The role of renal kallikrein and prostaglandin in the control of renin release

Renal prostaglandins and kallikrein are considered to play an important role in the control of renin release. Recently, we have shown that aprotinin, a kallikrein inhibitor, inhibits the stimulation of plasma renin activity (PRA) by either furosemide or a low sodium diet. However, the mechanisms of action of kallikrein are unknown. Since kallikrein may stimulate bradykinin and prostaglandin production, the present study examines the relationship of renal kallikrein and renal prostaglandins in the control of renin release. Furosemide and a low sodium diet stimulated PRA, urinary kallikrein excretion and urinary prostaglandin E2 excretion. Aprotinin and indomethacin inhibited both furosemide and low sodium diet stimulation of PRA. When maximum doses of both aprotinin and indomethacin were given, PRA was more strongly suppressed than by indomethacin alone. The stimulation of urinary kallikrein excretion by furosemide and by a low sodium diet was not inhibited by indomethacin. These results suggest that both renal kallikrein and prostaglandins play an important role in the control of renin release under sodium depletion. Renal kallikrein may also have a direct action on the kidney to release renin.     

The effect of aprotinin (a serine protease inhibitor) on renal function and renin release

We studied the effect of aprotinin, a reversible inhibitor of kallikrein and other serine proteases, upon urinary kallikrein and kinin excretion, renal function and hemodynamics, blood pressure, and plasma renin activity (PRA). When aprotinin was administered to anesthetized rats at 10,000 KIU/kg as a bolus, and at 1000 KIU/kg/min infusion for 60 minutes, urinary kininogenase activity and immunoreactive kallikrein, kinins, sodium, potassium, and water excretion, and PRA decreased significantly. Aprotinin also caused a 36% decrease (p less than 0.001) in renal blood flow (RBF), and a 37% decrease (p less than 0.001) in glomerular filtration rate (GFR), although neither blood pressure nor cardiac output changed. The effect of aprotinin on PRA was further studied in conscious rats before and after stimulation of renin release by isoproterenol or furosemide. Aprotinin (5,000 KIU/kg bolus and 1000 KIU/kg/min infusion for 60 minutes) did not alter basal or isoproterenol-stimulated PRA, but it blunted the increase in PRA as stimulated by furosemide. Aprotinin at a higher dose (20,000 KIU/kg bolus and 5000 KIU/kg/min infusion for 60 minutes) significantly lowered blood pressure and increased hematocrit and PRA. These effects may be due to inhibition of serine protease(s) or to other as yet unrecognized properties of this peptide resulting from its highly cationic nature. In conclusion, aprotinin at a low dose decreased kallikrein, kinin, sodium, and water excretion. These decreases may be due to the inhibition of kallikrein and/or other serine proteases or may be secondary to the renal hemodynamic changes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of sodium and angiotensin II on urinary active and inactive kallikrein in rats

To assess possible relationships between sodium balance, angiotensin II (ANG II), and renal active and inactive kallikrein, we studied the effects of sodium loading with 1% NaCl and chronic ANG II infusion (900 micrograms/kg per day) on the urinary excretion of total and active kallikrein for 6 days in conscious rats. We determined urinary total, active and inactive kallikrein by measuring kallikrein activity using a kininogenase assay before and after treatment with trypsin (200 micrograms/ml). Sodium loading produced a sustained increase in urinary total, active and inactive kallikrein excretion. Chronic infusion of ANG II induced a sustained increase in urinary total, active and inactive kallikrein excretion in rats on a regular diet. In rats loaded with sodium, however, ANG II did not induce any further changes in urinary kallikrein excretion. Thus, the present study suggests that both sodium loading and ANG II infusion might stimulate the synthesis of renal kallikrein. In addition, it is suggested that ANG II infusion might stimulate the synthesis of kallikrein, at least partly, via the same mechanism as sodium loading does.     

The effect of sodium and potassium loading on urinary kallikrein-like activity in young patients with borderline hypertension

We studied the effects of a potassium supplement on urinary kallikrein excretion in a setting of high sodium intake after sodium deprivation with diuretics in young patients with borderline hypertension. Eleven patients, who took the potassium supplementation during the high sodium diet period, showed lower increments in mean blood pressure with salt loading than 12 patients without the potassium supplementation. In the non-potassium-supplemented patients, urinary kallikrein was increased significantly when plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary aldosterone were increased during the diuretic treatment. It was decreased significantly when the other hormones were decreased during the sodium load. During the high sodium diet period, PRA, PAC and urinary aldosterone were greater in the potassium-supplemented patients than in the non-potassium-supplemented ones, but urinary kallikrein excretion was not higher when potassium was supplemented. Thus, the present results did not support the theory that the kallikrein-kinin system may be involved in the natriuretic and antihypertensive effects of potassium. In addition, these finding suggest that some kallikrein-modulating factor(s) may counteract the increased urinary kallikrein excretion with the augmented renin-angiotensin-aldosterone system during salt loading with potassium supplementation.     

Plasma Active and Inactive Renin and Urinary Kallikrein in Normal Subjects in Response to Hydrochlorothiazide,Spironolactone or Aldosterone Administration

The aim of this study has been to see whether acute variations in the proportions of circulating active and inactive renin in normal subjects were related to concurrent changes in the excretion of urinary kallikrein. Hydrochlorothiazide (50 mg/day) was given to 6 normal volunteers for 6 days; another group of 6 normal subjects received spironolactone (300 mg/day) for 6 days whereas synthetic aldosterone (0.5 mg/day) was administered i.m. for three days to 3 normal subjects. Both diuretics induced a sharp rise in active and total renin and a significant transient decrease in inactive renin so that the active: total renin proportion significantly increased. Urinary kallikrein excretion did not significantly change in either group. Parenteral administration of aldosterone induced a striking fall in all renin components without changing the proportions of active and inactive renin whereas urinary kallikrein excretion increased. These results indicate that changes in active: total renin proportions can occur without parallel variations in urinary kallikrein excretion. The latter cannot be used, therefore, as a reliable index of the possible role of renal kallikrein as activator in-vivo of inactive renin in man.     

The role of the renal kallikrein-kinin system in sodium metabolism in normal and low renin essential hypertension

In order to investigate the pathophysiological role of the renal kallikrein-kinin system in renin subgroups of essential hypertension, the quantity and activity of urinary kallikrein, urinary kinin excretion, and correlations of kallikrein and kinin excretions with renal sodium handling in the renal tubules were studied in 17 normal subjects, 23 patients with normal renin and 12 patients with low renin essential hypertension. Urine samples were collected by the 2-hour clearance method in the early morning. The quantity and activity of urinary kallikrein, and the urinary excretion of kinin were significantly lower in both low and normal renin patients than in normal subjects. Comparing the normal renin and the low renin group, no significant difference was found in the quantity of urinary kallikrein, while the activity of urinary kallikrein and urinary kinin excretion were significantly lower in low renin patients than in normal renin ones. Fractional excretions of sodium (FENa) and inorganic phosphorus (FEP), which reflect renal tubular and proximal tubular sodium reabsorption, respectively, were significantly lower in the low renin patients than in the normal renin ones. A significantly positive correlation was observed between the urinary kallikrein activity or urinary kinin excretion and FENa or FEP in both normal subjects and normal renin patients, but not in low renin patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bartter's syndrome and diabetes mellitus

Abstract. We here report a case of Bartter's syndrome occurring in association with diabetes mellitus. The patient, an insulin-dependent diabetic, presented with hypokalaemia, inappropriate kaliuresis and metabolic alkalosis. He had high plasma renin activity, relatively low plasma aldosterone, and resistance to infused angiotensin II. A high potassium diet raised total body potassium and serum potassium, did not affect plasma renin activity, but raised plasma aldosterone significantly and did not alter the resistance to angiotensin II. Indomethacin administered acutely reduced urinary potassium and kallikrein excretion and, on chronic administration, lowered plasma renin activity, urinary chloride excretion, and raised serum potassium. Salt restriction resulted in a prompt and significant reduction in urinary sodium and chloride excretion. Urinary kallikrein excretion was very high throughout, increased with sodium restriction, and decreased with sodium loading. Oral potassium supplementation partially corrected the hypokalaemia, but did not affect blood sugar control. In this patient the primary defect appears to have been primary urinary potassium wasting, rather than sodium or chloride wasting. The striking effects of indomethacin suggest that prostaglandins may play a fundamental role in the genesis of the syndrome.     

Relationship of urinary kallikrein excretion to renal water and sodium excretion

The circadian rhythms of urine volume and urinary excretion of sodium, potassium, kallikrein, and aldosterone were analyzed by a multivariate method (cosinor method) in 20 healthy Japanese women on an ordinary diet. The relationship of urinary kallikrein and aldosterone excretion to urine volume and urinary sodium and potassium excretion was studied by assessing the correlation of the circadian rhythms. The acrophases in the circadian rhythms of urine volume (16:51) and urinary sodium excretion (16:55) appeared after the acrophase of urinary kallikrein excretion (15:28). There was a highly significant correlation between the circadian rhythm of urinary kallikrein excretion and the circadian rhythms of urine volume (r = 0.948) and urinary sodium excretion (r = 0.921). These results suggest that the renal kallikrein-kinin system participates in the regulation of renal water and sodium excretion in persons on an ordinary diet. A highly significant relationship between the acrophases in the circadian rhythms of urine volume and sodium excretion (r = 0.935) also suggests that water and sodium excretion may have a mutual influence on the kidneys. There were positive correlations between the circadian rhythms of potassium excretion and kallikrein excretion and potassium excretion and sodium excretion; and the latter relationship was relatively closer than the former. The acrophase in the circadian rhythm of aldosterone excretion did not correlate well with the acrophases of the other urine variables including sodium excretion.     

Renal kallikrein activity in spontaneously hypertensive rats

To assess possible roles of the renal kallikrein-kinin system in the development of spontaneous hypertension, we determined daily excretion of urinary total and active kallikrein in 6-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats for up to 2 weeks. We also evaluated the effect of aprotinin, a reversible inhibitor of kallikrein and other serine proteases, on the development of hypertension in the 6-week-old SHR on ordinary intakes of sodium or on sodium loading with 1% NaCl for up to 2 weeks. Active kallikrein was determined by its kininogenase activity, and the generated kinins were radio-immunologically measured. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin (200 micrograms/ml). Urinary active kallikrein excretion was significantly reduced in 7-week-old SHR (1.5 +/- 0.2 microgram/day compared to 2.8 +/- 0.3 micrograms/day in WKY, P less than 0.05) and in 8-week-old SHR (1.6 +/- 0.2 microgram/day compared to 3.2 +/- 0.4 micrograms/day in WKY, P less than 0.01). Urinary total kallikrein excretion was also reduced in the 7- and 8-week-old SHR whereas the ratio of active to total kallikrein did not change. In addition, renal contents of total and active kallikrein were significantly lower in the 8-week-old SHR than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acetylsalicylic acid on renal function in patients with chronic heart failure

PURPOSE: We conducted a double-blind, placebo-controlled trial to determine whether the administration of acetylsalicylic acid has adverse effects on renal function in patients with moderate chronic congestive heart failure with and without stimulation of the renin system. PATIENTS AND METHODS: Forty patients were randomly assigned to one of the following four groups: Group 1, low sodium diet and placebo; Group 2, low sodium diet and acetylsalicylic acid; Group 3, normal sodium diet and placebo; or Group 4, normal sodium diet and acetylsalicylic acid. Patients were studied over 8 days. After Day 5, patients in Groups 2 and 4 received acetylsalicylic acid (500 mg three times a day). The low sodium diet consisted of 13.6 mmol of sodium per day and the normal sodium diet consisted of 136 mmol of sodium per day. RESULTS: The low sodium diet resulted in a highly significant increase in the plasma renin (2p = 0.0001), aldosterone (2p = 0.0006), and urinary prostaglandin E2 (2p = 0.01) concentrations and the renal potassium excretion (2p = 0.0009), whereas renal sodium excretion was significantly reduced (2p = 0.0001). Severe sodium depletion led to a reduction of the glomerular filtration rate (2p = 0.007), which was independent from cyclooxygenase inhibition. In patients on the low sodium diet, acetylsalicylic acid reduced the elevated urinary prostaglandin E2 levels to normal values without changing the renal sodium excretion rate. In patients with a normal sodium intake, acetylsalicylic acid significantly reduced the renal sodium excretion rate by 29% (2p = 0.04). CONCLUSION: We conclude that severe sodium depletion has adverse effects on kidney function in patients with heart failure due to a reduction in the glomerular filtration rate. Administration of acetylsalicylic acid in doses that reduce the synthesis of renal prostaglandin E2 significantly reduces renal sodium excretion.     

The Excretion of Human Urinary Kallikrein Quantity and Activity in Normal and Low Renin Subgroups of Essential Hypertension

In both low and normal renin essential hypertensive groups, urinary excretion of kallikrein quantity by direct radioimmunoassay and activity by kininogenase assay were significantly lower than those in normal subjects. In comparing between normal and low renin groups, no difference was found in kallikrein quantity, while kallikrein activity tended to be lower in the low renin group than in the normal renin group. A significant positive correlation was observed between kallikrein quantity and activity in the normal subjects, the normal renin group and the low renin group. However, the slope of the regression line in the low renin group was significantly more moderate than that in the normal renin group, and tended to be more moderate than that in normal subjects. The addition of kallikrein inhibitors (aprotinin and gabexate mesilate) resulted in a significant suppression of enzymatic activity but not of enzyme quantity.

These findings suggest that suppression of the renal kallikrein system in both groups of essential hypertension was confirmed by the decreased excretion of kallikrein both as enzyme quantity and activity, and that in the mechanism of the suppression of urinary kallikrein activity in the low renin group, the renal kallikrein inhibitors may play some role.     

Active and Inactive Renins in Human Urine

Urinary excretions of active and inactive renin were studied in normal subjects and in patients with hypertensive or renal disease. Excessive excretion of active and inactive renins was observed in some patients with no significant correlation to their plasma levels or the degree of proteinuria. Inactive renin excretion correlated to active renin excretion, but the clearance was lower than that of the active form. No correlation was found between the urinary kallikrein excretion and the active/inactive renin ratio in the urine or the plasma. Urinary renin activity was increased by acidification and by trypsin treatment, but not by cold exposure. Both active and inactive renins in the urine showed multiple peaks corresponding to molecular weights between 45,000 and 64,000 by gel filtration.     

Dissociation between kallikrein and aldosterone in Cushing's disease with periodic hormonogenesis

It has been suggested that the renal kallikrein-kinin system is dependent on mineralocorticoid activity. This hypothesis was studied in a patient with cyclic Cushing's syndrome combined with cortisol suppressible, dexamethasone non-suppressible ACTH secretion. The 24-h urinary excretions of sodium, potassium, cortisol, active and inactive kallikrein, aldosterone, and prostaglandin E2 (PGE2) were studied during normal and excessive cortisol secretion and after bilateral adrenalectomy. Kallikrein, PGE2 and potassium rose during cortisol overproduction while aldosterone and sodium decreased. Kallikrein, PGE2 and potassium were positively related to cortisol excretion, whereas urinary aldosterone and sodium showed a negative relationship to cortisol. Kallikrein was inversely related to aldosterone. Excretion of inactive kallikrein followed closely the changes of active kallikrein. During cortisol excess, as in our patient, the mineralocorticoid activity of cortisol will exceed that of aldosterone. This suggests that the alterations in kallikrein, aldosterone and PGE2 during cortisol excess in the present study were due to the mineralocorticoid potency of the steroid.     

Reduced ratio of active-to-total urinary kallikrein in essential hypertension

Urinary kallikrein excretion was studied in 34 patients with mild, normal-renin, essential hypertension without evidence of target organ damage and in 23 normotensive controls, using assays that measure both active (kininogenase activity) and total (active plus inactive) kallikrein. There was no significant difference in either active or total kallikrein excretion between the two groups. However, the ratio of active-to-total enzyme was decreased in the hypertensives (0.83 +/- 0.03 units/micrograms) compared to the normotensives (1.00 +/- 0.05 units/micrograms) (p less than 0.002). The active-to-total ratio was inversely related to sodium excretion in both groups, indicating that the proportion of active to inactive enzyme increased in response to reduced sodium intake. We conclude that, although absolute excretion of active and total kallikrein is not decreased, enzyme activity per microgram of total kallikrein excreted is reduced in mild, normal-renin essential hypertension. This abnormality may be due to a defective enzyme, or to a reduced excretion of active relative to inactive kallikrein. The latter could result from the presence of a urinary kallikrein inhibitor or to reduced activation of a proenzyme.     

Interrelations of the renal kallikrein-kinin system and renal prostaglandins in the conscious rat. Influence of mineralocorticoids.

To investigate possible relationships between mineralocorticoids, the renal kallikreinkinin system, and renal prostaglandins, we studied the effects of aldosterone and deoxycorticosterone acetate (DOCA) and of an inhibitor of kallikrein, aprotinin, on the urinary excretion of kallikrein and prostaglandin E-like substance (PGE) by the conscious rat. Aldosterone (0.25 mg/day, sc), injected into six rats for 14 consecutive days, increased PGE and kallikrein excretion from 52.3 +/- 8.7 (mean +/- SE) ng/day and 29.8 +/- 3.0 U/day to 141.5 +/- 30.7 ng/day (P less than 0.02) and 105.6 +/- 28.1 U/day (P less than 0.05), respectively. Similarly, injections of DOCA (5 mg/day) into 14 rats increased the excretion of PGE and kallikrein, measured before and after 10 days of treatment, from 41.6 +/- 3.9 ng/day and 39.4 +/-4.9 U/day to 194.3 +/- 20.7 ng/day (P less than 0.001) and 90.6 +/- 14.7 U/day (P less than 0.001), respectively. Injections of aprotinin for 4 days (50,000 KIU twice daily, sc) in conjunction with DOCA into eight rats pretreated with the steroid for 10 days decreased the urinary excretion of kallikrein and PGE, measured on the 4th day of aprotinin administration, by 61% (P less than 0.01) and 80% (P less than 0.001), respectively. Urinary potassium excretion decreased throughout the course of aprotinin treatment, whereas sodium excretion and urine volume decreased during the first 2 days but subsequently returned toward control values. This study demonstrates that mineralocorticoids enhance the urinary excretion of PGE, and this effect appears to be a consequence of activation of the renal kallikrein-kinin system by the steroids. Thus, changes in the intrarenal activity of the kallikrein-kinin system may modulate renal prostaglandin release.     

Activation of inactive plasma renin by tissue kallikreins.

It has been reported that inactive (acid-activable) human renin could be converted into the active form by adding urinary kallikrein to acid-pretreated plasma. Without prior acidification, however, only a small portion of the total amount of inactive renin present in plasma was converted (activated) by kallikrein, probably because native plasma contains protease (kallikrein) inhibitors that are destroyed by acid. We have separated inactive and active renin by DEAE-Sepharose column chromatography of normal human plasma at pH 7.5 and a linearly increasing sodium gradient. Inactive renin isolated in this way could be activated at pH 7.5 by highly purified pancreas and urinary kallikreins. With the semipurified preparation of inactive renin, prior acidification was not required for obtaining virtually complete activation by kallikrein. The kallikreins were effective at concentrations as low as 1 x 10(-8) mol/liter. It is therefore possible that one or more tissue kallikreins act as physiological activators of inactive renin.     

Renal changes induced by a cyclooxygenase-2 inhibitor during normal and low sodium intake

Cyclooxygenase-2 (COX-2) has been identified in renal tissues under normal conditions, with its expression enhanced during sodium restriction. To evaluate the role of COX-2-derived metabolites in the regulation of renal function, we infused a selective inhibitor (nimesulide) in anesthetized dogs with normal or low sodium intake. The renal effects elicited by nimesulide and a non-isozyme-specific inhibitor (meclofenamate) were compared during normal sodium intake. In ex vivo assays, meclofenamate, but not nimesulide, prevented the platelet aggregation elicited by arachidonic acid. During normal sodium intake, nimesulide infusion (n=6) had no effects on arterial pressure or renal hemodynamics but did reduce urinary sodium excretion, urine flow rate, and fractional lithium excretion. In contrast, nimesulide administration increased arterial pressure and decreased renal blood flow, urine flow rate, and fractional lithium excretion during low sodium intake (n=6). COX-2 inhibition reduced urinary prostaglandin E(2) excretion in both groups but did not modify plasma renin activity in dogs with low (8.1+/-1.1 ng angiotensin I. mL(-1). h(-1)) or normal (1.8+/-0.4 ng angiotensin I. mL(-1). h(-1)) sodium intake. Meclofenamate infusion in dogs with normal sodium intake (n=8) induced a greater renal hemodynamic effect than nimesulide infusion. These results suggest that COX-2-derived metabolites (1) are involved in the regulation of sodium excretion in dogs with normal sodium intake, (2) play an important role in the regulation of renal hemodynamic and excretory function in dogs with low sodium intake, and (3) are not involved in the maintenance of the high renin levels during a long-term decrease in sodium intake.     

Renal Kallikrein-Kinin System and the Depressor Effect of Angiotensin Converting Enzyme Inhibitors MK 421, SA 446, And Captopril In Rats

Responses in urinary kallikrein and kinin excretion and systolic blood pressure to MK 421, SA 446 or captopril were studied in normotensive rats fed on a regular or a low sodium diet to assess the role of renal kallikrein-kinin system in their hypotensive effect. MK 421, SA 446 or captopril were infused at a rate of 6 mg/kg/day by osmotic minipump implanted intraperito-neally for up to 6 days. The magnitude of fall in systolic blood pressure was greater on a low sodium diet when compared to on a regular diet, whereas the pattern of the fall was similar on both diets. The magnitude of falls in plasma angiotensin II and aldosterone concentration induced by MK 421, SA 446 and captopril was not significantly different between both regular and low sodium diets. Urinary kallikrein and kinin excretion and sodium excretion were increased during infusion of MK 421, SA 446 or captopril on a low sodium diet, however any significant changes were not found in each of them on a regular diet

The present results suggest that on a low sodium diet the augmented hypotensive response to angiotensin converting enzyme inhibitors in the rats might be due to the enhanced renal kallikrein-kinin system in addition to suppressed renin-angiotensin system     

Effect of the protease inhibitor aprotinin on renal hemodynamics in the pig

Aprotinin, the serine protease inhibitor that also inhibits glandular (urinary) kallikrein, or vehicle was infused into the aorta above the renal arteries of anesthetized pigs. Renal hemodynamic and functional parameters were followed over time and during hemorrhagic hypotension. Both renal cortical blood flow and glomerular filtration rate were maintained in vehicle-treated animals at mean arterial pressures as low as 70 mm Hg. As long as renal cortical blood flow and glomerular filtration rate were maintained during the progressive hypotension, urinary excretion rate of kallikrein (as defined by kinin-generating activity) was increased. In contrast, all aprotinin-treated animals had a decreased excretion rate, and the renal cortical blood flow declined with the mean arterial pressure during hemorrhage. The pattern of glomerular filtration rate and plasma renin activity was comparable in both aprotinin-treated and vehicle-treated hemorrhaged animals. Our findings suggest that the endogenous renal kallikrein-kinin system is required for functional renal vasodilatation to maintain renal cortical blood flow during hemorrhage and is therefore directly or indirectly responsible for adjustment of preglomerular resistance.     

Role of angiotensin II in the hormonal, renal, and electrolyte response to sodium restriction

Adrenal responses to angiotensin II (ANG II) are enhanced with restriction of sodium intake. To determine whether increased circulating ANG II levels are responsible for the enhanced responsiveness, the adrenal and blood pressure responses to ANG II in human subjects were assessed four times: in balance on a high and a low salt diet and before and after the administration of a converting enzyme inhibitor (enalapril). Before enalapril administration, sodium restriction significantly increased (p less than 0.02) plasma renin activity, ANG II, and aldosterone levels; the aldosterone response to ANG II was enhanced twofold (p less than 0.01); and the blood pressure response to ANG II infusion was reduced significantly (p less than 0.05). Despite a fixed and low plasma ANG II concentration when enalapril was employed, the adrenal response to ANG II on the low salt diet was enhanced to the same degree as that observed before administration of the converting enzyme inhibitor. Conversely, enalapril substantially altered the blood pressure response to ANG II with sodium restriction, completely preventing the reduction in responsiveness. If the subjects were first given enalapril and then sodium intake was restricted, ANG II levels did not change significantly but renal excretion of both sodium and potassium was substantially modified. The rate at which renal excretion of sodium fell to match intake was retarded strikingly (p less than 0.001); conversely, renal retention of potassium increased significantly (p less than 0.03) as low salt balance was attained. Possibly because of the potassium retention, aldosterone levels rose, but significantly less than when enalapril was absent.