Biological activity of des-(Asp1, Arg2, Val3)-angiotensin II in man

When des-(Asp¹, Arg², Val³)-angiotensin II was infused iv at rates of 308–5,550 pmol/kg·min for 10–120 min into 5 normal men and 2 patients with Bartter's syndrome, no significant change was observed in blood pressure (BP), plasma renin activity (PRA) or plasma aldosterone (PA), and the lowest dose did not inhibit a captopril-induced increase in PRA in the normal men, although des-(Asp¹, Arg²)-angiotensin II was reported in the same 5 normal men to cause a decrease in PRA and an increase in PA in this dose range and a rise in BP at 2,220 and 5,550 pmol/kg·min. However, an iv infusion of the pentapeptide at 9,000 pmol/kg·min for 15 min significantly raised BP in the 5 normal men but not in patients with Bartter's syndrome. BP returned to the pretreatment level 60 min after the cessation of the infusion, although the duration of the pressor actions of angiotensin II, angiotensin III and des-(Asp¹, Arg²)-angiotensin II were reported to be within 5 min in man. At the same dose level none of the 7 examined subjects showed any significant change in PRA or PA. Des-(Asp¹, Arg², Val³, Tyr⁴)-angiotensin II was infused iv at a rate of 41,480 pmol/kg·min into one of the normal men, but it caused no significant change in BP, PRA or PA. These results suggest that the pentapeptide and probably the tetrapeptide do not possess renin-suppressing and steroidogenic actions in man but the pentapeptide does elecit a minimal pressor action with a prolonged duration.     

Agonistic activities of isoleucine8-angiotensin II in man

In order to clarify the importance of C-terminal phenylalanine in angiotensin II (ANG II) molecule, agonistic activities of a C-terminal substituted peptide, isoleucine8-angiotensin II (Ile8-ANG II), were studied in comparison with those of sarcosine1-, isoleucine8-angiotensin II (Sar1-, Ile8-ANG II) and isoleucine5-angiotensin II (Ile5-ANG II) in 5 normal men. When infused iv at a rate of 600 pmol/kg X min for 30 min, Ile8-ANG II and Sar1-, Ile8-ANG II raised the blood pressure to the same extent (15/15 mmHg on the average), while the average blood pressure increase was 21/21 mmHg after an iv infusion of Ile5-ANG II at a rate of 5 pmol/kg X min for 30 min. Duration of the pressor action after the cessation of each infusion was 50-90, 90-120 and 10-25 min, respectively. In each case plasma renin activity (PRA) decreased and plasma aldosterone (PA) increased. When infused iv at a rate of 10 pmol/kg X min (maximum non-pressor dose) for 120 min, both Ile8-ANG II and Sar1-, Ile8-ANG II lowered PRA and increased PA gradually, but 100 mg oral captopril given immediately before these infusions caused no significant increase in PRA or no significant decrease in PA but again a decrease in PRA and an increase in PA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responsiveness of plasma aldosterone to angiotensin II in patients with diabetes mellitus

Aldosterone responsiveness to angiotensin II (A II) was evaluated in 65 diabetic patients with and without various diabetic complications versus 38 age-matched non-diabetic subjects. Plasma aldosterone (PA), together with plasma renin activity (PRA), was low and responded poorly to furosemide (80 mg, orally) plus upright posture (4 hours) stimulation in diabetic patients. When the PA response to stimulation relative to PRA response was estimated from the ratio of PA increase to PRA increase after stimulation (delta PA/delta PRA), the 38 non-diabetic subjects had ratios more than 3.0. Of the 65 diabetic patients, 48 had normal delta PA/delta PRA ratios (more than 3.0) and 17 had low delta PA/delta PRA ratios (less than 2.9). Graded A II infusions (1, 2, and 4 ng/kg/min each for 30 min) were performed under a low sodium intake (sodium, 120 mEq/day) in 25 of the 65 diabetic patients, whose delta PA/delta PRA ratios were normal in 15 and low in 10, and in 16 non-diabetic subjects. The PA responses to the graded A II infusions in the normal delta PA/delta PRA diabetic patients were similar to those in the non-diabetic subjects. However, the PA responses to the graded A II infusions in the low delta PA/delta PRA diabetic patients were significantly lower. It is concluded that, although the majority of diabetic patients have normal aldosterone responsiveness to A II, some diabetic patients have blunted aldosterone responsiveness to A II probably attributable to the abnormality of the adrenal cortex in addition to the impaired renin secretion.     

Effects of various doses of captopril on plasma aldosterone concentrations in patients with essential hypertension

Various doses (5 mg, 12.5 mg and 25 mg) of angiotensin I converting enzyme inhibitor (SQ 14,255, captopril) were administered to 8 patients with essential hypertension on a three-crossover study design, and the time course of mean blood pressure (MBP), plasma renin activity (PRA), plasma angiotensin converting enzyme activity (ACE-A), plasma cortisol (PC) and plasma aldosterone (PA) were determined following administration of the drug. MBP fell in a dose dependent manner, and PRA showed a minor but significant increases in cases receiving 5 and 12.5 mg of the drug. A large and significant increase in PRA was observed following 25 mg of captopril. ACE-A was also reduced in a dose dependent manner. There was no difference between changes in PC at any of the three dose levels. The serum potassium concentration was determined before and 3 hr after 25 mg of captopril treatment and no significant change was observed. In spite of the dose dependent and theoretical changes in the above parameters, lowered responses of PA to each dose of the drug were shown in reverse order against an increasing dose. That is to say, the grade of fall in PA following 25 of captopril was smaller than that following the other doses of the drug, and 5 mg induced a greater decrease in PA than 12.5 mg. Based on these findings, the relatively high dose of captopril in the present study was apparently more effective in increasing some factors which suppressed reduction of PA by a fall in angiotensin II than a low dose of the drug.     

Dopaminergic modulation of some central actions of angiotensin II in vivo

Studies were performed in 12 conscious sheep of both sexes to determine if a brain dopaminergic pathway is involved in modulating the central actions of angiotensin II (Ang II) in regulating body temperature and plasma renin activity (PRA). Previous data showed that intracerebroventricular (ICV) infusion of Ang II significantly decreased PRA and body temperature. In contrast, converting enzyme inhibitor SQ 20881 (SQ) or dopamine (DA) significantly increased PRA and body temperature of sheep. In the present study, ICV infusion of the DA antagonist metoclopramide (MCP) (20 micrograms/min) significantly decreased PRA to 68 +/- 5% of the basal level. When sheep were pretreated with ICV MCP (20 micrograms/min) for 2 hr and then infused ICV with MCP (20 micrograms/min) plus DA (20 micrograms/min), Ang II (25 ng/min), or SQ (1 microgram/min), the PRA and temperature responses to DA, Ang II, or SQ were all abolished or attenuated significantly. The converse did not hold. Sheep pretreated with SQ (1 microgram/min) still showed a significant increase in body temperature (0.43 +/- 0.05 degree C) when infused with DA (20 micrograms/min). These results support the hypothesis that a central DA pathway is involved in the modulation of the actions of centrally administered Ang II on temperature and PRA.     

Atrial natriuretic factor (ANF) inhibits the growth and the secretory activity of rat adrenal zona glomerulosa in vivo

A prolonged infusion with ANF induced atrophy of zona glomerulosa cells of rat adrenals and lowering of plasma concentration of aldosterone, without provoking significant changes in PRA. It also notably reduced the rise in the aldosterone plasma level caused by the acute stimulation with angiotensin II. Zona fasciculata cells and the blood concentration of corticosterone did not display any significant change. These findings are interpreted to indicate that ANF exerts an inhibitory effect on the growth and secretory activity of rat zona glomerulosa.     

Effects of an angiotensin II antagonist; [sarcosine 1, isoleucine 8] angiotensin II, on blood pressure, plasma renin activity and plasma aldosterone concentration in hypertensive and normotensive subjects taking oral contraceptives.

To examine the involvement of renin-angiotensin-aldosterone system in the etiology of oral contraceptive induced hypertension, normal women (Group I), normotensive (Group II) and hypertensive (Group III) women taking Ovulen (R) were infused with a competitive angiotensin II (AII) antagonist, [1-sarcosine, 8-isoleucine] angiotensin II. The angiotensin II antagonist was infused at a rate of 600 ng/kg/min for 30 min 1.5 hrs after intravenous injection of 40 mg of furosemide. Blood pressure was monitored and pre-infusion and post-infusion plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were determined. Pre-infusion PRA and PAC showed no significant differences among these three groups. In response to the AII antagonist infusion blood pressure rose in Groups I and II, but blood pressure responses in Group III were variable. Four out of the total 6 subjects had pressor responses and only one subject had a significant blood pressure reduction. In both Groups I and II, PRA decreased and PAC rose after infusion of the antagonist. In Group III, PRA decreased to a lesser degree and PAC showed no consistent change. These data suggest that the renin-angiotensin-aldosterone system in hypertensive women or oral contraceptives is different from that of the normotensive users. However, the pathophysiology of oral contraceptive induced hypertension is not homogenous and angiotensinogenic hypertension is uncommon.     

Direct measurement of immunoreactive renin during changes of posture in man.

For several years, it has been possible to determine renin by a direct RIA. In the present study, plasma active renin concentration (PRC) was related to plasma renin activity (PRA) and aldosterone as a function of a standardized posture test. Using PRC, our target was to define the shortest necessary test duration. The three parameters were examined in 10 healthy male subjects (22-34 years old). Salt balance was determined in 24-hour urine, and plasma potassium and sodium were measured. Volunteers were hospitalized for 1 night, and at 8 a.m. the next morning they were subjected to the following postural changes: 3 h active orthostasis and 3 h recumbency. Frequent blood samples were taken. Orthostasis induced a significant rise in PRC, PRA and aldosterone already after 15 min. PRC and PRA reached a maximum level after 90 min of orthostasis and remained relatively stable, while aldosterone reached its highest level already after 30 min and then gradually decreased. Significant correlations were found between PRA and PRC (p < 0.001), between PRC and aldosterone (p < 0.001), and between PRA and aldosterone (p < 0.001). The PRC/PRA ratio changed during the course of the test, especially in supine subjects. When subjects returned to the supine position, all the parameters measured began a continual decrease. There were no significant changes in serum potassium and sodium levels throughout the duration of the test.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of bromocriptine on the control of plasma aldosterone diurnal variation in normal supine man.

In order to investigate the role of prolactin in the control of the circadian rhythm of plasma aldosterone (PA), plasma renin activity (PRA), cortisol (PC), aldosterone and prolactin (PRL) levels were determined in samples at 4-hour intervals from 5 normal supine men over a period of 24 h under basal conditions and subsequently over a period of 24 h during suppression of prolactin release by bromocriptine (CB-154). After suppression of prolactin, statistically signific1nt circadian rhythms in PC and PA have been detected with a moderate decrease of PA concentration, while the PC level remained unalterated. PRA rhythmicity persisted with a significant shift of acrophase and remarkable reduction of plasma levels. Moreover, during CB administration a significant correlation was obtained between PA and PC, while no correlation was detected between PA and PRA. These data are consistent with the following concepts: (a) the prolactin does not play a significant role in the regulation of circadian rhythm and concentration of plasma aldosterone in normal supine men, and (b) bromocriptine induces a remarkable reduction of PRA and a variable decrease in plasma aldosterone, but it does not influence the secretion of cortisol in normal subjects.     

Role of the renin-angiotensin system in drinking of seawater-adapted eels Anguilla japonica: a reevaluation

The role of ANG II, a potent dipsogenic hormone, in copious drinking of seawater eels was examined. SQ-14225 (SQ), an angiotensin-converting enzyme inhibitor, infused intra-arterially at 0.01-1 microgram. kg(-1). min(-1), depressed drinking and arterial blood pressure in a dose-dependent manner. The inhibition was accompanied by a small decrease in plasma ANG II concentration, which became significant at 1 microgram. kg(-1). min(-1). After the infusate was changed back to the vehicle, the depression of drinking and arterial pressure continued for >2 h, although plasma ANG II concentration rebounded above the level before SQ infusion. By contrast, infusion of anti-ANG II serum (0.01-1 microgram. kg(-1). min(-1)) did not suppress drinking and arterial pressure, although plasma ANG II concentration decreased to undetectable levels. Plasma atrial natriuretic peptide and plasma osmolality, which influence drinking rate in eels, did not change during SQ or antiserum infusions. These results suggest that the renin-angiotensin system plays only a minor role in the vigorous drinking observed in seawater eels. The results also suggest that the antidipsogenic and vasodepressor effects of SQ in seawater eels are not due solely to the inhibition of ANG II formation in plasma.     

Plasma aldosterone, renin activity, and cortisol responses to heat exposure in sodium depleted and repeleted subjects.

The effect of 90-min heat exposure (46 degrees C, 35 mbar) on plasma aldosterone (PA) patterns was studied and the respective roles of plasma renin activity (PRA), adrenocorticotropin (ACTH), Na+ and K+ concentrations in the control of PA response were in investigated in eight subjects on a low sodium diet and in five subjects on a high sodium diet. In all subjects, transitory PA increases of varying importance were observed, which were not related to sweat losses (less than 1% bodyweight) or to rectal temperature rise. In sodium-repleted subjects, basal PA and PRA levels as well as heat-induced rises were low (mean PA peak level = 12.62 +/- 1.15 ng/100 ml). They were enhanced by sodium depletion and PA reached a mean peak level of 34.07 +/- 2.73 ng/100 ml. But, in both conditions, the heat-induced PA peaks were 3-times higher than the initial levels. PA correlated with PRA in all but one of the sodium-repleted subjects and in 6 of the 8 sodium-depleted subjects. ACTH release, as measured by plasma cortisol (PC) levels, occurred in those subjects who noted an increased feeling of annoyance and discomfort. Thus, PA correlated positively with PC in 4 sodium-depleted subjects. A high sodium intake improved heat-tolerance. Plasma K+ and Na+ concentrations were not significantly modified by exposure to heat. PA increases can occur without concomitant changes in PRA, PC, K+ or Na+, which suggests that an additional factor may play a role in aldosterone regulation during acute heat exposure.     

Regulations of plasma aldosterone in young hyperkalemic patients with stable chronic renal failure.

In a group of four young patients with stable chronic renal failure and hyperkalemia sodium restriction induced a remarkable increase in plasma renin activity (PRA) and plasma aldosterone (PA), a decrease in the elevated serum potassium (SK) and a rise in potassium excretion. During high sodium intake the levels of PRA and PA were lower than those found in the healthy control group suggesting that enhanced suppressibility of the renin-angiotensin-aldosterone system (RAAS) was the main cause of hyperkalemia. During sodium restriction despite a marked increase in PRA and PA levels poor correlations were found between these variables indicating disorganisation within the RAAS and probably a diminished role for renin-angiotensin in the regulation of aldosterone production in three hyperkalemic patients with chronic glomerulonephritis. On the other hand, in the same patients significant correlations were found between fluctuations of SK and PA on constant normal and low sodium diets supporting the concept of an (at least) equal role of potassium and RAAS in the acute regulation of PA. A prominent role for SK was found in an unusual hyperkalemic patient with interstitial nephritis when PRA was suppressed and the elevated SK showed a definite postural rise inducing dramatic increases in PA in the upright posture. Reversion of the postural SK rise masked again the governing role of SK.     

Influence of physical training on blood pressure, plasma renin, angiotensin and catecholamines in patients with ischaemic heart disease

Eighteen patients with ischaemic heart disease were trained for 3 months, three times a week. The effectiveness of the training programme was demonstrated by increases of 27% in peak oxygen uptake and 29% in exercise duration, and by a decrease in resting and submaximal heart rates. Blood pressure, however, was not significantly affected during the training period. At rest and at submaximal exercise plasma renin activity (PRA) was lower after training. Plasma angiotensin I concentration (PA I) and angiotensin II concentration (PA II) were not significantly affected. Plasma aldosterone concentration (PAC), only measured at rest, was not significantly changed after the training period, while plasma norepinephrine (PNE) and epinephrine (PE) concentrations were significantly decreased, but only at high levels of exercise. A reduced sympathetic tone after training, suggested by the lower heart rates and the tendency to a decrease in PNE, is a likely explanation for the decrease in PRA. However, despite this decrease, PA I, PA II, and PAC were not significantly changed after training; the reason for this disrepancy is unknown.     

Renal effects of the acute inhibition of angiotensin-converting enzyme. I. 2) Studies during moderate potassium depletion]

We have investigated the relative roles of angiotensin II on the renal function and urinary excretion of some prostanoids in healthy women submitted to different conditions of potassium balance. To this aim we have evaluated the effects of an acute inhibition of angiotensin converting enzyme by enalapril (E). The renal function was explored by clearance (cl.) method during induced hypotonic polyuria (oral water load followed by 5% dextrose solution infusion). During 60 min cl. period the urinary PGE2, 6-keto-PGF1 alpha and TxB2 were determined by RIA method. Each subject received paired studies, in absence and presence of E (10 mg administered per os 1 hour before the water load). Basal values of plasma renin activity (PRA) and urinary aldosterone (excreted during the 24 hours before the water load) were also determined by RIA method. This study protocol was applied in normal potassium balance (n = 6) and induced moderate potassium depletion (n = 6). This paper concerns the group in potassium depletion in both absence (D4) and presence of E (D4.E). Potassium depletion was induced by adaptation to a normal sodium (150 mmol/d) and low potassium (< or = 10 mmol/d) dietary intake combined to natriuretic treatment. The water and NaCl net losses were restored by 0.9% NaCl solution infusion. The cumulative potassium deficit achieved at the end of the depletive treatment was 214 +/- 54 mmol. This treatment induced significant decrease in basal plasma potassium concentration and increase in PRA without affecting urinary aldosterone and plasma sodium concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of aldosterone on vascular angiotensin II receptors in the rat

The effect of aldosterone on the density and affinity of binding sites for 125I-labelled angiotensin II was investigated in a particulate fraction prepared from the rat mesenteric arteriolar arcades. The infusion of aldosterone 6.6 micrograms/h intraperitoneally via Alzet osmotic minipumps for 6 d produced an increase in the density of binding sites for 125I-labelled angiotensin II without change in affinity. After sodium depletion, mesenteric artery angiotensin II receptors were down-regulated as expected. An increase in the number of binding sites could be found when aldosterone was infused into sodium-depleted rats with no change in the elevated plasma renin activity. The intraperitoneal infusion of angiotensin II (200 ng X kg-1 X min-1 for 6 d) simultaneously with aldosterone resulted in down-regulation of vascular angiotensin II receptors, whereas after intravenous angiotensin II infusion (at 60 ng X kg-1 X min-1) the density of angiotensin II binding sites rose with aldosterone infusion. Plasma renin activity (PRA) was reduced and plasma angiotensin II increased in a dose-dependent fashion after angiotensin II infusion. An aldosterone concentration of 3 ng/mL for 18 h produced an increase in the number of angiotensin II binding sites in rat mesenteric artery smooth muscle cells in culture. We conclude that increased plasma aldosterone may result in up-regulation of vascular angiotensin II receptors independently of changes in plasma renin activity, and may in certain physiological states effectively antagonize the down-regulating action of angiotensin II.     

Comparison of the biological effects of two angiotensin II analogues in hypertensive patients with sodium depletion

The effects on blood pressure (BP), plasma aldosterone concentration (PAC) and plasma renin activity (PRA) of two angiotensin II analogues (AII A), i.e., 1-sarcosine, 8-isoleucine angiotensin II (Sar¹, I1e⁸-AII) and 1-sarcosine, 8-alanine angiotensin II (Sar¹, Ala⁸-AII), were investigated in patients with hypertension with various etiologies on sodium depletion. The changes of BP, PAC and PRA on infusion of Sar¹, Ile⁸-AII and Sar¹, Ala⁸-AII were very similar. With both compounds, there were significant inverse correlations between the pre-infusion PRA and the changes in BP and PAC, and a significant positive correlation between the pre-infusion PRA and change in PRA. The slopes of the regression lines for the correlations of changes in BP, PAC and PRA, plotted as functions of the pre-infusion PRA for Sar¹, Ile⁸-AII and Sar¹, Ala⁸-AII were not statistically different. In clinical investigations, the two compounds seemed equally useful for detecting renin-dependency in hypertension.     

Involvement of sodium retention hormones during rehydration in humans

We investigated the relation between involuntary dehydration and the mechanisms affecting Na+ retention in the body, focusing on the renin-angiotensin-aldosterone system. Six adult males were dehydrated to 2.3% of their body weight by an exercise-heat regimen, followed by rehydration (180 min) with tap water (H2O-R) or 0.45% NaCl solution (Na-R). We measured plasma renin activity (PRA) and aldosterone levels (PA) before dehydration (control), after dehydration, and at 60, 120, and 180 min of rehydration. During the 3-h rehydration period, subjects, restored 51% of the water lost during H2O-R and 71% during Na-R (P less than 0.05). Plasma volume was reduced by an average of 4.5% after dehydration. After 180 min of rehydration, plasma volume restoration during Na-R was to 174% of that lost, and during H2O-R it was to 78% of that lost. We found significant correlations between the change in plasma volume and PRA (r = -0.70, P less than 0.001) and between PRA and PA (r = 0.71, P less than 0.001). In both recovery conditions, PRA increased significantly after dehydration (P less than 0.05) and decreased almost to the control level by 180 min of rehydration, at which time the plasma volume deficit was restored. The change in PA paralleled that in PRA. The rate of sodium excretion was correlated with PA levels in both groups (r = -0.58, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The action of angiotensin on the isolated perfused cat heart

The effects of angiotensin I (AI) and angiotensin (AII) on myocardial contractility, heart rate and coronary perfusion were observed in the isolated perfused cat heart. AII (10^?11 mol) and AI (10^?10 mol) both caused slowly developing sustained increases in systolic pressure of approximately 55%. There were inconsistent small increases in heart rate. Coronary perfusion was initially diminished, but later increased to above control values during the positive inotropic effect. The actions of both AI and AII were blocked by 1 sar 8 ile AII (10^?9 mol). The converting enzyme inhibitors SQ 20881 (10^?8 mol) and SQ 14225 (10^?8 mol) blocked the effect of AI. The actions of AII or AI were not blocked by α or β adrenergic blockade or by prior treatment with reserpine.     

Effect of enalapril (MK-421), an orally active angiotensin I converting enzyme inhibitor, on blood pressure, active and inactive plasma renin, urinary prostaglandin E2, and kallikrein excretion in conscious rats

The angiotensin I converting enzyme (ACE) inhibitor enalapril (MK-421), at a dose of 1 mg/kg or more by gavage twice daily, effectively inhibited the pressor response to angiotensin I for more than 12 h and less than 24 h. Plasma renin activity (PRA) did not change after 2 or 4 days of treatment at 1 mg/kg twice daily despite effective ACE inhibition, whereas it rose significantly at 10 mg/kg twice daily. Blood pressure fell significantly and heart rate increased in rats treated with 10 mg/kg of enalapril twice daily, a response which was abolished by concomitant angiotensin II infusion. However, infusion of angiotensin II did not prevent the rise in plasma renin. Enalapril treatment did not change urinary immunoreactive prostaglandin E2 (PGE2) excretion and indomethacin did not modify plasma renin activity of enalapril-treated rats. Propranolol significantly reduced the rise in plasma renin in rats receiving enalapril. None of these findings could be explained by changes in the ratio of active and inactive renin. Water diuresis, without natriuresis and with a decrease in potassium urinary excretion, occurred with the higher dose of enalapril. Enalapril did not potentiate the elevation of PRA in two-kidney one-clip Goldblatt hypertensive rats. In conclusion, enalapril produced renin secretion, which was in part beta-adrenergically mediated.(ABSTRACT TRUNCATED AT 250 WORDS)     

19-hydroxyandrostenedione and 6 beta-hydroxyandrostenedione: new steroids regulated by the renin-angiotensin system in man

The changes of plasma 19-hydroxyandrostenedione (19-OH-A-dione) and 6 beta-hydroxyandrostenedione (6 beta-OH-A-dione) during the infusion of angiotensin II were evaluated and were compared with those of plasma aldosterone in man. Angiotensin II was infused into 5 normal subjects with an infusion pump at rates of 0.5, 1.0, 2.0 and 4.0 ng/kg per min. Each dose was infused for 20 min. Plasma 19-OH-A-dione rose significantly following the infusion of angiotensin II at a rate of 0.5 ng/kg per min and plasma 6 beta-OH-A-dione rose significantly following the infusion of angiotensin II at a rate of 1.0 ng/kg per min. In contrast, plasma aldosterone did not change significantly until the infusion rate reached 4.0 ng/kg per min. These results indicate that the secretion of 19-OH-A-dione and 6 beta-OH-A-dione is under the control of angiotensin II and the release of 19-OH-A-dione and 6 beta-OH-A-dione is induced earlier by the smaller doses of angiotensin II prior to the secretion of aldosterone. As 19-OH-A-dione and 6 beta-OH-A-dione amplify the action of aldosterone in bioassays using adrenalectomized rats and work as sodium-retaining and hypertensinogenic agents in intact rats, they are newly recognized biologically active steroids which are regulated by the renin-angiotensin system in man.