Renal conversion of plasma DOPA to urine dopamine [letter]

Brown, M. J.; Allison, D J

doi:10.1111/j.1365-2125.1981.tb01210.x

Cited by 57 publications

(24 citation statements)

References 5 publications

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“…The basis of the renal specificity lies in the sequential transformation of the dipeptide to dopamine under the actions of -y-glutamyltransferase (EC 2.3.2.2) and dopa decarboxylase (L-amino-acid decarboxylase; EC 4.1.1.26) both of which are highly concentrated in the proximal tubular cells of the kidney (Albert et al, 1961;Goldstein et al, 1972). There is a great deal of evidence, that under physiological conditions, renal dopamine is largely synthesised extraneuronally in the proximal tubule from circulating L-dopa and that the suggested dopaminergic nerves make little significant contribution to urine dopamine levels (Baines & Chan, 1980;Brown & Allison, 1981;Lee, 1982Lee, , 1986. Gludopa was natriuretic with sodium excretion more than doubling and the response persisting beyond the infusion period, confirming our previous work in man.…”

Section: Discussionsupporting

confidence: 71%

The effect of carbidopa and indomethacin on the renal response to gamma‐ L‐glutamyl‐L‐dopa in normal man.

Jeffrey

MacDonald

Marwick

et al. 1988

Brit J Clinical Pharma

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1 The renal response to y-L-glutamyl-L-dopa (gludopa, 25 ,ug kg-1 min-') was investigated in seven normal male volunteers. The effects of oral carbidopa (100 mg) and indomethacin (100 mg) on the response to gludopa were studied in the same group. 2 Gludopa at this dose level produced a 900-fold increase in urine dopamine excretion and caused a natriuresis and suppression of plasma renin activity with only minor effects on pulse rate and blood pressure. 3 Carbidopa inhibited the increase in dopamine excretion by 97% and abolished the renal actions of gludopa. 4 The increase in urine dopamine produced by gludopa was not altered by indomethacin and the urine sodium output was similar to that caused by gludopa alone. 5 Gludopa is an effective renal dopamine prodrug whose activity can be blocked by the dopa decarboxylase inhibitor carbidopa. The results with indomethacin suggest that dopamine and the prostaglandins form separate natriuretic systems in the kidney.

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Section: Discussionsupporting

confidence: 71%

The effect of carbidopa and indomethacin on the renal response to gamma‐ L‐glutamyl‐L‐dopa in normal man.

Jeffrey

MacDonald

Marwick

et al. 1988

Brit J Clinical Pharma

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“…Carbidopa, a peripheral decarboxylase inhibitor, was used by these investigators to demon strate that the Tyr-induced enhancement of urinary catecholamine excretion was me diated peripherally. Since dopamine excre tion, under normal circumstances, reflects re nal production of dopamine [26], and since the kidneys have little Tyr hydroxylase activ ity [26], it seems likely that enhanced renal dopamine production occurs in response to Tyr-induced elevations in circulating levels of L-dihydroxyphenylalanine (L-dopa) [5,7], The physiologic importance of renal produc tion of dopamine is controversial. It has been suggested that dopamine is an important na triuretic agent [28], However, a dissociation between dopamine and sodium excretion is apparent in our study since treatment with Tyr stimulated dopamine production (ta ble II) without enhancing sodium excretion (table I).…”

Section: Discussionmentioning

confidence: 99%

Physiologic Responses to Chronic Dietary Tyrosine Supplementation in DOCA-Salt-Treated Rats

et al. 1986

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The antihypertensive effect of chronic administration of L-tyrosine (Tyr) was investigated in a two-part study. In the first experiment, adult male Sprague-Dawley rats were assigned to 1 of 4 treatment groups: (1) control diet plus unilateral nephrectomy (Nphx) and 0.15 M NaCl (Sal) as the sole drinking solution (C-CTRL); (2) control diet plus deoxycorticosterone acetate (DOCA, 268 μg/rat/day), Nphx, and Sal (C-DOCA); (3) control diet supplemented with 2.5% L-p-Tyr plus Nphx and Sal (Tyr-CTRL), and (4) Tyr plus DOCA, Nphx, and Sal (Tyr-DOCA). Systolic blood pressure (SBP) increased within 2 weeks after initiation of treatment with DOCA-salt and remained elevated throughout the duration (8 weeks) of the study (p < 0.001). Dietary administration of Tyr to DOCA-treated rats failed either to affect SBP in normotensive rats or the elevation of SBP in DOCA-treated rats. Dietary supplementation with Tyr induced a significant elevation in urinary excretion of free dopamine (week 1, 3, 5, and 7) and a decreased excretion of free norepinephrine (week 1) without regard to DOCA treatment. Metabolic reponsiveness (change in colonic temperature) and cardiovascular responsiveness (change in heart rate) to subcutaneous administration of the β-adrenergic agonist, isoproterenol, were significantly prolonged while α₂-adrenoceptor number (cerebral cortical membranes; ³H-yohimbine binding) was reduced in rats receiving Tyr. In the second experiment, similar rats were assigned to 1 of 3 treatment groups: (1) control diet plus Nphx and Sal, (2) control diet plus Nphx, DOCA and Sal, and (3) Tyr plus DOCA, Nphx, and Sal; however, Tyr was not started until DOCA-salt-induced hypertension developed (4 weeks). Neither acute (2.5 h post-meal) nor chronic (4 weeks) effects of administration of Tyr on SBP were noted. Thus, the Tyr-induced changes observed in these studies include a chronic increase in free dopamine, and a transient decrease in norepinephrine, excretion. No significant effects of Tyr on blood pressure of DOCA-salt-treated rats were observed.

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“…We have measured the fraction metabolised to L-dopa, the immediate precursor of renal dopamine (Baines & Chan, 1980;Brown & Allison, 1981), and calculated the relevant first order rate constants associated with this process.…”

mentioning

confidence: 99%

The pharmacokinetics of γ‐glutamyl‐l‐dopa in normal and anephric rats and rats with glycerol‐induced acute renal failure

Boateng¹,

Barber²,

MacDonald³

et al. 1990

British J Pharmacology

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AB9 2ZD and tDepartment of Clinical Pharmacology, The Royal Infirmary, Edinburgh EH3 9YW1 The pharmacokinetics of y-glutamyl-L-dopa (gludopa) and its metabolite, L-dopa, have been studied in normal rats at three dose levels of gludopa: 2 mg kg-1, 5 mg kg-1 and 7.5 mg kg-'. The extent of metabolism in normal rats, and the pharmacokinetics in anephric rats and rats with glycerol-induced acute renal failure (ARF) were also studied at a gludopa dose of 2 mg kg 1.2 Gludopa was extensively metabolised to L-dopa with only about 10% of an injected dose being excreted unchanged. Normal rats had a rapid gludopa clearance of 50.9 + 9.6 ml min -1 kg1 and elimination rate constant of 2.99 + 0.27h1. The mean residence time and half-life were 20.9 + 1.4 and 14.4 + 1.0 min, respectively. The apparent volume of distribution at steady state was 1.05 + 0.181 kg -. 3 No statistically significant differences were found in the main pharmacokinetic parameters between ARF and controls for either gludopa or its metabolite L-dopa. 4 In anephric rats and controls the kidneys were found to contribute about 68.5% and 67.2% to the elimination of gludopa and the metabolite L-dopa, respectively. 5 These results confirm that gludopa is an efficient pro-drug for L-dopa, and that the kidneys are the major site of gludopa metabolism. It seems likely that the renal specificity of gludopa persists in ARF.

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Renal conversion of plasma DOPA to urine dopamine [letter]

Cited by 57 publications

References 5 publications

The effect of carbidopa and indomethacin on the renal response to gamma‐ L‐glutamyl‐L‐dopa in normal man.

The effect of carbidopa and indomethacin on the renal response to gamma‐ L‐glutamyl‐L‐dopa in normal man.

Physiologic Responses to Chronic Dietary Tyrosine Supplementation in DOCA-Salt-Treated Rats

The pharmacokinetics of γ‐glutamyl‐l‐dopa in normal and anephric rats and rats with glycerol‐induced acute renal failure

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