(+)-sulpiride antagonises the renal effects of gamma-L-glutamyl-L-dopa in man.

1. gamma-L-glutamyl-L-dopa (gludopa) was given by intravenous infusion to six healthy salt-replete men on two occasions, with and without pretreatment with (+)-sulpiride. 2. Gludopa increased sodium excretion, glomerular filtration rate and effective renal plasma flow whilst decreasing plasma renin activity. 3. (+)-sulpiride had no significant effect on baseline natriuresis, renal haemodynamics or plasma renin activity, but significantly attenuated the rise in sodium excretion, glomerular filtration rate and effective renal plasma flow produced by gludopa. 4. (+)-sulpiride abolished the acute fall in plasma renin activity seen with gludopa. 5. (+)-sulpiride raised serum prolactin concentration but did not affect the ris in urine dopamine excretion rate caused by gludopa. 6. Gludopa exerts its renal effects by stimulating specific dopamine receptors which are principally of the DA1 subtype.     

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

1. The renal response to gamma-L-glutamyl-L-dopa (gludopa, 25 micrograms kg-1 min-1) 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.     

DA-1 RECEPTORS MEDIATE RENAL EFFECTS OF THE DOPAMINE PRODRUG, GLUDOPA, IN CONSCIOUS RABBITS

1. Eight male rabbits were implanted with Doppler flow probes around the lower abdominal aorta and left renal artery. A 2 week recovery period was allowed prior to the experiment. 2. Normal saline, gludopa at 25 micrograms/kg per min and at 100 micrograms/kg per min were each infused i.v. for 60 min. One week later the same protocol was administered to four of these animals in addition to DA-1 antagonist SCH 23390 (0.3 mg/kg i.v.) before gludopa infusion. 3. Gludopa elicited significant increases in urine flow, urinary sodium excretion and renal blood flow, and decreased renal vascular resistance. These changes were abolished by the DA-1 antagonist. Blood pressure, heart rate and hindlimb blood flow remained unchanged. 4. Urine dopamine excretion was increased 1200-fold and 7800-fold after gludopa administration at 25 micrograms/kg per min and 100 micrograms/kg per min, respectively, while plasma dopamine concentration and plasma renin activity (PRA) were not significantly altered. However, PRA was elevated by gludopa with DA-1 antagonism. 5. The renal vasodilation, natriuresis and diuresis produced by gludopa in conscious rabbits appears to be mediated by locally generated dopamine via DA-1 receptors.     

Disposition of gamma-glutamyl levodopa (gludopa) after intravenous bolus injection in healthy volunteers.

1. The pharmacokinetics of gludopa in healthy volunteers were studied at two doses, 250 micrograms kg-1 and 100 micrograms kg-1, after rapid intravenous bolus injection. 2. Gludopa had a clearance of 4.43 +/- 1.50 ml min-1 kg-1 and 4.92 ml min-1 kg-1 at the higher and lower doses, respectively. Corresponding half-lives were 29.2 +/- 3.7 min and 32.5 +/- 5.6 min, and volumes of distribution were 0.183 +/- 0.052 l kg-1 and 0.235 +/- 0.07/ l kg-1. 3. Urinary excretion of dopamine rose sharply after injection of gludopa at both doses, peaking at 30 min. At this time, amounts were over 215 and 60 times baseline values at the higher and lower dose of gludopa, respectively. Urinary dopamine rose in parallel with urinary levodopa excretion, supporting the view that levodopa is the precursor of urinary dopamine. 4. Less than 1% of the injected dose of gludopa was excreted unchanged in the urine. 5. These findings suggest that, in man, gludopa is an efficient pro-drug for dopamine. Gludopa may find therapeutic use in conditions where the beneficial renal effects of dopamine may be indicated.     

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

1. gamma-L-glutamyl-L-dopa (gludopa) and placebo were given by intravenous infusion to 12 healthy salt replete men for 10 h in a single-blind randomised fashion. 2. Gludopa caused a cumulative natriuresis of 46.5 mmol compared with placebo with a biphasic pattern and this was associated with a small reduction in body weight. 3. A small fall in arterial blood pressure and rise in pulse rate was seen with gludopa. 4. Plasma renin activity, atrial natriuretic peptide and urine kallikrein excretion were unchanged by gludopa but a small fall in urine aldosterone excretion, urine flow rate and free water clearance occurred. 5. The renal effects of gludopa are modest and last for only a few hours after the start of infusion.     

Domperidone treatment in man inhibits the fall in plasma renin activity induced by intravenous gamma-L-glutamyl-L-dopa.

The dopamine pro-drug gamma-L-glutamyl-L-dopa (gludopa) was administered intravenously to six normal subjects at a dose of 12.5 micrograms min-1 kg-1, either with or without the dopamine antagonist domperidone. A control was provided by the intravenous infusion of domperidone and saline on a separate occasion. Intravenous gludopa produced a significant natriuresis, whether administered alone or in combination with domperidone. After gludopa infusion, there was a significant fall in plasma renin activity, an effect which was attenuated significantly by concomitant treatment with domperidone. These observations suggest that blockade of renal DA2 dopamine receptors has little or no effect on gludopa-induced natriuresis, but that at least part of the dopaminergic inhibition of renin release is mediated by renal DA2 receptors.     

THE DOPAMINE PRODRUG, GLUDOPA, DECREASES BOTH RENAL AND EXTRARENAL NORADRENALINE SPILLOVER IN CONSCIOUS RABBITS

1. Renal and total noradrenaline (NA) spillover rates were examined under control conditions and during graded infusions of gludopa (γ-l-glutamyl-l-dopa) in conscious rabbits. 2. Gludopa infusion at 25 and 100 μg/kg per min did not alter mean arterial pressure (MAP) and heart rate (HR), but had significant dose-related effects on the renal dopamine (DA) system. At the high dose there were pronounced increases in urinary DA excretion (>6000-fold) and renal DA content (> 100-fold); renal NA content doubled. 3. Renal venous DA increased after gludopa infusion, but arterial plasma DA concentrations were not significantly changed. Mean arterial plasma gludopa and l-dopa concentrations reached 890, 3190 ng/mL and 3, 10 ng/mL at low and high doses, respectively. 4. Gludopa resulted in a pronounced dose-dependent fall in renal NA spillover, which at 100 μg/kg per min accounted for almost half of the reduction in overall NA spillover rate. 5. The significant falls in renal and extrarenal NA spillover rate during gludopa infusion are consistent with suppression of renal and overall sympathetic activity. Gludopa-induced inhibition of renal NA spillover is likely to be due to the actions of DA generated in the kidney on presynaptic DA-2 and α-2 receptors. A central sympathoinhibitory mechanism may explain the reduced total NA spillover.     

Pharmacokinetics, bioavailability, metabolism, tissue distribution and urinary excretion of gamma-L-glutamyl-L-dopa in the rat

gamma-L-Glutamyl-L-dopa (gludopa) is believed to be a dopamine prodrug specific for the kidney. Its pharmacokinetics have been studied in the rat given 50 mg kg-1 intravenously (i.v.) and 60 mg kg-1 intraperitoneally (i.p.). By the i.v. route, elimination followed apparent first order kinetics and was biphasic with a t 1/2 alpha of 7 min and terminal half-life of 67 min. After i.p. administration absorption was rapid (t 1/2 ab 6 min), elimination was monophasic with a terminal half-life almost identical following i.v. dosing (65 min), and bioavailability was 40%. In tissues (liver and kidney) gludopa was biotransformed to four intact catecholic products (L-dopa, dopamine, DOPAC and gamma-L-glutamyl-dopamine) which appeared quickly (peaks at 15 min) and which were almost completely cleared by 4 h. Dopamine was the major kidney metabolite accounting for 69% of total catechol content with an AUC 31 times greater than in liver where it accounted for only 34% of total catechols. In rat urine eight major metabolites (5.7% of the dose) and at least 12 minor metabolites were detected of all of which 85% was dopamine. A higher percentage of the dose was excreted as intact catechols in man (15.7%) but fewer metabolites were detected (L-dopa, dopamine, DOPAC). It is confirmed that gludopa is kidney specific in rat but that the pharmacological effects of dopamine are likely to be short lived due to rapid clearance. Gludopa appears to be less dopamine specific in man.     

Effects of dopamine prodrugs and fenoldopam on glomerular hyperfiltration in streptozotocin-induced diabetes in rats.

The effects of dopamine (DA) prodrugs (L-dopa and gludopa) and of a D1-selective agonist (fenoldopam) on glomerular hyperfiltration were studied in the early stage of diabetes in rats. Wistar rats received one injection of streptozotocin (STZ) and were treated 1 week later with L-dopa (2 x 10 mg/kg/day, s.c.), gludopa (2 x 3 or 2 x 10 mg/kg/day, s.c.), or fenoldopam (2 x 0.3 or 2 x 1 mg/kg/day, s.c.). Their renal functions were compared with those of untreated diabetic and nondiabetic control rats. STZ injection led to hyperglycemia that was kept moderate (20-25 mmol/L) by daily insulin therapy (2-4 U of NPH insulin). Within 2 weeks, glomerular hyperfiltration (polyfructosan clearance) developed in diabetic rats (30% increase vs. nondiabetic control). A rise in renal plasma flow (PAH clearance) was sometimes observed. One week of treatment with either L-dopa, gludopa, or fenoldopam normalized the glomerular filtration rate and decreased filtration fraction. These corrections occurred despite similar metabolic disturbance and kidney hypertrophy. Gludopa was less well tolerated by diabetic rats than L-dopa. Results with L-dopa showed that the normalization of glomerular hyperfiltration was linked to DA synthesis and stimulation of D1 receptors, since it was reversed by carbidopa, a dopa decarboxylase inhibitor, and by SCH 23390, a D1-selective antagonist. These data show that DA prodrugs and a D1 agonist can suppress diabetic glomerular hyperfiltration in the very early course of the disease in rats.     

Lack of effect of lithium on the renal response to DA1-dopamine receptor stimulation by fenoldopam in normal man.

1. The effect of oral lithium (300 mg) on the renal response to the selective DA1-dopamine receptor agonist fenoldopam was investigated in seven normal men. Lithium had no influence on sodium excretion and renal haemodynamics during fenoldopam infusion. The fenoldopam-induced rise in PRA was enhanced in the presence of lithium. We conclude that a previously described interaction between lithium and the dopamine agonist gludopa is not mediated by DA1-dopamine receptors or is confined to higher doses of lithium.     

The pharmacokinetics of gamma-glutamyl-L-dopa in normal and anephric rats and rats with glycerol-induced acute renal failure.

1. The pharmacokinetics of gamma-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-1. 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 kg-1 and elimination rate constant of 2.99 +/- 0.27 h-1. 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 +/- 0.18 l kg-1. 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.     

The renal effects of atrial natriuretic peptide in man are not attenuated by (+)-sulpiride.

1. Human alpha atrial natriuretic peptide (ANP) was infused intravenously for 1 h in eight healthy salt-replete men on two occasions, with and without pretreatment with (+)-sulpiride. 2. ANP increased sodium excretion and urine flow rate but did not alter blood pressure or plasma renin activity. 3. (+)-sulpiride had no significant effect on baseline creatinine clearance, sodium excretion or urine flow rate and did not alter the increases in these parameters with ANP. 4. It is unlikely that the renal effects of ANP are mediated by dopamine DA1-receptors in man.     

Frusemide, ACE inhibition, renal dopamine and prostaglandins: acute interactions in normal man.

1. The acute effects of intravenous frusemide (30 mg) on prostaglandin dependent renal haemodynamics, urinary prostaglandin excretion, urinary dopamine excretion and electrolyte excretion were studied in six salt replete healthy volunteers with and without pretreatment with the angiotensin converting enzyme (ACE) inhibitor, ramipril (5 mg) and compared with the effects of ramipril alone in order to clarify the role of the renin-angiotensin system in these responses. 2. Frusemide increased natriuresis (UNaV), kaliuresis (UKV), inulin clearance and plasma renin activity (PRA) and ramipril pretreatment significantly enhanced these effects suggesting that the acute generation of angiotensin II (AII) may attenuate these actions of intravenous frusemide. 3. Frusemide increased para-aminohippurate (PAH) clearance, osmolar clearance and urine flow but did not change filtration fraction or urinary kallikrein excretion. Pretreatment with ramipril did not affect these responses. 4. Frusemide increased the excretion of urinary PGE2 and 6-keto-PGF1 alpha. Ramipril pretreatment did not suppress this rise in prostaglandin excretion. Since the frusemide induced prostaglandin dependent renal haemodynamic changes were also not suppressed with ACE inhibition, this suggests that in salt-replete volunteers AII does not significantly modulate renal prostaglandin production after frusemide. 5. Urinary free dopamine excretion increased with frusemide alone. With ramipril pretreatment this rise showed a tendency to increase. AII may therefore inhibit the rise in urinary dopamine excretion after frusemide. However this requires further study.     

Renal effects of gastrin C-terminal tetrapeptide (as pentagastrin) and cholecystokinin octapeptide in conscious rabbit and man.

Pentagastrin and cholecystokinin octapeptide (CCK8) were infused i.v. at three different doses in two sets of 4 conscious rabbits following a repeated measurements design (130, 1,300 and 13,000 pmol kg-1 min-1 pentagastrin; 5, 50 and 450 pmol kg-1 min-1 CCK8). In man, two different doses of pentagastrin (13 and 65 pmol kg-1 min-1) were infused in two groups of 6 subjects, and CCK8 (2 pmol kg-1 min-1) in a third group. According to published human postprandial levels, plasma CCK8-like immunoreactivity concentrations were supraphysiological at all doses infused. In the rabbit, pentagastrin produced a dose-related fall in urine flow and free water clearance, but no significant change in systemic and renal haemodynamics, electrolyte excretion and measured plasma constituents; however, in human subjects, pentagastrin increased renal sodium excretion and reduced potassium excretion but did not change glomerular filtration rate. In the rabbit, CCK8 produced a dose-related fall in plasma renin activity, plasma calcium concentration and mean arterial blood pressure; dose-dependent increases in effective renal plasma flow, glomerular filtration rate and renal sodium excretion. In man, changes in sodium and potassium excretion similar to pentagastrin were observed; there were no significant changes in plasma renin activity, plasma calcium concentration, blood pressure, effective renal plasma flow or glomerular filtration rate. The pharmacological renal effects of pentagastrin in conscious water-loaded rabbits resemble vasopressin. In contrast, CCK8's most striking effect was vasodilatation and was unusual in inhibiting rather than stimulating renin release. In man the net changes in urine composition found during infusion of these peptides are similar to those produced by the potassium-sparing diuretics, amiloride and triamterene.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of the new calcium channel blocking drug isradipine

Summary The acute effect of a single oral dose of isradipine 5 mg on blood pressure, renal haemodynamics, electrolyte excretion and plasma renin activity was studied in 10 healthy males.Isradipine did not produce a significant change in systolic or diastolic blood pressure, and glomerular filtration rate, renal plasma flow, renal vascular resistance, and urinary albumin excretion remained constant. There was a marked natriuretic and diuretic effect about 1–3 h after isradipine. Plasma renin activity showed a slight, insignificant increase 1 h after dosing. Uric acid clearance and 2-microglobulin excretion showed no significant changes, despite an increase in sodium clearance, suggesting an additional mechanism of action other than the proximal tubular natriuretic effect of isradipine in normotensive volunteers.     

Effects of calcium antagonism on the resting and exercise-stimulated renin-aldosterone axis

The effect of short-term calcium antagonism with felodipine on blood pressure and on some biochemical plasma variables such as catecholamines, renin and aldosterone was studied in 10 normal volunteers at rest and during incremental bicycle exercise. At rest, diastolic blood pressure was slightly decreased during felodipine, whereas systolic pressure and heart rate were not significantly changed. The plasma noradrenaline concentration and plasma renin activity were increased during felodipine treatment; the plasma adrenaline and aldosterone concentrations on the contrary, were not significantly changed. The rises in plasma renin activity, plasma aldosterone and plasma adrenaline and noradrenaline concentrations produced by exercise were not significantly affected by felodipine. The plasma calcium concentration was significantly higher during felodipine treatment than during placebo and this was accompanied by an increased urinary calcium excretion. It is concluded that the rise in plasma renin activity during calcium antagonism with felodipine is not accompanied by a significant increase in plasma aldosterone. Furthermore, the present data suggest that, at least during exercise, calcium antagonism does not interfere with the mechanisms underlying the exercise-induced activation of renin and aldosterone release.     

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.

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 mumol kg-1 h-1; L-dopa and gludopa: 1-200 mumol kg-1 h-1). 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 mumol kg-1 h-1) infusion of gludopa: the glycerol-induced reduction of renal flow and increase in RR were significantly attenuated. A high dose of gludopa (100 mumol kg-1 h-1) 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.(ABSTRACT TRUNCATED AT 250 WORDS)     

Change in Plasma Renin Substrate in Lithium–intoxicated Nephrectomized Rats,and the Effect of Sodium on Plasma Renin and Plasma Renin Substrate in Lithium–intoxicated Rats

Abstract The possible effect of lithium intoxication on the synthesis of renin substrate was investigated in rats given food containing 70 mmol of lithium and 125 mmol of sodium/kg dry weight for nine days. The increase in renin substrate five hours after bilateral nephrectomy was found to be identical with the increase in control rats given no lithium. This indicates that the decrease in renin substrate seen during lithium intoxication is solely a result of the increased concentration of plasma renin. A second experiment examined whether administration of extra sodium might counteract the changes in plasma renin substrate and plasma renin that occur during lithium intoxication. In lithium–treated rats given a low–sodium diet there was a pronounced fall in renin substrate and a rise in renin as compared to the control rats. These changes were almost abolished by the administration of a high–sodium diet, but this also led to a fall in the serum lithium concentration. After administration of additional lithium, the change in renin substrate was the same as in the lithium–treated low–sodium group, and the change in renin was intermediate. The data indicate that sodium counteracts the changes in plasma renin substrate and plasma renin by increasing the renal lithium clearance, but that in addition the change in plasma renin which occurs during lithium intoxication, may be counteracted by sodium through other mechanisms.     

CHANGES OF URINARY DOPAMINE EXCRETION EARLY AFTER BALLOON MITRAL COMMISSUROTOMY IN MITRAL STENOSIS

1. In order to investigate the changes of reduced urinary free dopamine excretion (uDA) in heart failure, 15 patients with symptomatic mitral stenosis were investigated on their uDA, endogenous creatinine (Cr) clearance, urinary excretion of sodium (UNaV), fractional excretion of sodium (FENa), plasma noradrenaline (pNA) and plasma L-dopa concentration before and early after percutaneous transvenous mitral commissurotomy (PTMC) by the clearance study. The delivery of L-dopa to renal proximal tubules (plasma L-dopa x Cr clearance), and the conversion ratio of plasma L-dopa to urinary dopamine in the kidney [uDA/(plasma L-dopa x Cr clearance)] were also estimated. 2. After successful PTMC, uDA, UNaV and FENa showed a significant but incomplete improvement and the changes of uDA were correlated positively with those of cardiac index (CI) (r = 0.665, P < 0.01), not with changes of pulmonary wedge pressure. While plasma L-dopa and plasma L-dopa x Cr clearance improved, uDA/(plasma L-dopa x Cr clearance) was not significantly changed early after PTMC. 3. From these results, it was suggested that reduced uDA tended to increase incompletely in relation with functional recovery of heart, and that increased plasma L-dopa and a delivery of L-dopa to renal proximal tubules have some positive role on urinary dopamine excretion, at least, early after PTMC.     

The effects of piretanide on catecholamine metabolism, plasma renin activity and plasma aldosterone: a double-blind study versus furosemide in healthy volunteers

In a double-blind, crossover study, 8 male volunteers (mean age: 25.9 years) received successively 6 different regimens of two diuretics, piretanide and furosemide, with a 1-week wash-out period between each drug regimen. Piretanide (6 mg) or furosemide (40 mg) were given either once daily at 08.00 hours or twice daily at 08.00 and 12.00 hours or at 08.00 and 20.00 hours. Each of these phases lasted for 1 week. Serial measurements were performed on plasma renin activity, plasma aldosterone, plasma adrenaline, plasma noradrenaline, plasma dopamine, cumulative urinary excretion of aldosterone, urine volume and urine osmolality. Plasma catecholamines showed no clinically relevant changes during all three regimens of piretanide or furosemide dosage. Piretanide and furosemide both induced a short-term increase in plasma renin activity with a maximum about 4 hours after dosing which returned to initial levels after approximately 12 hours regardless of whether a single or twice daily dose had been given. After 1 week of piretanide given once daily, lower plasma renin activity was found than after furosemide. Furosemide given once daily caused higher plasma aldosterone concentrations than did piretanide. The lowest plasma aldosterone concentrations were found during the twice-daily piretanide regimen at 08.00 and 20.00 hours. Aldosterone excretion in urine was also higher during furosemide than during piretanide administration. Piretanide given twice daily at both 08.00 and 12.00 hours or 08.00 and 20.00 hours caused the most insignificant changes in aldosterone excretion. It is suggested that piretanide, in comparison to furosemide, activates the counter-regulatory mechanisms, which may diminish the antihypertensive effect of the diuretic, to a much lesser extent.