Effect of physiological levels of atrial natriuretic peptide on hormone secretion: inhibition of angiotensin-induced aldosterone secretion and renin release in normal man

Large doses of atrial natriuretic peptide (ANP) inhibit renin and aldosterone secretion in normal man, but the effect of physiological levels is unknown. We, therefore, studied the effect of a low infusion rate of alpha-human ANP (alpha hANP; 0.5 microgram/min for 180 min) on the plasma corticosteroid response to graded physiological doses of angiotensin II (0.5, 1.0, 2.0, and 4.0 ng/kg X min, each for 30 min) and ACTH (6.25, 12.5, 25, and 50 mIU, each for 30 min) in six normal men eating a low salt diet (10 mmol sodium and 100 mmol potassium daily). The angiotensin II and ACTH infusions were given from 0900-1100 h on separate days, during which randomized infusions of placebo or alpha hANP were given from 0800-1100 h according to a single blind protocol. Plasma immunoreactive ANP levels were less than 10 pmol/L on the placebo day compared to 30-50 pmol/L during the alpha hANP infusions, and were not altered by either ACTH or angiotensin II. Compared with the control observations, there was no significant change in arterial pressure or heart rate during either the alpha hANP or angiotensin II infusions. ACTH infusions evoked an incremental response in plasma aldosterone and cortisol, and the dose-response relationship was unaltered by alpha hANP. In contrast, while an incremental and significant increase in plasma aldosterone in response to angiotensin II occurred with the placebo infusion, no significant increase occurred in response to angiotensin during the alpha hANP infusion. The slope of the angiotensin II/aldosterone regression line was significantly less during all alpha hANP infusions compared to that during the placebo infusion (P less than 0.02). In addition, on the ACTH infusion day significant suppression of both PRA (P less than 0.05) and plasma angiotensin II (P less than 0.008) occurred during the alpha hANP infusion compared to that during the placebo infusion, whereas PRA was equally suppressed by angiotensin II in the presence or absence of alpha hANP. alpha hANP also increased urine volume [176 +/- 31 (+/- SEM) vs. 113 +/- 19 mL/mmol creatinine with placebo; P less than 0.03] and sodium excretion (2.14 +/- 0.48 vs. 0.58 +/- 0.22 mmol/mmol creatinine with placebo; P less than 0.004) on the ACTH infusion days. With angiotensin II, urine volume was also significantly increased by alpha hANP (150 +/- 27 vs. 81 +/- 15 mL/mmol creatinine with placebo; P less than 0.03), and urine sodium excretion doubled.(ABSTRACT TRUNCATED AT 400 WORDS)     

The Effects of Acth on the Renin-Aldosterone System in Normotensive Man

The present study examined the effects of low dose ACTH administration (0.1 mg/day for 2 days) on plasma renin concentration, (PRC), activity (PRA) and substrate (PRS), cortisol and aldosterone in man. Six healthy male volunteers on a diet calculated to contain 150 mmol Na/day received an infusion of 5% dextrose (6 ml/h) for 24 hours, then ACTH (Synacthen, Ciba-Geigy) was added to the infusion at the rate of 100 μg per day, for 48 h. Blood samples were taken four hourly for determination of plasma cortisol aldosterone, PRC, PRA and PRS. There was a highly significant increase in plasma cortisol and aldosterone concentrations during ACTH infusion compared with dextrose infusion, but no significant increase in active or inactive PRC, PRA or PRS. In a separate study of 15 healthy male volunteers, dexamethasone (1 mg at 2300 h) suppressed plasm a cortisol but had noeffecton PRC. These results do not support the view that stimulation of aldosterone by ACTH ismediated through the renin angiotensin system.     

Studies on the mechanism by which ACTH stimulates renin activity and angiotensin II formation in man

Ten IU of ACTH (1-24) per day was infused for 34 h (starting at 7 a.m.) into 8 normal men on a constant diet containing 135 mM Na+ per day. All subjects retained between 152 and 181 mM of sodium. Potassium balance was negative. Plasma renin activity (PRA) and plasmaangiotensin II (P-A-II) started to rise in most subjects after 6 to 8 h of infusion, reached a maximum after 24 h and then tended to decline. As shown previously, the rise in PRA is not due to a rise in plasma renin substrate concentration. Systolic, but not diastolic blood pressure increased significantly on the second day of ACTH-infusion. Plasma cortisol (P-F) was continuously stimulated by ACTH. Plasma aldosterone (P-aldo) increased rapidly 1 h after ACTH administration, then tended to fall, and increased again in most subjects, roughly in parallel with PRA. No significant changes in electrolyte balance, PRA, P-A II, P-F, and P-aldo occurred in 3 subjects receiving 'sham' infusions. Additional experiments in subjects treated with propranolol or indomethacin allowed the conclusion that the effect of ACTH on PRA and P-A II is not mediated by renal beta-adrenergic receptors, but perhaps (partially?) by prostaglandins. Since the infusion rate of ACTH was not much higher than the secretion rate of ACTH in the early morning hours, it is possible that ACTH is physiologically involved in the regulation of renin secretion.     

Prolonged ACTH infusion suppresses aldosterone secretion in spite of high renin activity

Five normal young males on a low sodium diet received iv ACTH (1-24) infusions (10 IU/24 h) for 100 h in addition to diuretics. The aim of the study was to find out whether the biphasic effect of ACTH on aldosterone (initial stimulation followed by 'escape') could be prevented by keeping plasma renin activity (PRA) at a fairly constant high level. PRA was around 20 ng/kg/min before and towards the end of the ACTH infusion. Plasma aldosterone and aldosterone excretion rates were, nevertheless, only transiently stimulated, but the first was relatively more suppressed than the latter at the end of the ACTH infusion. Plasma 18-OH-corticosterone followed the same pattern. Even on the last infusion day, aldosterone and 18-OH-corticosterone levels were still higher than in normal ambulatory sodium-replete men. The fasciculata steroids cortisol, 11-deoxycorticosterone and corticosterone were continuously stimulated by ACTH. It is concluded that the biphasic response of zona glomerulosa steroids to ACTH is basically independent of renin and angiotensin II. However, the marked suppression of aldosterone secretion observed in sodium-replete individuals during prolonged ACTH treatment was not seen in this study. Angiotensin II or a different factor associated with sodium depletion may, therefore, partly protect the zona glomerulosa from adverse effects of ACTH observed in the sodium-replete state.     

Effect of sodium balance and calcium channel-blocking drugs on plasma aldosterone responses to infusion of angiotensin II in normal subjects and patients with essential hypertension

To study the role of calcium movements in mediating the effects of sodium chloride on the response of plasma aldosterone to angiotensin II (AII), we administered calcium channel-blocking drugs (nifedipine and diltiazem) and calcium infusions to normal subjects during high and low sodium intakes before and after AII infusion. AII was also infused in 13 patients with essential hypertension eating a high sodium diet. In preliminary studies, the effects of nifedipine (20 mg, orally) on blood pressure, PRA, plasma aldosterone, and plasma cortisol concentrations were determined. Sensitivity to infused AII was calculated as the slope of the linear regression of the increase in plasma aldosterone as a function of the AII infusion rate (nanograms per dl/ng AII/kg X min). During sodium restriction (10 meq Na/day), both drugs significantly (P at least less than 0.05) reduced AII sensitivity. During the high sodium diet (200 meq Na/day), only diltiazem decreased AII sensitivity, and the reduction was less (P less than 0.05) than that during the low sodium diet. There was a significant (P less than 0.001) inverse correlation between the initial plasma aldosterone sensitivity to AII and the change in sensitivity induced by the calcium channel-blocking drugs in normal subjects (r = -0.89) and hypertensive patients (r = -0.70). Five hypertensive patients had greater than normal aldosterone sensitivity to AII, which was significantly (P less than 0.05) reduced by nifedipine. Calcium infusion increased the aldosterone sensitivity to AII during the low sodium diet, but not during the high sodium diet. The results suggest that in normal subjects, increased plasma aldosterone responses to AII induced by reduction in sodium intake are partially mediated by increased extracellular to intracellular calcium movements, since they are blocked by the structurally different calcium channel-blocking drugs nifedipine and diltiazem. In hypertensive patients eating a high sodium diet, increased aldosterone responses to AII infusion were blocked by nifedipine, indicating that they are at least partly mediated by increased extracellular to intracellular calcium flux.     

The role of adrenocorticotropin in the cortisol and aldosterone responses to angiotensin II in conscious dogs

The role of ACTH in the cortisol and aldosterone responses to iv angiotensin II (AII) infusion, (5, 10, and 20 ng kg-1 min-1) in dogs was evaluated by examining the effect of AII infusion in conscious dogs pretreated with dexamethasone to suppress endogenous ACTH secretion. AII infusion in untreated dogs produced dose-related increases in plasma cortisol and aldosterone concentrations. The plasma ACTH concentration also increased. Dexamethasone treatment lowered the basal cortisol concentration from 1.7 +/- 0.1 to 0.7 +/- 0.1 micrograms/dl (P less than 0.05) and the ACTH concentration from 52 +/- 3 to 41 +/- 4 pg/ml (P less than 0.05), and abolished the cortisol response to all doses of AII, indicating that ACTH was necessary for the response. On the other hand, the basal aldosterone concentration was not significantly affected by dexamethasone, although the aldosterone response to the highest dose of AII was reduced. Additional experiments were performed to determine if the cortisol and aldosterone responses to AII (20 ng kg-1 min-1) in dexamethasone-treated dogs are restored if the ACTH concentration is maintained near control levels by iv infusion of synthetic alpha ACTH-(1-24) (0.3 ng kg-1 min-1). AII still failed to increase the plasma cortisol concentration in this group of dogs; however, the aldosterone response was fully restored. To evaluate the effect of elevated ACTH levels on the steroidogenic effects of AII, dogs were treated with dexamethasone and a higher dose of ACTH (0.4 ng kg-1 min-1). This dose of ACTH increased the plasma cortisol concentration from 1.7 +/- 0.1 to 3.5 +/- 0.8 micrograms/dl (P less than 0.05), but did not significantly affect the plasma aldosterone concentration. In the presence of constant elevated levels of ACTH, AII (10 and 20 ng kg-1 min-1) increased the plasma cortisol concentration in dexamethasone-treated dogs, although the response to the 10 ng kg-1 min-1 dose was smaller than the response in untreated dogs. Infusion of AII at 5 ng kg-1 min-1 did not increase the plasma cortisol concentration. In contrast, the increased plasma aldosterone produced by AII infusion in dexamethasone-treated dogs was not altered in the presence of elevated ACTH levels. Finally, AII infusion did not alter the clearance of cortisol. Collectively, these results demonstrate that an increase in plasma ACTH is necessary for the cortisol response to AII infusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Lack of enhanced responsiveness of plasma 18-hydroxycorticosterone and aldosterone to adrenocorticotropin as well as to angiotensin-II during moderate sodium depletion in type II diabetic subjects with normoreninemia.

Responses of plasma aldosterone (PA) and its precursor steroids to alpha ACTH-(1-24) (85.2 nmol, iv) injection and graded angiotensin-II (AII) infusions (3.90 and 7.80 pmol/kg.min for 30 min at each dose) on both 170 and 100 mmol sodium intakes were assessed in 25 type II diabetic subjects with normoreninemia and 11 age-matched normal subjects. The diabetic subjects and the normal subjects did not differ in mean blood pressure, serum electrolytes, and creatinine clearance, except for an increase in fasting plasma glucose (P less than 0.001) in the diabetic subjects. A 100-mmol sodium intake for 4 days produced an increase in basal plasma renin activity (P less than 0.01), plasma 18-hydroxycorticosterone (18-OHB; P less than 0.05), and PA (P less than 0.05), and a decrease in urinary sodium excretion (P less than 0.001) in the two groups. These parameters were similar in the two groups. ACTH injection produced significant increases in plasma cortisol, plasma corticosterone, plasma 18-OHB, and PA (P less than 0.005 or P less than 0.001), and graded AII infusions produced significant increases in plasma 18-OHB and PA (P less than 0.05 or P less than 0.01) during both 170- and 100-mmol sodium intakes in the two groups. In the diabetic subjects, however, the responses of plasma 18-OHB and PA to both ACTH injection and graded AII infusions on a 100-mmol, but not on a 170-mmol, sodium intake were subnormal (P less than 0.05 or P less than 0.01) and were similar to those on a 170-mmol sodium intake. These results indicate a lack of enhanced responsiveness of plasma 18-OHB and PA to both ACTH and AII during moderate sodium restriction in nonazotemic type II diabetic subjects with normoreninemia. It appears that these subjects have selective unresponsiveness of adrenal zona glomerulosa to sodium depletion per se, but not to ACTH or AII.     

The Effects of Saralasin, an Angiotensin II Antagonist on Blood Pressure and the Renin-Angiotensin-Aldosterone System in Normal and Hypertensive Subjects

Summary: The effects of saralasin, an angiotensin II antagonist, on blood pressure and the renin-angiotensin-aldosterone system in recumbent normal and hypertensive subjects.
Blood pressure reduction with saralasin infusion was seen only in hypertensive patients with abnormally elevated basal plasma renin and angiotensin II levels, and after sodium depletion the reduction in blood pressure was more marked. In normal subjects, and in hypertensives with plasma renin and angiotensin II levels within the normal range, there was no marked fall in blood pressure across saralasin infusion regardless of the sodium status of the individual.
Plasma aldosterone concentration fell during saralasin infusion in those subjects with high baseline renin and angiotensin II levels. This fall occurred in the sodium replete and deplete states. In the normal subjects, and those hypertensives with normal plasma renin levels, there was no fall in aldosterone in the sodium replete state. However, after sodium depletion the expected rise in aldosterone was abolished during saralasin infusion, the plasma aldosterone falling to within the normal sodium replete range, rising again after the saralasin infusion was stopped.
This study supports the concept of a direct role for renin and angiotensin II in the maintenance of hypertension in those subjects with elevated basal plasma renin. Plasma aldosterone would appear to be controlled, at least in part, by the prevailing plasma angiotensin II level in those subjects with elevated basal levels of angiotensin II; that is in high renin hypertensives, and in normal subjects and normal renin hypertensives who are sodium deplete.     

Effects of angiotensin II infusion on the early morning surge of ACTH and o-CRH-provoked ACTH secretion in normal man

The question of whether elevated plasma angiotensin II (AII) levels modulate ACTH secretion in man still awaits a definite answer. We performed two sets of experiments pertinent to that problem: Seven healthy young males each received AII (5 ng/kg/min) and sham infusions on different days in a randomized sequence from 03.00 h to 06.00 h in the morning, while plasma ACTH and cortisol were measured every 20 min. Mean blood pressure rose by about 10 mmHg during AII infusion. Mean plasma ACTH levels were slightly higher with AII than with sham infusion in every single individual (P less than 0.05). Differences in a pre- and post-infusion period were significant. Plasma cortisol levels were almost identical with or without AII infusion. Nine healthy young males received AII (5 ng/kg/min) or sham infusions on different days from 16.30 h to 20.00 h in a randomized sequence and a 100 micrograms o-CRH injection at 17.00 h. Plasma ACTH and cortisol were measured every 15 or 30 min between 16.30 h and 20.00 h. Mean blood pressure rose by about 14 mmHg during AII infusion. The rapid increment and further change in plasma ACTH and cortisol was not significantly different between the AII and sham infusion studies. Conclusions: The dose of AII infused was probably just above the threshold of ACTH stimulation, although AII plasma levels obtained were probably far above the physiological range. On the adrenal level, a vasoconstrictor effect of AII may have prevented stimulation of cortisol. This may be different in states of sodium depletion with reduced vascular effects of AII.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of the factors modulating antidiuretic hormone excretion in man in response to the osmolar stimulus: effects of oestrogen and angiotensin II

The aim of this study was to assess the influence of hormones known to regulate fluid and electrolyte balance on the release of antidiuretic hormone induced by raising serum osmolality. The stimulus provoked by the infusion of a 2.5% NaCl solution induces an increase of urinary [arginine-8]-vasopressin from 1.12 to 2.64 ng/h in men and from 1.65 to 7.27 ng/h in women as has been previously reported. These results were compared to those obtained in males infused with angiotensin II (AII) before and during a hypertonic sodium load and in males infused with hypertonic saline on the fourth day of administration of ethinyl-oestradiol. During the combined infusion of AII and then hypertonic saline, the mean hourly urinary excretion of AVP increased from 2.8 to 5.67 ng/h. Within each group the increase of urinary AVP was highly significant. The rise of urinary AVP during AII infusion was significantly different from the rise observed both in untreated males and untreated females, lying in between. The mean hourly excretion rate of AVP increased before and after hypertonic saline loading from 2.65 to 5.3 ng/h in males pre-treated with ethinyl-oestradiol. The significant difference observed between males and females is reduced when males treated with oestrogen were compared to female subjects. In each group plasma renin activity decreased to low values during the salt-loading test. During oestrogen treatment PRA and plasma renin substrate rose, while urinary aldosterone remained almost unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endogenous angiotensin-aldosterone-pressure relationships during sodium restriction

The effects of moderate restriction of dietary sodium and potassium supplementation on plasma levels of renin, angiotensin II, aldosterone, and cortisol and on arterial pressure were studied in 12 patients with mild essential hypertension. To define hormone-blood pressure relationships, venous hormone levels were measured hourly and intra-arterial pressure continuously for 24 hours after 4 to 6 weeks of sodium restriction, 4 to 6 weeks of potassium supplementation, and a similar period of control diet. Our results show that compared with the control diet, moderate sodium restriction was associated with increased levels of aldosterone but no overall change in renin, angiotensin II, or cortisol levels. Further, slopes of regression lines relating log renin and log angiotensin II to aldosterone were increased, as were log cortisol/aldosterone regression lines. On the contrary, regression lines of log renin and log angiotensin II versus arterial pressure were unaltered by sodium restriction. Hormone and blood pressure relationships were not changed by the potassium supplemented diet. Although confirmatory data are needed, our findings suggest that moderate sodium restriction enhances aldosterone responsiveness to endogenous angiotensin II and adrenocorticotropic hormone without diminishing the pressor activity of endogenous angiotensin II. These results may explain in part the disappointingly small hypotensive effect of modest sodium restriction in mild essential hypertension.     

Adrenocorticotropin-stimulated secretion of aldosterone and cortisol, computed from plasma and red blood cell measurements.

The dynamic response of the adrenal cortex to ACTH infusion is analyzed by simulating the distribution, binding, and metabolism of cortisol and aldosterone in a multicompartmental model. The model includes the effects of temperature and cortisol concentration on aldosterone binding in plasma and the distribution between plasma and red blood cells, as verified by new observations. The secretion rates of cortisol and aldosterone were computed from serial measurements of plasma concentrations of endogenous steroids and infused tracers. The model was validated by observations after iv injection of a bolus of cortisol. Nineteen normal volunteers were studied on the fourth day on a diet containing 10 meq sodium. Endogenous ACTH was suppressed by dexamethasone, and alpha-1-24ACTH was infused at two different rates in various sequences over a 4-h period. During each hour of constant ACTH infusion, plasma cortisol continued to increase, while plasma aldosterone rose quickly, reaching a plateau within 20--30 min. Cortisol secretion approached a maximim rate after 20--30 min of ACTH infusion; the continued increase of plasma cortisol resulted from the slow equilibrium with other compartments. Aldosterone secretion rose quickly to a peak and then declined to a lower level after 20 min of ACTH infusion; the lower rate of secretion was maintained for the duration of the constant infusion of ACTH, falling abruptly within a few minutes after stopping the infusion. The characteristic differences in plasma steroid responses to various sequences of ACTH infusions can be explained by the more rapid changes in aldosterone secretion and the different clearance rates of cortisol and aldosterone, which vary with plasma cortisol concentration. The temperature at which blood is separated significantly affects plasma aldosterone measurements.     

Potassim-aldosterone-renin interrelationships.

The present study was performed to assess the sensitivity of the renin-angiotensin-aldosterone axis to small changes in plasma potassium concentration within the physiologic range. Small increments in potassium levels were accomplished by graded constant infusions of potassium chloride over 2 h (0.17 meq/min; 0.33 meq/min; 0.5 meq/min) in 8 normal subjects on a 10 meq sodium-100 mgq potassium intake. Plasma levels of aldosterone, renin activity, angiotensin II, cortisol, potassium and sodium were measured at frequent intervals. There were no significant changes observed in plasma sodium, renin activity or angiotensin II levels while cortisol levels declined in the expected diurnal pattern. During the 0.17 meq/min (10 meq/h) infusion potassium levels did not increase significantly until 120 min while plasma aldosterone levels rose significantly at 30-60 min. The mean increment above control during the lowest infusion rate was 0.2 meq/liter (5%) for plasma potassium and 13 ng/100 ml (46%) for plasma aldostreone. Although there was a stepwise increase in the increments above control of both potassium and aldosterone levels as the rate of the infusion was increased, the most sensitive area of the dose response curve appears to be 0.1-0.5 meq/liter. in six normal subjects the potassium-lowering effect of glucose ingestion (0.25 g/kg/15 min over a 2-h period) was assessed. The mean maximal potassium decrement below control 0.3 meq/liter (8%) at 90 min was coincident with the mean plasma aldosterone decrement below control of 11 ng/100 ml (46%). Plasma aldosterone then rose to peak levels at 180 min (mean increment 22 ng/100 ml above nadir) while potassium levels remained below control. The rise in plasma aldosterone was associated with a parallel but more rapid rise in plasma renin activity, peaking at a level 108% above control. Ninety minutes after the termination of the glucose ingestion, plasma aldosterone returned to control levels but now in the setting of reduced levels of plasma potassium and elevated levels of plasma renin activity. The data support an important role for physiologic changes in extracellular potassium concentration in the control of aldosterone secretion and indicate that interpretation of studies assessing acute changes in plasma aldosterone must carefully consider minor simultaneous changes in plasma potassium levels. The data also document that acute changes in extracellular potassium concentration play a role in the regulation of renin secretion.     

DOPAMINERGIC BLOCKADE OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM: EFFECT OF HIGH AND LOW SODIUM INTAKES

Recent investigations suggest that dopamine inhibits aldosterone secretion. To test the hypothesis that dopamine contributes to the reduced aldosterone secretion on a high sodium intake, eight normal subjects were studied in metabolic balance on both 200 and 10 mmol sodium diets. On each diet, the subjects received a constant 4 h intravenous infusion of the dopamine antagonist, metoclopramide (MCP). Although MCP significantly increased plasma aldosterone (PA) throughout the infusion on both diets, the maximum increment in PA was greater on the low (37 +/- 5 ng/dl) than on the high (14 +/- 4 ng/dl) sodium intake (P less than 0.02). The greater response on the low sodium intake could not be ascribed to changes in potassium, cortisol or ACTH. However, plasma renin activity (PRA) and angiotensin II (AII) levels were significantly (P less than 0.01) increased by MCP while on the low but not the high sodium intake. We conclude that the rise in PA while on a high sodium intake reflects dopaminergic antagonism by MCP directly at the level of the adrenal gland. On the low sodium intake, the enhanced PA response to MCP probably reflects both a direct adrenal effect and an indirect effect mediated via activation of the renin-angiotensin system.     

Dose effect of adrenocorticotropin on aldosterone and cortisol biosynthesis in cultured bovine adrenal glomerulosa cells: in vitro correlate of hyperreninemic hypoaldosteronism.

In some critically ill patients, aldosterone secretion is diminished despite hyperreninemia. These same patients demonstrate appropriately elevated plasma ACTH and cortisol levels. In addition, infusion of ACTH or angiotensin-II (AII) fails to elicit the normal aldosterone response, implying that the defect is at the level of the zona glomerulosa (ZG) cell. To test the hypothesis that elevated ACTH levels induce this defect, Percoll-purified bovine ZG cells were plated in serum-free defined medium and cultured for 5 days. On days 1-4, cells were exposed to various concentrations of ACTH for 1 h. On the fifth day of culture, half of the wells pretreated with ACTH were treated for 1 h with AII (10(-7) M); the other half of the wells received another dose of ACTH for 1 h. Additionally, cells were exposed to daily 1-h pulses of AII (10(-7) M) alone or in combination with ACTH (10(-8) M) for 5 days. Acutely dispersed bovine ZG cells showed dose-dependent increases in aldosterone when incubated with ACTH, potassium, or AII, with minimal cortisol production. Acutely dispersed bovine fasciculata cells produced no aldosterone, but demonstrated a dose-dependent cortisol response to ACTH and AII, but not potassium. On day 1 of culture, the ZG cells demonstrated a significant (P less than 0.001 in all cases) dose-related increase in aldosterone secretion in response to ACTH. However, continued daily pulsation with ACTH resulted in a dose-dependent decrease in aldosterone secretion, with a concomitant dose- and time-related rise in cortisol production. Indeed, ACTH-induced cortisol production in ZG became similar to ACTH-induced cortisol production in zona fasciculata cells. The addition of AII to the daily ACTH pulse did not significantly alter the aldosterone or cortisol response patterns to ACTH alone. In contrast, ZG cells treated with AII alone for 5 days showed a minimal change in cortisol production and no reduction in aldosterone production until day 4. Northern blot analysis of total RNA isolated from ZG cells pulsed with ACTH for 5 days demonstrated a parallel dose-dependent increase in 17 alpha-hydroxylase mRNA, which did not occur in cells pulsed with AII alone. These in vitro results suggest that elevated ACTH levels over time induce 17 alpha-hydroxylase activity in ZG cells, thereby shifting steroid biosynthesis from an aldosterone-producing to a cortisol-producing pathway. It is likely that the chronically elevated ACTH levels in critically ill patients induce a similar change in ZG cell biosynthesis, resulting in their hyperreninemic hypoaldosterone state.     

Selective hypopituitarism with severe hyponatremia and secondary hyporeninism.

A female patient presenting clinically a severe hyponatremia was found to have a selective hypopituitarism with predominant ACTH and partial FSH, LH, and GH deficiency as well as a suppression of plasma renin activity and aldosterone. The adrenal cortex responded well in cortisol increase to ACTH infusion and in plasma aldosterone increase to angiotensin II infusion. The patient had pressor hyperreactivity to angiotensin II. The hyponatremia was caused by a negative sodium balance induced by excessive urinary loss which remained unaffected by mineralocorticoid treatment. Substitution doses of cortisol, however, corrected the disturbance with an increase in plasma renin activity and improvement in the sodium balance. The data are interpreted as indicating a direct or indirect regulatory (permissive?) effect of low doses of cortisol on plasma renin activity correcting the underlying disturbance--the secondary hyporeninism.     

Intracerebroventricular atrial natriuretic peptide infusion augments the adrenocorticotropin and angiotensin II responses to hemorrhage in sheep

The central actions of atrial natriuretic peptide (ANP) in rats include inhibition of arginine vasopressin (AVP) release, and less consistently, ACTH suppression and hypotension. To explore any such inhibitory actions on basal and stimulated levels of AVP and ACTH, we have studied the effect of intracerebroventricular (ICV) infusion of ANP on the hemodynamic and hormonal response to acute hemorrhage in conscious sheep. Two groups of 5 sheep received rat ANP(101-126) by ICV infusion (0.5 microgram bolus followed by 0.5 microgram/h for 3 h, or 5 micrograms bolus followed by 5 micrograms/h for 3 h) as well as artificial cerebrospinal fluid control infusions in random order. One hour after the start of the ICV infusion, acute hemorrhage (15 ml/kg BW within 10 min) was performed. Basal levels before hemorrhage of mean arterial pressure (MAP), heart rate and plasma hormones were unaltered by either dose of ICV ANP. After hemorrhage, the fall in MAP and rise in heart rate were similar in each group. However, compared to control infusions the response to hemorrhage of ACTH (433 +/- 147 to 2,175 +/- 588 vs. control 541 +/- 103 to 893 +/- 244 ng/l; p less than 0.016) and angiotensin II (AII) (18 +/- 3 to 94 +/- 23 vs. control 18 +/- 4 to 58 +/- 8 pmol/l; p less than 0.001) were significantly greater during high-dose ANP infusion. Although peak AVP levels more than doubled those observed on the control day, the increase did not reach statistical significance (p less than 0.1053). Plasma concentration of cortisol, aldosterone, epinephrine and norepinephrine were not significantly different in control and ANP-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal, hemodynamic, and hormonal responses to atrial natriuretic peptide infusions in normal man, and effect of sodium intake

The effect of 60-min constant iv infusions of alpha-human atrial natriuretic peptide (alpha hANP; 200 micrograms), sufficient to increase the steady state venous plasma alpha hANP concentration to levels found in patients with some circulatory disorders, was studied in six normal men equilibrated on a high sodium diet (200 mmol daily) and again when equilibrated on a low sodium intake (10 mmol daily). In each instance, the responses to alpha hANP were compared to those to control infusions given on the preceding day. The mean steady state plasma immunoreactive ANP concentration during the infusions was 320 pmol/liter and was the same during both diets. Thus, the MCR of alpha hANP was unaffected by major changes in sodium intake. Compared to control day observations, infusions of alpha hANP induced a more than 3-fold increase in sodium excretion and at least a 2-fold increase in urine volume and calcium and magnesium excretion in subjects ingesting 200 mmol sodium daily. During the low sodium diet, alpha hANP was still diuretic and induced comparable magnesium excretion, but the natriuresis was only 11% of that during the high salt diet. No significant changes in blood pressure or heart rate occurred during alpha hANP infusions during either diet, although during both diets there was a significant rise in plasma norepinephrine (P less than 0.02), which persisted well beyond the disappearance of immunoreactive ANP from plasma. Despite this sympathetic activation, renin and aldosterone production was reduced by alpha hANP. During low salt intake, alpha hANP significantly decreased PRA (mean pretreatment, 1.79; posttreatment, 1.25 nmol/liter/h; P less than 0.03), angiotensin II (mean pretreatment, 49; posttreatment, 28 pmol/liter; P less than 0.008), and plasma aldosterone (mean pretreatment, 554; posttreatment 307 pmol/liter; P less than 0.007), whereas values during control infusions did not change. Similar percent decreases in PRA and aldosterone also occurred during the high salt diet. Plasma cortisol and arginine vasopressin did not change during the alpha hANP infusions on either diet. We conclude that steady state levels of alpha hANP in plasma, similar to those in patients with some circulatory disorders, significantly increase sodium excretion and inhibit all elements of the renin-angiotensin-aldosterone system. The natriuretic, but not the hormonal or chronotropic, effects of alpha hANP are reduced by sodium depletion in normal man.     

Blood Pressure and Metabolic Effects of ACTH in Normotensive and Hypertensive Man

ACTH administration (0.5 mg Synacthen Depot I/M 12 hourly for 5 days) significantly increased systolic blood pressure in normotensive subjects (n=6) and mild essential hypertensives (n=6) but not in 2 Addisonian women, indicating that the pressure rise was adrenally dependent. ACTH administration was associated with urinary sodium retention, hypokalaemia, elevation of fasting blood glucose, lymphopaenia and eosinopaenia. Body weight was increased only in the normotensive subjects. Plasma renin concentration fell and renin substrate rose. Inactive renin fell in the hypertensive subjects only. Plasma cortisol, 11-deoxycortisol, corticosterone, deoxycorticosterone, 17α-hydroxyprogesterone and 17-hydroxy, 20-dihydroprogesterone were all increased by ACTH treatment. Plasma aldosterone rose initially in the normotensives but then fell. ACTH administration in man produces metabolic and hormonal changes similar to those produced by ACTH in sheep but the rise in bloodpressure is systolic only in man. The steroid(s) responsible for the blood pressure rise with ACTH in man have not been defined.     

The Effect of Captopril on Renin,Angiotensin II,Cortisol and Aldosterone During Acth-Infusion in man

Prolonged low-dose ACTH infusion (5 or 10 iU/24h) leads to a transient increase in plasma renin activity and angiotensin II concentration in normal man. In order to find out whether the increase in angiotensin II stimulates aldosterone secretion, 12 normal men received ACTH (10 IU/24h) for 34 hours altogether, 6 with and 6 without simultaneous administration of captopril, 50 mg every 6 hours.

Captopril prevanted the increase in plasma angiotensin II during ACTH infusion and lowered its levels below those on the control day two hours after a new dose of the converting enzyme inhibitor was given. The increase in plasma cortisol was similar in both groups. The increase in plasma aldosterone was significantly blunted by captopril. The early blood pressure rise and the kaliuresis during ACTH infusion were also significantly decreased in the captopril group. These results suggest that angiotensin II mediates in part the effect of ACTH on aldosterone and blood pressure during the first 2 days of infusion. Since captopril reduced plasma angiotensin II for some time below normal, it is alternatively possible that ACTH requires normal plasma angiotensin II levels for a full effect on aldosterone secretion.