Plasma catecholamines and urinary excretion of their main metabolites in three models of portal hypertension

We have measured, by a specific radioenzymoassay, the plasma concentration of dopamine (DA) and norepinephrine (NE) and by gas chromatography the urinary excretion of some catecholamine metabolites (HVA, homovanillic acid, DOPAC, dihydroxyphenyl acetic acid; VMA, vanilmandelic acid, and DOPEG, dihydroxyphenyl glycol) in three groups of rats with portal hypertension: cirrhotic rats (CR), rats with progressive portal hypertension (PPH) and rats with progressive hepatic congestion (PHC). The three groups of rats had portal hypertension. PPH and PHC had also intrahepatic hypertension. CR rats showed an increased urinary excretion of NE and DA metabolites with a normal plasma concentration of these catecholamines, suggesting an increased turnover of NE and DA in this experimental model. PPH animals had a high plasma DA concentration with a decreased urinary excretion of catecholamine metabolites. PHC showed high plasma DA and NE levels with normal or increased urinary excretion of its metabolites. These results suggest that an increased neural activity is present in the early stages of experimental cirrhosis in rats and this alteration does not seem directly related to the portal hypertension but perhaps to the intrahepatic hypertension or to the hepatocellular damage.     

Relationship between urinary excretion of homovanillic acid and norepinephrine metabolites in normal subjects and patients with orthostatic hypotension

Patients with neurogenic orthostatic hypotension due to multiple system atrophy (MSA) or pure autonomic failure (PAF) excrete lower amounts of homovanillic acid (HVA) than do normal subjects. There is a highly significant correlation between the rates of excretion of HVA and norepinephrine metabolites. The regression line relating excretion of the dopamine and norepinephrine metabolites suggests that about one third of dopamine formed in noradrenergic neurons is converted to norepinephrine and the remainder metabolized, mainly to HVA. About one fourth of urinary HVA appears to be derived from a source independent of norepinephrine; this source is probably brain dopaminergic neurons.     

Influence of adjuvant arthritis on main urinary metabolites of prostaglandin F and E in rats

The influence of adjuvant arthritis in rats on main urinary metabolites (MUM) of prostaglandin (PG) F and E type was studied.1) In our model rats, urinary excretion of PGE-MUM increased on day 11 prior to the appearance of secondary lesions, but that of PGF-MUM did not change significantly during the observed period (21 days). The excretion of PGE-MUM was not proportional to the increase in both hind paws volume.2) Indomethacin, which diminished primary lesions but did not suppress secondary lesions, reduced the increase in urinary excretion of PGE-MUM.3) Prednisolone and azathiopurine, which suppressed both primary and secondary lesions, increased the excretion of PGE-MUM over adjuvant control values on days 4 and 8.The facts described above suggest that the increase of endogenous PGE during days 4 to 8 may be important in the suppression of secondary lesions in adjuvant arthritis in rats.     

Effect of furosemide on urinary excretion of prostaglandin E in normal volunteers and pateints with essential hypertension

Urinary excretion of prostaglandin E was measured radioimmunologically in 19 healthy persons ( 15 men and 4 women ) and in 16 patients ( 10 men and 6 women ) with essential hypertension before and after the administration of furosemide. The excretion rates were increased from 26.3±3.0 to 64.5±11.3 ng/hr in the former and from 11.9±2.7 to 26.9±85 ng/hr in the latter. There was a significant difference between them, healthy subjects showing a greater increase than patients with essential hypertension.There was an obvious sexual difference in urinary excretion of prostaglandin. In men, greater increase in the excretion rates was found than in the women. Greater increases were also obtained in healthy men than in hypertensive men and in healthy women than in hypertensive women. The present results suggest that furosemide enhances urinary excretion of prostaglandin E by mechanisms which entails either an increase in prostaglandin synthesis or a decrease in renal metabolism.     

Long term 'marine diet' in Eskimos is not associated with altered urinary excretion of total tetranor prostaglandin metabolites

The total urinary excretion of tetranor prostaglandin metabolites, measured as tetranorprostanedioic acid (TPD), was quantified in traditionally living Greenland Eskimos (E) and compared with that in Caucasian Danes (D). TPD excretion (microgram/24h) was not significantly different between both groups, neither for males (331 +/- 62.4 (E) vs. 331 +/- 25.7 (D), mean +/- SEM, n = 9 and 10) nor for females (190 +/- 31.7 (E) vs. 264 +/- 27.4 (D), n = 11 and 10, P2 greater than 0.05). Since urinary prostaglandin metabolites are thought to reflect the total prostaglandin turnover in vivo, these results suggest that a long-term intake of relatively large amounts of polyunsaturated fatty acids of the (n-3) family does not alter total prostaglandin turnover in vivo. This is in contrast to stimulated prostanoid formation in vitro, and thus suggests a different regulatory role of dietary and tissue fatty acids for 'stimulated' and 'basal' prostaglandin production.     

Interaction between prostanoids and nitric oxide in the control of tubular function in rats with chronic bile duct ligation.

Recent work indicates that both nitric oxide and cyclooxygenase products play an important role in the renal alterations of liver cirrhosis, although the interactions between them have not been completely established. The purpose of this study was to assess the effect of simultaneous blockade of nitric oxide synthase and cyclooxygenase in rats with chronic bile duct ligation and in control, sham-operated rats. Compared with control rats, chronic bile duct ligation rats, 23-25 days after surgery, showed a decreased mean arterial pressure, natriuresis, and kaliuresis, without differences in glomerular filtration rate, and an increased urinary nitrite excretion. Nitric oxide synthesis inhibition by administration of N(G)-nitro-L-arginine methyl ester induced, in control rats, an increase in mean arterial pressure, without significant changes in natriuresis or glomerular filtration rate. In chronic bile duct ligation rats, N(G)-nitro-L-arginine methyl ester induced an increase in mean arterial pressure, natriuresis, and kaliuresis, together with a reduction in urinary nitrite excretion and an increase in prostaglandin E2 excretion. Cyclooxygenase inhibition with indomethacin induced in both experimental groups a marked inhibition in urinary prostaglandin E2 excretion without significant changes in Na+ or K+ excretion, and a significant increase in urinary nitrite excretion in control rats. N(G)-Nitro-L-arginine methyl ester in addition to indomethacin prevented the indomethacin-induced increase in nitrite excretion and dramatically reduced sodium excretion in both experimental groups. Thus, the present study suggests that both nitric oxide and cyclooxygenase products interact in the control of urinary sodium excretion and that each system is activated in the absence of the other one.     

Catecholamine metabolism in children with Asperger’s and Kanner’s syndromes

In a stable state children with Asperger’s and Kanner’s syndromes demonstrate a similar decrease in plasma norepinephrine. In the aggravated state, these changes become more expressed and are characterized by a decrease in plasma tyrosine, norepinephrine, normetanephrine, and by an increase in dopamine and homovanillic acid and a decrease in excretion of norepinephrine and an increase in excretion of homovanillic acid, epinephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG). In the aggravated state children with Kanner’s syndrome were characterized by increased plasma MHPG, decreased excretion of tyrosine and increased expression of normetanephrine. The observed imbalance in dopamine and epinephrine/norepinephrine systems suggests importance of combined analysis of changes in catecholamines and their metabolites as the most informative approach in the study of the effect of autistic disorders.     

Suppression of norepinephrine secretion by dopamine in children with neuroblastoma: evidence for precursor inhibition in catecholamine pathway

To elucidate catecholamine (CA) secretory dynamics in neuroblastoma, urinary excretion of CAs and their metabolites was serially measured in 6 patients aged 3 months to 3 years before and during treatment. After tumor extirpation, increased urinary CAs were promptly normalized; the reduction reflected the amount of CA production from the tumor. Urinary dopamine (DA) showed the most prominent reduction, whereas DA content in the tumor was very small, indicating that the DA produced was immediately released from the tumor and metabolized in extra-tumor tissues. In contrast, patients receiving chemotherapy continued to excrete excess DA and homovanillic acid (HVA), which were increased further at recidivation. One patient showed an inverse correlation between DA and norepinephrine (NE) excretion; a decrease in DA was associated with an increase in NE and plasma DA-beta-hydroxylase (DBH) activity. A similar inverse correlation was also noted between NE and vanillylmandelic acid (VMA) or 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion, while HVA and dihydroxyphenylacetic acid (DOPAC) were positively correlated with DA excretion. Urinary HVA and VMA were lineally correlated but in a patient excreting an enormous amount of DA, urinary VMA was markedly suppressed in terms of HVA excretion. Excessive DA induced an increase in renal water output but did not enhance Na and K excretion. These results indicate that endogenous DA overload in neuroblastoma inhibits NE production by suppressing DBH activity as well as by forming VMA and MHPG. This precursor regulation appears to be the characteristic of the CA metabolic pathway.     

Effect of MPTP-induced parkinsonism in monkeys on the urinary excretion of HVA and MHPG during debrisoquin administration

During debrisoquin administration to three monkeys there were significant reductions in excretion rates of HVA, the major dopamine metabolite, and MHPG, the major norepinephrine metabolite. Excretion rates of HVA were highly correlated to those of MHPG. The regression line relating HVA and MHPG excretion suggests that a portion of HVA (about 25%) is derived from a source independent of norepinephrine metabolites. There was a striking reduction of this portion of HVA excretion after MPTP-induced destruction of dopaminergic nigrostriatal neurons. These results support the view that the rate of HVA formation in brain dopaminergic neurons can be estimated from the relationship of urinary excretion rates of HVA and MHPG before and during debrisoquin treatment.     

Urinary prostaglandin E2 excretion in renal allotransplantation in man

The urinary prostaglandin E₂ excretion was measured daily for 28 days in 15 patients (10 men and 5 women) after renal allotransplantation. Patients with acute oliguric renal failure immediately after the transplantation showed high urinary PGE₂ concentrations, but no or minimal increase in the total excretion rates. The median PGE₂ excretion was 211 μg/24 h after establishment of stable renal function, but with great individual variations. Rejection crises were characterized by a two-fold increase in PGE₂ excretion, with a subsequent fall induced by the steroid treatment. The PGE₂ excretion correlated better with urinary sodium excretion than diuresis.The pathophysiological role of the renal prostaglandin ssynthesis remains incompletely defined. The prostaglandin E₂ (PGE₂) appears to act as a modulator of the renal salt and water excretion (1,2) and prostaglandins are important mediators of the immunresponses (3,4). The eraly renal allograft rejection is an event characterized by salt and water retention together with decreasing renal function (5). Antibodies against renal tissue as well as cytotoxic leukocytes (“killer cells”) are active in the process (6,7) and many hormonal systems are involved, among them renin and vasopressin (8). Both hormones are known to stimulate the synthesis of prostaglandin in the kidneys and interact with its effect (9,10,11). The present material was therefore designed to study the urinary excretion of PGE₂ in the kidney allografts before and during rejection crises.     

Effect of norepinephrine and vasopressin on renal kallikrein excretion in rats

The purpose of this study was to investigate the effect of norepinephrine and vasopressin on urinary kallikrein excretion in the rat. Two studies were undertaken: (a) acute experiments in which the rats were infused with 30% dextrose in water with the addition of norepinephrine or vasopressin, (b) chronic experiments in which the drugs were infused during seven days through an osmotic minipump. In acute experiments, urinary kallikrein excretion increased without modification in urinary flow and glomerular filtration rate. In chronic experiments, urinary kallikrein excretion was not modified in norepinephrine-treated rats and decreased in vasopressin-infused animals. This decrease followed the modifications of the urine flow. In chronic experiments the dextrose infusion increased urinary kallikrein excretion. In all the groups studied a positive correlation between urine flow and urinary kallikrein excretion was observed. It is concluded that norepinephrine and vasopressin are important stimulators of the urinary kallikrein excretion only in those circumstances where it is necessary to eliminate an excess of water.     

Prostanoid biosynthesis in patients with cystic fibrosis

The urinary excretion rate (ng/h/1.73 m²) of prostanoids was determined with a capillary gas-liquid chromatographic mass spectrometric method in 19 patients with cystic fibrosis (CF) aged 1–29 years. Patients with CF showed an increased excretion of prostaglandin E₂ metabolites (PGE-M) and thromboxane B₂ and its metabolites at all ages. An imbalance in the excretion pattern of thromboxane B₂ metabolites also suggested a relative impairment of β-oxidation. There was no increased excretion of dinor-6-keto-PGF_1α, indicating normal prostacyclin biosynthesis. No correlation was found to genotype, clinical score, lung function or bacterial colonization but a significant negative relation was found between the main prostanoids in the urine and serum phospholipid levels of essential fatty acids. The results show that, contrary to the generally accepted decrease of prostanoid excretion in essential fatty acid deficiency, patients with CF increase their production parallel to the development of the deficiency. Since prostanoid synthesis is rate limited by arachidonic acid release, our data support a previously presented hypothesis about a pathological regulation of the release of arachidonic acid in CF.     

Long term ‘marine diet’ in Eskimos is not associated with altered urinary excretion of total tetranor prostaglandin metabolites

The total urinary excretion of tetranor prostaglandin metabolites, measured as tetranorprostanedioic acid (TPD), was quantified in traditionally living Greenland Eskimos (E) and compared with that in Caucasian Danes (D). TPD excretion (μg/24h) was not significantly different between both groups, neither for males (331 ± 62.4 (E) vs. 331 ± 25.7 (D), mean ± SEM, n = 9 and 10) nor for females (190 ± 31.7 (E) vs. 264 ± 27.4 (D), n = 11 and 10, P₂ > 0.05). Since urinary prostaglandin metabolites are thought to reflect the total prostaglandin turnover in vivo, these results suggest that a long-term intake of relatively large amounts of polyunsaturated fatty acids of the (n-3) family does not alter total prostaglandin turnover in vivo. This is in contrast to stimulated prostanoid formation in vitro, and thus suggests a different regulatory role of dietary and tissue fatty acids for ‘stimulated’ and ‘basal’ prostaglandin production.     

The effect of prostaglandin synthetase inhibitors on renal function: studies in normal rats during sodium or water diuresis and in rats with chronic renal insufficiency

The effect of acute infusion of the prostaglandin synthetase inhibitors - meclofenamate or indomethacin - was examined in awake rats. Studies were performed in normal rats undergoing either sodium or water diuresis and in salt-replete rats with chronic renal insufficiency. Prostaglandin synthetase inhibitors had no effect on renal plasma flow, glomerular filtration rate or fractional excretion of sodium in any of the groups. Absolute urinary excretion rates for sodium and potassium decreased only in the normal, salt-replete rats. In contrast, prostaglandin synthetase inhibitors consistently decreased urinary flow and osmolar clearance under all experimental conditions studied. In the normal, salt-replete rats the fall in urine flow was preceded by an increase in urinary excretion of cyclic AMP. These results show that inhibitors of prostaglandin synthesis enhance the ability of the kidney to reabsorb water. This effect may be secondary to increased cyclic AMP generation and to increased urea recirculation resulting in higher urea accumulation in the renal medulla.     

Atrial natriuretic factor inhibits the sympathetic nervous activity in one-kidney, one-clip hypertension in the rat

The one-kidney, one-clip model of rat hypertension was found to have an increased natriuresis following chronic infusion of atrial natriuretic factor (ANF). We have now found that this natriuretic effect of ANF is associated with a suppression of the initially elevated urinary excretion of norepinephrine and epinephrine and increase of the excretion of the main dopamine metabolite-dihydroxyphenylacetic acid as well as of the urinary dopamine to norepinephrine ratio. These data are compatible with the hypothesis that ANF suppresses the increased sympathetic activity in this model of hypertension and this action combined with opposite changes of dopamine may contribute to the natriuretic effect of ANF.     

The effect of prostaglandin synthetase inhibitors on renal function: Studies in normal rats during sodium or water diuresis and in rats with chronic renal insufficiency

The effect of acute infusion of the prostaglandin synthetase inhibitors — meclofenamate or indomethacin — was examined in awake rats. Studies were performed in normal rats undergoing either sodium or water diuresis and in salt-replete rats with chronic renal insufficiency. Prostaglandin synthetase inhibitors had no effect on renal plasma flow, glomerular filtration rate or fractional excretion of sodium in any of the groups. Absolute urinary excretion rates for sodium and potassium decreased only in the normal, salt-replete rats. In contrast, prostaglandin synthetase inhibitors consistently decreased urinary flow and osmolar clearance under all experimental conditions studied. In the normal, salt-replete rats the fall in urine flow was preceded by an increase in urinary excretion of cyclic AMP. These results show that inhibitors of prostaglandin synthesis enhance the ability of the kidney to reabsorb water. This effect may be secondary to increased cyclic AMP generation and to increased urea recirculation resulting in higher urea accumulation in the renal medulla.     

Effect of metabolic control on urinary excretion and plasma levels of catecholamines in diabetics.

Urinary excretion and plasma levels of catecholamines were determined in 20 normal and 39 diabetic subjects to evaluate the sympathetic activity. Diabetic patients were divided into 4 groups according to the metabolic control. Sympathetic activity showed no differences between normal and subjects with chemical diabetes (group I, n = 5). In insulin-treated diabetics in good metabolic control (group II, n = 11) only urinary excretion of free norepinephrine was significantly higher than normals (p less than .05). In insulin-treated diabetics in poor metabolic control (group III, n = 16) urinary excretion and plasma levels of norepinephrine showed a marked increase over groups I and II (p less than .001). In insulin-treated diabetics with ketosis (group IV, n = 7) urinary excretion and plasma levels of both norepinephrine and epinephrine showed the highest values (p less than .001 and less than .1). Finally, in groups III and IV, after achieving improved metabolic control, a significant decrease of urinary excretion and plasma levels of catecholamines was observed. The results confirm that there is an increased rate of catecholamine release in poorly controlled diabeties and suggest a close correlation between sympathetic activity and metabolic derangement in diabetes.     

Influence of age on orthostatic changes in plasma renin activity and urinary catecholamines in man.

The authors studied plasma renin activity (PRA), urinary epinephrine, norepinephrine and dopamine excretion and their mutual relationships in 54 healthy subjects under basal (recumbent) conditions and age-related orthostatic changes in these parameters. The test subjects were divided into six 10-years groups, according to their year of birth (1901-1910 to 1951-1960). In the oldest groups (1901-1910 and 1911-1920), both basal PRA values and norephrine and epinephrine excretion and their postural increase were smaller than in younger subjects. Conversely, urinary dopamine excretion and the dopamine/norepinephrine and epinephrine ratio rose with advancing age. There were no significant differences between the plasma sodium and potassium concentrations in the various groups. Urinary aldosterone excretion was slightly higher in the oldest group than in the others, but was still within the control value limits. The intravenous administration of Inderal reduced both resting PRA values and the orthostatic increase in the youngest age groups, so that their PRA approached the values in older subjects. Higher norepinephrine and epinephrine excretion and the lower dopamine/norepinephrine and epinephrine in young subjects may play a role in their higher PRA, especially in the orthostatic reaction. Diminution of sympathetic activity, with lower norepinephrine and epinephrine excretion and relatively high dopamine excretion, may have a direct bearing on the lower PRA values in older subjects. The diminished capacity of older subjects for catecholamine mobilization and raised renin secretion during an orthostatis stress may be related to the higher incidence of orthostatic forms of hypotension in old age.     

Renal synthesis of prostacyclin and thromboxane in healthy women: differential effects of a short-term saline loading

It is accepted that the urinary excretions of the stable metabolites of prostaglandin (PG)I2 and thromboxane(Tx) A2, 6-keto-PGF1alpha (6KPGF) and TxB2 respectively, provide an accurate estimate of both basal and stimulated renal synthesis of their precursors. The excretory profile of these metabolites has been evaluated in healthy women submitted to a short-term expansion in extracellular fluid volume. Salt retention (SR group, n=6) was induced by physiological saline (0.9% NaCl) i.v. infusions (2 L per day) over a period of 2 days. On the third day the increase in body weight was 0.92 +/- 0.27 kg (P<0.05). The results of the study have been compared to those previously obtained in normal balance of sodium and potassium (N group, n=20) and in induced salt depletion (SD group, n=14). A common study protocol was used. Basal values of plasma renin activity (PRA) and urinary aldosterone excretion were determined. Renal functional exploration [clearance (cl.) method] was performed during hypotonic polyuria (induced by oral water load) and subsequent moderate antidiuresis (induced by low-dose infusion of an antidiuretic hormone analogue). Urinary 6KPGF and TxB2 concentrations were estimated by RIA method and their urinary excretions were determined at both high and low urinary flow rates. The linear regressions of the urinary metabolite excretions vs. urinary flow rate were estimated by using the data obtained in both hypotonic polyuria and antidiuresis. Salt retention (SR vs. N group) was effective in decreasing the basal values of plasma renin activity and urinary aldosterone excretion. Moreover, during hypotonic polyuria it was effective in increasing the absolute and fractional excretions of sodium and chloride, in the absence of significant variations in mean arterial pressure and creatinine cl. Regarding urinary prostanoid excretions the following results were obtained. 1. Comparative data for hypotonic polyuria. In the SR vs. N group, the urinary excretion of 6KPGF was significantly higher, whereas that of TxB2 was not significantly different. In the SR vs. SD group, the urinary excretion of 6KPGF was not significantly different, whereas that of TxB2 was significantly lower. 2. Comparative data for the regression lines of the urinary prostanoid excretions vs. diuresis. In the SR vs. N group, the regression line slope for 6KPGF excretion was significantly higher, whereas that for TxB2 excretion was not significantly different. In the SR vs. SD group, the regression line slope for 6KPGF excretion was not significantly different, whereas that for TxB2 excretion was significantly lower. 3. Correlative data in the SR group during hypotonic polyuria. The plasma chloride concentration was positively correlated with urinary flow rate, absolute and fractional chloride excretions, and 6KPGF excretion but not with TxB2 excretion. In conclusion, functionally effective salt retention in healthy women induces a selective stimulation of renal synthesis of prostacyclin, unlike salt depletion, in which the synthesis of both PGI2 and TxA2 is upregulated.     

The effect of suppression of prostaglandin synthesis on renal function in rats with intact and reduced renal mass

The present study was undertaken to assess the role of prostaglandin system in the compensatory response to reduced nephron population, respective to renal function and electrolyte excretion. Intact and nephrectomized rats were divided in 4 groups: 1) rats pretreated with indomethacin, 2) rats pretreated with the vehicle of indomethacin, 3) rats pretreated with sulindac, and 4) rats pretreated with the vehicle of sulindac.In normal rats, indomethacin administration resulted in a mild decrease in creatinine clearance and a significant reduction of the urinary Na excretion. In the rats with reduced renal mass treated with indomethacin, the creatinine clearance did not differ from that in the control group. The 24 h urinary sodium excretion and the fractional excretion of sodium, however, were significantly lower in the indomethacin treated animals than in the control rats. No change in the creatinine clearance or in the sodium excretion was observed in all groups pretreated with sulindac.The urinary PGE₂ and thromboxane excretion was significantly lower in the indomethacin treated intact rats and the rats with reduced renal mass. Sulindac induced a slight decrease in urinary excretion of PGE₂ in intact rats. No significant change in urinary excretion of PGE₂ or thromboxane was seen after sulindac in the rats with reduced renal mass.The antinatriuretic effect of indomethacin was dissociated from changes in urine flow in all groups of animals, suggesting that the increase in Na reabsorption tool place in a water impermeable segment of nephron.These results suggest that the compensatory increase in urinary Na excretion per nephron in rats with reduced nephron population at least partly depends on an intact prostaglandin synthesis.