The renal and haemodynamic effects of a 10 h infusion of glutamyl‐L‐ dopa in normal man.

MacDonald, TM; Jeffrey, R. F.; Lee, M R

doi:10.1111/j.1365-2125.1989.tb03444.x

Cited by 13 publications

(8 citation statements)

References 20 publications

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“…Wilk et al, 1978;Lee, 1987;Jeffrey et al, 1988a,b;MacDonald et al, 1989;Cummings et al, 1990). Dopamine concentrations following gludopa administration were found to be much higher in the kidney than in mouse heart (Wilk et al, 1978) or rat liver (Cummings et al, 1990).…”

Section: Glycerol-induced Arfmentioning

confidence: 99%

Regional haemodynamic effects of dopamine and its prodrugs l‐dopa and gludopa in the rat and in the glycerol‐treated rat as a model for acute renal failure

Drieman

Kan

Thijssen

et al. 1994

British J Pharmacology

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1 In this study the renal selectivity of dopamine and its prodrugs L-dopa and gludopa, with respect to their effects on regional blood flow, vascular resistance and central haemodynamics was investigated in normal rats and in rats with glycerol-induced acute renal failure (ARF). 2 In normal, anaesthetized rats, dopamine as well as its prodrugs caused a dose-dependent reduction of vascular resistance in the kidney (RR), mesentery (MR) and hindquarters (HQR) (dose range: dopamine: 0. 1-5 ftmol kg-' h-i; L-dopa and gludopa: 1 -200 pmol kg'-h-'). Blood pressure and heart rate were affected at the highest dose only. 3 Administration of glycerol induced a preferential renal vasoconstriction; renal blood flow (-60%) and vascular resistance (+ 190%) were significantly more affected than MR (+40%) and HQR (+ 60%). This was only ameliorated by a low rate (10 pmol kg-' h-') infusion of gludopa: the glycerolinduced reduction of renal flow and increase in RR were significantly attenuated. A high dose of gludopa (100 gmol kg-' h-') or any dose of L-dopa or dopamine did not induce this beneficial effect. The glycerol-induced increase in MR and HQR was not attenuated by any of the treatments used. 4 The results indicate that gludopa is not renally selective at a pharmacodynamic level in normal, anaesthetized rats. Contrary to this, a low dose of gludopa does cause a renal selective vasodilatation and reduction of RR in rats with glycerol-induced ARF. This difference could be explained by a difference in renal vascular tone between normal rats and glycerol-induced ARF rats. A high dose of gludopa does not cause these renal-selective effects: renal resistance and renal flow are at the same level as following glycerol and saline. This is probably due to the systemic effects of the released dopamine.

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Section: Glycerol-induced Arfmentioning

confidence: 99%

Regional haemodynamic effects of dopamine and its prodrugs l‐dopa and gludopa in the rat and in the glycerol‐treated rat as a model for acute renal failure

Drieman

Kan

Thijssen

et al. 1994

British J Pharmacology

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“…Alternatively, the PRA-lowering effect is mediated centrally; the renin suppressing activity of L-dopa has been suggested to originate from CNS activity (9,15). At variance with the data discussed so far is a recent study on gludopa by MacDonald et al (78): a 10-h infusion at 25 pg/kg/min into healthy volunteers showed no effect on PRA. However, in that study the effects on natriuresis and urine volumes were also different from generally observed effects.…”

Section: Gludopamentioning

confidence: 67%

“…The results suggest that DA, formed in the kidney locally from L-dopa, reaches inhibitory but not excitatory DA receptors at the juxtaglomerular cells or that it reaches excitatory receptors at not sufficiently high levels to stimulate them. Plasma DA levels during gludopa infusion are low in comparison to the levels obtained during DA infusion: -4.5 nmol/L with gludopa 25 pg/kg/min (78), and 240 nmol/L with DA 3 pg/kg/min (51). Alternatively, the PRA-lowering effect is mediated centrally; the renin suppressing activity of L-dopa has been suggested to originate from CNS activity (9,15).…”

Section: Gludopamentioning

confidence: 96%

Prodrugs in Cardiovascular Medicine

Thijssen

Drieman

1990

Cardiovascular Drug Reviews

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“…y-GT will cleave the y-glutamyl moieties of gludopa and glu-5-HTP releasing the free amino acid precursors, L-dopa and L-5-HTP respectively, in relatively high quantities on both sides of the proximal tubular cells for subsequent decarboxylation. The enzyme has a tremendous capacity to metabolize y-glutamyl compounds, as shown by the very low recovery of unmetabolized gludopa in the urine (~1 % ) after its intravenous infusion in man [27,341. Administration of the two glutamyl compounds therefore offers the possibility of investigating whether there is competition between L-dopa and 5-HTP for renal LAAD in vivo in man.…”

Section: Discussionmentioning

confidence: 99%

Renal Metabolism and Effects of the Glutamyl Derivatives of l-Dopa and 5-Hydroxytryptophan in Man

Freestone

Samson

et al. 1996

Clinical Science

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1. Equimolar amounts of y-~-glutamyl-~3,4dihydrox yphen ylalanine (gludopa) and y-L-glutam yl-5-hydroxy-~-tryptophan were infused separately and together in eight healthy, salt-replete male subjects in a placebo-controlled, cross-over study to investigate whether the administration of one amine precursor affects the renal metabolism of the other and to determine whether dopamine or 5-hydroxytryptamine would be generated preferentially. The overall effect on sodium excretion was also measured when both precursors were administered simultaneously. 2. Administration of gludopa was associated with marked increases in the urinary excretion of L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid, together with a rise in the urinary excretion of sodium. y-~-Glutamyl-5-hydroxy-~-tryptophan, on the other hand, produced marked increases in the urinary excretion of 5-hydroxy-~-tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, and this was accompanied by a slight, but non-significant, reduction in sodium excretion. About 27% of the infused dose of gludopa (on a molar basis) was recovered in the urine as dopamine whereas 15% of the given dose of y-~-glutamyl-5-hydroxy-~-tryptophan was excreted as 5-hydroxytryptamine. 3. The urinary excretion values of L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid after the simultaneous infusion of gludopa and y-~-glutamyl-5hydroxy-L-tryptophan were not significantly different from those observed after infusion of gludopa only. Similarly, the urinary excretion values of 5-hydroxy-L-tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid during the co-infusion were similar to those measured after administration of y-Lglutamyl-5-hydroxy-~-tryptophan only. The net effect of the concomitant infusion of both glutamyl derivatives was an increase in urinary sodium excretion. 4. Our study in salt-replete individuals suggests that dopamine rather than 5-hydroxytryptamine was preferentially produced when equimolar amounts of their precursors were provided and that the natriuretic effect of dopamine, generated intrarenally from gludopa, was greater than the sodium retaining action of 5-hydroxytryptamine derived from y-~-glutamyl-5hydroxy-L-tryptophan. Comparison of the urinary metabolite data after the separate and concomitant infusion of the two glutamyl compounds provided no evidence of competitive inhibition of synthesis of either amine.dopamine and 5-HT are synthesized depending on the need to excrete or conserve sodium [2, 61. This Abbreviations: C,,, renal clearance of polyfructosan; C , , , renal clearance of p-aminohippurate; Cld,R, confidence interval of the difference between the means; Ldopa,

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The renal and haemodynamic effects of a 10 h infusion of glutamyl‐L‐ dopa in normal man.

Cited by 13 publications

References 20 publications

Regional haemodynamic effects of dopamine and its prodrugs l‐dopa and gludopa in the rat and in the glycerol‐treated rat as a model for acute renal failure

Regional haemodynamic effects of dopamine and its prodrugs l‐dopa and gludopa in the rat and in the glycerol‐treated rat as a model for acute renal failure

Prodrugs in Cardiovascular Medicine

Renal Metabolism and Effects of the Glutamyl Derivatives of l-Dopa and 5-Hydroxytryptophan in Man

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