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Biomedical subjects

W Kehr

Publications and source records attributed to W Kehr.

At least 37 records · Page 2Linked to original sources
PubMed1981

Endogenous dopa in rat brain. Occurrence, distribution and relationship to changes i catecholamine synthesis.

Dopa was isolated from rat brain by cation exchange chromatography and determined by a radioenzymatic method using catechol-O-methyl-transferase and [3H]-S-adenosyl-methionine as cofactor. The product [3H]-methoxytyrosine was purified by cation and anion exchange chromatography. For identification of presumed endogenous dopa isolated from rat brain and rat blood plasma the [3H]-labelled product was purified further by thin-layer chromatography. In the brain of rats killed by decapitation, dopa in a concentration of 7 ng/g was identified. When unstressed rats were killed by focussed microwave irradiation at 2.450 MHz and 8 kW for 1.3 s dopa levels as high as 20 ng/g were measured. The regional distribution of dopa in brain or rats killed by microwaves was similar to the distribution of catecholamines, dopa levels being highest in c. striatum and lowest in cerebellum. Inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine methylester HCl, 250 mg/kg i.p. 90 min before death did not change the brain dopa levels in rats killed by decapitation or in rats killed by microwaves. Compounds, such as haloperidol, chlorpromazine, apomorphine and pentobarbital which are known to increase or decrease catecholamine synthesis did not change the basal level of dopa. The data indicate that in rat brain, the main portion of dopa is associated with catecholamine-containing nerve terminals and that this portion is present in a pool which is only slowly metabolized. A second very small pool of dopa must exist, which is serving as precursor pool for catecholamines and which is turned over at a higher rate. It can be concluded that the basal dopa level cannot be used as an indicator of catecholamine synthesis.

Animals↗
PubMed1981

Conjoint radioenzymatic measurement of catecholamines, their catechol metabolites and DOPA in biological samples.

An assay is described for the simultaneous determination of dopamine, noradrenaline, adrenaline, dopa, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethanol, 3,4-dihydroxymandelic acid and 3,4-dihydroxy-phenylglycol, capable of detecting amounts in the femtomol range. The assay is based on the O-methylation of the catechol moiety utilizing S-[3H-methyl]-adenosyl-L-methionine and a partially purified catechol-O-methyl transferase to form the various O-[3H-methyl]-catechol derivatives. The O-[3H-methyl]-catechol derivatives are purified by thin layer chromatography, solvent partitions and/or ion exchange chromatography. The assay was successfully applied to biological sample. It was possible for the first time, to detect free 3,4-dihydroxyphenylglycol, free 3,4-dihydroxyphenylethanol and 3,4-dihydroxymandelic acid in a small volume (25 microliter) of blood plasma of man, rat, dog and rabbit. The conjoint measurement of catecholamines and their catechol metabolites in minute amounts of biological samples may contribute to a more detailed understanding of catecholamine metabolism in the peripheral and central nervous system.

Animals↗
PubMed1981

3-Methoxytyramine and normetanephrine as indicators of dopamine and noradrenaline release in mouse brain in vivo.

Intraperitoneal administration of pargyline HCl induced a dose-dependent accumulation of 3-methoxytyramine and normetanephrine in mouse brain in vivo. As judged by the decrease of 5-hydroxyindole acetic acid levels a dose of 200 mg/kg of pargyline appeared to inhibit monoamine oxidase completely. This dose led to an approximately linear accumulation of 3-methoxytyramine and normetanephrine during the first 3 hours. gamma-Butyrolactone, 750 mg/kg i.p. reduced the accumulation of 3-methoxytyramine despite a marked increase of dopamine. (+)-Amphetamine stimulated 3-methoxytyramine as well as normetanephrine accumulation at doses of 3 and 10 mg/kg i.p. In line with the concept of receptor-mediated negative feedback control of catecholaminergic transmission the dopamine receptor agonists apomorphine, 0.3 mg/kg i.p., lisuride, 0.05--0.3 mg/kg i.p., and bromocriptine, 10 mg/kg i.p., decrease 3-methoxytyramine formation while the dopamine receptor blocking agent haloperidol, 1 mg/kg i.p., led to a 3-fold increase. The alpha-adrenoceptor agonist clonidine, 0.1 mg/kg i.p., reduced the formation of normetanephrine and the alpha-adrenoceptor antagonists yohimbine, 10 mg per kg i.p., phenoxybenzamine, 20 mg/kg i.p., and mianserine, 50 mg/kg i.p., stimulated normetanephrine accumulation 1.5- to 4-fold. 3-Methoxytyramine and normetanephrine accumulating after inhibition of monoamine oxidase appear to be reliable indicators of dopamine and noradrenaline release and metabolism.

4-Butyrolactone↗
PubMed1979

Catecholamine and 5-hydroxytryptamine synthesis and metabolism following intracerebroventricular injection of dibutyryl cyclic AMP.

Two to seven days after bilateral implantation of polyethylene tubings into the lateral ventricles rats were injected intracerebroventricularly with dibutyryl cAMP or dibutyryl cGMP. The accumulation of dopa and 5-hydroxytryptophan after inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhyrazine HCl, served as a measure of catecholamine and 5-hydroxytryptamine synthesis in vivo. A dose of 100 microgram dibutyryl cAMP per rat but not dibutyryl cGMP increased the accumulation of dopa in all brain regions by 70 to 130%. Both nucleotides stimulated the formation of 5-hydroxytryptophan in the dopamine-rich part of the limbic system and diencephalon and in addition dibutyryl cAMP increased 5-hydroxytryptophan in C. striatum and cerebellum. Dibutyryl cAMP (25-200 microgram per rat) did not change the dopamine levels in the dopamine-rich parts of the brain but decreased the noradrenaline level of the C. striatum in a dose-dependent manner. The same doses of dibutyryl cAMP elevated the 5-hydroxytryptamine level in brain stem and the level of 5-hydroxyindole acetic acid in diencephalon and the limbic system. The disappearance of noradrenaline but not of dopamine after inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine methylester HCl was accelerated in most brain regions. The data are compatible with the view that dibutyryl cAMP stimulates tyrosine and tryptophan hydroxylase directly. In addition, dibutyryl cAMP appears to enhance the utilization of noradrenaline but not that of dopamine. The increased utilization of 5-hydroxytryptamine may be restricted to the diencephalon and the limbic system.

5-Hydroxytryptophan↗
PubMed1978

Impaired dopamine function and muscular rigidity induced by 6-aminonicotinamide in rats.

In corpus striatum, 6-aminonicotinamide (6-AN), 10 mg/kg i.p. lowered the concentration of dopamine and markedly reduced the disappearance of dopamine after synthesis inhibition with alpha-methyl-p-tyrosine. In the dopamine-rich part of the limbic system, the formation of DOPA after decarboxylase inhibition with 3-hydroxybenzylhydrazine was decreased. In diencephalon, 6-AN altered neither the steady-state level nor the utilization of noradrenaline. The data suggest that the muscular rigidity induced by 6-AN may be associated with disruption of dopaminergic transmission.

6-Aminonicotinamide↗
PubMed1977

Effect of lisuride and other ergot derivatives on monoaminergic mechanisms in rat brain.

The effects of the ergot derivative lisuride hydrogen maleate on synthesis, turnover and receptor activity of monoamines were compared with those of LSD, methysergide, yohimbine and methiothepin. In the dopamine (DA) rich areas, c. striatum and mesolimbic forebrain, lisuride, (30-100 mug/kg) decreased the rate of dopa formation after inhibition of the aromatic amino acid decarboxylase with NSD 1015, 100 mg/kp i.p. After axotomy of the ascending monoaminergic fibers, lisuride (0.5 mg/kg) antagonized the accumulation of dopa in c. striatum and mesolimbic forebrain even on the lesioned side; haloperidol effectively counteracted this lisuride-induced decrease in dopa formation. In the predominantly noradrenaline (NA)-innervated neocortex, lisuride in doses of 0.3 and 1.0 mg/kg increased dopa accumulation. Methysergide, yohimbine and methiothepin also stimulated tyrosine hydroxylation. After inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine methylester HCl, lisuride decelerated DA disappearance and accelerated NA disappearance. 3-Methoxytryramine (3-MY) accumulating after inhibition of monoamine axidase with pargyline HCl (100 mg/kg) was used as an indicator of DA release. Lisuride and LSD, 50 mug/kg administered twice, reduced 3-MT formation while methysergide, 50 mg/kp i.p. had no effect on 3-MT accumulation. All compounds except methiothepin reduced 5-hydroxytryptophan (5-HTP) accumulation in whole brain after NSD 1015. In addition, lisuride caused an increase in 5-hydroxytryptamine (5-HT) and a decrease in 5-hydroxyindole acetic acid concentration. In spinal reserpinized rats, lisuride was indistinguishable from LSD in inducing extension and athetoid movements of the hind legs. The data support the view that lisuride stimulates pre- and postsynaptic DA and 5-HT receptors and suggest that lisuride blocks NA receptors in the central nervous system.

Animals↗
PubMed1977

Catecholamine synthesis in rat brain after axotomy: interaction between apomorphine and haloperidol.

Axotomy of the ascending monoaminergic fibers by means of a complete cerebral hemitransection stimulated the formation of dopa during 30 min after inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl, 100 mg/kg i.p., in c. striatum and the dopamine-rich part of the limbic system. Apomorphine, 0.5 mg/kg i.p., antagonized the accumulation of dopa not only on the intact but also on the lesioned side. Haloperidol, 2 mg/kg i.p., stimulated dopa accumulation on the intact side but could not further stimulate the increase in dopa caused by transection. When both drugs were given together, the inhibitory effect of apomorphine was fully counteracted by haloperidol on both sides. In the predominantly noradrenaline-innervated occipito-temporal cortex dopa formation was slightly higher on the lesioned than on the intact side and was not markedly influenced by apomorphine. In the rest of the hemispheres the apomorphine-induced decrease in dopa formation was more pronounced on the intact than on the lesioned side and was fully antagonized by haloperidol. The dopamine concentration was slightly higher in the lesioned c. striatum as compared to the intact side irrespective of the drugs administered. In c. striatum and the limbic system haloperidol caused a decrease in dopamine on the intact side which was not antagonized by additional treatment with apomorphine. Hemitransection caused a decrease in noradrenaline especially in the hemisphere portion. Neither apomorphine nor haloperidol or both drugs in combination changed the latter effect. In general, the tyrosine concentration tended to be higher on the lesioned than on the intact side in all brain structures investigated. The data support the view that a local receptor-mediated feedback mechanism exists which is controlling dopamine synthesis even in the absence of impulse flow.

Animals↗
PubMed1977

Methoxytyrosine formation as an indicator of catechol-O-methyltransferase activity in rat liver in vivo.

The O-methyl derivative methoxytyrosine accumulated rapidly in rat liver after an intraperitoneal injection of L-dopa (50 mg/kg) in combination with 3-hydroxybenzylhydrazine, an inhibitor of the aromatic amino acid decarboxylase. Methoxytyrosine levels reached a plateau 40--60 min after i.p. injection of L-dopa, of which the tissue concentration declined monoexponentially. Injection of various doses of L-dopa revealed that methoxytyrosine formation was saturable and followed enzyme kinetics in rat liver. The catechol-O-methyltransferase inhibitors pyrogallol, tropolone and alpha-propyldopacetamide as well as the inhibitor of the aromatic amino acid decarboxylase benserazide inhibited the formation of methoxytyrosine dose-dependently and concomitantly increased the tissue concentration of dopa. The accumulation of methoxytyrosine from exogeneously applied L-dopa appears to be a reliable indicator of the in vivo activity of catechol-O-methyltransferase.

Amino Acids↗
PubMed1977

Agonist--antagonist interaction on dopamine receptors in brain, as reflected in the rates of tyrosine and tryptophan hydroxylation.

The effect of haloperidol and apomorphine, and both drugs in combination, on the first steps in the synthesis of catecholamines and 5-hydroxytryptamine (5-HT) has been studied in three rat brain regions. The rate of formation of dopa and 5-hydroxytryptophan (5-HTP) was studied by measuring the accumulation of these amino acids during 30 min after administration of the inhibitor of the aromatic L-amino acid decarboxylase, NSD 1015 (3-hydroxybenzylhydrazine HCl). Haloperidol caused an increase in dopa and no change in 5-HTP formation. The threshold dose was severalfold higher in the noradrenaline-predominated hemisphere portion than in the dopamine-rich striatal and limbic regions, suggesting a higher affinity of haloperidol for dopamine than for noradrenaline receptors. Apomorphine caused a decrease in dopa formation in all three brain regions studied, although the effect was much more pronounced in the regions dominated by dopamine. The threshold dose was about 30 microng/kg, i.e. an order of magnitude lower than the threshold dose for apparent postsynaptic dopaminergic receptor activation. This discrepancy is suggested to be due to preferential activation of inhibitory dopaminergic autoreceptors by low apomorphine doses. This phenomenon may also contribute to explain the complex dose-response curves of apomorphine. Low doses of apomorphine caused a decrease and high doses an increase in 5-HTP formation. These effects, like those on noradrenaline synthesis, are suggested to be secondary to activation of dopaminergic pre- and post-synaptic receptors. The interaction between apomorphine and haloperidol with respect to dopa formation appears to be largely explicable on the assumption of a competition between an agonist and an antagonist for dopaminergic receptors. However, very large doses of apomorphine cause a haloperidol-resistant inhibition of tyrosine, and probably also tryptophan, hydroxylation, which may be due to a direct inhibition of the aromatic amino acid hydroxylase involved.

5-Hydroxytryptophan↗