Renal Dopaminergic Activity Research Articles

Sodium-dependent modulation of systemic and urinary renalase expression and activity in the rat remnant kidney

The present study examined the influence of high-sodium intake on systemic and urinary renalase levels and activity in 3/4 nephrectomized (3/4nx) and Sham rats. The reduced circulating renalase levels in 3/4nx rats during normal-sodium intake were accompanied by increased plasma renalase activity. The sodium-induced increase of blood pressure in 3/4nx rats was accompanied by significant decreases in circulating renalase levels and activity as well as by a significant decrease in cardiac renalase levels in 3/4nx rats but not in Sham rats. During normal-sodium intake, no significant differences were observed in either urine renalase levels or activity between 3/4nx and Sham rats, not withstanding the ∼75% decrease in daily urine dopamine output observed in the rat remnant kidney. During high-sodium intake, urinary renalase levels increased in both 3/4nx and Sham groups by three-fold whereas urinary renalase activity increased in 3/4nx and Sham rats by greater than twelve-fold and greater than four-fold, respectively. This was accompanied by sodium-induced increases in daily urinary dopamine output in both 3/4nx and Sham rats by ∼2.3-fold and ∼1.6-fold, respectively. The reduced circulating renalase levels in 3/4nx rats are accompanied by increased plasma renalase activity, which appears to be related with decreased inhibition of the circulating enzyme. Differences in systemic and urinary renalase levels and activity between 3/4nx and Sham rats during high-sodium intake may contribute to activation of the sympathetic nervous system, hypertension and enhanced cardiovascular risk in CKD but do not appear to account for the decrease in renal dopaminergic activity in the rat remnant kidney.

Blunted renal dopaminergic system in a mouse model of diet-induced obesity

Obesity has reached epidemic proportions in the Western world and is implicated in the pathophysiology of essential hypertension. The aim of the present study was to evaluate sodium handling, blood pressure and renal dopaminergic system activity in a mouse model of obesity induced by exposure to a hypercaloric diet. From six to 18 weeks of age, animals were fed with a control diet or a high-fat high-simple-carbohydrate (HFHSC) diet. Renal function, blood pressure and urinary and plasmatic catecholamines and biochemical parameters were evaluated in both groups. In parallel, the effects of high sodium intake (HS, 1.0% NaCl, 3 days) on natriuresis, urinary catecholamine excretion and aromatic l-amino acid decarboxylase (AADC) activity were evaluated in control and obese mice. Mice exposed to the HFHSC diet presented obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia and increased blood pressure. This was accompanied, in obese mice, by decreases in urinary excretion of dopamine and metabolites as well as reduced AADC activity in renal tissues. During HS intake, absolute urinary dopamine excretion increased in control, but not in obese mice. This was accompanied in obese mice by a natriuretic resistance on day 1 of the HS diet. In addition, obese mice presented increased urinary and plasmatic noradrenaline levels, as well as an increased heart rate when compared with control mice. In conclusion, in this model of diet-induced obesity hyperinsulinemia, insulin resistance and increased sympathetic tone are associated with blunted renal dopaminergic activity. It is suggested that this may contribute to compromised sodium excretion and increased blood pressure in obesity.

Age-related changes in the renal dopaminergic system and expression of renal amino acid transporters in WKY and SHR rats

This study examined age-related changes in renal dopaminergic activity and expression of amino acid transporters potentially involved in renal tubular uptake of l-DOPA in Wistar Kyoto (WKY) and spontaneously hypertensive rats. Aging (from 13 to 91 weeks) was accompanied by increases in systolic blood pressure (SBP) in both WKY and SHR. The sum of urinary dopamine and DOPAC and the urinary dopamine/ l-DOPA ratio were increased in aged SHR but not in aged WKY. The urinary dopamine/renal delivery of l-DOPA ratio was increased in both rat strains with aging. LAT2 abundance was increased in aged WKY and SHR. The expression of 4F2hc was markedly elevated in aged SHR but not in aged WKY. ASCT2 was upregulated in both aged WKY and SHR. Plasma aldosterone levels and urinary noradrenaline levels were increased in aged WKY and SHR though levels of both entities were more elevated in aged SHR. Activation of the renal dopaminergic system is more pronounced in aged SHR than in aged WKY and is associated with an upregulation of renal cortical ASCT2 in WKY and of LAT2/4F2hc and ASCT2 in SHR. This activation may be the consequence of a counter-regulatory mechanism for stimuli leading to sodium reabsorption.

Renal dopaminergic system activity in rat remnant kidney up to twenty-six weeks after surgery

Aims In 3/4 nephrectomized (3/4nx) rats the renal dopaminergic system was suggested to be involved in the adaptive increase of sodium excretion two weeks after renal mass ablation. The aim of the present study was to evaluate the renal adaptations in sodium handling and renal dopaminergic system activity in 3/4nx rats up to twenty-six weeks after surgery. Main methods The rats were placed in metabolic cages for the collection of 24 h urine for evaluation of sodium, dopamine, dopamine precursor and metabolites. Blood pressure, aromatic L-amino acid decarboxylase (AADC) activity in proximal tubules and the effect of dopamine D 1 receptor selective antagonist (Sch-23390) on natriuresis was evaluated. Key findings A time-dependent increase in both systolic and diastolic blood pressure was observed in 3/4nx rats, and this was accompanied by a decrease in urinary levels of dopamine and in renal AADC activity at twenty-six weeks after renal mass ablation. In contrast to what has been found two weeks after renal mass ablation, the natriuretic response to volume expansion was progressively reduced in 3/4nx rats at ten and twenty-six weeks after surgery and this was accompanied by insensitivity of natriuresis to Sch-23390. Significance In conclusion the renal dopaminergic system activity is compromised in 3/4nx rats in a time-dependent manner after renal mass ablation. It is suggested that this may contribute to compromise sodium excretion and increase blood pressure, in chronic renal insufficiency.

Renal Dopaminergic System Activity in Uninephrectomized Rats up to 26 Weeks after Surgery

Background: Dopamine of renal origin exerts natriuretic and diuretic effects by activating D₁-like receptors located at various regions in the nephron. Two weeks after uninephrectomy the renal dopaminergic system was suggested to be involved in the adaptative increase of sodium excretion. Aim: The aim of the present study was to evaluate the renal adaptations in sodium handling and renal dopaminergic system activity in uninephrectomized (Unx) rats up to 26 weeks after the surgery. Results: A time-dependent increase in both systolic and diastolic blood pressure was observed in Unx rats up to 26 weeks after uninephrectomy. This was accompanied by a compensatory increase in aromatic L-amino acid decarboxylase at 2 weeks but not 10 and 26 weeks after uninephrectomy. In contrast to what has been found 2 weeks after uninephrectomy, at 10 and 26 weeks after surgery the natriuretic response to volume expansion was reduced in Unx rats and this was accompanied by insensitivity of natriuresis to dopamine D1 receptor selective antagonist (Sch23390). Conclusion: A time-dependent decrease in dopamine sensitive natriuresis is observed in Unx rats throughout the 26 weeks after uninephectomy. It is suggested that this may contribute to compromise sodium excretion and increase blood pressure.

CME test answers

The present study evaluates renal dopaminergic activity in 23 patients with heart failure (HF), 10 age-matched controls, and 10 young subjects during normal-salt (NS) intake and after 8 days of low-salt (LS) intake (patients with HF and age-matched controls only). LS intake produced a marked reduction in urine volume in patients with HF but failed to affect urine volume in age-matched controls. Urinary sodium and fractional excretion of sodium were markedly reduced by LS intake in patients with HF and age-matched controls. Daily urinary excretion of l-3,4-dihydroxyphenylalanine (l-dopa) and dopamine was lower in patients with HF than in age-matched controls. LS intake failed to alter l-dopa and dopamine urinary excretion in control subjects. In patients with HF, LS intake produced a significant decrease in urinary l-dopa excretion, but failed to alter the urinary excretion of dopamine. No significant differences were observed in urinary l-dopa, dopamine, and dopamine metabolite levels between aged controls and young healthy subjects. Urinary dopamine-l-dopa ratios in patients with HF on LS intake (24.5 ± 7.1) were significantly greater than those with NS intake (11.6 ± 1.3). Urinary dopamine-l-dopa ratios in old control subjects (LS, 9.7 ± 1.3; NS, 9.3 ± 1.1) did not differ from those in young healthy subjects (9.2 ± 0.8). LS intake produced a marked increase in plasma aldosterone levels in both patients with HF (84.6 ± 14.4 to 148.2 ± 20.4 pg/mL; P = 0.0008) and controls (102.1 ± 13.4 to 151.6 ± 15.7 pg/mL; P < 0.04). Plasma norepinephrine levels were not significantly affected by LS intake in controls (5.1 ± 1.62 to 6.3 ± 1.6 pmol/mL; P = 0.22), but were significantly increased in patients with HF (5.8 ± 0.8 to 7.1 ± 0.9 pmol/mL; P = 0.04). In conclusion, patients with HF are endowed with an enhanced ability to take up (or decarboxylate) filtered l-dopa, which might counterbalance the reduced renal delivery of l-dopa, contributing to a relative preservation of dopamine synthesis. This may result as a compensatory mechanism, activated by stimuli leading to sodium reabsorption. Age seems to have no influence on renal dopamine production. © 2001 by the National Kidney Foundation, Inc.

Blunted renal dopaminergic system activity in puromycin aminonucleoside-induced nephrotic syndrome

A primary tubular sodium handling abnormality has been implicated in the edema formation of nephrotic syndrome. Dopamine synthesized by renal proximal tubules behaves as an endogenous natriuretic hormone by activating D(1)-like receptors as a paracrine/autocrine substance. We examined the time courses of the urinary excretion of sodium, protein and dopamine in puromycin aminonucleoside (PAN)-treated and control rats. The rats were sacrificed during greatest sodium retention (day 7) as well as during negative sodium balance (day 14) for the evaluation of renal aromatic l-amino acid decarboxylase (AADC) activity, the enzyme responsible for the synthesis of renal dopamine. Also, the influence of volume expansion (VE) and the effects of the D(1)-like agonist fenoldopam (10 microg/kg bw/min) on natriuresis and on proximal tubular Na(+),K(+)-ATPase activity were examined on day 7. The daily urinary excretion of dopamine was decreased in PAN-treated rats, from day 5 and beyond. This was accompanied by a marked decrease in the renal AADC activity, on days 7 and 14. During VE, the fenoldopam-induced decrease in proximal tubular Na(+),K(+)-ATPase activity was more pronounced in PAN-treated rats than in controls. However, the urinary sodium excretion during fenoldopam infusion was markedly increased in control rats but was not altered in PAN-treated animals. PAN nephrosis is associated with a blunted renal dopaminergic system activity which may contribute to enhance the proximal tubular Na(+),K(+)-ATPase activity. However, the lack of renal dopamine appears not to be related with the overall renal sodium retention in a state of proteinuria.

Blunted renal dopaminergic system activity in HgCl 2-induced membranous nephropathy

The present study evaluated the possible role of the renal dopaminergic system in the sodium retention of HgCl 2-induced nephrotic syndrome. The time courses of urinary excretion of sodium, protein, dopamine and the precursor l-3,4-dihydroxyphenylalanine ( l-Dopa) were evaluated in HgCl 2-treated and control rats up to day 21. The renal aromatic l-amino acid decarboxylase (AADC) activity, the enzyme responsible for the synthesis of renal dopamine, was evaluated during negligible proteinuria accompanied with enhanced sodium retention (day 7), increased proteinuria accompanied with greatest sodium retention (day 14) as well as during increased proteinuria accompanied with negative sodium balance (day 21). Also, the influence of volume expansion (VE, 5% bw) and the effects of the D 1-like agonist fenoldopam (10 μg kg bw − 1 min − 1 ) on natriuresis and on proximal tubular Na +,K +-ATPase activity were examined on day 14. The daily urinary dopamine output and urinary dopamine / l-Dopa ratios were reduced in HgCl 2-treated rats from day 2 and beyond. This was accompanied by a marked decrease in renal AADC throughout the study. During VE, the fenoldopam-induced inhibition of proximal tubular Na +,K +-ATPase activity was similar between HgCl 2-treated and control rats. However, the urinary sodium excretion during fenoldopam infusion was markedly increased by 60% to 120% in control rats but was not altered in HgCl 2-treated rats. It is concluded that HgCl 2 nephrosis is associated with a blunted renal dopaminergic system activity. However, the lack of renal dopamine in HgCl 2 nephrosis does not appear to be related with the overall renal sodium retention in a state of proteinuria.

Effect of Saline Load and Metoclopramide on the Renal Dopaminergic System in Patients with Heart Failure and Healthy Controls

Dopamine of renal origin has natriuretic/diuretic actions by activating D1-like receptors of the nephron. Saline load increases renal dopamine production and natriuresis in healthy subjects, and, under these conditions, the activation of D2-like receptors also produces natriuresis/diuresis. Metoclopramide is a D2-like receptor antagonist. Patients with heart failure (HF) have an increased renal dopamine-synthesizing efficiency. However, the effect of salt loading was not explored in HF. We hypothesized that HF patients respond to salt loading with increased production of renal dopamine and that metoclopramide antagonizes this response. This was a randomized, controlled, crossover study exploring the effect of NaCl and metoclopramide on renal dopaminergic, sympathetic, renin-angiotensin-aldosterone, and arginine-vasopressin (AVP) systems activity on sodium handling in 9 HF patients and 9 controls. NaCl markedly increased renal dopamine production and natriuresis in both groups. Metoclopramide blunted these responses in HF patients but not in controls. NaCl decreased renin and aldosterone plasma levels in controls but not in HF patients. In these patients B-type natriuretic peptide (BNP) levels increased, but AVP was not affected. HF patients respond to salt loading with increased natriuresis. However, the mechanisms for this response are different from those found in healthy subjects. Metoclopramide has antinatriuretic effects only in HF patients.

Renal Dopaminergic System Activity in the Rat Remnant Kidney

Background: Renal dopamine exerts natriuretic and diuretic effects by activating D₁-like receptors. Uninephrectomy results in increased renal dopaminergic activity and dopamine-sensitive enhanced natriuresis. Methods: The present study evaluated renal adaptations in sodium handling and the role of dopamine in rats submitted to ¾ nephrectomy: right nephrectomy and excision of both poles of the left kidney (¾nx rats). Results: Two weeks after surgery the absolute urinary levels of dopamine were markedly reduced in ¾nx rats whereas the urinary dopamine excretion per % of residual nephrons was significantly increased in the remnant kidney of ¾nx rats. The V_max values for renal aromatic L-amino acid decarboxylase, the enzyme responsible for the synthesis of renal dopamine, were decreased in ¾nx rats. Renal catechol-O-methyltransferase activity, the enzyme responsible for the methylation of dopamine, was increased in ¾nx rats whereas the renal activities of monoamine oxidases A and B did not differ between ¾nx and Sham animals. Volume expansion (5% body weight) resulted in similar natriuretic responses in ¾nx and Sham rats. During D₁ antagonist administration (Sch-23390, 30 µg·h^–1·kg^–1) the natriuretic response to volume expansion was reduced in ¾nx rats more pronouncedly than in Sham animals. Conclusion: The decrease in absolute renal dopamine output in ¾nx rats is related with reduced renal synthesis and enhanced O-methylation of the amine. However, this is accompanied in ¾nx rats by increased renal dopamine excretion per residual nephrons and dopamine-sensitive enhanced natriuresis.

Differences in the renal dopaminergic system activity between Wistar rats from two suppliers.

Dopamine of renal origin reduces tubular sodium reabsorption and controls blood pressure. The present study evaluated renal dopaminergic activity and its response to uninephrectomy in Wistar Han rats from two suppliers, Harlan (W-H) and Charles River (W-CR). After uninephrectomy, the fractional excretion of sodium (FENa+) increased in both W-CR and W-H rats (W-CR: from 0.17 +/- 0.01 to 0.27 +/- 0.02%; W-H: from 0.39 +/- 0.04 to 0.54 +/- 0.04%, P < 0.05); however, in W-CR rats the FENa+ was lower than in W-H rats in both Sham and uninephrectomized (Unx) animals (P < 0.05). Systolic blood pressure in Unx W-CR rats was higher than in Unx W-H animals (131 +/- 3 vs. 122 +/- 2 mmHg, P < 0.05). Uninephrectomy was accompanied in W-H rats by increases in urinary levels (nmol g kidney(-1) day(-1)) of dopamine (10.3 +/- 0.5 vs. 8.3 +/- 0.7, P < 0.05) and 3,4-dihydroxyphenylacetic acid (DOPAC) (30.5 +/- 3.7 vs. 21.3 +/- 1.4, P < 0.05) and increases (P < 0.05) in maximal velocity values (Vmax in nmol mg prot(-1) 15 min(-1), 325 +/- 12 vs. 265 +/- 3) for renal aromatic L-amino acid decarboxylase (AADC), the enzyme responsible for the synthesis of renal dopamine. By contrast, in W-CR rats uninephrectomy did not change either the urinary levels of dopamine (7.1 +/- 0.5 vs. 7.6 +/- 0.7) and DOPAC (25.0 +/- 1.9 vs. 24.8 +/- 4.1) or AADC activity (Vmax 199 +/- 3 vs. 193 +/- 9). The Vmax values for renal AADC in W-CR rats were lower than those found in corresponding W-H animals. Wistar rats from different suppliers represent an important source of variability in the renal dopaminergic system activity. This may contribute to differences in sodium balance and blood pressure control in response to uninephrectomy.

Heart failure, aging, and renal synthesis of dopamine

The present study evaluates renal dopaminergic activity in 23 patients with heart failure (HF), 10 age-matched controls, and 10 young subjects during normal-salt (NS) intake and after 8 days of low-salt (LS) intake (patients with HF and age-matched controls only). LS intake produced a marked reduction in urine volume in patients with HF but failed to affect urine volume in age-matched controls. Urinary sodium and fractional excretion of sodium were markedly reduced by LS intake in patients with HF and age-matched controls. Daily urinary excretion of l-3,4-dihydroxyphenylalanine (l-dopa) and dopamine was lower in patients with HF than in age-matched controls. LS intake failed to alter l-dopa and dopamine urinary excretion in control subjects. In patients with HF, LS intake produced a significant decrease in urinary l-dopa excretion, but failed to alter the urinary excretion of dopamine. No significant differences were observed in urinary l-dopa, dopamine, and dopamine metabolite levels between aged controls and young healthy subjects. Urinary dopamine-l-dopa ratios in patients with HF on LS intake (24.5 ± 7.1) were significantly greater than those with NS intake (11.6 ± 1.3). Urinary dopamine-l-dopa ratios in old control subjects (LS, 9.7 ± 1.3; NS, 9.3 ± 1.1) did not differ from those in young healthy subjects (9.2 ± 0.8). LS intake produced a marked increase in plasma aldosterone levels in both patients with HF (84.6 ± 14.4 to 148.2 ± 20.4 pg/mL; P = 0.0008) and controls (102.1 ± 13.4 to 151.6 ± 15.7 pg/mL; P < 0.04). Plasma norepinephrine levels were not significantly affected by LS intake in controls (5.1 ± 1.62 to 6.3 ± 1.6 pmol/mL; P = 0.22), but were significantly increased in patients with HF (5.8 ± 0.8 to 7.1 ± 0.9 pmol/mL; P = 0.04). In conclusion, patients with HF are endowed with an enhanced ability to take up (or decarboxylate) filtered l-dopa, which might counterbalance the reduced renal delivery of l-dopa, contributing to a relative preservation of dopamine synthesis. This may result as a compensatory mechanism, activated by stimuli leading to sodium reabsorption. Age seems to have no influence on renal dopamine production. © 2001 by the National Kidney Foundation, Inc.

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.

Concerted action of dopamine on renal and intestinal Na(+)-K(+)-ATPase in the rat remnant kidney.

The present study evaluated renal and intestinal adaptations in sodium handling in uninephrectomized (Unx) rats and the role of dopamine. Two weeks after uninephrectomy, the remnant kidney in Unx rats weighed 33 +/- 2% more than the corresponding kidney in sham-operated (Sham) animals. This was accompanied by increases in urinary levels of dopamine and major metabolites [3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid] and increases in maximal velocity values (169 vs. 115 nmol. mg protein(-1). 15 min(-1)) for renal aromatic L-amino acid decarboxylase, the enzyme responsible for the synthesis of renal dopamine. High salt (HS) intake increased (P < 0.05) the urinary excretion of dopamine and DOPAC in Unx and Sham rats. However, the urinary levels of L-3,4-dihydroxyphenylalanine, dopamine, and DOPAC in Sham rats during HS intake were lower than in Unx rats. Blockade of dopamine D(1) receptors (Sch-23390, 2 x 30 microg/kg) reduced the urinary excretion of sodium in Unx (31% decrease) more pronouncedly than in Sham (19% decrease) rats. However, inhibition of renal Na(+)-K(+)-ATPase activity by dopamine was of similar magnitude in Unx and Sham rats. In parallel, it was observed that uninephrectomy resulted in a significant reduction in jejunal sodium absorption and Na(+)-K(+)-ATPase activity in jejunal epithelial cells. In jejunal epithelial cells from Sham rats, dopamine (1 microM) failed to inhibit Na(+)-K(+)-ATPase activity, whereas in Unx rats it produced a significant reduction. It is concluded that uninephrectomy results in increased renal dopaminergic activity and dopamine-sensitive enhanced natriuresis. Furthermore, it is suggested that decreased jejunal absorption of sodium may take place in response to partial renal ablation, as an example of renal-intestinal cross talk.

Aging, high salt intake, and renal dopaminergic activity in Fischer 344 rats.

The present study examined renal dopaminergic activity and its response to high salt (HS) intake in adult (6-month-old) and old (24-month-old) Fischer 344 rats. Daily urinary excretion of L-3, 4-dihydroxyphenylalanine (L-DOPA), dopamine, and its metabolites 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid was similar in adult and old rats; by contrast, daily urinary excretion of norepinephrine in old rats was almost twice that in adult animals. HS intake (1% NaCl) over a period of 24 hours resulted in a 2-fold increase in the urinary excretion of dopamine, DOPAC, and norepinephrine in adult animals but not in old animals. Norepinephrine and L-DOPA plasma levels did not change during HS intake and were similar in both groups of rats. The natriuretic response to an HS intake in old rats (from 4.7+/-0.4 to 10.7+/-2.0 nmol. kg(-1). d(-1); Delta=6.0+/-0.9 nmol. kg(-1). d(-1)) was less than in adult rats (from 5.2+/-0.4 to 13.5+/-2.5 nmol. kg(-1). d(-1); Delta=8.3+/-0.8 nmol. kg(-1). d(-1)). A diuretic response to HS intake was observed in adult rats (from 20.9+/-2.3 to 37.6+/-2.8 mL. kg(-1). d(-1)) but not in old rats (from 37.7+/-5.7 to 42.3+/-6. 0 mL. kg(-1). d(-1)). Dopamine levels and dopamine/L-DOPA ratios in the renal cortex of old rats were greater than in adult rats. HS intake increased both dopamine levels and dopamine/L-DOPA ratios in the renal cortex of adult rats but not in old rats. Aromatic L-amino acid decarboxylase activity was higher in old rats than in adult rats; HS intake increased L-amino acid decarboxylase activity (nmol. mg protein(-1). l5 min(-1)) in adult rats (from 67+/-1 to 93+/-1) but not in old rats (from 86+/-2 to 87+/-2). Dopamine inhibited Na(+),K(+)-ATPase activity in proximal tubules obtained from adult rats, but it failed to exert such an inhibitory effect in old rats. It is concluded that renal dopaminergic tonus in old rats is higher than in adult rats but fails to respond to HS intake as observed in adult rats. This may be due in part to the inability of dopamine to inhibit Na(+),K(+)-ATPase activity in old rats.

Assessment of renal dopaminergic system activity during the recovery of renal function in human kidney transplant recipients.

The urinary excretion of free dopamine has been used as an index of the renal synthesis of amine. However, it is now well recognized that in the kidney, newly-formed dopamine is significantly inactivated through deamination to 3,4-dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO). The aim of the present study was to assess the renal dopaminergic system activity during the recovery of renal function in kidney transplant recipients and to assess which parameters are appropriate for the evaluation of renal amine synthesis under these conditions. Twenty-four-hour urinary excretion of L-DOPA, dopamine and its metabolites (DOPAC; 3-MT; HVA) were continuously monitored in 19 renal transplant recipients from the first day of surgery until the twelfth day post-transplantation. In 11 patients (Group 1), renal function consistently recovered throughout the study (plasma creatinine levels decreased from 6.2 +/- 0.4 to 2.1 +/- 0.1 mg/dl). Eight patients presented with acute tubular necrosis (Group 2) and minimal renal function was maintained until the twelfth post-operative day. The urinary excretion of L-DOPA did not differ throughout the study between the two groups of patients. In contrast, the 24-h urinary levels of dopamine, DOPAC and HVA were significantly higher throughout the study in patients of Group 1: dopamine (Group 1, 179 +/- 26 to 422 +/- 51 nmol/24 h; Group 2, 25 +/- 3 to 57 +/- 13 nmol/ 24 h), DOPAC (Group 1, 698 +/- 57 to 3487 +/- 414 nmol/ 24 h; Group 2, 158 +/- 22 to 1014 +/- 193 nmol/24 h) and HVA (Group 1, 13,058 +/- 1199 to 20,387 +/- 1559 nmol/ 24 h; Group 2, 4140 +/- 848 to 15,219 +/- 1037 nmol/24 h). The recovery of renal function in renal transplant recipients is accompanied by an enhanced ability to synthesize dopamine and inactivate it to DOPAC and HVA. It is suggested that the urinary levels of DOPAC may be a useful parameter for the assessment of dopamine formation in renal tissues.

The role of renal dopaminergic activity in the pathophysiology of essential hypertension.

Although the pathogenesis of essential hypertension still remains unclear, it is now generally accepted that the kidney is deeply involved in the pathophysiology of this disease. This paper therefore, reviews current knowledge of the role of renal dopaminergic activity in essential hypertension. This is believed to be one of the most important renal diuretic and depressor systems. Suppression of urinary excretion of free dopamine (DA) is observed in essential hypertensives, particularly in those with low plasma renin activity (LRH) who demonstrate body fluid volume expansion. An increased natriuretic response to exogeneously administered DA is found, particularly in LRH, and suppressed biosynthesis of DA from L-dopa in the kidney has been suggested. Furthermore, this suppression of renal dopaminergic activity was also observed in young normotensive subjects with an apparent family history of hypertension before any evidence of hypertension emerged. From these findings, it is concluded that the decrease in renal dopaminergic activity is involved, at least in part, not only in the pathophysiology of essential hypertension, but also in the pathogenesis of this disease.

Assessment of renal dopaminergic system activity during cyclosporine A administration in the rat

1. Administration of cyclosporine A (CsA; 50 mg kg-1 day-1, s.c.) for 14 days produced an increase in both systolic (SBP) and diastolic (DBP) blood pressure by 60 and 25 mmHg, respectively. The urinary excretion of dopamine, DOPAC and HVA was reduced from day 5-6 of CsA administration onwards (dopamine from 19 to 46%, DOPAC from 16 to 48%; HVA from 18 to 42%). In vehicle-treated rats, the urinary excretion of dopamine and DOPAC increased (from 7 to 60%) from day 5 onwards; by contrast, the urinary excretion of HVA was reduced (from 27 to 60%) during the second week. 2. No significant difference was observed between the Vmax and Km values of renal aromatic L-amino acid decarboxylase (AAAD) in rats treated with CsA for 7 and 14 days or with vehicle. 3. Km and Vmax of monoamine oxidase types A and B did not differ significantly between rats treated with CsA for 7 and 14 days or with vehicle. 4. Maximal catechol-O-methyltransferase activity (Vmax) in homogenates of renal tissues obtained from rats treated with CsA for 7 or 14 days was significantly higher than that in vehicle-treated rats; Km (22.3 +/- 1.5 microM) values for COMT did not differ between the three groups of rats. 5. The accumulation of newly-formed dopamine and DOPAC in cortical tissues of rats treated with CsA for 14 days was three to four times higher than in controls. The outflow of both dopamine and DOPAC declined progressively with time and reflected the amine and amine metabolite tissue contents. No significant difference was observed between the DOPAC/dopamine ratios in the perifusate of renal tissues obtained from CsA- and vehicle-treated rats. In addition, no significant differences were observed in k values or in the slope of decline of both DA and DOPAC between experiments performed with CsA and vehicle-treated animals. 6. The Vmax for the saturable component of L-3,4-dihydroxyphenylalanine (L-DOPA) uptake in renal tubules from rats treated with CsA was twice that of vehicle-treated animals. Km in CsA- and vehicle-treated rats did not differ. 7. The decrease in the urinary excretion of sodium and an increase in blood pressure during CsA treatment was accompanied by a reduction in daily urinary excretion of dopamine. This appears to result from a reduction in the amount of L-DOPA made available to the kidney and does not involve changes in tubular AAAD, the availability of dopamine to leave the renal cells and dopamine metabolism. The enhanced ability of the renal tissues of CsA-treated animals to synthesize dopamine, when exogenous L-DOPA is provided, results from an enhanced activity of the uptake process of L-DOPA in renal tubular cells.

Assessment of renal dopaminergic system activity in the nitric oxide‐deprived hypertensive rat model

1. The present paper reports changes in the urinary excretion of dopamine, 5-hydroxytryptamine and amine metabolites in nitric oxide deprived hypertensive rats during long-term administration of NG-nitro-L-arginine methyl ester (L-NAME). Aromatic L-amino acid decarboxylase (AAAD) activity in renal tissues and the ability of newly-formed dopamine to leave the cellular compartment where the synthesis of the amine has occurred were also determined. 2. Twenty four hours after exposure to L-NAME, both systolic (SBP) and diastolic (DBP) blood pressure were increased by 20 mmHg; heart rate was slightly decreased. During the next 13 days both SBP and DBP increased progressively reaching 170 +/- 3 and 116 +/- 3 mmHg, respectively. 3. Baseline urinary excretion of L-DOPA, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) during the 4 day period of stabilization averaged 4.4 +/- 0.5, 13.8 +/- 0.3, 37.4 +/- 0.8, 180.0 +/- 2.7 and 206.1 +/- 6.7 nmol day-1, respectively. The urinary excretion of L-DOPA, dopamine and DOPAC, but not that of 3-MT and HVA, were increased from day 6-8 of L-NAME administration onwards (L-DOPA, up to 13.4 +/- 2.1; dopamine, up to 23.0 +/- 1.6; DOPAC, up to 62.8 +/- 3.7 nmol day-1). Baseline daily urinary excretion of 5-hydroxytryptamine and 5-hydroxyindolacetic acid (5-HIAA) averaged 73.5 +/- 1.1 and 241.7 +/- 5.4 nmol day-1, respectively. During the first week of L-NAME administration, the urinary excretion of both 5-hydroxytryptamine and 5-HIAA did not change significantly; however, as was found with dopamine and DOPAC, changes in the urinary excretion of 5-hydroxytryptamine were evident during the second week of L-NAME administration. 4. In experiments performed on homogenates of isolated renal tubules, the decarboxylation of L-DOPA to dopamine was dependent on the concentration of L-DOPA used (10 to 5000 microM) and saturable at 1000 microM. AAAD activity as determined in homogenates (Vmax, in nmol mg-1 protein h-1; Km in microM) was significantly (P < 0.01) higher in rats given L-NAME for 14 days (Vmax = 25 +/- 2; Km = 72 +/- 10) than in control rats (Vmax = 14 +/- 1; Km = 63 +/- 7), rats given L-NAME for 7 days (Vmax = 15 +/- 1; Km = 69 +/- 5) and rats given L-NAME plus L-arginine (Vmax = 13 +/- 1; Km = 60 +/- 3) for 14 days. 5. A considerable amount of the total dopamine formed from added L-DOPA in kidney slices escaped into the incubation medium. The application of the Michaelis-Menten equation to the net transport of newly-formed dopamine allowed the identification of a saturable (carrier-mediated transfer) and a non-saturable component (diffusion). No significant differences in the diffusional rate of transfer(0.14 +/- 0.02 micro mol-1) were observed between the four experimental groups. However, the saturable outward transfer of dopamine (Vmax, in micromol mg-1 protein h-1; Km in microM) was higher in control animals(Vmax= 2.3 +/- 0.2; Km = 568 +/- 67) than that in rats treated with L-NAME for 14 days (Vmax = 0.8 +/- 0.02;Km = 241 +/- 21), but similar to that observed in rats receiving L-NAME plus L-arginine (Vmax= 2.4+/- 0.2; Km= 618 +/- 61); the saturable dopamine outward rate of transfer in rats given L-NAME for 7days (Vmax = 3.9 +/- 0.2; Km = 1006 +/- 32) was higher than in controls.6. In conclusion, the present studies show that the hypertensive response resulting from the long-term administration of L-NAME is accompanied by an increased urinary excretion of dopamine and 5-hydroxytryptamine, which appears to follow an enhanced activity of renal AAAD. The observation that the increased AAAD activity can be reversed by the administration of L-arginine to L-NAME treated rats favours the view that the adaptational response which results in an enhanced AAAD activity probably involves a decrease in the generation of nitric oxide.

Renal dopamine spillover rate using 3H-dopamine radiotracer technique as an index of renal dopaminergic nerve activity.

Renal and total dopamine (DA) spillover rates at rest were measured in 25 conscious rabbits with chronically implanted renal vein catheters. Renal DA spillover rate was calculated from veno-arterial difference in plasma free DA concentrations across the kidney corrected by the fractional extraction of infused 3H-DA. Plasma free DA concentrations were 11.0 +/- 2.7 pg/ml in the artery and 14.3 +/- 3.6 in the renal vein. Renal and total DA spillover rates were 0.51 +/- 0.08, 2.61 +/- 0.30 ng/min, respectively, both of which were significantly (p < 0.001) lower than the respective norepinephrine (NE) spillover rates (renal: 16.3 +/- 1.4, total: 39.6 +/- 1.7). The fractional extraction of 3H-DA across the kidney (55 +/- 3%) and the total DA clearance (285 +/- 31 ml/min) were both significantly (p < 0.05) higher than that of 3H-NE (45 +/- 3) and the total NE clearance (198 +/- 9), respectively. The ratio of renal to the total spillover rate of DA (0.23 +/- 0.05) was significantly (p < 0.05) lower than that of NE (0.41 +/- 0.04). These results demonstrate that DA is released into plasma within the kidney and suggest that the measurement of renal DA spillover rate using 3H-DA radiotracer technique is useful to detect resting renal dopaminergic nerve activity.