Hypertension, hypokalemia and hypoaldosteronism with suppressed renin: a clinical study of a patient with Liddle's syndrome

A 24-yr-old woman with hypertension, hypokalemic alkalosis, low plasma renin and hypoaldosteronism was studied. Plasma aldosterone, renin and potassium returned to normal and blood pressure fell after sodium restriction or the administration of triamterene. Thiazide therapy also normalized her blood pressure while dexamethasone, spironolactone and furosemide did not improve her symptoms. Plasma aldosterone levels were low and responded poorly to a short term ACTH injection, but responded well to the maximal adrenal stimulation by ACTH-Z. Plasma levels of cortisol, corticosterone and deoxycorticosterone were within the normal range. Adrenal scintigram with 131I-adosterol and abdominal computed axial tomography did not reveal the presence of a sizeable adrenal tumor. In addition, the urinary kallikrein excretion was low after sodium restriction and showed no response to saline infusion. These findings suggest that the excessive secretion of unusual mineralocorticoids may not exist in this case. From these observations and the results of the therapeutic responses to the diuretic agents, we conclude that the primary cause of the disorder of this patient seems to be a renal defect in the distal tubule in handling sodium and potassium which is similar to that in Liddle's syndrome.     

Synergic effects of kallikrein-kinin and prostaglandins on renin release on infusion of isolated hog kidney with aldosterone

The effects of infusion of a large amount of aldosterone into the renal artery of isolated perfused hog kidney on the release of renin, prostaglandins (PG) and kinin and the excretion of urinary kallikrein were investigated. Infusion of aldosterone at a rate of 100 ng/min (100 to 800 ng/ml of perfusate) resulted in significant releases of renin, PG (PGE₂, 6-0-PGF_1α), and kinin and increase in urinary kallikrein. Infusion of aldosterone and an inhibitor of kallikrein, aprotinin, decreased the releases of renin, PG and kinin and infusion of aldosterone with indomethacin decreased the release of PG but increased that of kinin and urinary kallikrein without significant change in renin releases. These findings suggest that the release of renin by aldosterone may result from synergic effects of renal PG and the kallkrein-kinin system.     

Relationships among urinary kallikrein, mineralocorticoids and human hypertensive disease.

Urinary kallikrein excretion is reduced in patients with hypertension of unknown etiology. In addition, the excretion of this renal, kinin-forming enzyme was found to be elevated in hypertensive patients with primary aldosteronism. Aldosterone regulates kallikrein excretion, as normal subjects show increased kallikrein excretion in response to a low sodium intake, high potassium intake, or the synthetic mineralocorticoid, fludrocortisone, whereas kallikrein excretion falls during treatment with spironolactone. The relationship between kallikrein excretion and aldosterone activity may directly reflect the intrarenal activity of the kallikrein-kinin system, as determined by studies of kallikrein levels from isolated renal cells or of plasma kinin levels in man in response to postural changes or saline loads. Some patients with essential hypertension do not show a normal increase in kallikrein excretion in response to low dietary sodium intake despite an apparently normal aldosterone response, suggesting that there may be a defect in the renal kallikrein-kinin system in these patients. Whether these findings are of pathogenetic significance in human hypertensive disease remains to be determined.     

Renal responsiveness to aldosterone during exposure to head-down tilt bedrest

The kidneys represent a fundamental organ system responsible in part for the control of vascular volume. A 10% to 20% reduction in plasma volume is one of the fundamental adaptations during exposure to low gravity environments such as bedrest and space flight. Bedrest-induced hypovolemia has been associated with acute diuresis and natriuresis. Elevated baseline plasma renin activity and aldosterone levels have been observed in human subjects following exposure to head-down tilt and spaceflight without alterations in renal sodium excretion. Further, attempts to restore plasma volume with isotonic fluid drinking or infusion in human subjects exposed to head-down bedrest have failed. One explanation for these observations is that renal distal tubular cells may become less sensitive to aldosterone following exposure to head-down tilt, with a subsequent reduction in renal capacity for sodium retention. We hypothesized that elevated sodium and water excretion observed during prolonged exposure to bedrest and the subsequent inability to restore body fluids by drinking might be reflected, at least in part, by reduced renal tubular responsiveness to aldosterone. If renal tubular responsiveness to aldosterone were reduced with confinement to bedrest, then we would expect measures of renal sodium retention to be reduced when a bolus of aldosterone was administered in head-down tilt (HDT) bedrest compared to a control experimental condition. In order to test this hypothesis, we conducted an investigation in which we administered an acute bolus of aldosterone (stimulus) and measured responses in renal functions that included renal clearances of sodium and free water, sodium/potassium ratio in urine, urine sodium concentration, and total and fractional renal sodium excretion.     

Salt intake and depletion increase circulating levels of endogenous ouabain in normal men

High-salt diets elevate circulating Na+ pump inhibitors, vascular resistance, and blood pressure. Ouabain induces a form of hypertension mediated via the alpha2-Na+ pump isoform and the calcium influx mode of the vascular sodium calcium exchanger (NCX). Whereas elevated levels of an endogenous ouabain (EO) and NCX have been implicated in salt-sensitive hypertension, acute changes in sodium balance do not affect plasma EO. This study investigated the impact of longer-term alterations in sodium balance on the circulating levels and renal clearance of EO in normal humans. Thirteen normal men consumed a normal diet, high-salt diet, and hydrochlorothiazide (HCTZ), each for 5-day periods to alter sodium balance. EO and other humoral and urinary variables were determined daily. On a normal diet, urinary sodium excretion (140 +/- 16 meq/day), plasma EO (0.43 +/- 0.08 nmol/l) and urinary EO excretion (1.04 +/- 0.13 nmol/day) were at steady state. On the 3rd day of a high-salt diet, urine sodium excretion (315 +/- 28 meq/day), plasma EO (5.8 +/- 2.2 nmol/l), and the urinary EO excretion (1.69 +/- 0.27 nmol/day) were significantly increased, while plasma renin activity and aldosterone levels were suppressed. The salt-evoked increase in plasma EO was greater in older individuals, in subjects whose baseline circulating EO was higher, and in those with low renal clearance. During HCTZ, body weight decreased and plasma renin activity, aldosterone, and EO (1.71 +/- 0.77 nmol/l) rose, while urinary EO excretion remained within the normal range (1.44 +/- 0.31 nmol/day). Blood pressure fell in one subject during HCTZ. HPLC of the plasma extracts showed one primary peak of EO immunoreactivity with a retention time equivalent to ouabain. High-salt diets and HCTZ raise plasma EO by stimulating EO secretion, and a J-shaped curve relates sodium balance and EO in healthy men. Under normal dietary conditions, approximately 98% of the filtered load of EO is reabsorbed by the kidney, and differences in the circulating levels of EO are strongly influenced by secretion and urinary excretion of EO. The dramatic impact of high-salt diets on plasma EO is consistent with its proposed role as a humoral vasoconstrictor that links salt intake with vascular function in hypertension.     

Effect on maternal and fetal renal function and plasma renin activity of a high salt intake by the ewe

The effect on renal function of replacing maternal drinking water with a solution containing 0.17 M NaCl was studied in 9 ewes and their chronically catheterised fetuses over a period of 9 days. Maternal sodium intake increased from control values of 2.19 +/- 0.09 mmol/h to 44.3 +/- 7.4 (P less than 0.001) and 46.3 +/- 6.5 mmol/h (P less than 0.001) on the 3rd and 6th days of salt ingestion. Maternal plasma sodium levels were not affected, but the urinary sodium/potassium ratio increased from 0.15 +/- 0.07 to 2.26 +/- 0.34 (P less than 0.001) after 6 days and plasma renin activity fell from 2.87 +/- 0.76 to 1.00 +/- 0.25 ng/ml per h (P less than 0.05). The changes in maternal sodium intake had no effect on fetal plasma sodium levels nor on fetal plasma renin activity. Sodium excretion and fetal urinary sodium/potassium ratio did not change. However, 3 days after the ewes returned to drinking water fetal plasma renin activity was significantly higher than it was prior to maternal ingestion of 0.17 M NaCl. Fetal plasma renin activity was inversely related to fetal plasma sodium levels (P less than 0.01). The results show that changes in maternal sodium intake had no long term effect on fetal plasma sodium levels nor on fetal renal sodium excretion. The fall in maternal plasma renin activity in the absence of any change in the fetal renin activity, indicates that the fetal renin angiotensin system is controlled by factors other than those influencing the maternal renin angiotensin system. Since fetal urinary sodium/potassium ratios remained unchanged it would suggest that fetal sodium excretion is not influenced by maternal levels of aldosterone.     

Atrial natriuretic peptide administration to normal and salt depleted rats--effects on digoxin-like immunoreactive factor, aldosterone, ACTH, and renal function

In view of the known interrelationships between renin, aldosterone, and atrial natriuretic peptide (ANP), we sought to examine whether there also exists an interaction between ANP and digoxin-like immunoreactive factor (DLIF). We therefore studied the effects of ANP administration on normal and salt-depleted rats, and measured the effects on blood pressure, urine output, glomerular filtration rate, sodium excretion, aldosterone, ACTH, and DLIF levels. ANP administration resulted in a significant elevation of sodium excretion and glomerular filtration rate and a fall in blood pressure. DLIF concentrations in plasma rose significantly, as did urinary DLIF excretion. ANP administration resulted in a fall in aldosterone as well as ACTH. These observations suggest that ANP has a direct inhibitory effect on ACTH secretion. Our findings support the concept of an interrelationship between ANP and DLIF.     

Sex differences in prenatal programming of hypertension by dexamethasone

Prenatal dexamethasone has been shown to increase blood pressure in male offspring but the mechanism for the increase in blood pressure is unclear. The present study examined if prenatal programming by maternal injection of dexamethasone on days 15 and 16 of gestation affected the blood pressure comparably in female and male offspring. Our hypothesis was that males would be affected by prenatal dexamethasone to a greater extent than females and that either an increase in renal tubular transporter abundance or an increase in renin or aldosterone system would be associated with hypertension with prenatal programming. Prenatal dexamethasone increased blood pressure at two months and six months of age and resulted in proteinuria and albuminuria at six months in male but not female rat offspring. There was no effect of prenatal dexamethasone on blood pressure and proteinuria at one month in male and in female offspring. While prenatal dexamethasone increased male renal thick ascending limb sodium potassium two chloride cotransporter protein abundance at two months, prenatal dexamethasone on days 15 and 16 of gestation did not affect transporter abundance in males at other ages, nor did it affect proximal tubule sodium/hydrogen exchanger or distal convoluted tubule sodium chloride cotransporter protein abundance at any age. There was no difference in systemic renin or aldosterone in the prenatal dexamethasone group compared to same sex controls. In conclusion, male but not female offspring have an increase in blood pressure and urinary protein excretion with prenatal dexamethasone. The increase in blood pressure with prenatal programming was not associated with a consistent increase in renal tubular transporter protein abundance, nor plasma renin activity and serum aldosterone.     

Circulation, kidney function, and volume-regulating hormones during prolonged water immersion in humans.

To investigate whether prolonged water immersion (WI) results in reduction of central blood volume and attenuation of renal fluid and electrolyte excretion, these variables were measured in connection with 12 h of immersion. On separate days, nine healthy males were investigated before, during, and after 12 h of WI to the neck or during appropriate control conditions. Central venous pressure, stroke volume, renal sodium (UNaV) and fluid excretion increased on initiation of WI and thereafter gradually declined but were still elevated compared with control values at the 12th h of WI. Atrial natriuretic peptide (ANP) concentration in plasma initially increased threefold during WI and thereafter declined to preimmersion levels, whereas plasma renin activity, plasma aldosterone, and norepinephrine remained constantly suppressed. It is concluded that, compared with the initial increases, central blood volume (central venous pressure and stroke volume) is reduced during prolonged WI and renal fluid and electrolyte excretion is attenuated. UNaV is still increased at the 12th h of WI, whereas renal water excretion returns to control values within 7 h. The WI-induced changes in ANP, plasma renin activity, plasma aldosterone, and norepinephrine may all contribute to the initial increase in UNaV. The results suggest, however, that the attenuation of UNaV during the later stages of WI is due to the decrease in ANP release.     

Urine dopamine in starving obese subjects

In seven obese female subjects undergoing a period of therapeutic starvation, the excretion of sodium, potassium and dopamine and plasma levels of renin and aldosterone were measured. Sodium excretion increased during starvation and was maximal on the 2nd day. The urinary excretion of dopamine was significantly higher on day 4 and it remained elevated till the end of the study. Plasma renin activity and plasma aldosterone levels were also higher on the 4th-6th days of starvation. These findings suggest that dopamine may not play a significant role in the natriuresis of starvation.     

Role of atrial natriuretic peptide in mineralocorticoid escape phenomenon in patients with primary aldosteronism

The withdrawal effect of spironolactone treatment on natriuresis was studied in relation to atrial natriuretic peptide (ANP) in five patients with primary aldosteronism due to adenoma. The patients had been treated with spironolactone for 2-3 months before they were admitted. After admission, blood pressure, body weight, and urinary excretion of sodium were measured daily. Venous samples were obtained twice a week for measurements of plasma levels of ANP, plasma renin activity (PRA), and plasma concentrations of aldosterone (PAC), cortisol, and deoxycorticosterone. The study was performed for 7 days during the treatment with spironolactone and for 18 days after stopping the administration. Plasma volume was determined two times, during the control period and on the 13th day after stopping spironolactone. Urinary sodium excretion decreased initially and returned to the control levels successively. Body weight and plasma volume increased, and blood pressure rose steadily. PRA and the plasma concentrations of cortisol and deoxycorticosterone decreased significantly (P less than 0.05); however, high levels of PAC did not alter significantly. Plasma ANP levels increased significantly (P less than 0.05) from 26 +/- 4 pg/ml during the control period to 195 +/- 47 pg/ml on the 13th day after stopping spironolactone. The data of the urinary sodium excretion showed the escape from sodium-retaining effect of aldosterone, and this escape could be explained by the increase in plasma ANP. Furthermore, ANP might contribute to the decrease in cortisol and deoxycorticosterone in plasma because of the direct inhibitory action of ANP on steroidogenesis.     

Role of endogenous ANP on endocrine function investigated with a monoclonal antibody

Substantial volume expansion in conscious rats induces a strong natriuresis, cyclic GMP excretion, increase in cyclic GMP in plasma and kidney tissue, decrease in plasma renin activity and plasma aldosterone concentration. These effects are directly related to an increase in plasma levels of atrial natriuretic peptides. The renal response and the changes in plasma and kidney cyclic GMP, plasma renin activity and aldosterone could be totally blocked by simultaneous administration of monoclonal antibodies directed against ANP. From this study it seems to be clear that the rise in cyclic GMP and the inhibition of the renin-aldosterone system is not a direct effect of volume expansion but is specifically mediated by the released ANP. The great importance of ANP in acute volume expansion made us wonder about the role of ANP in chronic volume expansion and under basal conditions without volume loading. Chronic volume loading was induced pharmacologically by the sodium retaining vasodilatator minoxidil. Under both chronic volume expansion and basal conditions the neutralization of the circulation ANP by antibody administration leads to reduced plasma cyclic GMP levels. No alterations in urinary sodium excretion, plasma renin activity and plasma aldosterone concentration could be observed: In conclusion, the monoclonal antibody directed against ANP is a useful tool for the investigation of the physiological role of endogenous ANP.     

Hypertension,hypokalemia, hyporeninemia and severe target organ damage.

A 51-year-old woman with a 20-year history of severe hypertension and target organ damage had nondiuretic hypokalemia, kaluresis, suppressed plasma renin activity and elevated urinary excretion of aldosterone. Renal arteriography demonstrated unilateral renal artery stenosis secondary to fibromuscular hyperplasia. Blood pressure responded only minimally to almost all antihypertensive agents. Spironolactone, 300 to 400 mg/d, produced distinct improvement in blood pressure, which was maintained for 13 months.     

Antagonism of the effects of furosemide by in domethacin in normal and hypertensive man

Furosemide and the prostaglandin synthetase inhibitor, indomethacin, were administered singly and in combination to four normal subjects and six patients with essential hypertension in order to determine whether the antihypertensive, natriuretic and other effects of furosemide could be altered by inhibition of prostaglandin synthesis. In all subjects indomethacin treatment alone resulted in a significant elevation of blood pressure and a fall in plasma renin without any change in sodium excretion. Furosemide alone resulted in a significant blood pressure fall with a rise in plasma renin and urinary aldosterone with a marked increase in urinary sodium loss. These effects were either obviated or blunted by addition of indomethacin. The results are compatible with the hypothesis that the antihypertensive and natriuretic effects of furosemide might be mediated at least in part by prostaglandin synthesis. In addition, the effects of indomethacin should be considered when using this drug in hypertensive patients and in subjects requiring diuretic therapy.     

Vasoactive factors in decompensated cirrhosis. Effect of acute plasma expansion

Plasma volume expansion was performed in 16 cirrhotic patients with ascites, 8 with avid sodium retention (sodium retainers) and 8 with normal sodium balance (sodium excretors). No natriuretic response was observed in sodium retainers (daily UNa = 7.1 +/- 1.5 mEq before expansion and 20.8 +/- 7.8 after expansion; p = not significant). After expansion plasma renin activity and plasma aldosterone showed a fall in both groups, whereas urinary kallikrein excretion decreased significantly in sodium retainers (27.1 +/- 9.7 before expansion and 7.8 +/- 6.4 after expansion; p less than 0.05). Baseline PGE were higher than normal in sodium retainers (997.0 +/- 134.3; p less than 0.02 vs. controls) and increased after expansion. Plasma octopamine was always within normal range. These results suggest that: a) reduction of effective plasma volume is not the main factor involved in sodium retention; b) the renin-angiotensin-aldosterone system has only a permissive role; c) prostaglandin system is activated and could have a protective role in maintaining renal function in cirrhotic patients.     

Activity and inhibition of prostasin and matriptase on apical and basolateral surfaces of human airway epithelial cells

Prostasin is a membrane-anchored protease expressed in airway epithelium, where it stimulates salt and water uptake by cleaving the epithelial Na(+) channel (ENaC). Prostasin is activated by another transmembrane tryptic protease, matriptase. Because ENaC-mediated dehydration contributes to cystic fibrosis (CF), prostasin and matriptase are potential therapeutic targets, but their catalytic competence on airway epithelial surfaces has been unclear. Seeking tools for exploring sites and modulation of activity, we used recombinant prostasin and matriptase to identify substrate t-butyloxycarbonyl-l-Gln-Ala-Arg-4-nitroanilide (QAR-4NA), which allowed direct assay of proteases in living cells. Comparisons of bronchial epithelial cells (CFBE41o-) with and without functioning cystic fibrosis transmembrane conductance regulator (CFTR) revealed similar levels of apical and basolateral aprotinin-inhibitable activity. Although recombinant matriptase was more active than prostasin in hydrolyzing QAR-4NA, cell surface activity resisted matriptase-selective inhibition, suggesting that prostasin dominates. Surface biotinylation revealed similar expression of matriptase and prostasin in epithelial cells expressing wild-type vs. ΔF508-mutated CFTR. However, the ratio of mature to inactive proprostasin suggested surface enrichment of active enzyme. Although small amounts of matriptase and prostasin were shed spontaneously, prostasin anchored to the cell surface by glycosylphosphatidylinositol was the major contributor to observed QAR-4NA-hydrolyzing activity. For example, the apical surface of wild-type CFBE41o- epithelial cells express 22% of total, extractable, aprotinin-inhibitable, QAR-4NA-hydrolyzing activity and 16% of prostasin immunoreactivity. In conclusion, prostasin is present, mature and active on the apical surface of wild-type and CF bronchial epithelial cells, where it can be targeted for inhibition via the airway lumen.     

Effects of captopril and enalapril on sodium excretion and blood pressure in sodium-deficient dogs

Inhibition of angiotensin I-converting enzyme (ACE) (kininase II) provides a powerful new method for evaluating the role of the renin-angiotensin-aldosterone and kallikrein-kinin systems in the control of aldosterone secretion, renal function, and arterial blood pressure. This study compares the effects of long-term administration of a sulfhydryl inhibitor, captopril, with a nonsulfhydryl inhibitor, enalapril (1-[N-[1-(ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-L-proline), in conscious sodium-deficient dogs. Plasma aldosterone concentration (PAC), plasma renin activity (PRA), urinary sodium excretion (UNaV), arterial pressure (AP), blood kinins (BK), urinary kinins (UK), and urinary kallikrein activity (UKA) were determined during long-term inhibition of ACE in sodium-deficient dogs. In response to captopril administration (20 mg/(kg . day], PAC decreased from 38.9 +/- 6.7 to 14.3 +/- 2.3 ng/dl, PRA increased from 3.58 +/- 0.53 to 13.7 +/- 1.6 ng/(ml . h), UNaV increased from 0.65 +/- 0.27 to 6.4 +/- 1.2 meq/day, AP decreased from 102 +/- 3 to 65 +/- 2 mm Hg, BK increased from 0.17 +/- 0.02 to 0.41 +/- 0.04 ng/ml, UK increased from 7.2 +/- 1.5 to 31.4 +/- 3.2 micrograms/day, and UKA decreased from 23.6 +/- 3.1 to 5.3 +/- 1.2 EU/day. Quantitatively similar changes in AP, UNaV, and PAC were observed in sodium-deficient dogs in response to long-term enalapril administration (4 mg/(kg X day]. In sodium-deficient dogs maintained on captopril or enalapril for several days, angiotensin II (AngII) infusion (3 ng/(kg X min] restored PAC, UNaV, and AP to levels observed in untreated sodium-deficient dogs. These data indicate that the long-term hypotensive and natriuretic actions of inhibitors of ACE are mediated by inhibition of AngII formation and that the renin-angiotensin system plays an essential role in regulating aldosterone secretion, renal function, and AP during sodium deficiency.     

Tissue kallikrein activation of the epithelial Na channel

Epithelial Na Channels (ENaC) are responsible for the apical entry of Na(+) in a number of different epithelia including the renal connecting tubule and cortical collecting duct. Proteolytic cleavage of γ-ENaC by serine proteases, including trypsin, furin, elastase, and prostasin, has been shown to increase channel activity. Here, we investigate the ability of another serine protease, tissue kallikrein, to regulate ENaC. We show that excretion of tissue kallikrein, which is secreted into the lumen of the connecting tubule, is stimulated following 5 days of a high-K(+) or low-Na(+) diet in rats. Urinary proteins reconstituted in a low-Na buffer activated amiloride-sensitive currents (I(Na)) in ENaC-expressing oocytes, suggesting an endogenous urinary protease can activate ENaC. We next tested whether tissue kallikrein can directly cleave and activate ENaC. When rat ENaC-expressing oocytes were exposed to purified tissue kallikrein from rat urine (RTK), ENaC currents increased threefold in both the presence and absence of a soybean trypsin inhibitor (SBTI). RTK and trypsin both decreased the apparent molecular mass of cleaved cell-surface γ-ENaC, while immunodepleted RTK produced no shift in apparent molecular mass, demonstrating the specificity of the tissue kallikrein. A decreased effect of RTK on Xenopus ENaC, which has variations in the putative prostasin cleavage sites in γ-ENaC, suggests these sites are important in RTK activation of ENaC. Mutating the prostasin site in mouse γ-ENaC (γRKRK186QQQQ) abolished ENaC activation and cleavage by RTK while wild-type mouse ENaC was activated and cleaved similar to that of the rat. We conclude that tissue kallikrein can be a physiologically relevant regulator of ENaC activity.     

Atrial natriuretic peptide--cyclic GMP coupling and urinary sodium excretion during acute volume expansion in man

The present study examines hormonal and renal responses to acute volume expansion in normal man, with particular emphasis on the atrial natriuretic peptide (ANP)--cyclic GMP coupling. Two liters of isotonic saline were infused into eight normotensive male subjects over a 1-h period. Plasma and urinary measurements were made before, during, and up to 300 min after the start of the saline infusion. With the initial increase in urinary sodium excretion there were increases in plasma ANP and plasma cyclic GMP, which reached maximum levels at 15 min after the end of the saline infusion. Urinary cyclic GMP increased gradually during saline infusion up to approximately 60 min after the end of the infusion. Plasma ANP and plasma and urinary cyclic GMP excretion gradually declined thereafter. By contrast, urinary sodium excretion remained elevated up to the end of the observation period. The saline infusion was associated with marked reductions in plasma renin activity and aldosterone, which persisted up to the end of the study. These results suggest a coupling between the increases in plasma ANP, the production of cyclic GMP, and urinary sodium excretion, in particular during the initial renal response to acute volume expansion. However, other mechanisms including the suppression of the renin--angiotensin--aldosterone system may become increasingly important in the later natriuretic response to acute volume expansion.     

Effect of NH4Cl acidosis on the function of renin-angiotensin-aldosterone system in newborn infants.

The present study was undertaken to assess the influence of acute metabolic acidosis on the activity of renin-angiotensin-aldosterone system and renal function in a group of seven one-week-old neonates with mean birth weight of 2164 g (range: 1300-3750 g) and mean gestational age of 34 weeks (range: 28-40 weeks) undergoing oral NH4Cl load. NH4Cl was given in a dose of 2.8 mEq/kg to evaluate renal acidification. Prior to and following NH4Cl administration blood acid-base parameters, plasma urinary electrolytes, creatinine and aldosterone concentration as well as plasma renin activity, glomerular filtration rate, urine flow rate and net acid secretion were measured. NH4Cl administration significantly depressed blood pH (P < 0.05), total CO2 content (P < 0.01) and base excess (P < 0.01) and resulted in a significant elevation of plasma potassium concentration (P < 0.05). Furthermore, NH4Cl ingestion significantly increased urine flow rate, sodium, chloride and net acid excretion. In response to NH4Cl acidosis no consistent change in plasma renin activity and plasma aldosterone concentration could be detected. There was, however, an about 50% increase in urinary aldosterone excretion from the control value of 4.1 +/- 1.2 micrograms/day to 6.8 +/- 2.3 micrograms/day (P < 0.05) after NH4Cl administration. These data suggest that the responsiveness of neonatal adrenals to stimulation by metabolic acidosis is blunted, acidosis therefore, may play a minor role in the neonatal hyperfunction of renin-angiotensin-aldosterone system.