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PubMed2000

Muscarinic antagonists in substantia nigra influence the decarboxylation of L-dopa in striatum.

This study was designed to investigate whether anticholinergic drugs acting at the level of the substantia nigra can affect basal extracellular dopamine concentrations and the levodopa (L-dopa)-induced increases in dopamine levels in the striatum. Dual probe in vivo microdialysis in freely moving rats was used. One microdialysis probe was implanted in the substantia nigra and the other in the ipsilateral striatum. Muscarinic receptor antagonists were perfused into the substantia nigra and changes in neurotransmitter levels in the substantia nigra and at the axon terminals in the striatum were monitored simultaneously. Nigral perfusion of the non-selective muscarinic receptor antagonist trihexyphenidyl (1 mM) produced an increase in extracellular dopamine and gamma-aminobutyric acid (GABA) levels in the substantia nigra. Perfusion with the muscarinic M(1) receptor antagonist telenzepine (0.1 microM) produced a significant decrease in nigral dopamine and GABA levels in the substantia nigra. The muscarinic M(2) receptor antagonist methoctramine (75 microM) produced an increase in dopamine levels in the substantia nigra. No significant changes in nigral extracellular GABA levels were observed. The L-dopa-induced increases in extracellular dopamine levels in the striatum were clearly attenuated under nigral perfusion of these drugs. This in vivo study demonstrates that anticholinergic drugs perfused at the level of the substantia nigra can modulate dopamine and GABA levels and attenuate the L-dopa decarboxylation in the striatum, possibly via modulation of the nigrostriatal dopaminergic system. We add further evidence that the substantia nigra is an important site of action of antimuscarinic drugs. The attenuation of L-dopa-induced dopamine release in the striatum exerted by nigral perfusion of these antimuscarinic drugs is probably mediated via different mechanisms. This attenuation is regarded as a beneficial effect of the muscarinic antagonists as adjuncts to L-dopa in Parkinson's disease treatment. We postulate that drugs that enhance dopamine release, after L-dopa administration, in a less extreme way than L-dopa administered on its own could prevent further neurodegeneration and dyskinesias thought to result from extremely high extracellular dopamine levels following L-dopa treatment.

Analysis of Variance↗
PubMed2003

The effects of chronic L-DOPA therapy on pharmacodynamic parameters in a rat model of motor response fluctuations.

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy in Parkinson's disease (PD) is complicated by motor response fluctuations and dyskinesia. The relative contributions of disease severity and chronic L-DOPA therapy to the development of motor fluctuation are not well defined clinically. Experimental studies have been limited partly because models for the antiparkinsonian effects on akinesia have not been employed. Therefore, we employed a model of akinesia using forepaw adjusting steps that have been well characterized to reflect the effect of lesions and the antiparkinsonian effect of dopaminergic drugs and transplants. We administered L-DOPA (12.5 mg/kg) intermittently for 4 weeks to rats with severe nigrostriatal lesions produced by injecting 6-hydroxydopamine into the medial forebrain bundle. The peak magnitude responses to L-DOPA increased after treatment compared to the pretreatment baseline. The latency to peak response to L-DOPA became shorter and reversed after the discontinuation of treatment. The duration of response showed minor changes. The pattern of changes in response to apomorphine was similar to that of L-DOPA except that the peak magnitude did not increase despite chronic L-DOPA treatment. The changes in D1 and D2 receptor binding did not correlate with behavioral changes. In summary, long-term intermittent L-DOPA treatment resulted in priming of antiparkinsonian effects on improving akinesia in a rat model of severe PD. These observed changes do not mirror all aspects of motor response fluctuations in advanced PD patients and suggest differential contributions of dopaminergic treatment and lesion severity to motor complication patterns.

Animals↗
PubMed2000

Effect of gamma-L-glutamyl-L-dopa on phosphate excretion.

gamma-L-glutamyl-L-DOPA (gludopa) is a dopamine prodrug that is relatively specific for the kidney. Because dopamine is phosphaturic, the present study compared the phosphaturic effects of the infusion of equimolar doses of gludopa (n = 8), L-DOPA (n = 8), and gamma-L-glutamyl-L-tyrosine (glutyrosine, n = 6). Glutyrosine was used as a control to evaluate the effect of the glutamyl portion of gludopa on phosphate excretion. Sprague-Dawley rats (350 to 400 g) were anesthetized with 5-sec-butylethyl-2-thyobarbituric acid (Inactin; 100 mg/kg, IP) and underwent thyroparathyroidectomy. Clearances were taken during the infusion of normal saline vehicle, followed by the infusion of gludopa, L-DOPA, or glutyrosine, all infused at the rate of 10 nmol/kg bolus and 0.8 nmol/kg/min (iv). To determine the contribution of glutamyl derivative to phosphate excretion, gludopa or L-DOPA was infused in the presence of SCH23390, a DA-1 receptor antagonist. Gludopa infusion significantly increased dopamine excretion (from 1.9+/-0.2 ng/min to 17.0+/-3.9 ng/min, delta15.0+/-3.9 ng/min, P < .008) and fractional excretion of phosphate (from 2.6%+/-0.6% to 34.8%+/-1.8%, delta32.0%+/-1.6%, P < .001). L-DOPA infusion significantly increased dopamine excretion (from 1.4+/- 0.4 ng/min to 9.7+/-1.6 ng/min, delta8.3+/-1.5 ng/min, P < .001) and fractional excretion of phosphate (from 1.7%+/-0.6% to 8.2%+/-2.0%, delta6.4%+/-1.5%, P < .004). Glutyrosine infusion significantly increased fractional excretion of phosphate (from 2.8%+/-0.8% to 17.5%+/-5.2%, delta14.6%+/-4.8%, P < .03) without changing dopamine excretion (delta0.5+/-0.2 ng/min). Infusion of gludopa in the presence of SCH23390 increased fractional excretion of phosphate (from 5.7%+/-2.5% to 12.6%+/-3.5%, delta6.8%+/-2.3%, n = 6, P < .03), whereas SCH23390 completely blocked the phosphaturic effect of L-DOPA. We conclude that gamma-L-glutamyl-L-DOPA is more phosphaturic than L-DOPA in the rat because of the combined effects of dopamine and the glutamyl moiety.

Animals↗
PubMed1997

An L-DOPA-like depressor action of L-threo-dihydroxyphenyl-serine in the rat caudal ventrolateral medulla.

We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter and/or neuromodulator in the central nervous system (1). In this study, we investigated whether or not L-threo-dihydroxyphenylserine (L-threo-DOPS), a synthetic amino acid structurally related to L-DOPA, microinjected into the caudal ventrolateral medulla (CVLM) and the rostral ventrolateral medulla (RVLM) shows cardiovascular actions similar to those of L-DOPA in anesthetized rats. When L-threo-DOPS was microinjected into CVLM, it produced dose-dependent (0.01-3 ng) depressor and bradycardic responses. D-threo-DOPS (3 ng) produced no effect. The responses to L-threo-DOPS (1 ng) were almost completely blocked by L-DOPA methyl ester (1 microg), a competitive antagonist for L-DOPA, supporting the existence of an L-threo-DOPS-sensitive recognition site for L-DOPA in CVLM. Microinjection of L-threo-DOPS into RVLM, however, showed no effect (0.001-100 ng), which contrasted with the cardiopressor action of L-DOPA applied in RVLM. In RVLM, there may exist an L-threo-DOPS-insensitive recognition site for L-DOPA.

Animals↗
PubMed2002

L-DOPA does not cause neurotoxicity in VMAT2 heterozygote knockout mice.

One of the most useful treatments of Parkinson's disease (PD) is dihydroxyphenylalanine (L-DOPA) administration. However, L-DOPA has been suggested to be toxic to dopamine (DA) neurons and perhaps contribute to the progression of the disease. Sequestration of DA and dopaminergic neurotoxins into vesicles by the vesicular monoamine transporter 2 (VMAT2) is a key factor in preventing cellular damage. Mice with reduced expression of VMAT2 (VMAT2 heterozygote knockout mice; VMAT2 (+/-)) are more sensitive to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine. In this study, we subjected VMAT2 (+/-) mice to subchronic administration of L-DOPA to determine if it was toxic in this model. VMAT2 wild-type (VMAT2 (+/+)) and VMAT2 (+/-) mice were given i.p. injections of L-DOPA:carbidopa (50:5 mg/kg) three times a day for 28 days. Biochemical analysis revealed a significant increase in striatal DA levels in both groups of mice treated with L-DOPA. L-DOPA treatment significantly decreased DAT levels in VMAT2 (+/+) mice, but not in VMAT2 (+/-) mice. VMAT2 protein levels, an index of terminal integrity and the number of tyrosine hydroxylase (TH)-positive nigral cells remained unchanged after L-DOPA treatment. These data indicate that in an animal model that displays increased susceptibility to dopaminergic injury, a subchronic administration of L-DOPA does not induce toxicity.

Animals↗
PubMed1991

A comparison between the effect of intentional modulations and the action of L-dopa on gait in Parkinson's disease.

The aims of the present study were to analyze how L-Dopa allows parkinsonian patients to increase their gait velocity and to compare these L-Dopa-induced modifications with those achieved by consciously attempting to walk as fast as possible (intentional modulations). The 'intentional modulations' of velocity were also compared with those of healthy elderly subjects. The results showed that parkinsonian patients walked more slowly, with shorter strides and shorter durations of swing phase, and longer durations of stance and double support phases, although no differences were observed for cycle duration. The mechanisms involved in increasing gait velocity were found to differ according to whether this was achieved through the action of L-Dopa, or by intentional increases in velocity. Intentional increases in velocity were greater than those caused by the effect of L-Dopa. The patients, however, used efficient strategies to increase their velocity when under the influence of L-Dopa. As L-Dopa leads to a ceiling effect on stride length, the patients can increase their velocity by modifying the cycle to such an extent that it compensates for the limitation in stride length. This strategy effectively increases velocity, despite the L-Dopa ceiling effect. The effects of L-Dopa on locomotion and, more generally, on motor control aspects are discussed.

Aged↗
PubMed1996

Inhibition of catalase in mesencephalic cultures by L-DOPA and dopamine.

Catalase activity in cell cultures of fetal rat mesencephalon was decreased by 42 and 50%, respectively, after exposure to L-3,4-dihydroxyphenylalanine (L-DOPA, 100 microM) or dopamine (100 microM) for 48 h. Catalase activity was also decreased 21% by 10 microM hydroquinone. Ascorbic acid (200 microM), an agent that suppresses the autoxidation of L-DOPA and dopamine, blocked the anti-catalase effect of L-DOPA, but not that of dopamine. Inhibitors of the A and B forms of monoamine oxidase (20 microM clorgyline plus 20 microM pargyline) had no effect on the anti-catalase action of either L-DOPA or dopamine. The latter results suggest that products of the oxidative deamination of dopamine by monoamine oxidase are not involved in the suppression of catalase activity. However, autoxidation reactions of L-DOPA may play a role since ascorbate suppressed the anti-catalase effect of L-DOPA. On the contrary, the basis for the failure of ascorbate to similarly block the anti-catalase effect of dopamine is uncertain. L-DOPA and dopamine (25 microM) also inhibited crystalline catalase in solution after incubation for 1 h at neutral pH (40-50% inhibition). Inhibition was blocked by 0.45 M ethanol, indicating a need for autoxidation and the formation of compound II, which is an enzymatically inactive form of catalase. The ability to model the enzyme inhibition in purely chemical experiments indicates a probable mechanism for loss of enzymatic activity in cell cultures. Inhibition of catalase may contribute to cell damage during incubation of cultures with L-DOPA, dopamine, or other autoxidizable compounds.

Animals↗
PubMed2002

Personality traits and striatal 6-[18F]fluoro-L-dopa uptake in healthy elderly subjects.

Positron emission tomography (PET) studies have been carried out to examine dopaminergic correlates of human personality traits. In patients with Parkinson's disease, right caudate 6-[(18)F]fluoro-L-dopa ((18)F-dopa) uptake has recently been reported to correlate with a depression/anxiety related-personality trait of harm avoidance. The present study aimed to further study personality and striatal dopaminergic function, now with (18)F-dopa in healthy individuals, and to determine specifically whether the link between harm avoidance and (18)F-dopa uptake is a general phenomenon, seen also in healthy subjects. Twenty-five Caucasian neurologically healthy elderly subjects (mean age=60 years; 13 men, 12 women) were scanned with 3D (18)F-dopa PET, coregistered with magnetic resonance imaging, and each subject filled out the Temperament and Character Inventory (TCI) and the Karolinska Scales of Personality (KSP). The TCI harm avoidance did not correlate with right caudate (18)F-dopa uptake (r=-0.08, P=0.71, uncorrected, effects of age and sex partialled out), or with the (18)F-dopa uptake in any other striatal region (r=-0.07-0.16, P>0.47). Correlations with other personality scales, including the TCI novelty-seeking and the KSP detachment, were also non-significant. The results indicate that the previous positive findings concerning harm avoidance and (18)F-dopa uptake in Parkinson's disease are disease-related, and that they can not be generalized to healthy individuals.

Aged↗
PubMed1999

GABA may function tonically via GABA(A) receptors to inhibit hypotension and bradycardia by L-DOPA microinjected into depressor sites of the nucleus tractus solitarii in anesthetized rats.

We have proposed that DOPA is a transmitter of the primary baroreceptor afferents terminating in the rat nucleus tractus solitarii (NTS). GABA is a putative inhibitory neuromodulator for baroreflex inputs in the NTS. GABA may inhibit DOPAergic transmission. Drugs were microinjected into depressor sites of the NTS in anesthetized rats. DOPA (10-60 ng) elicited dose-dependent depressor responses. GABA (3-300 ng) elicited dose-dependent pressor responses. Nipecotic acid (100 ng) elicited pressor responses. Bicuculline (10 ng) elicited depressor responses. Responses to DOPA (30 ng) were inhibited by pretreatment with GABA and nipecotic acid, but potentiated by bicuculline, when vascular responses to pretreated drugs returned to basal levels. DOPA ME, a competitive DOPA antagonist, did not displace specific [3H]GABA binding. Prior DOPA ME (1 microg) inhibited by one-half pressor responses to 300 ng GABA. GABA seems to inhibit tonically via GABA(A) receptors depressor responses to DOPA and to elicit pressor responses partially by inhibition of tonic function of endogenous DOPA to activate depressor sites in the NTS. These findings further support the above proposal.

Anesthesia↗
PubMed2000

L-DOPA produces strong induction of c-fos messenger RNA in dopamine-denervated cortical and striatal areas of the common marmoset.

Common marmosets (Callithrix jacchus) with near-complete unilateral 6-hydroxydopamine denervation of the dopaminergic input received a single injection of saline or L-DOPA (15mg/kg plus 6.25mg/kg benserazide). Using in situ hybridization, the effects of these treatments on c-fos messenger RNA expression in the cerebral cortex, the striatal complex and the external layer of the pallidum were studied. Moreover, receptor autoradiography was used to determine the levels of dopamine D(1) and D(2) receptors in these areas. In the cerebral cortex, animals treated with L-DOPA displayed a high expression of c-fos messenger RNA restricted to the dopamine-denervated hemisphere. No changes in the levels of cortical D(1) and D(2) receptors were found in the dopamine-denervated hemisphere. L-DOPA treatment also induced a strong expression of c-fos messenger RNA in the striatal complex in the dopamine-denervated hemisphere. The levels of striatal D(2), but not D(1), receptors were increased in the dopamine-denervated hemisphere. In the external pallidum, the major terminal region for D(2) dopamine receptor-containing striatal projection neurons, L-DOPA treatment induced c-fos messenger RNA expression in both the intact and the dopamine-denervated hemispheres.Thus, using c-fos messenger RNA as a biochemical marker of postsynaptic neuronal activation, these results provide evidence that near-complete dopamine depletion causes a profound supersensitization to L-DOPA treatment in the cerebral cortex and in the striatal complex, but not in the external layer of the pallidum, of the primate brain. The cortical response may be unique to the primate brain, but c-fos messenger RNA activation within the striatum has also been reported in the rodent. The effects of L-DOPA probably depend both on a direct activation of supersensitized dopamine receptors by dopamine produced in the few remaining, but hyperactive, dopaminergic nerve terminals and in serotonergic nerve terminals, as well as on indirect actions of L-DOPA related to activation of circuitries connecting cerebral cortex and basal ganglia structures. These results provide novel information on the mechanisms underlying L-DOPA's action in the cerebral cortex, striatum and external pallidum in a primate model of Parkinson's disease.

Animals↗
PubMed2000

Metabolism of protein-bound DOPA in mammals.

Protein-bound 3,4-dihydroxyphenylalanine (DOPA) can be generated in mammalian cells by both controlled enzymatic pathways, and by uncontrolled radical reactions. Protein-bound DOPA (PB-DOPA) has reducing activity and the capacity to inflict secondary damage on other important biomolecules such as DNA. This may be mediated through replenishment of transition metals or from catechol-quinone-catechol redox cycles in the presence of cellular components such as ascorbate or cysteine, resulting in amplification of radical damaging events. The generation of PB-DOPA confers on protein the ability to chelate transition metals generating protein 'oxychelates'; this may be amongst the factors, which localise such damage. Tissue levels of PB-DOPA are increased in a number of age-related pathologies such as atherosclerosis and cataract formation. We discuss the detoxification, and the subsequent proteolysis and excretion of components of PB-DOPA. We contrast the fact that in marine organisms, and particularly in extracellular proteins, PB-DOPA and other DOPA-polymers can play important functional roles in adhesion and the provision of tensile properties.

Animals↗
PubMed2006

Structure and bonding of the multifunctional amino acid L-DOPA on Au(110).

In investigations of the proteins which are responsible for the surface adhesion of the blue mussel Mytilus edulis, an unusually frequent appearance of the otherwise rare amino acid 3-(3,4-dihydroxyphenyl)-L-alanine (L-DOPA) has been observed. This amino acid is thought to play a major role in the mechanism of mussel adhesion. Here we report a detailed structural and spectroscopic investigation of the interface between L-DOPA and a single-crystalline Au(110) model surface, with the aim of understanding fundamentals about the surface bonding of this amino acid and its role in mussel adhesion. Molecular layers are deposited by organic molecular beam deposition (OMBD) in an ultrahigh-vacuum environment. The following experimental techniques have been applied: ex situ Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), low-energy electron diffraction (LEED), high-resolution electron energy loss spectroscopy (HREELS), and scanning tunneling microscopy (STM). Vibrational spectra of isolated L-DOPA molecules and the zwitterionic bulk have been calculated using density functional theory (DFT). The predicted modes are assigned to observed spectra, allowing conclusions regarding the molecule-substrate and molecule-molecule interactions at the L-DOPA/Au(110) interface. We find that zwitterionic L-DOPA forms a monochiral, one-domain commensurate monolayer on Au(110), with the catechol rings on top of [110] gold rows, oriented parallel to the surface. The (2 x 1)-Au(110) surface reconstruction is not lifted. The carboxylate group is found in a bidentate or bridging configuration, the amino group is tilted out of the surface plane, and the hydroxyl groups do not dehydrogenate on Au(110). Similar to the case for the bulk, molecules form dimers on Au(110). However, the number of hydrogen bridge bonds between L-DOPA molecules is reduced as compared to the bulk. Thicker layers which are deposited onto the commensurate interface do not order in the bulk structure. In conclusion, our study shows that the aromatic ring system of L-DOPA functions as a surface anchor. Since it is also known that the hydroxyl groups support cross-link reactions between L-DOPA residues in the mussel glue protein, we can conclude that the catechol ring supports surface adhesion of mussel proteins via two independent functions.

Adhesiveness↗
PubMed1990

A comparison of oral and rectal absorption of L-dopa esters in rats and mice.

Short-chain alkyl esters of L-dopa were administered to rats and mice via oral and rectal routes. Plasma L-dopa esters and L-dopa were determined in the systemic and portal circulation by HPLC. A comparison of isopropyl, butyl, and 4-hydroxybutyl esters of L-dopa demonstrated significantly higher levels of the esters in both systemic and portal blood samples following rectal administration than following oral administration. In most cases, oral administration resulted in nondetectable (less than 0.01 micrograms/ml) levels of the esters in plasma. Correspondingly, the plasma levels of L-dopa itself were consistently higher following rectal administration. At very high oral doses (500 mg L-dopa equivalents/kg body weight), systemic plasma levels of the butyl ester could be detected (1.25 micrograms/ml at 10 min), which might indicate saturation of the esterase activity of the small intestine. These studies indicate that the systemic availability of L-dopa from short-chain alkyl esters of L-dopa may be best optimized by rectal administration, which avoids the relatively high esterase activity characteristic of the small intestine.

Administration, Oral↗
PubMed1991

Distribution and kinetics of 3-O-methyl-6-[18F]fluoro-L-dopa in the rhesus monkey brain.

Most attempts to model accurately [18F]-DOPA imaging of the dopamine system are based on the assumptions that its main peripheral metabolite, 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]3-OM-DOPA), crosses the blood-brain barrier but is present as a homogenous distribution throughout the brain, in part because it is not converted into [18F]DOPA in significant quantities. These assumptions were based mainly on data in rodents. Little information is available in the primate. To verify the accuracy of the above assumptions, we administered 18F-labeled 3-OM-DOPA to normal rhesus monkeys and animals with lesions of the DA nigrostriatal system. No selective 18F regional accumulation in brain was apparent in normal or lesioned animals. The plasma metabolite analysis revealed that only the negatively charged metabolites (e.g., sulfated conjugates) that do not cross the blood-brain barrier were found in significant quantities in the plasma. A one-compartment, three-parameter model was adequate to describe the kinetics of [18F]3-OM-DOPA. In conclusion, assumptions concerning [18F]3-OM-DOPA's behavior in brain appear acceptable for [18F]DOPA modeling purposes.

Animals↗
PubMed2002

Oxidative and non-oxidative mechanisms of neuronal cell death and apoptosis by L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine.

1. The present study was designed to evaluate the nature of intervening agents in L-DOPA- and dopamine-induced neurotoxicity in Neuro-2A cells. 2. In the absence of cells and in conditions of light protection, at 37 degrees C, L-DOPA or dopamine (1 mM) in culture medium degraded spontaneously in a time-dependent manner, this being prevented by ascorbic acid (200 microM) and other antioxidants, namely glutathione (1 mM), N-acetyl-L-cysteine (1 mM), sodium metabisulphite (200 microM), but not N-ter-butyl-alpha-phenylnitrone (1 mM) and deferoxamine (100 microM). 3. The viability of Neuro-2A cells declined following treatment with L-DOPA or dopamine in a concentration- and time-dependent manner. The decrease in cell viability by L-DOPA (10+/-4% of control) or dopamine (15+/-4% of control) was markedly attenuated by antioxidants (ascorbic acid, glutathione, N-acetyl-L-cysteine and sodium metabisulphite). Autoxidation of L-DOPA or dopamine was accompanied by the formation of H(2)O(2) in a time-dependent manner, this being completely prevented by ascorbic acid at 24 h or markedly reduced at 48 h. 4. Protective effects of 100 U ml(-1) catalase (40+/-1% of control) against L-DOPA-induced cell death were lower than those conferred by 200 microM ascorbic acid (70+/-3% of control). Catalase-induced protection (59+/-5% of control) against dopamine-induced cell death was similar to that conferred by 200 microM ascorbic acid (57+/-4% of control). L-DOPA-induced neuronal cell death was also accompanied by increases in caspase-3 activity, this being insensitive to ascorbic acid. Dopamine-induced increase in caspase-3 activity occurred only when autoxidation of the amine was prevented by ascorbic acid. 5. It is suggested that in addition to generation of H(2)O(2) and quinone formation, L-DOPA- and dopamine-induced cell death may result from induction of apoptosis, as evidenced by increases in caspase-3 activity. Dopamine per se induces apoptosis by a mechanism independent of oxidative stress, as evidenced by the fact that increases in caspase-3 activity occurred only when autoxidation of the amine was prevented.

Animals↗
PubMed2006

Cardiovascular responses to combined treatment with selective monoamine oxidase type B inhibitors and L-DOPA in the rat.

BACKGROUND AND PURPOSE: Postural hypotension is a common side-effect of L-DOPA treatment of Parkinson's disease, and may be potentiated when L-DOPA is combined with selegiline, a selective inhibitor of monoamine oxidase B (MAO-B). Rasagiline is a new, potent and selective MAO-B inhibitor, which does not possess the sympathomimetic effects of selegiline. We have studied the effects of these selective MAO inhibitors, L-DOPA and dopamine on the cardiovascular system of the rat. EXPERIMENTAL APPROACH: Blood pressure and heart rate was measured in conscious rats following acute or chronic administration of rasagiline, selegiline and L-DOPA, by comparison with the selective MAO-A inhibitor clorgyline, or the MAO-A/B inhibitor tranylcypromine. Cardiovascular responses, catecholamine release, and modification of pressor response to dopamine were studied in pithed rats. KEY RESULTS: In conscious rats neither rasagiline nor selegiline caused significant potentiation of the effects of L-DOPA (50, 100, 150 mg.kg(-1)) on blood pressure or heart rate at doses which selectively inhibited MAO-B, but L-DOPA responses were potentiated by clorgyline and tranylcypromine. In rats treated twice daily for 8 days with L-DOPA and carbidopa, selegiline (5 mg.kg(-1)) but not rasagiline (0.2 mg.kg(-1)) caused a significant hypotensive response to L-DOPA and carbidopa, although both drugs caused similar inhibition of MAO-A and MAO-B. In pithed rats, selegiline but not rasagiline increased catecholamine release and heart rate, and potentiated dopamine pressor response at MAO-B selective dose. CONCLUSIONS AND IMPLICATIONS: The different responses to the two MAO-B inhibitors may be explained by the amine releasing effect of amphetamine metabolites formed from selegiline.

Animals↗
PubMed1996

Enzymic sulphation of dopa and tyrosine isomers by HepG2 human hepatoma cells: stereoselectivity and stimulation by Mn2+.

HepG2 human hepatoma cells, labelled with [35S]sulphate in media containing L-3,4-dihydroxyphenylalanine (L-dopa), (D-dopa), DL-m-tyrosine or D-p-tyrosine, were found to produce the [35S]sulphated forms of these compounds. Addition to the labelling media of m-hydroxybenzylhydrazine, an aromatic amino acid decarboxylase inhibitor, greatly enhanced the production of L-dopa O-[35S]sulphate and DL-m-tyrosine O-[35S]sulphate, with a concomitant decrease in the formation of dopamine O-[35S]sulphate and m-tyramine O-[35S]sulphate. With 3'-phosphoadenosine 5'-phospho[35S]sulphate as the sulphate donor., HepG2-cell cytosol was shown to contain enzymic activity catalysing the sulphation of L-dopa, D-dopa, L-m-tyrosine, D-m-tyrosine, L-p-tyrosine and D-p-tyrosine. The pH optimum of the enzyme, designated dopa/tyrosine sulphotransferase, was determined to be 8.75 with D-m-tyrosine as the substrate. The enzyme exhibited stereoselectivity for the D-form of dopa or tyrosine isomers. Addition of 10mM MnCl2 to the reaction mixture resulted in a remarkable stimulation of dopa/tyrosine sulphotransferase activity, being as high as 267.8 times with D-p-tyrosine as the substrate. Quantitative assays revealed L-dopa, D-dopa and D-m-tyrosine to be better substrates than L-p-tyrosine. When the HepG2-cell cytosol was subjected to DEAE Bio-Gel and hydroxyapatite column chromatography, dopa/tyrosine sulphotransferase was co-eluted with the thermolabile 'M-form' phenol sulphotransferase. Furthermore dopa/tyrosine sulphotransferase displayed properties similar to that of the M-form phenol sulphotransferase with respect to thermostability and sensitivity to 2,6-dichloro-4-nitrophenol. Whether the M-form phenol sulphotransferase is truly (solely) responsible for the dopa/tyrosine sulphotransferase activity present in HepG2 cells remains to be clarified.

Blood Platelets↗
PubMed1988

Derivation of urinary dopamine from plasma dopa.

1. We estimated the extent to which circulating dopa (3,4-dihydroxyphenylalanine) is the source of urinary dopamine (DA; 3,4-dihydroxyphenethylamine). Tritiated dopa ([3H]dopa) was infused for 90 min into the left renal artery of seven anaesthetized foxhounds, and levels of labelled and unlabelled dopa and DA were measured in the ureteral urine and in the femoral arterial and left renal venous plasma. 2. Only a small percentage of [3H]dopa delivered to the kidneys was excreted as [3H]DA (0.59% from the left kidney, 0.68% from the right); however, the arterial concentration of endogenous dopa (1220 pg/ml) and the renal plasma flows (144 and 141 ml/min by p-aminohippurate clearances) were such that all of the urinary excretion of endogenous DA (about 1 ng/min from each kidney) could be accounted for by uptake and decarboxylation of circulating endogenous dopa. 3. Plasma dopa is the main source of urinary DA.

Animals↗