Dopamine Excretion Research Articles

Mechanism of sodium load-induced hypertension in non-insulin dependent diabetes mellitus model rats: defective dopaminergic system to inhibit Na-K-ATPase activity in renal epithelial cells.

Obesity-related non-insulin dependent diabetes mellitus (NIDDM) is frequently accompanied by hypertension. The present study was designed to clarify this mechanism. We first determined the blood pressure in male Wistar fatty rats (WFR), one of the NIDDM model rats, and in Wistar lean rats (WLR) as the control, with a normal (0.7% NaCl) or high (7% NaCl) salt diet. We observed no difference in systolic and mean blood pressures between WFR and WLR. WFR, however, became extremely hypertensive as a result of ingesting the high salt diet. We next investigated the mechanism for sodium sensitivity in WFR. Although the urinary excretion of dopamine (DA), a potent natriuretic factor, which reflects the ability for renal DA production, was preserved in WFR, the sodium balance with the high salt diet was positive. Moreover, Na-K-ATPase activity in isolated proximal convoluted tubules (PCT) from WFR with a normal salt diet was significantly (p<0.05) higher than that from WLR. A high salt load produced a significant (p<0.05) decrease in Na-K-ATPase activity in WLR but not in WFR. Similarly, Na-K-ATPase activity in WLR with a normal salt diet was significantly (p<0.05) inhibited by DA (10(-5) M), but this was not true in WFR. Furthermore, urinary excretion of norepinephrine in WFR with a high salt diet was the highest among all the groups. These results indicate that WFR tend to develop salt-sensitive hypertension that could be caused by the excessive sodium retention occurring as the results of a defective dopaminergic system in the kidney that fails to inhibit Na-K-ATPase activity. Augmentation of the renal sympathetic nervous system may play some role in this setting.

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.

Dietary potassium and magnesium supplementation in cyclosporine-induced hypertension and nephrotoxicity

Cyclosporine A (CsA)-induced hypertension and nephrotoxicity are aggravated by high sodium intake. Accumulating evidence suggests that potassium and magnesium supplementation could protect against the detrimental effects of dietary salt. In the present study, we tested the hypothesis of whether concurrent supplementation with potassium and magnesium could protect against the development of CsA-induced hypertension and nephrotoxicity more effectively than supplementation with one mineral alone. Eight-week-old spontaneously hypertensive rats (SHRs) were divided into four groups (N = 10 in each group): (1) CsA group (5 mg/kg subcutaneously) receiving high-sodium diet (Na 2.6%, K 0.8%, Mg 0.2% wt/wt); (2) CsA group receiving a high-sodium, high-potassium diet (Na 2.6%, K 2.4%, Mg 0.2%); (3) CsA group receiving high-sodium, high-magnesium diet (Na 2.6%, K 0.8%, Mg 0.6%); and (4) CsA group receiving high-sodium, high-potassium, high-magnesium diet (Na 2.6%, K 2.4%, Mg 0.6%). CsA induced severe hypertension and deteriorated renal functions in SHRs on high-sodium diet. Histologically, the kidneys showed severe thickening of the media of the afferent artery with fibrinoid necrosis. Potassium supplementation lowered blood pressure (198 +/- 5 vs. 212 +/- 2 mm Hg, P < 0.05) and partially prevented the development of proteinuria (-25%, P < 0.05). Magnesium supplementation decreased blood pressure to the same extent but improved renal functions more effectively than potassium. The greatest protection against CsA toxicity was achieved when dietary potassium and magnesium supplementations were combined. Urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion, a marker for renal proximal tubular damage, increased progressively in CsA-treated SHRs on the high-sodium diet. Neither potassium nor magnesium influenced urinary NAG excretion. We also estimated the activity of the renal dopaminergic system by measuring 24-hour urinary dopamine excretion rates. CsA suppressed the renal dopaminergic system during high-sodium diet. Magnesium supplementation, alone and in combination with potassium, protected against the development of renal dopaminergic deficiency in CsA-treated SHRs on high-sodium diet. Magnesium supplementation increased plasma-free ionized magnesium (iMg) and bone magnesium by 50 and 16%, respectively. Our findings indicate that both potassium and magnesium supplementations showed beneficial effects against CsA-induced hypertension and nephrotoxicity. The protective effect of magnesium clearly exceeded that of potassium. The greatest protection against CsA toxicity was achieved when potassium and magnesium were combined. We also provide evidence that the development of CsA-induced glomerular, tubular, and vascular lesions are associated with renal dopaminergic deficiency.

Effects of high salt diets and taurine on the development of hypertension in the stroke-prone spontaneously hypertensive rat.

Taurine is present in high concentrations in mammalian tissues and has been implicated in cardiovascular control mechanisms. The aim of the present study was to evaluate the ability of taurine to attenuate salt-induced elevations in blood pressure and markers of damage to the kidney and cardiovascular system in stroke prone spontaneously hypertensive rats (SPSHR). Male SPSHR (6 weeks old) were placed on high salt diets that contained 1% (w/w) NaCl added to their normal chow for 84 days and then were switched to 3% added NaCl for the remaining 63 days of the study. SPSHR was given 1.5% taurine in the drinking water (n = 8), a taurine free diet (n = 8) or normal chow (n = 8). A final control group (n = 6) was not given high salt diets. High salt diets caused an acceleration in the development of hypertension in all groups. Taurine supplementation reduced ventricular hypertrophy and decreased urinary excretion of protein and creatinine. The taurine free diet did not alter serum or urinary excretion of taurine, but did result in elevated urinary nitrogen excretion, increased serum cholesterol levels, and impaired performance in a spatial learning task. Alterations in dietary taurine intake did not alter urinary or serum electrolytes (Na+, K+), but taurine supplementation did attenuate a rise in serum calcium seen with the high salt diets. Urinary excretion (microg/24h) of epinephrine and dopamine was significantly reduced in SPSHR given 1% NaCl in the diet, but this effect was not seen in SPSHR on taurine free or supplemented diets. Taurine supplementation showed cardioprotective and renoprotective effects in SPSHR given high salt diets.

Catecholamines and their metabolites in the brain and urine of rats with experimental Parkinson's disease.

The content of catecholamines and their metabolites in the brain and the relationship between cerebral catecholamine levels and their urinary excretion were studied in rats with 6-OHDA-induced hemiparkinsonism. 6-OHDA reduced brain concentrations of dopamine, DOPAC, and homovanilic acid and urinary excretion of dopamine, dioxyphenilalanine, and DOPAC by more than 90%. A positive correlation was found between the concentrations of these metabolites in the urine and striatum. Measurement of urinary catecholamines and their metabolites is a perspective test for evaluating the status of the dopaminergic nigrosostriate system of the brain in experimental parkinsonism.

Roles of renal dopamine and kallikrein-kinin systems in antihypertensive mechanisms of exercise in rats.

We have previously shown that both renal dopamine (DA) and kallikrein-kinin systems are activated by exercise in mild hypertensives. We aimed to confirm the effects of exercise on the renal DA system and the stimulatory effects of DA on the renal kallikrein-kinin system in rats. In experiment 1, 12 male Dahl salt-sensitive (DS) rats given a 4% salt diet were divided into two groups. Rats in the exercise group were forced to run at 8 m/min, 60 min/day, 5 days/week for 4 weeks. Daily urinary volume, urinary excretion of sodium, free DA, and kallikrein activity were measured weekly. Renal aromatic-L-amino-acid decarboxylase (AADC) activities were assayed at the end of the experiment. In experiment 2, 15 male Sprague-Dawley (SD) rats were randomly divided into 3 groups, a DA-5 (5 microg of DA/kg/min), a DA-10 (10 microg of DA/kg/min), and a control group. DA or vehicle was administered subcutaneously with an osmotic pump for 2 weeks. Daily urinary volume, urinary excretion of sodium, aldosterone, DA, and kallikrein activity were measured weekly. Plasma renin activity, aldosterone concentration, and renal kallikrein mRNA levels were determined at the end of the experiment. In experiment 1, urinary excretion of free DA and renal AADC activities in the exercise group were significantly higher than those in the non-exercise group at week 4. In experiment 2, renal kallikrein mRNA levels and urinary volume were significantly increased in the DA-10 group compared to the control group, although there were no differences in urinary kallikrein activities. Plasma aldosterone concentration was significantly decreased in the DA-10 group compared to that in the control group despite a lack of differences in plasma renin activities. In conclusion, exercise increased the urinary excretion of free DA, probably through increased renal AADC activity in DS rats. DA amplified renal kallikrein mRNA levels and decreased plasma aldosterone levels, probably through its suppression of aldosterone in the adrenal glands. Activation of the kallikrein-kinin system might be counteracted by post-transcriptional modification of aldosterone. These results suggest that exercise enhances renal dopamine production by activating renal AADC activity, which in turn stimulates the renal kallikrein-kinin system.

Renal dopamine and noradrenaline excretion during CNS-induced natriuresis in spontaneously hypertensive rats: influence of dietary sodium.

Abnormalities in dopamine (DA) and noradrenaline (NA) activities and sodium handling may be involved in the pathogenesis of hypertension. The present study was designed to investigate whether any differences exist between normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in urinary excretion of DA, NA and sodium after 15 weeks on a low, medium or high sodium diet and during a subsequent elevation of the cerebroventricular fluid sodium concentration (CNS-induced natriuresis). Seven features were noted: (1) Basal sodium and DA excretion after the diet regimen was correlated to the dietary sodium content in both strains, except that sodium and DA excretion in SHR showed no further increase after the high sodium diet over and above that after medium sodium diet. (2) For any given sodium diet, SHR excreted more DA and NA as compared with WKY. (3) Blood pressure in SHR, as opposed to that in WKY, was higher after medium and high sodium diet than after low sodium diet. (4) During CNS-induced natriuresis NA excretion decreased or remained unchanged in WKY, but increased in SHR. (5) The DA/NA excretion ratio during CNS-induced natriuresis increased in WKY while decreased in SHR, which would not favour a natriuretic/vasodilatory response in the latter. (6) The ability of SHR to respond with CNS-induced natriuresis was attenuated after high sodium diet. (7) The magnitude of CNS-induced natriuresis was in both strains correlated to the sodium diet; the higher the dietary sodium content, the greater the natriuretic response. In conclusion, the study shows some clear differences in the catecholamine and sodium handling between WKY and SHR which may be involved in the pathogenesis of hypertension in SHR. Furthermore, increased sodium in the diet sensitizes the brain and kidney to increase the ability to respond with natriuresis for a given sodium stimulus.

RENAL DOPAMINERGIC MECHANISMS IN RENAL PARENCHYMAL DISEASES, HYPERTENSION, AND HEART FAILURE

The recovery of renal function in renal transplant recipients is accompanied by an enhanced ability to synthesize dopamine (DA), which may contribute to maintain sodium homeostasis. Patients suffering from chronic renal parenchymal disease, a well-recognized form of salt sensitive (SS) hypertension, have a reduced ability to produce DA that correlates well with deterioration of renal function. In patients afflicted with IgA nephropathy, but normal renal function, urinary excretion of DA correlated positively with BP responses to changes from 200 to 20 mmol/day salt intake. In black salt resistant (SR) normotensives (NT) and SR hypertensives, under low salt intake (40 mmol/day), but not SS-NT and SS-HT, the saline infusion induced increments of DA and DOPAC urinary excretion correlated significantly with increments of sodium urinary excretion and sodium fractional excretion. Patients afflicted with heart failure (HF) have a reduced delivery of L-DOPA to the kidney, accompanied by an increase in DA/L-DOPA urinary ratios. This suggests that HF patients have an increased ability to take up or decarboxylate L-DOPA. Sodium restriction resulted in a significant decrease in urinary L-DOPA, DA and DOPAC in HF patients, suggesting that the system responds to sodium. It is concluded that activity of renal dopaminergic system may be altered in SS subjects, despite the level of their BP, and an enhanced delivery of L-DOPA to the kidney may be beneficial in edema formation states.

Effect of γ-L-glutamyl-L-DOPA on phosphate excretion

γ- L -glutamyl- L -DOPA (gludopa) is a dopamine prodrug that is relatively specific for the kidney. Because dopamine is phosphaturic, the present study compared the phosphaturic effects of the infusion of equimolar doses of gludopa (n = 8), L -DOPA (n = 8), and γ- L -glutamyl- L -tyrosine (glutyrosine, n = 6). Glutyrosine was used as a control to evaluate the effect of the glutamyl portion of gludopa on phosphate excretion. Sprague-Dawley rats (350 to 400 g) were anesthetized with 5-sec-butyl-ethyl-2-thyobarbituric acid (Inactin; 100 mg/kg, IP ) and underwent thyroparathyroidectomy. Clearances were taken during the infusion of normal saline vehicle, followed by the infusion of gludopa, L -DOPA, or glutyrosine, all infused at the rate of 10 nmol/kg bolus and 0.8 nmol/kg/min ( IV ). To determine the contribution of glutamyl derivative to phosphate excretion, gludopa or L -DOPA was infused in the presence of SCH23390, a DA-1 receptor antagonist. Gludopa infusion significantly increased dopamine excretion (from 1.9 ± 0.2 ng/min to 17.0 ± 3.9 ng/min, Δ15.0 ± 3.9 ng/min, P < .008) and fractional excretion of phosphate (from 2.6% ± 0.6% to 34.8% ± 1.8%, Δ32.0% ± 1.6%, P < .001). L -DOPA infusion significantly increased dopamine excretion (from 1.4 ± 0.4 ng/min to 9.7 ± 1.6 ng/min, Δ8.3 ± 1.5 ng/min, P < .001) and fractional excretion of phosphate (from 1.7% ± 0.6% to 8.2% ± 2.0%, Δ6.4% ± 1.5%, P < .004). Glutyrosine infusion significantly increased fractional excretion of phosphate (from 2.8% ± 0.8% to 17.5% ± 5.2%, Δ14.6% ± 4.8%, P < .03) without changing dopamine excretion (Δ0.5 ± 0.2 ng/min). Infusion of gludopa in the presence of SCH23390 increased fractional excretion of phosphate (from 5.7% ± 2.5% to 12.6% ± 3.5%, Δ6.8% ± 2.3%, n = 6, P < .03), whereas SCH23390 completely blocked the phosphaturic effect of L -DOPA. We conclude that γ- L -glutamyl- L -DOPA is more phosphaturic than L -DOPA in the rat because of the combined effects of dopamine and the glutamyl moiety. (J Lab Clin Med 2000;135:52-6)

Urinary dopamine excretion in healthy volunteers: effect of sodium diet and acute water load

Urinary dopamine excretion in healthy volunteers: effect of sodium diet and acute water load

Chronic oral L-DOPA increases dopamine and decreases serotonin excretions.

Given the common pathways for uptake and synthesis for dopamine and serotonin, enhanced renal dopamine synthesis in response to increased substrate 3,4-dihydroxyphenylalanine (L-DOPA) is postulated to decrease renal serotonin synthesis. The present study compared the effects of chronic oral administration of L-DOPA on dopamine and serotonin excretion in vivo, with the effects of enhanced dopamine synthesis per nephron due to adaptation to reduced renal mass (RRM). Four groups of rats were studied: sham-operated rats and rats with RRM in the absence and presence of chronic oral L-DOPA. L-DOPA (2 mg. 100 g body wt(-1). day(-1)) for 6-14 days increased calculated dopamine synthesis per nephron in sham-operated rats from 2.0 +/- 0.3 (n = 7) to 13.6 +/- 1.8 pg. day(-1). nephron(-1) (n = 7, P < 0.05) and in rats with RRM from 6.1 +/- 1.3 (n = 7) to 39.3 +/- 5.2 pg. day(-1). nephron(-1) (n = 7, P < 0.05). Chronic oral L-DOPA concomitantly decreased serotonin synthesis per nephron in sham-operated rats (1.6 +/- 0.1 to 1.0 +/- 0.1 pg. day(-1). nephron(-1), n = 7, P < 0.05) and in rats with RRM (5.6 +/- 0.9 to 2.6 +/- 0.4 pg. day(-1). nephron(-1), n = 7, P < 0.05). Both serotonin and dopamine synthesis per nephron were increased in rats with RRM. In conclusion, chronic oral administration of L-DOPA enhances dopamine excretion and decreases serotonin excretion in normal rats and in rats with reduced renal mass. Both dopamine and serotonin excretions per nephron were elevated by renal mass reduction.

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.

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.

Regulation of Dopamine-Induced Natriuresisby the Dopamine-Metabolizing Enzyme Catechol-O-Methyltransferase

Dopamine (DA) is an intrarenal natriuretic hormone involved in sodium homeostasis. A study was performed to elucidate two possible regulatory pathways of DA-induced natriuresis, i.e., metabolism and precursor delivery. This was done by use of an intraperitoneal injection of a catechol-O-methyltransferase (COMT) inhibitor, entacapone, or intravenous infusion of the DA precursor, L-dopa. Entacapone (30 mg/kg i.p.) induced a more than fivefold increase in renal sodium excrection which occurred without changes in renal haemodynamics. The natriuretic response was highly dependent on DA D₁-like receptor activation, since the selective D₁-like receptor antagonist SCH23390 attenuated the natriuretic response by 61%, while the selective D₂-like receptor antagonist sulpiride was ineffective. The urinary excretion of DA did not increase. Infusion of L-dopa (60 μg/h/kg) only induced a twofold increase in sodium excretion, but the urinary excretion of DA increased more than 17-fold. The L-dopa-induced natriuretic response occurred without increments in glomerular filtration rate and could be blocked with the D₁-like receptor antagonist SCH23390. It is concluded that the DA-metabolizing enzyme COMT is involved in the regulation of the natriuretic effect of intrarenal DA. It may be speculated that intrarenal DA activity is not primarily determined on the basis of delivered precursor, but on that of the level of DA metabolism.

Renal Effects of L-DOPA in Heart Failure

We examined whether low-dose L-DOPA treatment induces natriuresis and diuresis in patients with congestive heart failure who have cardiac decompensation despite treatment with digoxin, a diuretic, and an angiotensin-converting enzyme inhibitor and who respond acutely to intravenously infused dopamine. In a randomized, double-blind, placebo-controlled crossover study, 11 patients with severe congestive heart failure received L-DOPA (0.10 g, p.o., t.i.d., for 1 day and then 0.25 g, p.o., t.i.d., for 2 days after a washout period of > or = 1 day), with assessments of plasma and urinary levels of catechols, urinary volume, and sodium content, and clinical and laboratory measures of improvement of congestive heart failure. L-DOPA elicited short-term, dose-related increases in urinary volume and sodium excretion. At the 0.10-g dose, L-DOPA increased plasma L-DOPA levels and urinary L-DOPA excretion by about fivefold, whereas at the 0.25-g dose, L-DOPA increased plasma and urinary L-DOPA by >50-fold. Twenty-four-hour urinary dopamine excretion increased by about fivefold after the low dose of L-DOPA and approximately 50-fold after the high dose. The results demonstrate that oral L-DOPA treatment can produce beneficial natriuretic and diuretic effects in selected patients with congestive heart failure. The bioavailability of oral L-DOPA appears to vary with the dose. These results support findings from previous studies about beneficial cardiac functional effects of L-DOPA in patients with refractory heart failure.

γ-L-glutamyl-L-DOPA inhibits Na+-phosphate cotransport across renal brush border membranes and increases renal excretion of phosphate

For treatment of phosphate (Pi) overload in various pathophysiological states, an agent that selectively increases renal Pi excretion would be of major value. Previously, we have shown that dopamine (DA) inhibits Na(+)-Pi cotransport in renal epithelia. However, the administration of DA or its immediate precursor L-DOPA increases DA in multiple tissues. Synthetic dipeptide gamma-L-glutamyl-L-DOPA (gludopa) can serve as an inactive precursor (pro-pro-drug) of DA. This study tested the hypothesis that, because of the unique colocalization of gamma-glutamyltransferase (gamma-GT), aromatic amino acid decarboxylase, Na(+)-Pi cotransporter, and Na(+)-L-DOPA cotransporter in brush border membrane (BBM) of proximal tubular cells, gludopa may elicit phosphaturia by action of DA generated within the kidney. Thyroparathyrectomized rats were given placebo, or gludopa, or gludopa + gamma-GT inhibitor acivicin. Urinary excretion of Pi, Ca2+, Na+, K+, DA, cAMP, and cGMP was determined, and Na(+)-Pi cotransport was measured in BBM prepared from kidneys of rats at the end of the experiment. The administration of gludopa resulted in: (a) an inhibition of Na(+)-Pi cotransport, but not cotransport of Na(+)-proline and Na(+)-alanine in BBM; (b) an increase (+300%) of fractional excretion (FE) of Pi and a drop (-35%) of plasma Pi, whereas the plasma levels and FEs of Ca2+, Na+, and K+ were unchanged; (c) an increase in urinary excretion of cAMP. but not cGMP; (d) a 1000-fold increase of urinary excretion of DA, without a change in excretion of norepinephrine; and (e) an incubation of gludopa with BBM in vitro, which caused a release of L-DOPA, and the in vivo administration of acivicin, which blocked actions of gludopa to inhibit Na(+)-Pi cotransport and to increase urinary excretions of Pi and DA. We conclude that colocalization of enzymes of biotransformation, BBM transporters, and the autocrine/paracrine DA system in cells of proximal tubules constitutes a cellular basis for the potent and specific phosphaturic action of gludopa.

Effect of glucocorticoids on renal dopamine production

This study assess the effects of glucocorticoids on dopamine excretion and evaluates the participation of renal dopamine in the effects of glucocorticoids on renal function and Na + excretion. Dexamethasone (i.m.; 0.5 mg/kg) was administered to male Wistar rats on day 2 or on days 2 and 5. Daily urinary excretions of Na +, dihydroxyphenylalanine (DOPA), dopamine and dihydroxyphenylacetic acid were determined from day 1 to day 7. Renal function was evaluated 8 h after dexamethasone administration in a separate group. The first dose of dexamethasone increased about 100% diuresis and natriuresis, increased urinary DOPA and renal plasma flow, and did not affect urinary dopamine or the other parameters evaluated. These effects were not affected by previous administration of haloperidol. The second dexamethasone dose increased about 200% diuresis and natriuresis, increased urinary dopamine, DOPA, dihydroxyphenylacetic acid, U osm× V and both glomerular filtration rate and renal plasma flow. Carbidopa administered before the second dexamethasone dose blunted both the diuretic and the natriuretic response whereas haloperidol abolished or blunted all the effects of the second dexamethasone dose. These results show that modifications in renal dopamine production produced by corticoids may contribute to the effects of these hormones on Na + balance and diuresis and suggest that regardless the factor that promotes an increase in renal perfusion and glomerular filtration rate during long term administration of glucocorticoids, a dopaminergic mechanism is actively involved in the maintenance of these hemodynamic changes.

Low platelet-poor plasma concentrations of serotonin in patients with combat-related posttraumatic stress disorder

Background: Combat-related posttraumatic stress disorder (CR-PTSD) is associated with a dysregulation of various neurotransmitter systems. Methods: We assessed levels of platelet-poor plasma (PPP) norepinephrine (NE), and serotonin (5-HT), and 24-hour urinary excretion of NE, dopamine (DA), and homovanillic acid (HVA) in 17 male outpatients with untreated chronic CR-PTSD (age, 33.1 ± 7.4 years) and 10 normal control subjects (age, 35.8 ± 2.7 years). Results: Compared with the control subjects, the PTSD patients showed significantly lower PPP 5-HT levels, elevated PPP NE levels, and significantly higher mean 24-hour urinary excretion of all three catecholamines (NE, DA, and HVA). The 24-hour urinary HVA values of the CR-PTSD patients correlated significantly and positively with the total Impact of Event Scale scores and the avoidance symptoms cluster scores, and the PPP 5-HT levels correlated negatively with the Hamilton Anxiety Rating Scale scores. The PPP NE/5-HT ratio was significantly higher in the study group than in the control subjects. Conclusions: We believe this combined enhanced noradrenergic activity and diminished 5-HT activity may be relevant to the neurobiology of CR-PTSD.

Exercise, A Measure to Lower Blood Pressure and Reduce Other Risks

By 1990, exercise had been proven to lower blood pressure, and subsequently the intensity of exercise recommended was lowered from moderate to mild (lactic threshold or 50% maximum oxygen uptake). Exercise is now recommended as a useful measure to lower blood pressure in many guidelines for the management of hypertension. The antihypertensive mechanism is multifactorial involving sympathicolytic as well as diuretic actions through activation of relevant metabolic pathways; that is, decrease in endogenous ouabain-like substance, increase in s-taurine and prostaglandin E and urinary dopamine and kallikrein excretion, etc. Other metabolic changes seem to operate simultaneously, and other risk factors, such as sugar and lipid metabolism and insulin resistance are improved. Prospective epidemiologic study has suggested that a physically active lifestyle will prevent cardiovascular complications.

Effects of weight cycling on urinary catecholamines: sympathoadrenal role in refeeding hypertension.

We sought to determine whether the sympathetic nervous system plays a role in the hypertensive response to refeeding from a very low-calorie diet (VLCD). Cycles of weight loss and regain were induced in the obese spontaneously hypertensive rat (SHROB) model of genetic obese hypertension. A 12-day VLCD (1/6 of baseline calories) was alternated with 4-6 weeks of ad libitum chow refeeding for three cycles. Control SHROB ate chow ad libitum. Urine was collected for 24 h before and after each period of VLCD, and catecholamines were measured radioenzymatically. Tail cuff blood pressures and body weight were measured in parallel with urine collections. Kidneys were collected for assay of alpha2-adrenergic receptor density. VLCD induced rapid weight loss, but all the lost weight was regained during refeeding. Blood pressure fell during caloric restriction, but rose above baseline during refeeding. Urinary excretion of norepinephrine, epinephrine and dopamine changed several fold during weight cycling. Urinary catecholamines paralleled the changes in blood pressure, falling during caloric restriction and rebounding during refeeding. Dopamine showed the greatest decreases during weight loss and rises during weight regain, whereas epinephrine changed the least and norepinephrine was intermediate. Weight cycling elevated blood pressure above the initial baseline throughout the rapid weight gain phase of refeeding. The density of alpha2-adrenergic receptors was decreased in both the renal medulla and cortex of weight cycled SHROB, consistent with receptor down-regulation owing to overstimulation. The exacerbations of hypertension during weight regain in SHROB coincide with sustained activation of sympathoadrenal activity, as reflected in urinary catecholamine excretion and adrenergic receptor down regulation.