Excretion Of DOPAC Research Articles

Role of Chronic Inhibition of Dopamine-Metabolizing Enzymes in the Regulation of Renal Sodium and Phosphate Excretion in the Rat Remnant Kidney

Background/Aims: The present study examined the effects of chronic selective or combined inhibition of type A monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) on daily urinary excretion of dopamine and metabolites and on natriuresis and phosphaturia in 3/4 nephrectomized (3/4nx) and Sham rats. Methods: The 3/4nx and Sham rats were placed in metabolic cages and received the MAO-A-selective inhibitor Ro-411049 (7.5 mg·kg^–1 bid) and/or the COMT-selective inhibitor BIA 3-202 (30 mg·kg^–1 bid) orally for 3 days during high sodium diet. Results: Selective COMT inhibition increased the urinary excretion of the deaminated metabolite (3,4-dihydroxyphenylacetic acid, DOPAC) and decreased the urinary excretion of the methylated (3-methoxytyramine, 3-MT) and deaminated plus methylated metabolite (homovanillic acid, HVA) in both groups. Selective MAO-A inhibition increased the urinary excretion of 3-MT and reduced the urinary excretion of both DOPAC and HVA in either 3/4nx or Sham rats. Combined inhibition of MAO-A and COMT did not significantly change the urinary excretion of DOPAC and markedly decreased the urinary excretion of 3-MT and HVA in both groups. Selective or combined inhibition of MAO-A and COMT did not alter the daily urinary excretion of dopamine, sodium or phosphate in either 3/4nx or Sham rats. Conclusions: Chronic selective or combined inhibition of MAO-A and COMT is not of major importance in regulating the dopamine-dependent natriuresis and phosphaturia in either 3/4nx or Sham rats.

Renal dopaminergic mechanisms in renal parenchymal diseases and hypertension.

The present report addresses the status of the renal dopaminergic system activity in patients afflicted with different renal disorders and in the remnant kidney of uninephrectomized (UNX) rats, based on the urinary excretion of L-DOPA, dopamine and amine metabolites. In renal transplant recipients with good recovery of graft function (group 1, n=11), the daily urinary excretion of DOPAC, but not that of HVA, was found to increase progressively throughout the first 12 days post-transplantation from 698+/-57 nmol in the first day to 3498+/-414 nmol on day 9, and then remained constant until day 12. This resulted in a 6-fold increase in the urinary DOPAC/dopamine ratios. In renal transplant recipients with acute tubular necrosis (group 2, n=8), the urinary levels of dopamine, DOPAC and HVA were approximately 30% of those in group 1. In a group of 28 patients with chronic renal parenchymal disorders, the daily urinary excretion of L-DOPA, free dopamine and dopamine metabolites (DOPAC and HVA) correlated positively with the degree of deterioration of renal function (P<0.01). However, the U(Dopamine/(L)-DOPA) and U(DOPAC/Dopamine) ratios in patients with chronic renal insufficiency were found to be similar to those observed in patients with normal renal function. In 14 IgA nephropathy (IgA-N) patients with near normal renal function, the changes in 24 h mean blood pressure when going from 20 to 350 mmol/day sodium intake correlated negatively with the daily urinary excretion of dopamine (r(2)=0.597, P<0.01). The urinary excretion of L-DOPA and dopamine in IgA-N patients with salt-sensitive (SS) blood pressure was lower than in salt-resistant (SR) patients (P<0.05), irrespective of their daily sodium intake. However, the rise in urinary dopamine output during salt loading (from 20 to 350 mmol/day) was greater (P<0.05) in IgA-N SS patients (21.2+/-2.5% increase) than in SR patients (6.3+/-1.4% increase). Fifteen days after the surgery, uninephrectomy (UNX) in the rat was accompanied by an enhanced (P<0.05) urinary excretion of dopamine (36+/-3 vs 26+/-2), DOPAC (124+/-11 vs 69+/-6) and HVA (611+/-42 vs 354+/-7) (nmol/g kidney/kg body weight). This was accompanied by an increase in V(max) values for renal aromatic L-amino acid decarboxylase in the remnant kidney of UNX rats (P<0.05). Sch 23390, a D1 dopamine receptor antagonist, produced a marked reduction in the urinary excretion of sodium in UNX rats, whereas in sham-operated rats the decrease in urinary sodium did not attain a significant difference. It is concluded that the study of the renal dopaminergic system in patients afflicted with renal parenchymal disorders should address parameters other than free urinary dopamine, namely the urinary excretion of L-DOPA and dopamine metabolites (DOPAC and HVA). It is also suggested that in SS hypertension of chronic renal parenchymal diseases, renal dopamine produced in the residual tubular units may be enhanced during a sodium challenge, thus behaving appropriately as a compensatory natriuretic hormone.

Complex analysis of efficiency of transplantation of embryonic nerve tissue to rats with hemiparkinsonism

Effect of transplantation of embryonic ventral mesencephalon preparation containing dopaminergic neurons on repair of the dopaminergic nigrostriatal system was studied in rats with hemiparkinsonism induced by 6-hydroxydopamine. Transplantation of embryonic ventral mesencephalon into denervated striatum led to a more than 50% decrease in apomorphine-induced rotation, recovery of dopamine and DOPAC levels in the brain, and to an increase in DOPAC excretion and the DOPAC-dopamine ratio in daily urine of rats with hemiparkinsonism. Dopaminergic neurons of the transplant survived, forming a network of tyrosine hydroxylase-positive processes growing beyond the transplant and reinnervating the adjacent compartments of the striatum. A positive correlation between urinary excretion of DOPAC and brain concentration of dopamine was revealed in denervated rats after transplantation of ventral mesencephalon. Intrastriatal transplantation of cell preparations of embryonic striatum containing no dopaminergic neurons and isolated local injury to the striatum did not affect regeneration of the denervated nigrostratal system.

Acidic Catecholamine Metabolites and 5-Hydroxyindoleacetic Acid in Urine: The Influence of Diet

Concentrations of vanillylmandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), vanillic acid (VA) and 5-hydroxyindoleacetic acid (5-HIAA) in urine from healthy subjects were determined by a high-performance liquid chromatography system with a mixed-mode (C18/anion-exchange) column and an 8-channel electrochemical detector, in order to study the influence of diet, diurnal variation and age. The urinary excretion of 5-HIAA increased significantly after eating banana, pineapple, tomato, kiwi fruit and walnut. An increase in the urinary excretion of DOPAC and HVA after eating banana and that of VA after taking vanilla was also noted. The urinary excretion of VMA was not significantly influenced by any of the foods examined. The urinary excretion of 5-HIAA in the first-morning urine increased beyond the upper limit of the reference value when banana was taken at 2000 h the previous day. The excretion of all metabolites in the second-morning urine in the fasting state was within respective reference ranges. Diurnal variation of the excretion of VMA, DOPAC, HVA and 5-HIAA in urine was relatively small, but that of VA was large. The concentrations (mmol/mol creatinine) of VMA, DOPAC, HVA, 5-HIAA and VA in the first-morning urine from healthy subjects increased from 7 days after birth to 1 year and then decreased to adult levels at 13 years of age.

Sodium and dopamine excretion in prehypertensive Dahl rats during severe hypervolaemia

As opposed to the salt-resistant Dahl-R rat the salt-sensitive Dahl-S has a defective renal dopamine DA1 receptor that may be involved in its susceptibility to develop hypertension during a high salt diet. To compare the ability of prehypertensive Dahl-R and Dahl-S to respond to a severe isotonic sodium load, renal function was monitored during a severe form of acute isotonic volume expansion (10% VE). Mean arterial blood pressure before VE was similar in Dahl-R and Dahl-S and decreased in both strains by 6% during VE. The accumulated sodium excretion during VE in Dahl-R was 411 +/- 64 micromol 100 min(-1) g(-1) kidney wt (kw) which was not different from that in Dahl-S (420 +/- 95 micromol 100 min(-1) g(-1) kw). The accumulated dopamine excretion (a mirror of renal dopamine synthesis) during VE was also similar in Dahl-R (134 +/- 13 ng 100 min(-1) g(-1) kw) and Dahl-S (126 +/- 16 ng 100 min(-1) g(-1) kw). The excretion of DOPAC, the main metabolite of Dahl-S, glomerular filtration rate and systemic haematocrit did not differ between the strains before, during or after VE. To conclude, in spite of a defective renal DA1 receptor prehypertensive Dahl-S do not respond with an attenuated natriuretic or dopamine excretory response when subjected to a severe isotonic sodium load. The results do not support a sodium retaining role over a defective DA1 receptor in the salt-sensitive hypertension in Dahl-S.

Metabolism of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and dopamine after oral administration to rats and dogs.

The metabolism of an orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and of dopamine (DA), were studied by use of thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) for identification and analysis of urinary and biliary metabolites after p.o. and/or i.v. administration to rats and dogs. The conjugated/free ratios of the metabolites were also determined. The urinary metabolites and order of the excretion in rats after p.o. dosing of TA-870 (30 mg/kg) were DA greater than homovanillic acid (HVA) greater than 3,4-dihydroxyphenylacetic acid (DOPAC) greater than 3-hydroxyphenylacetic acid (3-HPAC). Those in dogs (33.5 mg/kg p.o.) were DA greater than HVA greater than de-ethoxycarbonylated TA-870 (DEC-TA-870) not equal to DOPAC. The urinary metabolites and order of the excretion in rats after p.o. dosing of DA (12 mg/kg, equimolar dose to TA-870) were DA greater than DOPAC greater than HVA greater than 3-HPAC, while those in dogs (13.5 mg/kg) were DOPAC greater than DA greater than HVA. The composition of the main urinary metabolites of TA-870 are similar in rats and dogs but after p.o. dosing of DA, excretion of DOPAC in dogs is much (ca. 3 times) higher than that in rats. After administration of DA and TA-870, 3-HPAC was found as a novel metabolite of DA, which was thought to be formed by dehydroxylation of DOPAC or DA with intestinal flora.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary excretion of monoamines and their metabolites in patients with Parkinson's disease: Response to long-term treatment with levodopa alone or in combination with a dopa decarboxylase inhibitor and clinical correlations

Urinary excretion of DA, DOPAC, 3-MT, HVA, NMA, MA, VMA and 5-HIAA were studied in 33 parkinsonian patients treated with 1.5-7.5 g of levodopa daily for up to six months and in 30 patients receiving levodopa (800-1,000 mg) combined with a dopa decarboxylase inhibitor, benserazide (200-250 mg). Basal urinary excretions were within normal limits except for that of 3-MT which was significantly lower in parkinsonian patients as compared to controls. Levodopa induced an increase of about 400 fold in urinary DA; DOPAC was increased about 300 fold, 3-MT only about 70 fold, but HVA about 300 fold. Urinary NMA and MA did not change but VMA was increased significantly. On the other hand, urinary 5-HIAA was significantly decreased. The amounts of excreted DA and its subsequent metabolities were increased with the continuation of treatment, suggesting inductive phenomena in enzyme systems. During combined treatment with levodopa and benserazide urinary DA was increased, but only to about one tenth the extent seen with levodopa alone. The excretion of DOPAC was about one 20th, of 3-MT about one fourth and of HVA one 25th that seen during levodopa treatment. No signs of enzyme induction were seen. NMA was lowered significantly but MA remained unchanged. VMA was increased and significantly more than during therapy with levodopa alone. 5-HIAA was again significantly decreased and the decrease was significantly greater than that seen with levodopa alone. Some statistically significant correlations were seen between the excretions of NMA, MA and VMA and cardiovascular side effects, indicating an affection on the NA-ergic system by levodopa treatment. Significant correlation between 5-HIAA excretion and clinical improvement of tremor during levodopa treatment may suggest that participation of 5-HT in the mechanism of tremor.