Plasma Free Dopamine Research Articles

Influence of intra-abomasal administration of L-DOPA on circulating catecholamines and feed intake in cattle

Dopamine has multiple physiological functions including feed intake control in which it can act as an anorectic or orexigenic agent. This study had the objective to evaluate intra-abomasal administration of L-DOPA (levodopa; L-3,4-dihydroxyphenylalanine) from -Mucuna prurienson circulating catecholamines, indicators of energy metabolism and feed intake in cattle. Eight Holstein steers (340 ± 20 kg) fitted with ruminal cannula were used in a replicated 4 x 4 Latin Square design experiment. Intra-abomasal infusion of L-DOPA at 0, 0.5, 1 and 2 mg/kg BW was carried out for seven days and blood samples were collected at 0, 30, 60, 120, 240 and 480 min from L-DOPA infusion on day 7. The area under the curve (AUC) of plasma L-DOPA and free dopamine increased quadratically with the administration of L-DOPA. However, the AUC of plasma total dopamine had a positive linear response with the increase of L-DOPA. Conversely, the serum 5-hydroxytriptophan (5-HTP), plasma serotonin, serum serotonin, serum tyrosine, plasma glucose and plasma free fatty acids were not affected by the intra-abomasal infusion of L-DOPA. The circulating concentration of the epinephrine, norepinephrine, serotonin, glucose and free fatty acids did not change with L-DOPA infusion. It can be concluded that intra-abomasal L-DOPA administration produced a strong increase in circulating dopamine with no change in energy metabolites and feed intake in cattle.

Association of High Levels of Plasma Free Dopamine With Future Coronary Events in Patients With Coronary Artery Disease

There is an intimate relationship between activation of the sympathetic nervous system and myocardial ischemia. This study examined whether plasma levels of dopamine, a precursor of norepinephrine, may provide prognostic information in coronary artery disease (CAD). Plasma levels of free dopamine were measured by high-performance liquid chromatography in 210 consecutive patients with stable CAD. The patients were prospectively followed up for a period of < or =36 months until occurrence of a clinical coronary event. Coronary events occurred in 37 patients during follow-up. In Kaplan-Meier survival analysis, higher dopamine levels (> or =30 pg/ml) resulted in a higher event probability (p<0.01). Multivariate Cox hazards analysis showed that higher dopamine levels were a significant and independent risk factor for future coronary events (hazard ratio 3.3, 95% confidence interval 1.3-8.1, p<0.01). Furthermore, patients with higher dopamine levels had lower left ventricular (LV) ejection fraction and higher levels of brain natriuretic peptide, C-reactive protein, and fibrinogen than those with lower dopamine levels. Plasma levels of free dopamine are increased in association with a decrease in LV function and an increase in inflammatory risk markers. Higher free dopamine levels are an independent risk factor for future coronary events in CAD patients.

Treatment for ovarian hyperstimulation syndrome using an oral dopamine prodrug ,docarpamine

Dopamine treatment constitutes a major advance towards the management of severe ovarian hyperstimulation syndrome (OHSS) by causing renal and mesenteric vasodilatation as well as diuretic and positive inotropicactions. Docarpamine ,an oral dopamine prodrug ,is converted into dopamine after enteral administration ,and the generated dopamine causes renal vasodilatation and diuresis. The purpose of this study wasto assess whether docarpamine had beneficial effects in patients with OHSS. Twenty-seven patients ,hospitalized because of OHSS and refractory to the initial therapy with intravenous albumin ,were treatedby docarpamine ,after informed consent had been obtained. A 750-mg tablet of docarpamine was taken every 8 h. In some cases ,the plasma levels of free dopamine were measured. The daily urinary outputs beforeand 1 ,2 ,3 and 4 days after the docarpamine treatment were 839 ± 424 ml ,1121 ± 608 ml ,1168 ± 504 ml ,1325 ± 815 ml and 1133 ± 509 ml ,respectively. There were significantdifferences between the first and each of the others (p < 0.05). In 19 (86.4%) of 22 patients treated ,clinical symptoms associated with ascites were gradually improved after administrating docarpamine.The plasma free dopamine concentration rose to as high as 55.9 ± 33.2 mg/ml during the first hour ,which corresponded to the usual intravenous drip infusion treatment with dopamine. Moreover ,therewere no major adverse effects of docarpamine in this study. This was the first demonstration of docarpamine treatment in patients with intravenous albumin-resistant OHSS. Although no effect was seen inpregnant women ,diuresis was increased in some women ,and ascites decreased. These findings indicate that oral docarpamine administration could be one of the options in the management of patients with OHSSusing dopamine therapy.

Effects of caffeine on the uncoupling protein family in obese yellow KK mice.

1. The hypothesis that caffeine upregulates uncoupling protein (UCP)-1, UCP-2 and UCP-3 expression, which contribute to thermogenesis, was investigated in obese mice. 2. The mRNA levels of UCP-1, -2 and -3 in brown adipose tissue (BAT), UCP-2 in white adipose tissue (WAT), and UCP-2 and -3 in skeletal muscle were measured using real-time quantitative reverse transcription-polymerase chain reaction analysis in obese yellow KK mice 4 h after the subcutaneous administration of either 60 mg/kg caffeine or physiological saline. Plasma free fatty acids, adrenaline, noradrenaline and dopamine levels were also measured. 3. In caffeine-injected obese mice, UCP-1 mRNA levels were significantly increased by 1.5-fold in BAT, UCP-2 mRNA levels were increased by 1.8- and 2.5-fold in BAT and skeletal muscles, respectively, and UCP-3 mRNA levels were increased 1.7- and 3.4-fold in BAT and skeletal muscles, respectively, compared with control mice injected with physiological saline. There was no difference in UCP-2 mRNA levels in WAT between the two groups. 4. Plasma free fatty acids and adrenaline levels were significantly elevated in mice treated with caffeine compared with those injected with physiological saline. 5. It was concluded that caffeine upregulates the expression of UCP-1, UCP-2 and UCP-3 in BAT and UCP-2 and UCP-3 in skeletal muscles, which may contribute to thermogenesis in obese mice.

Peripheral dopamine in hypertension and associated conditions.

The purpose of this study is to review the role of dopamine in hypertension and associated conditions. The analysis of literature indicates that present knowledge is mostly based on poor markers and indirect evidence of dopaminergic activity and only few molecular biological data. Alternative markers such as plasma dopamine sulfate emerge as a possible substitute for the low plasma free dopamine detectability, one of the main obstacles in understanding the relationship between circulating dopamine and its receptor actions in hypertension. Essential hypertension represents a heterogeneous entity: based on evidence in borderline and non-modulating hypertension, the tubular dopamine receptor defect may be compensated by increased dopamine synthesis (dopamine beta-hydroxylase suppression-mediated?) and release; alternatively, compatible with data in stable, salt-sensitive and low renin-hypertension, the receptor defect may be amplified by a deficient dopamine synthesis, basal and in response to salt and volume expansion. Secondary forms of hypertension (renovascular, renal, polycystic kidneys, mineralocorticoid, pheochromocytoma) associated conditions (renal and heart failure, diabetes, hypovolaemia, mastocytosis) or iatrogenic (cocaine abuse) are mostly reflected by increased dopamine indices, some of them proposed to be counteracting the activation of prohypertensive mechanisms. In conclusion dopamine should thus be monitored in hypertension while respecting several associated conditions affecting peripheral dopaminergic activity. Catecholamine synthesis and metabolism enzymes' and dopamine receptors' targeting are essential for advancing the understanding of dopamine's diagnostic and therapeutic implications.

Effects of a new orally active dopamine prodrug, docarpamine, on refractory ascites: a pilot study

OBJECTIVE: Refractory ascites is a debilitating condition in patients with cirrhosis. Recently, docarpamine, an orally active dopamine prodrug, was reported to increase renal blood flow, glomerular filtration, and sodium excretion. This suggests docarpamine may be useful for the treatment of refractory ascites. METHODS: In this study, we investigated docarpamine metabolism in cirrhotic patients and its effect on refractory ascites. RESULTS: Blood samples were obtained from seven cirrhotic patients and six healthy subjects after administration of 750 mg docarpamine, and plasma levels of free dopamine were measured. In healthy subjects, maximum plasma concentration (C max), time taken to reach C max (T max), elimination half-life (T 1/2), and area under the plasma concentration-time curve (AUC) of plasma free dopamine were 76.8 ± 24.1 ng/ml, 1.3 ± 0.2 h , 0.8 ± 0.1 h, and 97.5 ± 21.1 ng · h /ml, respectively. In patients with cirrhosis, C max (53.1 ± 24.9 ng/ml), T 1/2 (0.8 ± 0.1 h), and AUC (100.6 ± 45.6 ng · h /ml) were no different from healthy subjects when comparing each parameter, whereas T max (2.7 ± 0.2) was significantly longer than that of healthy subjects. We treated 10 cirrhotic patients with refractory ascites with docarpamine or placebo and the same dose of diuretics used before hospitalization. After 8 wk of docarpamine treatment, ascites disappeared completely in three of the five patients and decreased in the remainder. However, in five patients treated with placebo, ascites was not changed or increased. Side effects were not observed in any case. CONCLUSIONS: Docarpamine was found to metabolize in cirrhotic patients as well as in normal subjects and may be an effective treatment for refractory ascites.

Differential catecholamine responses to protein intake in healthy and hypertensive subjects.

Protein intake-induced natriuresis previously related to increased urinary dopamine excretion was reexamined in an extensive controlled study comparing healthy and hypertensive subjects. In healthy subjects, ingestion of 1 g/kg wt tuna induced natriuresis that was associated, between postprandial hours 1 and 2, with increased plasma tyrosine [191 +/- 13% (mean +/- SE); P < 0.01], 3, 4-dihydroxyphenylalanine (104 +/- 12%, P < 0.05 in plasma; 162 +/- 20%, P < 0.05 in urine), plasma free dopamine (156 +/- 32%; P < 0. 05), and dopamine sulfate (191 +/- 11%, P < 0.001 in plasma; 199 +/- 15%, P < 0.01 in urine) but affected urinary free dopamine excretion only at limits of significance. Hypertensive subjects had less (P < 0.02) natriuresis and, despite comparable plasma tyrosine and dopamine sulfate increases, no increase in plasma and urinary 3, 4-dihydroxyphenylalanine and plasma free dopamine. Their plasma and urinary free epinephrine responses were less (P < 0.05) than the borderline increases in control subjects. Compared with control subjects, they significantly increased plasma 3, 4-dihydroxyphenylalanine sulfate (P < 0.05), epinephrine sulfate (P < 0.05), and the dopamine sulfate-to-free dopamine ratio (P < 0.02). Postprotein natriuresis is thus associated with nutritional priming-induced plasma but not urinary free dopamine increase. Hypertensive subjects have attenuated natriuretic and plasma free dopamine responses and less free epinephrine increase. This may partly result from higher circulating 3,4-dihydroxyphenylalanine, dopamine, and epinephrine sulfoconjugates leaving fewer free amines for biological actions.

Changes in plasma free and sulfoconjugated dopamine in patients with congenital heart disease who underwent cardiac operation.

It has been suggested that plasma sulfoconjugated dopamine (DA) may serve as a source or reservoir for free DA in plasma. Moreover, it has also been reported that the plasma levels of conjugated DA may be used as an index predicting heart failure in patients with heart disease. Therefore, in the present study, we have measured the plasma levels of free and sulfoconjugated DA in patients with congenital heart disease who underwent total corrective operations. The patients were divided into two groups with (6 patients with tetralogy of Fallot, TOF) or without (5 patients with ventricular septal defect without pulmonary hypertension, VSD) cyanosis (mean age of 2.11 years). Blood samples were collected before and after operation from the patients, and plasma free and sulfoconjugated DA levels were measured using high performance liquid chromatography. Preoperative levels of free DA in patients in both groups were higher than the level in age matched control subjects. The plasma level of conjugated DA in TOF was higher than that in the controls and was the highest in VSD before operation. DA infusion early after operation caused a rise in plasma free and conjugated DA, however, the levels of increased free DA were lower in the VSD than in the TOF group. After discontinuing DA infusion, the plasma levels of free DA remained higher, while those of conjugated DA decreased to a level lower than the preoperative values in both groups. As the plasma levels of free and sulfoconjugated DA vary with hemodynamics, it was assumed that the difference in the plasma sulfoconjugated DA level between the groups before operation was due to the influence of pulminary blood flow on catecholamine homeostasis. Since the decrease in conjugated DA has been postulated to be an index of sustained heart failure, it is conceivable that it takes a long time for patients who underwent cardiac operations in infancy to recover from heart failure.

Urinary Dopamine and Renal Handling of L–DOPA in Fasted Spontaneously Hypertensive Rats

A defective renal dopaminergic system has been suggested to contribute, via impaired sodium excretion, to the pathogenesis of hypertension. Data according renal dopamine (DA) release in hypertension, however, are inconsistent. In the present study, we compared urinary DA excretion (U_DAV), plasma free DA (P_DA), and renal tissue DA contents (T_DA) of young spontaneously hypertensive rats (SHR), Wistar–Kyoto (WKY), and Sprague–Dawley (SD) rats. Since the protein intake dominantly controls U_DAV, fasted animals were used to exclude the influence of feeding. Conscious WKY and SHR had a similar U_DAV which was lower compared to SD rats. Thiopental anesthesia increased U_DAV in SHR and WKY but not in SD rats. T_DA was higher in SHR compared to SD and WKY rats. To investigate the tubular capacity to generate DA, the response to L–DOPA infusion was assessed in two doses. 1 nmol/min/100 g body weight L–DOPA increased U_DAV approximately 30–fold in all strains but did not affect tubular sodium excretion or renal hemodynamics. In contrast, infusion of 3 μmol/min/100 g body weight L–DOPA increased U_DAV by five orders of magnitude and induced natriuresis, diuresis, and tachycardia. These effects were assigned to an increase in P_DA and no significant differences were observed among the strains. We conclude that, regarding renal DA, (1) the differences among SHR, WKY, and SD rats rather appear to be strain related than hypertension associated; (2) the renal capacity of DA generation from L–DOPA is not impaired in SHR; (3) tubular DA at physiological concentrations does not alter sodium excretion significantly in normo– or hypertensive rats, and (4) the influence of anesthesia on U_DAV should be considered in comparative studies.

Sulfoconjugation and renal excretion contribute to the interpatient variation of exogenous catecholamine clearance in critically ill children.

To delineate the contributions of sulfoconjugation, renal excretion, and patient age to the wide interpatient variability in exogenous dobutamine and dopamine plasma clearance. Simultaneous plasma free and sulfoconjugated dobutamine and/or dopamine, respective urine free catecholamine, and serum creatinine were determined on stable critically ill children receiving unchanged continuous infusions of dobutamine and/or dopamine for at least 1 hr. Free dobutamine and dopamine clearance rates were calculated. Pediatric and neonatal intensive care units in university settings. Forty-seven stable critically ill neonates and children. Continuous infusions of dobutamine and/or dopamine: nine patients received dopamine only, 27 patients received dobutamine only, and 11 patients received both simultaneously. Fractions of plasma dobutamine and dopamine sulfoconjugated were 0.73 +/- 0.05 and 0.76 +/- 0.05, respectively. Free plasma dobutamine and dopamine clearances were 102 +/- 15 mL/kg/min and 250 +/- 38 mL/kg/min, respectively. Linear regression analyses demonstrated relationships of the fraction of plasma dobutamine and dopamine sulfoconjugated to the respective free plasma clearances (r2 = .30, p < .01, and r2 = 0.29, p < .01, respectively), and, more impressively, to the natural logarithm of the respective free plasma clearances (r2 = 0.58, p < .001, and r2 = 0.39, p < .01). Patients with serum creatinine concentrations >2 mg/dL had lower free plasma dobutamine and dopamine clearance rates than those patients with serum creatinine of <2 mg/dL (6 +/- 1 vs. 107 +/- 15 mL/kg/min for dobutamine and 40 +/- 38 vs. 270 +/- 39 mL/kg/min for dopamine, respectively, p < .05 for both by Mann-Whitney U test). No relationship was noted between free catecholamine clearance and age. Sulfoconjugation and renal excretion are important determinants of the wide interpatient variability in plasma free dobutamine and dopamine clearance rates.

Plasma catechols and monoamine oxidase metabolites in untreated Parkinson's and Alzheimer's diseases

Prior studies have documented functional and pathological compromise of the peripheral sympathetic nervous system in patients with Parkinson's disease, suggesting the possibility of reduced catecholamine release into the circulation. We measured free plasma catechols in early and untreated patients with Parkinson's disease, but found no evidence of reduced concentrations, compared to control subjects or a group of patients with probable Alzheimer's disease. Rather, there was a significant elevation of plasma norepinephrine within the Parkinson's disease group. Furthermore, 6 of 15 untreated Parkinson's disease patients (40%) displayed markedly elevated plasma concentrations of the catecholamine MAO metabolites, DOPAC or DOPEG. Despite this finding, platelet MAO-B activity measured in these and all other Parkinson's disease patients fell well within the range of the control subjects, and was also statistically similar to the group with Alzheimer's type dementia. Plasma dopa levels were similar in all groups, whereas the majority of patients in the three groups had plasma free dopamine and epinephrine concentrations below the limits of detection. These trends toward increased, rather than decreased, circulating catechol concentrations suggest that peripheral sympathetic nervous system catecholamine production and release is not severely compromised in patients with early Parkinson's disease. In addition, we were unable to confirm certain previous reports of elevated MAO-B activity in patients with Parkinson's or Alzheimer's diseases.

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.

Plasma total and free dopamine, norepinephrine and epinephrine. Response to treadmill exercise

Plasma total and free dopamine, norepinephrine and epinephrine. Response to treadmill exercise

Dopaminergic abnormalities in borderline essential hypertensive patients.

To explore whether an altered metabolic pathway of dihydroxyphenylalanine (DOPA) may be related to some previously observed dopamine abnormalities in borderline hypertension, we measured basal and DOPA-induced (500 mg orally) changes in blood pressure and pulse rate as well as in three hourly plasma and urine samples. We found that borderline hypertensive patients compared with controls 1) showed a higher baseline urinary excretion of methoxytyramine, a marker of exocytotic dopamine release, with a greater DOPA-induced decrease of systolic blood pressure without reflex tachycardia; 2) had in response to DOPA a blunted plasma DOPA and free dopamine increase but an accentuated plasma dopamine sulfate and urinary DOPAC excretion; and 3) eliminated comparable quantities of dopamine in urine despite a lower rise in the glomerular DOPA load. Furthermore, although DOPA elicited natriuresis in both groups, its effect was greater in borderline hypertensive patients, who lacked the urinary sodium correlation with urinary dopamine excretion seen in control subjects. These data are compatible with increased basal exocytotic dopamine release and accelerated neuronal and renal (extraneuronal) dopamine generation from administered DOPA in borderline hypertension. The DOPA-induced hypernatriuresis exceeding augmented dopamine in borderline hypertensive patients, contrasting with the urinary sodium and dopamine correlation in control subjects, suggests that DOPA induced an additional natriuresis in borderline hypertensive patients by a decrease in renal sympathetic tone because of its central inhibition of sympathetic outflow, which also may account for the absence of reflex tachycardia.

腎臓内で誘導されたＤｏｐａｍｉｎｅとＮａ利尿作用の関係について

This study was undertaken to elucidate the relationship between natriuresis and renally formed dopamine in pentobarbital-anesthetized rats that were loaded with 0.9% NaCl. Infusion of dopamine resulted in marked increases in urinary free dopamine excretion, plasma free dopamine concentration, urine volume and urinary sodium excretion. Infusion of carbidopa markedly decreased urinary free dopamine excretion, but did not affect urine volume and urinary sodium excretion. Infusion of L-dopa markedly increased urinary free dopamine excretion and plasma free dopamine concentration, but did not affect urine volume and urinary sodium excretion. When carbidopa was infused with L-dopa or dopamine, carbidopa significantly inhibited the increase in urinary and plasma free dopamine induced by L-dopa, but did not inhibit the increases in urinary and plasma free dopamine, urinary sodium excretion and urine volume induced by dopamine. These data indicated that there is no correlation between renally formed dopamine and natriuresis, and furthermore suggested that renally formed dopamine is not essential for natriuresis.

CATECHOLAMINE (CA) SECRETION AND RESPONSE TO A STANDING POSITION IN NORMOTENSIVE CHILDREN

Sulfoconjugation is a long time recognized metabolic pathway of CA, but its importance has only recently been appreciated. The degree of conjugation depends on the type of CA: epinephrine (E), norepinephrine (NE) and dopamine (DA). Basal free and conjugated (total) plasma CA levels (radioenzymatic method) were evaluated in 35 normotensive children (aged 6 nonths-5 years). In 16 of them a standing test was performed. Twenty-one normotensive adults were also studied. It was found a positive and significant correlation between total DA and total NE in both, children and adults (r=0.42, p<0.05; r=0.45, p< 0.05). The DA and NE conjugation degree were similar in all groups, meanwhile the E conjugation degree was significantly lower in the youngest children (6 months-5 years group, p<0.01). In response to standing, 10 out of 16 children showed an increase in free NE and DA (p<0.05 and p<0.01), while only an increase in free DA levels was observed in the rest of the groups. These data showed that the sulfooonjugation mechanisms are similar in children as in adults. Moreover, besides the already reported plasma NA response to standing, a significant plasma free DA increase was found.

Cardiorenal Effects of an Orally Active Dopamine Prodrug (TA-870) in Patients with Congestive Heart Failure

The effects of TA-870, a newly synthesized orally active dopamine prodrug, on the cardiorenal functions were investigated in 12 patients with severe chronic congestive heart failure. A single oral dose of TA-870 (1,200 mg) improved left ventricular fractional shortening and mean circumferential velocity on M-mode echocardiography (p less than 0.01 for both). Renal plasma flow and glomerular filtration rate improved with TA-870 (p less than 0.01 and p less than 0.05, respectively); urine volume and sodium excretion increased (p less than 0.01 for both). Blood pressure and heart rate did not change during the 4-h experimental period. Mean plasma free dopamine levels peaked 1 h after dosing. These data suggest that the cardiorenal effects of oral TA-870 are comparable with those of continuous intravenous injections of dopamine. Thus, TA-870 appears to be a useful alternative drug to intravenous dopamine.

A Novel Orally Active Dopamine Prodrug TA-870. I. Renal and Cardiovascular Effects and Plasma Levels of Free Dopamine in Dogs and Rats

Intraduodenal administration of N-(N-acetyl-L-methionyl)-O, O-bis(ethoxycarbonyl)dopamine (TA-870), a newly synthesized dopamine derivative, increased the renal blood flow (RBF) and mesenteric blood flow in anesthetized dogs, while blood pressure and heart rate were less affected. It also increased the glomerular filtration rate, urine volume, and urinary sodium excretion in saline-loaded anesthetized dogs. In conscious dogs, TA-870 and dopamine hydrochloride (DA-HCl) increased RBF in parallel with increases in plasma free dopamine (free-DA) concentration. At an equimolar dose of 71 mumols/kg, p.o., the effect of TA-870 continued for greater than 4 h, while that of DA-HCl lasted for only 2 h: the peak free-DA concentration and maximum increase in RBF were 155 +/- 57 ng/ml and 56 +/- 15%, respectively, for TA-870, and those for DA-HCl were 32 +/- 13 ng/ml and 36 +/- 10%. Similarly, TA-870 showed greater increases in both RBF and plasma free-DA concentration than DA-HCl in anesthetized rats. In contrast to enteral administration, intravenously administered TA-870 exhibited weaker effects than intravenous DA-HCl in anesthetized dogs. In conclusion, TA-870 is an orally effective dopamine prodrug capable of producing higher and more sustained plasma concentrations of dopamine than DA-HCl when administered by the enteral route.

Plasma free dopamine in human hypertension.

The concentration of plasma free dopamine (PDA) is said to be much lower than that of other catecholamines and its physiological significance remains unclear. Our recent studies using a newly developed radioenzymatic method disclosed the fairly distinctive features of PDA in patients with various types of hypertension. PDA was also confirmed as a variable responsive to postural change, dietary sodium loading and dopamine receptor antagonist. The results suggest that PDA could be a sensitive marker to represent the peripheral dopaminergic function, which might play an inherent role as a physiological regulator responsible for the cardiovascular and endocrine system.

Effects of oral and intravenous administrations of dopamine and L-DOPA on plasma levels of two isomers of dopamine sulfate in man

The levels of two isomers of dopamine sulfate, dopamine-3-O-sulfate (DA3S) and dopamine-4-O-sulfate (DA4S), in human plasma were measured by HPLC-fluorometry. The basal plasma levels of DA3S and DA4S in the early morning were 13.8±1.9 and 3.2±0.5 pmoles/ml, respectively (means±S.E.M.). Oral administrations of dopamine (50 mg/body) and 1-dihydroxyphenylalanine (L-DOPA, 250 mg/body) increased the plasma levels of these dopamine sulfates almost 100-fold to 1807±266 and 1674±195 pmoles/ml of DA3S, and 466±83 and 321±76 pmoles/ml of DA4S. Intravenous dopamine infusion (5 μg/kg/min for 30 min) markedly increased the plasma free dopamine concentration, as expected, but increased the levels of DA3S and DA4S only slightly to 110±32 and 25±9 pmoles/ml, respectively. In contrast, intravenous L-DOPA (25 mg/body) resulted in a slight increase of free dopamine followed by marked increases of DA3S and DA4S to 691±219 and 139±40 pmoles/ml, respectively. These data indicate that O-sulfation of dopamine, especially 3-O-sulfation, is the main pathway for metabolism of intravenously and orally administered L-DOPA and orally ingested dopamine. This sulfation is suggested to occur in the gut wall.