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PubMed1989

Inhibition of brain dopa-decarboxylase by RO 4-4602 infused ICV blocks alcohol drinking induced in rats by cyanamide.

Following the stereotaxic implantation of chronic cannulae for intracerebroventricular (ICV) infusion, rats were given an alcohol preference test to establish their preferred concentration in comparison with water. After alcohol was removed, 15 mg/kg cyanamide was then injected subcutaneously for 4 days in order to maximize volitional intake of single solutions of alcohol, which in these animals ranged from 7 to 15%. The L-dopa-decarboxylase inhibitor benserazide (Ro 4-4602) injected subcutaneously twice daily in doses of 50-100 mg/kg failed to alter the rats' alcohol consumption either in terms of g/kg or proportional values. However, when given ICV twice daily in concentrations of 10 ng-2.0 micrograms per 5.0 microliters volume, benserazide attenuated the rats' alcohol drinking significantly. This reduction occurred in a dose-dependent manner in terms of both absolute and proportional intakes of alcohol. Pre-treatment of the animals with 1.0 microgram benserazide given ICV, when alcohol was removed from the test situation, did not abolish the subsequent ingestion of alcohol but its peripheral administration (50 mg/kg) enhanced drinking. These results suggest that the interference with the metabolic pathway of dopamine or serotonin synthesis, possibly through the mechanism of reduced formation of aldehyde adducts in the brain, markedly alters the pattern of voluntary drinking in the rat. Alternatively, benserazide could act by its central inhibition of aldehyde dehydrogenase, which in turn would concomitantly elevate levels of acetaldehyde and thereby reduce alcohol drinking.

Alcohol Drinking↗
PubMed1984

The pharmacology of Parkinson's disease: basic aspects and recent advances.

Basic aspects and recent advances in the understanding of the pharmacological mechanism of action of the clinically most used antiparkinson drugs are reviewed. Recent human and animal biochemical investigations clearly confirm and extend previous findings indicating that benserazide is much more potent than carbidopa as peripheral decarboxylase inhibitor. L-DOPA in combination with benserazide or carbidopa constitutes the best available therapy for Parkinson's disease (PD). To reduce peaks and rapid fluctuations of L-DOPA plasma levels (possibly responsible for peak-dose dyskinesias and end-of-dose deterioration) a slow-release formulation of L-DOPA in combination with benserazide or with benserazide plus catechol-O-methyltransferase inhibitors should be developed. In parkinsonian patients under long-term L-DOPA therapy monoamine oxidase inhibitors type B (MAO-B) e.g. (-)deprenyl and direct dopamine receptor agonists (bromocriptine, lisuride, pergolide etc.), due to their L-DOPA-sparing effects, alleviate in some cases L-DOPA-induced side-effects e.g. dyskinesias and on-off phenomena. However, since (-)deprenyl, due to its metabolism to (-)methamphetamine and (-)amphetamine, seem to have indirect sympathomimetic activity, new selective MAO-B inhibitors devoid of indirect sympathomimetic effects should be tested clinically to assess the functional role of pure MAO-B inhibition in the therapy of PD. The auxiliary therapy with direct dopamine receptor agonists of the D-2 subtype represents another valid approach which should be further investigated in order to find novel dopamine agonists, less expensive than bromocriptine, and strictly selective for D-2 receptor sites.

Animals↗
PubMed2004

Influence of dipeptidyl peptidase inhibitors on growth, peptidase activity, and ammonia production by ruminal microorganisms.

The aim was to investigate known and potential new inhibitiors of dipeptidyl peptidases (DPP) for their effects on ruminal microorganisms. Gly-Phe diazomethylketone (GPD), Ala-Ala chloromethylketone (AAC), benserazide (DL-serine 2-(2,3,4- trihydroxybenzyl) hydrazide), and diprotin A (Ile-Pro-Ile) inhibited DPP activities of Prevotella albensis, P. ruminicola, P. bryantii, P. brevis, and mixed ruminal microorganisms, though incompletely and, except for diprotin A, without absolute specificity for any of the peptidases. Leucine aminopeptidase activity of Streptococcus bovis was also inhibited by GPD and benserazide. The inhibitors had no effect on the growth of the bacteria, except for GPD, which inhibited growth of P. albensis when only peptides were available for growth. Benserazide had some inhibitory effects on the growth of Megasphaera elsdenii and Prevotella spp., even in the absence of peptides. The predatory activity of ciliate protozoa on bacteria was unaffected by DPP inhibitors. Ammonia production from casein by mixed ruminal microorganisms was inhibited significantly (P < 0.05) by AAC (29% inhibition) and benserazide (33%). It was concluded that DPP inhibitors can influence the rate of NH3 production in the rumen and may form the basis for developing protein-sparing feed additives for ruminants.

Amino Acid Chloromethyl Ketones↗
PubMed1983

The participation of hypothalamic dopamine in morphine-induced prolactin release in man.

In order to assess the role of dopamine in opiate-induced prolactin secretion, morphine alone or in combination with the dopamine blocker metoclopramide, or the L-aromatic aminoacid decarboxylase inhibitor benserazide, was administered to a group of normal adult men. Morphine (10 mg) stimulated prolactin release in all subjects; however, the effect was totally abolished when 10 mag metoclopramide or 200 mg benserazide were given before the opiate agonist. The prolactin releasing effect of a sub-maximal metoclopramide dose (1 mg) was potentiated by morphine. In vitro, benserazide was totally inactive in stimulating prolactin release by isolated anterior pituitary cells. Moreover, benserazide failed to alter the inhibiting action of dopamine on prolactin release. The data suggest that opiates stimulate prolactin release in man by acting through dopaminergic mechanisms.

Adult↗
PubMed1998

Uptake and intracellular fate of L-DOPA in a human intestinal epithelial cell line: Caco-2.

The aim of the present study was to examine the kinetic characteristics of the L-3,4-dihydroxyphenylalanine (L-DOPA) transporter and the fate of newly formed dopamine in Caco-2 cells. In the presence of 50 microM benserazide (an inhibitor of aromatic L-amino acid decarboxylase), L-DOPA was rapidly accumulated in Caco-2 cells. At equilibrium (30 min of incubation) the intracellular L-DOPA concentration was 10.2 +/- 0.1 microM at a medium concentration of 0.5 microM. In saturation experiments the accumulation of L-DOPA was saturable with a Michaelis-Menten constant (Km) of 60 +/- 10 microM and a maximal reaction velocity (Vmax) of 6.6 +/- 0.3 nmol . mg protein-1 . 6 min-1; at 4 degrees C the amount of L-DOPA accumulated in the cells was nonsaturable. When cells were incubated with increasing concentrations of L-DOPA (10-100 microM) in the absence of benserazide, a substantial amount of the L-DOPA that was taken up was decarboxylated to dopamine, with an apparent Km of 27.2 microM. In experiments performed in cells cultured in polycarbonate filters, the accumulation of L-DOPA in the presence of benserazide was greater when the substrate was applied from the basolateral cell border than when it was applied from the apical cell border. In the absence of benserazide, L-DOPA applied from the basolateral cell border resulted in a nonlinear formation of dopamine (Km = 43 +/- 7 microM, Vmax = 23.7 +/- 1.2 nmol . mg protein-1 . 6 min-1). The amount of dopamine leaving the cell through the apical cell border was lower than the amount that escaped through the basolateral cell border, and the process was saturable (Km = 623 +/- 238 microM, Vmax = 0.19 +/- 0.02 nmol . mg protein-1 . 6 min-1). In conclusion, the data presented here show that Caco-2 cells are endowed with an efficient L-DOPA uptake system, and intracellular L-DOPA was found to be rapidly converted to dopamine, some of which diffuses out of the cell. The utilization of Caco-2 cells cultured on polycarbonate filters probably provides a better way to look at processes such as the outward transfer of intracellular molecules, namely, the outward transfer of newly formed dopamine.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1987

Bioavailability of L-dopa after Madopar HBS administration in healthy volunteers.

Eight healthy male and fasted volunteers received alternatively either one HBS capsule of Madopar 125 or two HBS capsules of Madopar 125 or one standard capsule of Madopar 125 at weekly intervals with and without benserazide pretreatment (50 mg t.i.d. for 6 days). In this trial the Madopar formulations were administered 9.5 h after the last dose of benserazide. Serial blood samples were collected at various time intervals up to 12 h after Madopar dosing. Levodopa plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection. After Madopar HBS without benserazide pretreatment the peak concentration (Cmax) of levodopa was lower and occurred at later times (tmax) than after standard Madopar. The mean values for tmax were 2.4, 2.8 and 0.8 h, whereas those for Cmax were 0.25, 0.56 and 1.38 micrograms/ml for one HBS capsule, two HBS capsules and standard Madopar, respectively. The mean relative bioavailability (versus standard Madopar) was 58 and 67% (value normalized to dose) for one and two HBS capsules, respectively. The parameter of half-value duration (= time span where plasma concentrations are equal to or higher than the half Cmax) was on average 3.5, 3.8 and 0.8 h for one HBS capsule, two HBS capsules and standard Madopar, respectively. Following benserazide pretreatment the mean tmax values for levodopa were 2.8, 2.3 and 0.8 h and the mean Cmax values were 0.35, 0.60 and 1.33 micrograms/ml, respectively, for one HBS capsule, two HBS capsules and standard Madopar. The relative bioavailability (versus standard Madopar) was 57 +/- 14 and 63 +/- 21% (value normalized to dose) for one and two HBS capsules, respectively. The mean values of the half-value duration were 3.6, 4.2 and 1.3 h for one HBS capsule, two HBS capsules and standard Madopar, respectively. For most of the parameters measured, the interindividual variability after Madopar HBS was less pronounced than after standard Madopar. In conclusion, according to these kinetic data, Madopar HBS shows the characteristics of a controlled-release formulation. The reduced bioavailability of the HBS form (60% of that of the standard form) suggests that a higher daily dose of Madopar HBS should be used for clinical practice.

Administration, Oral↗
PubMed1977

Effect of 1-5 hydroxytryptophan infusion on growth hormone and prolactin secretion in man.

The effect of a new soluble ester of 1-5 hydroxytryptophan (1-5 HTP, Ro 3-5940, 200 mg infusion) on prolactin (PRL) and growth hormone (GH) release was tested in 11 young, healthy subjects (6 men, 5 women). To minimize side-effects, peripheral decarboxylase inhibition was achieved with benserazide (Ro 4-4602.) PRL increased significantly (P less than 0.01) after benserazide alone in all subjects. A further significant increase (P less than 0.01) of PRL plasma levels occurred only in women up to 90 min after the infusion of 1-5 HTP was discontinued. Benserazide administration had no effect of basal GH levels, but a significant increase of GH release (P less than 0.01) was noticed 30-120 min after the end of 1-5 HTP infusion in both men and women. The mean peak value of GH plasma levels after 1-5 HTP administration was 32.0 +/- 8.8 ng/ml. It was postulated that benserazide penetrated at the level of the pituitary, decreasing the synthesis of dopamine and consequently reducing its known inhibitory effect on PRL release. The PRL increase (statistically significant only in women), as well as the release of GH after 1-5 HTP infusion, was considered as further evidence for stimulatory serotoninergic control of both PRL and GH secretion.

5-Hydroxytryptophan↗
PubMed1980

Dose and sex related effects of aromatic aminoacids decarboxylase inhibitors on serum prolactin in humans.

Single doses of carbidopa and benserazide, two inhibitors of aromatic aminoacids decarboxylase, have been given orally to healthy women and men aged 19 to 32 years. Serum prolactin levels increased in respect to baseline levels when 80, 125 or 250 mg of carbidopa and 10, 20, 30, 50, 80 or 125 mg of benserazide were given. The carbidopa doses of 20 and 50 mg were ineffective. Carbidopa induced the enhancement of serum prolactin at a later time and over a longer time span than benserazide. The effect on serum prolactin is dose dependent for both drugs. The hyperprolactinaemia obtained with 250 mg of carbidopa and with 125 mg of benserazide is significantly larger in women than in age matched men. The observed prolactin increase fits with the hypothesis that a diminution of the inhibitory effect of dopamine at the pituitary and/or at the median eminence levels may occur in connection to the pharmacologically impaired monoamine synthesis. An effect of serotonin cannot, however, be excluded.

Administration, Oral↗
PubMed2003

Cost analysis of ropinirole versus levodopa in the treatment of Parkinson's disease.

BACKGROUND: Not all patients with Parkinson's disease (PD) respond to levodopa and others develop dyskinesias. Ropinirole, a dopamine agonist, is associated with fewer dyskinesias than levodopa. OBJECTIVE: To examine the economic impact of reducing dyskinesias using ropinirole instead of levodopa plus benserazide in PD was examined. The research question addressed was: is the added cost of ropinirole offset by savings due to avoided cases of dyskinesia? METHODS: A cost-minimisation analysis was performed from both the societal and Ministry of Health (MoH) of Ontario, Canada perspectives, using 5-year data from a study of dyskinesia outcomes comparing ropinirole with levodopa plus benserazide. A predictive model was developed to capture resource utilisation over 5 years, such as medication costs, medical consultations, hospital admissions, nursing home admissions, caregiver time and productivity loss. The model was based on a previously reported clinical trial which determined dyskinesia rates to be 20% for ropinirole and 45% for levodopa. Standard costing lists were used, and costs were discounted at various rates. Constant 1999 Canadian dollars ($Can) were applied, and no increases were assumed over the time horizon of the analysis. A multivariate sensitivity analysis with changes in key parameters was also performed. RESULTS: From a societal perspective, ropinirole was cost saving. From the MoH perspective, the analysis yielded an incremental expected daily cost/patient of $Can4.41 for substituting levodopa plus benserazide with ropinirole. Ropinirole resulted in daily savings/patient of $Can0.17 in non-drug healthcare costs. In the sensitivity analysis, the direction of results did not change despite changes of 15 to 20% in key parameters, suggesting robustness of the model. CONCLUSIONS: From the societal perspective, in comparison with levodopa plus benserazide, the added cost of ropinirole is offset by savings due to avoided cases of dyskinesia.

Adult↗
PubMed2003

Commonly used L-amino acid decarboxylase inhibitors block monoamine oxidase activity in the rat.

The effects of the peripheral aromatic amino acid decarboxylase (AADC) inhibitors, carbidopa and benserazide, and the central AADC inhibitor, 3-hydroxybenzylhydrazine (NSD-1015) on peripheral and brain monoamine oxidase (MAO) A and B activity were investigated in the rat. In vitro, carbidopa, benserazide and NSD-1015 all potently inhibited hepatic MAO A and B activity (IC(50) 10-50 micro M). In ex vivo studies following systemic drug administration, NSD-1015 (100 mg/kg ip) produced 88% and 96% inhibition of hepatic and striatal MAO A and B activity respectively. Carbidopa (12.5 mg/kg i.p.) and benserazide (50 mg/kg i.p.) had no effect on striatal MAO A activity or hepatic MAO B activity. However, they inhibited striatal MAO B activity by 45 +/- 10% and 36 +/- 10% respectively. In conclusion, carbidopa and benserazide may not only protect L-DOPA from peripheral decarboxylation, but also increase striatal dopamine content through MAO inhibition. NSD-1015 should not be used to investigate the neuromodulatory role of L-DOPA as it potently inhibits rat striatal MAO.

Animals↗
PubMed2001

BIA 3-202, a novel catechol-O-methyltransferase inhibitor, enhances the availability of L-DOPA to the brain and reduces its O-methylation.

1-[3,4-Dihydroxy-5-nitrophenyl]-2-phenyl-ethanone (BIA 3-202) is a new long-acting catechol-O-methyltransferase (COMT) inhibitor with limited access to the brain. The present study evaluated the interference of BIA 3-202 upon levels of L-3,4-dihydroxyphenylalanine (L-DOPA) and metabolites in plasma (3-O-methyl-L-DOPA) and brain [3-O-methyl-L-DOPA, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] in rats orally treated with L-DOPA (20 mg/kg) plus benserazide (30 mg/kg). At different time points (1, 3 and 6 h) after the administration of BIA 3-202 (0, 3, 10 and 30 mg/kg) or L-DOPA plus benserazide, rats were sacrificed and the right striatum was quickly dissected out and stored for the assay of L-DOPA, 3-O-methyl-L-DOPA, dopamine and amine metabolites. Levels of L-DOPA, 3-O-methyl-L-DOPA, dopamine, DOPAC and HVA in the striatum in L-DOPA plus benserazide-treated rats were higher than in vehicle-treated rats. However, this increase in striatal L-DOPA, dopamine, DOPAC and HVA was, in a dose- and time-dependent manner, even higher (P<0.05) in rats given BIA 3-202 (3, 10 and 30 mg/kg). This effect was accompanied by a marked decrease in 3-O-methyl-L-DOPA levels in the striatum of L-DOPA plus benserazide-treated rats. Increases in levels of L-DOPA and decreases in 3-O-methyl-L-DOPA levels in plasma also accompanied the administration of BIA 3-202. BIA 3-202 did not significantly affect levels of DOPAC and HVA in the striatum in vehicle-treated rats. It is concluded that administration of BIA 3-202 enhances the availability of L-DOPA to the brain by reducing its O-methylation in the periphery, which may prove beneficial in parkinsonian patients treated with L-DOPA plus an aromatic amino acid decarboxylase inhibitor.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Subacute L-DOPA in mice: biochemical and behavioural effects.

Mice, pretreated orally with L-DOPA (200 mg/kg) plus benserazide (50 mg/kg) (L-DOPA-B) responded when challenged 24 h later with the same drug combination, with significantly greater locomotor stimulation than animals pretreated with the vehicle. The enhanced response was not due to an intrinsic effect of benserazide. Nor was it dependent on a change in central dopamine (DA) receptor sensitivity, because the two pretreatment groups (L-DOPA-A and vehicle) did not differ in their locomotor response to a range of apomorphine doses (300--3,000 micrograms/kg, IP). The enhanced response was, however, due to DA receptor stimulation because it was antagonised by premedication of the mice with haloperidol or pimozide. Moreover, the enhanced response to L-DOPA-B chf L-DOPA alone (without benserazide) (1,200 mg/kg, orally). Animals which had been pretreated with L-DOPA-B had significantly higher brain levels of L-DOPA and DA after a subsequent challenge dose of L-DOPA-B administered 24 h later. Thus the enhanced response to L-DOPA-B observed in the present experiment appears to be dependent on some mechanism which produces higher concentrations of L-DOPA (and consequently DA) in the brain.

Animals↗
PubMed1976

Effects of dopaminergic stimulants on cyclic nucleotide levels in mouse brain in vivo.

Dopaminergic stimulants (amantadine, amphetamine, apomorphine, nomifensine and L-dopa plus benserazide) increased cyclic GMP levels in the medial forebrain and cerebellum of mice. Cyclic AMP levels were not significantly altered under these conditions. Drug-induced stereotyped behaviour correlated in intensity and duration to the changes in cyclic GMP levels in the medial forebrain. Amantadine, apomorphine and nomifensine showed a linear dose response relationship, but differed as to the extent and time course of the increase in cyclic GMP. Amantadine and apomorphine were were more effective in elevating cyclic GMP in the medial forebrain than in the cerebellum. Amphetamine produced an exponential dose-related elevation of cyclic GMP in both parts of the brain, being more effective in the cerebellum than in the medial forebrain at high doses, thus indicating a complex mechanism of action. L-Dopa (50 mg/kg) and benserazide (40 mg/kg) alone did neither significantly increase cyclic GMP levels nor induce stereotyped behaviour. However, in animals pretreated with benserazide (15 min prior to L-odopa) L-dopa produced a significant elevation of cyclic GMP and stereotyped behaviour.

Amantadine↗
PubMed1982

Human pharmacokinetics of long term 5-hydroxytryptophan combined with decarboxylase inhibitors.

L-5-Hydroxytryptophan (5HTP) and its major metabolites 5-hydroxytryptamine (5HT) and 5-hydroxyindoleaceticacid (5HIAA) were measured in blood and cerebrospinal fluid from neurological patients receiving steady state treatment with 5HTP. There was accumulation of 5HT in blood platelets and 5HIAA in plasma in all patients, despite concomitant administration of the L-aromatic amino acid decarboxylase inhibitors, carbidopa and benserazide. There was no correlation between the 5HTP dose and the circulating concentrations of the aminoacid or its metabolites. Preliminary comparison of the biochemical and therapeutic effects of carbidopa versus benserazide suggest that 5HTP: carbidopa is superior to 5HTP: benserazide. A direct proportionality between plasma 5HTP concentrations and the levels of 5HTP in the lumbar cerebrospinal fluid was found. The binding to serum proteins of 5HTP in the clinically relevant concentration range of 10 to 100 microM was investigated; 19% of circulating 5HTP was bound to serum proteins. 5HTP did not displace protein-bound tryptophan in serum.

5-Hydroxytryptophan↗
PubMed1987

Effect of L-threo-3,4-dihydroxyphenylserine(L-threo-DOPS) on brain and serum MHPG levels in mice: evidence for NE formation in CNS.

Effects of L-threo-DOPS on brain and serum concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), a major metabolite of 1-norepinephrine(NE) were studied in mice. An intraperitoneal(i.p.) injection of L-threo-DOPS markedly increased both serum and brain MHPG levels in mice. This increase in the brain was dose-dependent at doses up to 800 mg/kg, and lasted for 4 h or more. Though the increase in serum total-MHPG was 3-4 times greater than that in brain MHPG, the decline was rapid as compared with the case of brain MHPG. The L-threo-DOPS-induced increase in MHPG was inhibited by i.p. pretreatment with benserazide, a peripheral decarboxylase inhibitor, in both serum and brain. This inhibition in the brain, however, was observed at about 20 times higher doses of benserazide than that in serum. On the contrary, an intracerebroventricular(i.c.v.) injection of benserazide inhibited the increase in brain MHPG to about the same degree as that in serum MHPG. These results suggest that the L-threo-DOPS-induced increase in brain MHPG is not likely to originate in peripheral organs including the brain capillary, and that L-threo-DOPS can be converted to NE by aromatic L-amino acid decarboxylase(AADC) in the brain parenchyma.

Animals↗
PubMed1995

Contrasting effects of peripheral decarboxylase inhibitors on plasma activity of aromatic-L-amino acid decarboxylase and semicarbazide-sensitive amine oxidase in Parkinson's disease.

The peripheral decarboxylase inhibitors benserazide and carbidopa, often administered in combination with L-dopa in the treatment of Parkinson's disease, are also very good inhibitors of semicarbazide-sensitive amine oxidase (SSAO). In untreated patients and in patients treated with L-dopa alone, plasma SSAO activity is normal. In patients treated with L-dopa plus benserazide or carbidopa (Madopar or Sinemnet), however, plasma SSAO activity is strongly inhibited, contrary to the paradoxical 3-fold increase in plasma aromatic-L-amino acid decarboxylase activity we reported previously. Single-dose and longitudinal studies show that the SSAO inhibition proceeds rapidly and increases even further to nearly complete inhibition after continued treatment, while aromatic-L-amino acid decarboxylase activity only transiently decreases after a single dose and increases slowly with continued treatment above pretreatment levels. Dialysis experiments confirm that the binding of benserazide to SSAO is irreversible, especially after chronic treatment. The lack of knowledge about the exact function of SSAO precludes definite conclusions about the effect of this chronic SSAO inhibition on patients. Careful follow-up studies of patients treated with Madopar or Sinemet might provide further information about the possible physiological role of SSAO.

Aged↗
PubMed1996

Locally formed 5-hydroxytryptamine stimulates phosphate transport in cultured opossum kidney cells and in rat kidney.

UNLABELLED: Renal proximal tubular cells have been shown to express aromatic L-amino acid decarboxylase (L-AAAD), which converts L-dopa into dopamine and 5-hydroxytryptophan [(OH)Trp] into 5-hydroxytryptamine (5-HT; serotonin). Because 5-HT receptors have been demonstrated in proximal cells, we hypothesized that 5-HT may act as an autocrine/paracrine modulator of proximal transport. We evaluated this possibility in opossum kidney (OK) cells, a renal epithelial cell line with a proximal phenotype expressing 5-HT1B receptors, and in intact anaesthetized rats. 5-HT synthesis by OK cells increased with incubation time and (OH)Trp concentration, and was abolished by benserazide, an L-AAAD inhibitor. 5-HT reversed parathyroid hormone (PTH)-induced cAMP accumulation in a pertussis toxin-sensitive manner and reduced the PTH inhibition of P(i) uptake without affecting the NaP(i)-4 mRNA level. The effects of 5-HT on cAMP generation and Na-P(i) co-transport were reproduced by (OH)Trp, except in the presence of benserazide, and by L-propranolol and dihydroergotamine, two 5-HT1B receptor agonists. In rats, (OH)Trp and dihydroergotamine decreased fractional P(i) excretion. Benserazide abolished the effect of (OH)Trp but not that of dihydroergotamine. IN CONCLUSION: (i) locally generated 5-HT blunts the inhibitory effect of PTH on Na-P(i) co-transport in OK cells; (ii) endogenous 5-HT decreases P(i) excretion in rats; and (iii) 5-HT is a paracrine modulator involved in the physiological regulation of renal P(i) transport.

5-Hydroxytryptophan↗
PubMed1994

Increase in plasma 3,4-dihydroxyphenylalanine (DOPA) appearance rate after inhibition of DOPA decarboxylase in humans.

Concentrations of DOPA in plasma are relatively high as compared to norepinephrine. The significance of plasma DOPA has not been elucidated. One would expect that substantial amounts of DOPA are derived from sympathetic nerves. There appears, however, neither to be a depot of DOPA in nerves nor is there a close correlation between plasma DOPA and sympathetic activity. The aim of the present study was to obtain further information about plasma DOPA by studying DOPA kinetics in healthy humans both with and without inhibition of DOPA decarboxylase by benserazide. Plasma DOPA and other catecholamines were measured by reverse-phase HPLC with electrochemical detection and DOPA clearance and appearance rate were studied using infusion of 3H-DOPA. The plasma clearance of DOPA was 1.02 1 min-1. Approximately 20% of this value could be explained by DOPA being decarboxylated in the kidneys and excreted as dopamine. The DOPA appearance rate was 1.13 micrograms min-1 and the extremities accounted for approximately 1/5 of this value. After inhibition of DOPA decarboxylase by benserazide the DOPA appearance rate increased 7-fold, whereas the DOPA clearance only decreased slightly and insignificantly. These findings are probably explained by two factors: (1) There is normally a large production of DOPA in some tissues from which DOPA spillover into plasma only occurs to a minor extent and tracer DOPA only mixes with this compartments to a small degree; (2) These compartments are permeable to benserazide, which blocks the decarboxylation of DOPA, which then leaves the tissues and spillover to plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗