EFFECT OF ACTH ADMINISTRATION ON URINARY KALLIKREIN EXCRETION IN MAN

1. The effect of ACTH administration on urinary kallikrein excretion and its relationship to changes in plasma and urine electrolytes, renin concentration and steroids was examined in normotensive and mildly hypertensive subjects. 2. ACTH administration produced hypokalaemia, initial urinary sodium retention, a fall in active plasma renin concentration, a transient rise in plasma aldosterone concentration and sustained rises in plasma deoxycorticosterone concentration and urinary kallikrein activity. 3. Changes in patients with mild hypertension were similar in pattern to normotensives, but urinary kallikrein concentrations were lower. 4. The effects of ACTH on urinary kallikrein excretion appeared to be independent of aldosterone and correlated most closely with deoxycorticosterone concentrations.     

The influence of tetracosactide and adrenal steroids on renal kallikrein activity and urinary kallikrein excretion in rats

The effect of adrenal steroids (mineralo- and glucocorticoids) as well as that of the adrenocorticotrophic peptide tetracosactide (beta 1-24 corticotropin) on the renal kallikrein activity and on the urinary kallikrein excretion of rats was investigated. After the animals had been adapted to metabolic cages, they were injected with deoxycorticosterone acetate (15 mg/kg day), corticosterone (40 mg/kg day), both steroids combined or the vehicle (sesame oil). Additional groups of rats received tetracosactide (0.05, 0.1 or 0.2 mg/day) or the vehicle (100 microliter of 38 X 10(-3) M ZnCl2). After four days of treatment the urinary kallikrein excretion was higher in deoxycorticosterone-treated rats than in their controls. This increase was prevented when corticosterone was administered simultaneously. The renal kallikrein activity of corticosterone as well as that of deoxycorticosterone plus corticosterone-treated rats was subnormal. A dose-related reduction of both the renal kallikrein activity and the urinary kallikrein excretion was observed 2 days after starting the tetracosactide administration. It may be concluded that a stimulation of the endogenous release of glucocorticoids in the rat reduces the renal kallikrein activity and that glucocorticoids can prevent the stimulating effect of mineralocorticoids.     

Changes in blood pressure,urinary kallikrein,and urinary prostaglandin E2 in rats with streptozotocin-induced diabetes

Summary To reveal the mechanism of hypertension in diabetes mellitus, changes in blood pressure were measured in streptozotocin (STZ)-induced diabetes mellitus in male Wistar rats. Development of diabetes mellitus and elevation of blood pressure were observed in rats which received 60 mg/kg STZ, but not in rats which received 20 mg/kg STZ. In the rats which developed diabetes mellitus after STZ, the plasma renin activity, renal renin content, plasma aldosterone, and urinary kallikrein activity were all significantly reduced. The urinary excretion of prostaglandin E₂ (PGE₂) was significantly increased at 1 week after STZ in diabetic rats, but it gradually returned to control values and showed a tendency to decrease at 4 weeks after the treatment compared to the rats of the control groups. The pressor responsiveness to norepinephrine in the conscious unrestrained state in the STZ-induced diabetic rats was not remarkably changed compared to that of control rats. These results indicate that blood pressure gradually increases with the progress of diabetes. It is suggested that the changes in urinary excretion of PGE₂ and urinary kallikrein activity may be related to the regulation of blood pressure in STZ-induced diabetic rats. On the other hand, it is considered unlikely that the reninangiotensin system and vascular responsiveness play an important role in the occurrence of hypertension in diabetes mellitus.     

Antihypertensive effects and pharmacokinetics of single and consecutive administration of doxazosin in patients with mild to moderate essential hypertension

A single dose of doxazosin, a long-acting postsynaptic alpha 1-adrenoceptor antagonist, was administered to seven patients with essential hypertension. Following administration of a single dose, all the patients except one who was forced to be discharged from the hospital for work, continuously received doxazosin once daily (o.d.) for evaluation of its consecutive dosing effect. The antihypertensive effect, pharmacokinetics, and effects on the plasma renin activity (PRA) of doxazosin were investigated. Following a 2-mg single dose of doxazosin, the systolic blood pressure (SBP) decreased significantly up to 12 h, whereas consecutive dosing produced a significant decrease in the SBP up to 24 h and a significant decrease in the mean blood pressure up to 24 h as compared with placebo. The pharmacokinetic parameters of doxazosin in both single- and consecutive-dose study were 18.9 and 25.8 ng/ml in Cmax, 11.1 and 12.9 h in half life (t1/2), and 182.0 and 273.0 ng h/ml in area under the curve (AUC)24(0), respectively. No significant changes were observed in PRA and plasma concentration of catecholamines. Neither were there any observable changes in endogenous creatinine clearance and in the urinary excretion rates of Na, K, and Cl. Doxazosin was well tolerated by all patients, and no untoward effects were observed. Doxazosin effectively reduces blood pressure and, because of its long t1/2 and minimal effects on PRA catecholamines, and electrolytes, seems to be a useful antihypertensive agent in patients with essential hypertension.     

Effects of acute and long-term beta-adrenoceptor blockade with propranolol on haemodynamics,plasma catecholamines and renin in essential hypertension

Summary The effect of an acute intravenous and repeated oral doses of propranolol on haemodynamics, plasma and urinary catecholamines and plasma renin activity was studied in patients with essential hypertension. Intravenous injection of propranolol 5 mg produced a fall in cardiac output but had no consistent effect on blood pressure. Treatment with oral propranolol for 24 weeks lowered cardiac output and blood pressure; total peripheral resistance did not differ from the pretreatment values. Neither acute intravenous nor chronic oral administration of the beta-blocker affected the resting plasma levels of noradrenaline and adrenaline. Long-term treatment with propranolol reduced urinary excretion of vanilmandelic acid without affecting urinary catecholamine excretion. Acute intravenous injection of propranolol decreased plasma renin activity less than did chronic oral treatment with the drug. The observed time course of plasma renin activity was compatible with the view that suppression of this enzyme contributed to the antihypertensive effect of propranolol.     

The effect of 8 weeks treatment with the calcium antagonist felodipine on blood pressure, heart rate, working capacity, plasma renin activity, plasma angiotensin II, urinary catecholamines and aldosterone in patients with essential hypertension.

The effect of 8 weeks treatment with the calcium antagonist felodipine--a new long-acting dihydropyridine derivative--in a dose of 10 mg twice daily was studied in 10 male patients with essential hypertension, WHO grade I-II, aged 25-62 years. Diastolic blood pressure was reduced in supine and upright position. Systolic blood pressure was reduced only in the upright position. Heart rate was unchanged in the supine and decreased in the upright position. During dynamic exercise blood pressure was reduced. The maximal working capacity decreased, whereas the maximal heart rate attained was unchanged. Twenty-four hour urinary noradrenaline excretion, plasma renin activity and 24 h urinary aldosterone excretion were increased. Plasma angiotensin II and 24 h urinary adrenaline excretion were unchanged. In conclusion, felodipine is an effective long-acting blood pressure lowering drug with minor side effects. After 8 weeks on felodipine treatment heart rate was not increased, although the activity of the sympathetic nervous system and the renin-aldosterone system seemed enhanced.     

Impaired renal kallikrein activity and elevated blood pressure normalized by orally applied kallikrein in essential hypertension

Urinary kallikrein excretion was significantly lower in patients with essential hypertension (0.48 +/- 0.05 EU/24 h) than in normotensive controls (1.26 +/- 0.14 EU/24 h). Oral administration of hog pancreatic kallikrein normalized decreased urinary kallikrein and reduced arterial pressure. The treatment-induced rise in urinary kallikrein was due to an enhanced release of endogenous enzyme, as was determined by radioimmunoassay. It is proposed that in the hypertensive patients the low urinary kallikrein excretion reflects a defect in renal kallikrein formation which is normalized by oral kallikrein. The hypotensive action of oral kallikrein, as well as its stimulating effects on renal kallikrein release, suggest that the kallikrein-kinin system is involved in blood pressure regulation and that impaired renal kallikrein activity may be a factor in the maintenance of essential hypertension.     

A comparison of the acute effects of cicletanine and bendrofluazide on urinary electrolytes and plasma potassium in essential hypertension

The acute effects on urinary electrolyte excretion and plasma potassium were compared of the anti-hypertensive dihydrofuropyridine cicletanine with the thiazide bendrofluazide in 6 patients with uncomplicated essential hypertension. Cicletanine 50 mg or 100 mg and bendrofluazide 5 mg caused no acute decrease in blood pressure compared to placebo for 24 h after treatment. In the 24 h after a single dose of cicletanine 50 mg there was no increase in urinary sodium, potassium or volume compared to placebo. After a single dose of cicletanine 100 mg there was a significant increase in 2 h urinary sodium excretion compared to cicletanine 50 mg and in the first 6 h a significant increase in urinary potassium compared to placebo. Urine volume did not change significantly. After bendrofluazide 5 mg urinary sodium excretion increased significantly in the first 6 h as well as in the subsequent 18 h compared to placebo and both cicletanine 50 mg and 100 mg. Urinary potassium excretion was also significantly increased in the first 6 h after bendrofluazide compared to placebo, and urine volume significantly increased from 6 to 24 h after bendrofluazide 5 mg compared to placebo and cicletanine 100 mg. Plasma potassium was significantly reduced and plasma renin activity significantly increased 24 h after bendrofluazide 5 mg but these measurements were not significantly different from placebo after cicletanine 50 or 100 mg. These results suggest that cicletanine 100 mg has milder acute natriuretic effects than the thiazide bendrofluazide 5 mg. In contrast cicletanine 50 mg is associated with no major acute renal effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on mechanisms of antinephritic action of SA-446 an angiotensin I converting enzyme inhibitor (1). A comparison with actions of spironolactone, kallidinogenase and saralasin

The present study was made to clarify the mechanisms of the antinephritic action of SA-446, an angiotensin I converting enzyme inhibitor, on crescentic-type anti-GBM nephritis in rats as compared to the actions of spironolactone (an antialdosterone agent), kallidinogenase (a kallikrein agent) and saralasin (an angiotensin II antagonist). SA-446 (25 mg/kg/day, p.o.) had a tendency to reduce the urinary protein excretion and plasma urea nitrogen content. In addition, this drug remarkably inhibited not only glomerular histopathological changes (i.e., crescent formation, the adhesion of capillary walls to Bowman's capsule and fibrinoid necrosis) but also the elevation of blood pressure. Spironolactone (25 mg/kg/day, p.o.) and kallidinogenase (25 KU/day, i.m.) also showed beneficial effects on glomerular histopathological changes and hypertension, although both drugs were not as effective as SA-446. However, saralasin (72 micrograms/day, s.c.) caused a marked aggravating action on this nephritis. This nephritic model showed a marked low activity of plasma renin all through the 40 day experimental period. In this model, the urinary aldosterone excretion was increased, in spite of the decrease in plasma renin activity. SA-446 and kallidinogenase significantly inhibited the decrease in plasma renin activity and the increase in urinary aldosterone excretion. Spironolactone inhibited only the increase in the aldosterone excretion. However, saralasin decreased the plasma renin activity under the control level and strongly increased the urinary aldosterone excretion (about 1.8 times the control level on the 20th day). These results suggest that the antinephritic effect of SA-446 may be related to the antihypertensive action and the increase in renal blood flow through activation of the kallikrein-kinin and prostaglandins systems.     

Renal kallikrein excretion as a distal nephrotoxicity marker during cadmium exposure in rats

Cadmium exposure is known to induce hypertension, but development of hypertension is not universal in exposed animals. However, the cellular uptake of cadmium could also exert renal cytotoxic effects which have been, until now, essentially only studied at the proximal tubule level. Kallikrein is an enzyme synthetized in renal cortex and excreted in the urine in the distal tubule. Therefore, to evaluate the distal renal effect of cadmium, we studied the daily urinary kallikrein excretion (UKE) in conscious unrestrained female Brown Norway rats during long-term chronic exposure to 2 dosages of cadmium given subcutaneously 3 times a week, a low dose (LD): 0.25 mg/kg and a high dose (HD): 1 mg/kg. Neither dose of cadmium was able to induce significant hypertension in the treated animals. HD administration for 24 weeks resulted in a decreased UKE associated with an increase in plasma renin activity and sodium and potassium excretions. LD administration had no significant effect on UKE. Twenty weeks after stopping cadmium administration, a persistent reduction in UKE was still observed; furthermore, the group which had been previously administered a LD of cadmium, now also exhibited a reduced UKE. During this re-examination period in both groups, the UKE reductions were associated with normal systolic blood pressure, glycosuria, natriuresis. Our data show that cadmium administration can influence UKE, plasma renin activity, plasma aldosterone concentration and electrolyte excretion without inducing any variation of blood pressure. This may reflect a nephrotoxic, non-hypertensive effect. Since this effect persisted after stopping cadmium administration, it may indicate a prolonged irreversible nephrotoxic effect at the distal nephron level. Thus, UKE may be a useful non-invasive index to evaluate distal nephrotoxicity.     

Dissociation of biochemical and hypotensive effects of debrisoquine in hypertensive patients

Summary The 24 h urinary excretion of adrenaline, noradrenaline, metadrenaline, normetadrenaline and vanillylmandelic acid, plasma renin activity and plasma and urinary debrisoquine were measured before and during chronic treatment with oral debrisoquine in 14 in-patients with essential hypertension. There was a significant fall (mean ±SD) in the 24 h urinary excretion of vanillylmandelic acid (15.3±2.8 to 6.7±1.9 μmol) noradrenaline (199.0±105.8 to 125.2±43.3 nmol) and plasma renin activity (0.71±0.47 to 0.40±0.20 pmol Angio I ml⁻¹ h⁻¹) while the urinary normetadrenaline/noradrenaline ratio increased (10.4±6.1 to 17.1±5.1). No significant change was seen in the output of adrenaline or of O-methylated metabolites. Debrisoquine produces extensive noncompetitive inhibition of platelet monoamine oxidase in vivo at low therapeutic plasma concentrations. These changes support the view that treatment with debrisoquine produces intraneuronal inhibition of monoamine oxidase and post-ganglionic blockage. There was a significant correlation between the change in standing diastolic blood pressure and the daily dose (r_s=−0.52), pre-dose plasma concentration (r_s=−0.85) and mean daily urinary recovery (r_s=−0.80), of debrisoquine. The full extent of the biochemical changes were seen at low dose and low plasma concentration and were not directly correlated with the fall in standing or supine blood pressure.     

Long term treatment of moderate hypertension with the beta1-receptor blocking agent metoprolol

Summary The effect of submaximal work and insulin-induced hypoglycaemia on plasma catecholamines and renin activity was studied in nine males with moderate hypertension before treatment, after one month on placebo and after three months of metoprolol treatment. The maintenance dose used was 50–150 mg three times daily. The placebo caused no change in blood glucose, blood pressure, pulse rate, plasma catecholamines and renin activity, neither under basal conditions nor following submaximal work or insulin-induced hypoglycaemia. Metoprolol significantly reduced blood pressure, pulse rate and plasma renin activity under basal conditions whereas plasma catecholamines were unchanged. During metoprolol treatment the increase in blood pressure and pulse rate in response to submaximal work was reduced, but the plasma noradrenaline response was enhanced and plasma adrenaline unaltered. The decrease in pulse rate after work was positively correlated with the mean plasma metoprolol concentration. The fall in blood glucose after insulin 0.1 IU/kg body weight i. v. and its return to normal was unaffected by metoprolol. Before metoprolol, hypoglycaemia was followed by a pronounced increase in plasma adrenaline, with a maximum after 45 min. During metoprolol the adrenaline increase was even more pronounced. Hypoglycaemia was also followed by a two-fold increase in plasma noradrenaline, both before and during treatment with metoprolol. Plasma renin activity during submaximal work and insulin-induced hypoglycaemia varied as much before as during treatment with metoprolol.     

Mechanism of antihypertensive effect of atenolol in patients with borderline hypertension during short-term treatment. A comprehensive study

Short-term treatment with 1-(p-carbamoyl-methylphenoxy)-3-isopropylamino)-2-propanol (atenolol, Tenormin) (100 mg/d for 5 days) was conducted in 12 patients with labile essential hypertension. Before and at the end of the treatment, cardiohemodynamics, renal hemodynamic and excretory function, and renal pressor (renin-angiotensin-aldosterone) and depressor (renal kallikrein-kinin and prostaglandin) systems were examined. Atenolol decreased cardiac output (CO) without affecting total peripheral resistance. Atenolol also decreased plasma renin activity, plasma aldosterone concentration, urinary excretion of kallikrein-kinin, and urinary excretion of potassium whereas it increased plasma potassium concentration. Urinary excretion of prostaglandin E and sodium was not affected by atenolol. Glomerular filtration rate decreased, but renal plasma flow remained unchanged during the treatment by atenolol. A significant positive correlation was found between the changes in CO and in systolic blood pressure (SBP) while negative correlation was observed between the changes in total peripheral resistance and in SBP. A significant positive correlation was also noted between urinary kallikrein excretion and renal plasma flow. The change in urinary kinin excretion was conversely correlated to that in SBP. This study demonstrates that the hypotensive mechanism of atenolol is very complex. Decrease in CO and inhibition of renin-angiotensin-aldosterone system may mainly be responsible for hypotension. It is likely that potassium retaining action of atenolol partly contributes to its hypotensive action. It is also hypothetized that renal kallikrein-kinin system may play a role in modulating the hypotensive action of atenolol.     

Investigations on the Antihypertensive Activity of Timolol and Bendroflumethiazide and the Combination in Dogs and Rats

Abstract The effects of timolol and bendroflumethiazide, either alone or combined in a fixed ratio of 4:1, on blood pressure, plasma renin activity, and plasma potassium concentration, have been investigated in normotensive and renal hypertensive dogs, and in normotensive and spontaneously hypertensive rats. In addition, the urinary kallikrein excretion has been measured in normotensive and hypertensive rats. When administered to hypertensive dogs and rats, the drug combination significantly reduced the blood pressure. Marginal reductions were observed in normotensive animals or after the administration of the single drugs. The thiazide–induced hypokalemia and hyperreninaemia were almost completely antagonised by the concomitant administration of timolol in both animal species. A highly significant elevation of urinary kallikrein excretion was also observed in rats treated with the drug combination. A less marked increase of kallikrein excretion was noted in the bendroflumethiazide treated rats. The possibility that renal haemodynamic changes, in addition to the inhibition of the increase in plasma renin, play a role in the observed antihypertensive effects is discussed.     

Effect of benazepril monotherapy in subjects with hypertension associated with renal dysfunction

Nine hypertensive patients with mild to moderate renal dysfunction were entered into a protocol to assess the blood pressure, humoral and renal effects of the angiotensin converting enzyme inhibitor, Benazepril (CGS14824A, 2 to 20 mg twice daily) in patients with hypertension and moderate renal insufficiency (mean creatinine clearance 56 ml/min/1.73 m2). Specifically monitored, prior to and following 12 weeks of Benazepril monotherapy, were plasma renin activity and plasma aldosterone, the clearances of creatinine, Tc99m-diethylenetriaminepentaacetic acid (TC99m-DTPA) and para-amino-hippurate, and the 24-hour urinary excretion of protein. Blood pressure was well controlled. Plasma renin activity was stimulated, and plasma aldosterone was suppressed. Mean serum potassium increased from 3.9 to 4.2 mEq/L. Benazepril monotherapy had no adverse renal hemodynamic effect. Benazepril appears to be an effective antihypertensive agent in hypertensive patients with moderately impaired renal function.     

The effects of beta-adrenoceptor blockade on renin, angiotensin, aldosterone and catecholamines at rest and during exercise.

1 beta-adrenoceptor blockade with metoprolol provoked, both at rest and during exercise, a decrease of 'active' renin and angiotensin II together with an increase of 'inactive' renin and unchanged 'total' renin. The significant exercise-provoked increases in angiotensin II, plasma renin activity and 'active', 'inactive' and 'total' renin when on placebo, were reduced by metoprolol. 2 No significant change in serum sodium and potassium and in plasma aldosterone was found during beta-adrenoceptor blockade at rest. During exercise plasma aldosterone dropped significantly without any change in serum sodium or potassium. 3 Plasma noradrenaline increased significantly at rest on metoprolol. The increase in plasma noradrenaline and adrenaline during exercise was similar on placebo and on metoprolol.     

Plasma atrial natriuretic peptide and the renin-aldosterone system during long-term administration of the diuretic xipamide in man

Summary We have studied the effect of xipamide on plasma α-atrial natriuretic peptide and the reninaldosterone-kallikrein system in twelve healthy men, using a double-blind cross-over design. After a run-in period on placebo for 1 week the subjects were treated with either placebo (n=6) or xipamide 20 mg once daily (n=6) for 16 weeks and were then switched to the alternative medication for another 16 weeks. The plasma concentration of α-atrial natriuretic peptide fell after 1 week of xipamide administration and increased during prolonged xipamide administration but remained suppressed. The changes in plasma α-ANP observed after 1 week of xipamide were negatively correlated with the changes in haematocrit and haemoglobin. Plasma renin activity (PRA), aldosterone concentration (PAC), and urinary excretion of aldosterone and kallikrein increased after 1 week of xipamide administration, levelled off during the second and fourth weeks, but remained elevated during further prolonged xipamide administration for 16 weeks. The xipamide-induced changes in PRA and PAC were positively correlated with the changes in the haematocrit and haemoglobin. Our data suggest that the changes in plasma renin, aldosterone, and α-atrial natriuretic peptide during xipamide administration may be related to diuretic-induced volume contraction.     

Effects of beta 1-adrenoceptor agonism on plasma renin activity in normal men.

The contribution of beta 1-adrenoceptors to the regulation of plasma renin activity was investigated in nine healthy sodium-replete volunteers: seven subjects received a cumulative intravenous dose of 75 micrograms/kg prenalterol, a predominant beta 1-adrenoceptor agonist, and two subjects only vehiculum. In the seven actively treated subjects beta 1-adrenoceptor agonism increased (P less than 0.001) systolic intra-arterial pressure by an average of 16 +/- 4 mm Hg and heart rate by 19 +/- 3 beats min. These increases were significantly (P less than 0.04) different from the changes observed in the two control subjects (+ 3 +/- 4 mm Hg and -1 +/- 4 beats/min, respectively). Plasma renin activity, however, tended to decrease in both the actively (-38%) and saline (-28%) treated subjects. Predominant beta 1-adrenoceptor agonism, powerful enough to increase systolic pressure and heart rate does not increase plasma renin activity in supine sodium-replete normal man.     

The influence of ibuprofen,diclofenac and sulindac on the blood pressure lowering effect of hydrochlorothiazide

Summary In an open triple crossover study in 8 patients with essential hypertension, the possibility has been investigated of whether the blood pressure lowering effect of hydrochlorothiazide 50 mg once daily was attenuated by co-administration for 4 weeks of ibuprofen 400 mg t.i.d., diclofenac 25 mg t.i.d. or sulindac 200 mg b.i.d. Only a slight, statistically non-significant change was found, with the exception of a significant increase in systolic blood pressure after 4 weeks treatment with ibuprofen. There was considerable variation in the blood pressure response during treatment with all three NSAIDs, with slight rises in blood pressure in 13 out of 24 periods. Body weight increased significantly on treatment both with ibuprofen and diclofenac, whereas the increase on sulindac was less and was transient. No significant change was found in various biochemical parameters, including plasma electrolytes, plasma renin activity (PRA), aldosterone, albumin and creatinine, in haematocrit or in the 24-h urinary excretion of sodium and potassium. The sole exception was a decrease in PRA during ibuprofen treatment. From these observations it is concluded that ibuprofen and diclofenac differ from sulindac in their interaction with the diuretic action of hydrochlorothiazide. It appears that all three NSAIDs can safely be combined with hydrochlorothiazide in hypertensive patients, but blood pressure should be monitored carefully when an NSAID are added.     

HUMORAL DETERMINANTS OF Na+ EXCRETION AFTER INTRAVENOUS NaCl LOADING IN NORMAL VOLUNTEERS

1. Twelve healthy volunteers maintained on a 100 mmol/day Na⁺ diet, were given an intravenous infusion of 2L saline (0.9%) between 10.00 and 13.00h on 2 study days at least 1 week apart. Urine collections (90 min) were made from 08.30 to 16.00 h. Either carbidopa 100 mg or indomethacin 50 mg was given orally at 07.45 h on one study day and placebo was given on the other (in random order). 2. On the placebo day, saline infusion caused significant decreases in plasma albumin concentration, plasma renin activity (PRA), plasma aldosterone concentration and urinary aldosterone excretion, with 2 to 3-fold increases in plasma atrial natriuretic peptide (ANP) concentration and urinary dopamine: noradrenaline ratio (DA:NA), whereas mean urinary kallikrein and prostaglandin E₂ (PGEI) excretion rates were unchanged. Carbidopa decreased urinary DA:NA and indomethacin decreased urinary PGE₂ excretion, compared with the placebo day. Excretion of sodium (Na⁺) decreased below baseline in two out of six carbidopa-treated subjects and in three out of six indomethacin-treated subjects, but showed little or no change in the remainder. 3. These preliminary observations suggest that some subjects in the early phase of natriuresis after an intravenous Na⁺ load can be identified as having prostaglandin-dependent or dopamine-dependent mechanisms for Na⁺ excretion.