompanied by an increased release of DOPAC. The results presented demonstrate that most of the DOPAC does not originate from a recently released pool of dopamine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1978

Estrogen 2-hydroxylase: activity in rat tissues.

Incubation parameters for a radioderivative assay for estrogen 2-hydroxylase have been examined. The assay was found to be specific and sensitive if a chromatographically purified preparation of COMT was used. Estradiol was found to be a better substrate for the 2-hydroxylase than estrone or estriol. The liver had significantly higher estrogen 2-hydroxylase activity than any other tissue examined. The estrogen 2-hydroxylase was highly localized in the microsomal fraction in both the liver and the brain. The male rat was found to have significantly more estrogen 2-hydroxylase activity in the liver than the female rat. In addition, in the male rat liver, the estrogen 2-hydroxylase activity was reversibly inducible by testosterone and was not affected by phenobarbital. In the male and female rat brain the estrogen 2-hydroxylase activities were similar.

Animals↗
PubMed1983

The absence of a catechol estrogen effect on blood pressure in the male rat.

Since catechol estrogens are potent competitive inhibitors of catechol-O-methyl transferase (COMT), it has been suggested that they may prolong the half-life of catecholamines which in turn can cause hypertension. Thus, experiments were carried out to study the effect of catechol estrogens on blood pressure in the male rat following chronic administration. Results demonstrate that 2-hydroxyesterone (2,3-dihydroxyestra-1,3,5(10)-trien-17-one) and 2-hydroxy-estradiol (estra-1,3,5(10)-triene-2,3,17 beta-triol) even when administered in high doses do not alter blood pressure.

Animals↗
PubMed1976

Noradrenaline synthesis from L-DOPA in rodents and its relationship to motor activity.

Evidence has been obtained for an increase in noradrenaline (NA) turnover after administration of L0DOPA to rodents. Normal mice, and those pre-treated with either reserpine or alpha-methyl-p-tyrosine (AMPT) were given L-DOPA (200 mg/kg) plus MK 486 (alpha-methyldopahydrazine; 25 mg/kg). In all cases L-DOPA produced a rise in cerebral dopamine (DA) levels. Cerebral NA levels were increased by L-DOPA in reserpinised and AMPT-treated mice. The same dose of L-DOPA produced no change in NA in normal mice, although pre-treatment with the monoamine oxidase inhibitor pargyline (200 mg/kg) resulted in a greater rise in NA 1 hr after L-DOPA compared to animals receiving pargyline alone. This evidence suggests that NA is synthesized from- L-DOPA in all these situations. But whole brain 3-methoxy-4-hydroxyphenylglocol sulphate (MOPEG-SO4), a major metabolite of NA, measured after administration of the same dose of L-DOPA plus MK 486, was unaltered in normal and AMPT-treated rats, and was significantly decreased in reserpinised rats. However, an elevation of whole brain MOPEG-SO4 was found in reserpinised and AMPT-treated rats after a lower dose of L-DOPA (50 mg/kg). This discrepancy may be explained by high doses of L-DOPA causing inhibiton of catechol-O-methyl transferase (COMT), which is suggested by the observation that the forebrain homovanillic acid (HVA): 3,4-dihydroxyphenylacetic acid (DOPAC) ratio was significantly lower after the high dose of L-DOPA than in untreated mice. Such an inhibition would prevent formation of MOPEG-SO4. Pretreatment with dopamine-beta-hydroxylase inhibitor FLA (63(bis-(1-methyl-4-monopiperazinyl-thiocarbonyl)disulphide) prevented the increase in NA And MOPEG-SO4 formation observed following L-DOPA induced motor activity in these groups of animals suggesting the involvement of NA in the production of such behaviour.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Differences in activity in cerebral methyltransferases and monoamine oxidases between audiogenic seizure susceptible and resistant mice and deermice.

The specific acitivity of cerebral histamine N-methyltransferase (HMT) was significantly lower in the audiogenic seizure-susceptible (SS) 21-day old DBA/2J mouse when compared to the non-susceptible 70-day old DBA/2J mouse but not when compared to the seizure resistant (SR) C57B1/6J mouse at 21 days of age. There was no significant difference between the two strains at 70 days of age. The lower HMT specific activity was also observed in a SS mutant of the deermouse Peromyuscus maniculatus, relative to the SR, wild-type animal. The activity of cerebral catechol-O-methyltransferase (COMT) was significantly lower in the DBA/2J mice relative to the C57B1/6J at 21 and 70 days while, in Peromyscus, it was higher in the SS mutant than in the SR animal. The activity of MAO, B was lower in the 21-day old, relative to the 70-day old DBA/2J and the 21-day old C57B1/6J mice. There were no differences in MAO A or B between SS and SR Peromyscus. The findings raise the possibility that cerebral methylation may operate at characteristic rates in SS animals.

Acoustic Stimulation↗